Featured CME Topic: Complementary and Alternative Medicine

Inflammation: Nutritional, Botanical, and Mind-body Influences

David P. Rakel,
MD,

and Adam Rindfleisch,

MD, MPHIL

Abstract: Chronic inflammation is becoming an important risk factor to identify in regard to inhibiting disease onset and its progression. Nutritional science attempted to improve health by manipulating fats so that we could consume healthy nonsaturated fats while simultaneously allowing foods to have a longer shelf-life. However, despite our good intentions, trans-fats and partially hydrogenated oils have been found to promote inflammation and adversely affect health. This article reviews how essential fatty acids, the ratio of omega-3 to omega-6 fatty acids, glycemic load, the Mediterranean diet, specific foods and botanicals, and the mind-body relation influence the inflammatory cascade. Key Words: botanicals, essential fatty acids, inflammation, mindbody, nutrition, omega-3 fatty acids, trans-fatty acids

The Invention of Partially Hydrogenated Trans-fatty Acids

t is interesting to look back in time and see how things we thought were helpful actually resulted in medical harm. The case of trans-fatty acids is a good example. Back in the 1950s, we realized that the type of fat that clogged the arteries, therefore leading to heart attacks, strokes, and claudication was of the saturated fat type. The food scientists wanted to find a way to be able to use poly-unsaturated fatty acids (PUFA) in cooking because they thought that these fats would be healthier and would allow for a reduction in the amount of saturated fats in the diet. They got together and figured out a way to manipulate a poly-unsaturated fat so that it could be used in cooking instead of the saturated fat that was clogging

the arteries. The challenge was that poly-unsaturated fats spoiled very quickly. Since saturated fats were more stable, the food scientists figured out a way to manipulate the polyunsaturated vegetable oils so they would last longer on the shelf without spoiling. Two things were done to the polyunsaturated fat to make it more stable (Fig. 1). First, they heated the vegetable oil. Heating the oil changes the shape of the fat from a cis configuration to a trans configuration. In the natural state (cis) of the oil, the methyl (CH3) and the carboxyl (COOH) groups are on the same side of the double bond. In the trans configuration, they are on opposite sides of the double bond. In the trans state, the fat is more stable and will not break down as easily. Heating the polyunsaturated fats also broke double bonds in the fatty acid chain. The food scientists then infused hydrogen gas into the heated oil, which allowed them to partially hydrogenate the oil. These partially hydrogenated oils (corn oil, soy oil, and so on) could then be used in foods, which would subsequently last much longer without spoiling. If you look at any product that has any sort of shelf life,

Key Points
Foods rich in partially hydrogenated oils and transfatty acids increase inflammation. The most appropriate ratio of omega-6 to omega-3 fatty acids is approximately 4:1. This requires increasing the intake of omega-3 fatty acids and reducing the intake of omega-6 fatty acids. Eating charred, grilled, or burnt foods can increase inflammation. Eating foods with a high glycemic index and load increases inflammation and free radical production. The mind-body interface can play a significant role in triggering the inflammatory cascade, and stress and depression should be addressed as part of the therapeutic approach to inflammatory disorders. Both the cause and treatment of chronic inflammation are related to lifestyle choices. Improvement in nutrition, weight, exercise, and stress will have the most beneficial long-term influences.

From the Department of Family Medicine, University of Wisconsin Integrative Medicine and Faculty Development and Integrative Medicine, University of Wisconsin Medical School, Madison, WI. Supported by NIH grants, Co-PI R01 grant, The Placebo Effect in Clinical Practice from NCCAM, NIH. http://www.nccam.nih.gov/fi/concepts/ rfa/at-02 001.htm; Co-PI R-25 grant for Complementary and Alternative Medicine education in medical school curriculums; grant No. 1-R25ATO 0529 01A1 from NCCAM, NIH. Reprint requests to Dr. David Rakel, Department of Family Medicine, University of Wisconsin Medical School, 621 Science Dr., Madison, WI 53711. Email: drakel@fammed.wisc.edu. Accepted December 13, 2004. Copyright 2005 by The Southern Medical Association 0038-4348/05/9803-0303

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Does Food Preparation Have an Influence on Inflammation?

We have learned how reheating vegetable oils can increase the amount of TFAs, but can overcooking our food also increase inflammation? Overcooking, broiling, grilling, and eating charred food can be a significant source of environmental heat-generated advanced glycation end products (AGEs). One study divided 24 diabetic subjects into two groups. One group was fed a diet high in AGEs (H-AGE) and the other was fed a diet low in AGEs (L-AGE). After 6 weeks, tumor necrosis factor (TNF) rose to 86.3% in the H-AGE group and declined by 20% in the L-AGE group. CRP increased by 35% in the H-AGE group and decreased by 20% in the L-AGE group. Low density lipoprotein increased by 32% in the H-AGE group and reduced by 33% in the L-AGE group.8 This study would suggest that we should encourage our diabetic patients (and maybe others) to eat fresh foods that have been cooked mainly by steaming and boiling.

Fig. 1 Polyunsaturated fat is made more stable by heating and

infusing hydrogen gas, which creates a partially hydrogenated trans-fatty acid. From Rakel DP. The Anti-inflammatory Diet, in Integrative Medicine. Philadelphia, W.B. Saunders, 2003.

chances are you will see partially hydrogenated oil in the ingredients (chips, crackers, granola bars, frosted cupcakes). We have now realized the potential dangers of these partially hydrogenated trans-fatty acids.

Benefits of Omega-3 Fatty Acids on Inflammation

The potential benefit of omega-3 fatty acids was first documented by Dyerberg et al9 and Bang et al10 in the 1970s, when they made the observation that despite obesity and a high fat diet, Inuit Eskimos in Greenland had a very low death rate from heart disease. This observation raised the question of whether or not the type of fat eaten mattered more than the amount consumed. This population consumed a lot of fat, but the majority was from cold-water marine animals and consisted of omega-3 polyunsaturated fats. To understand how these fats influence inflammation it is important to understand the different types and their molecular makeup (saturated, monounsaturated, and polyunsaturated) (see Fig. 2). Saturated fats (animal flesh) have no double bonds and are completely saturated with hydrogen atoms. Monounsaturated fats (olive oil, canola oil) have only one double bond, and polyunsaturated fats (vegetable oil, fish oil) have numerous double bonds, resulting in less hydrogen saturation. The naming of a PUFA helps us understand where the first double bond occurs. An omega-3 fat has the first double bond after the third carbon and an omega-6 fat has the first double bond after the sixth carbon. For example, eicosapentaenoic acid (EPA), one of the essential fatty acids found in fish oil, is classified as EPA (20:5 omega-3). This means that this is a 20-carbon essential fatty acid with 5 double bonds, with the first located after the third carbon. Although the placement of these double bonds would seem trivial, it actually plays a large role in regard to inflammation. Omega-3 fatty acids such as EPA and docosahexaenoic acid have a beneficial influence on inflammation and tumorigenesis, but omega-6 fatty acids, which include arachidonic acid (AA) and linoleic acid (found in partially hy 2005 Southern Medical Association

Risks of Partially Hydrogenated Oils on Inflammation

The dietary risk of excess trans-fatty acids (TFA) in relation to heart disease is well established.1 Dietary intake of these fats has been associated with worsening lipid profiles2 and elevated markers of inflammation.3,4 Research from 823 women from the Nurses Health Study showed that those who ate the most trans-fatty acids had higher levels of interleukin (IL)-6 and C-reactive protein (CRP). The effect was greater in those with an elevated body mass index.5 The evidence is so compelling that the Danish government has decided that oils and fats containing more than 2% industrially produced TFAs will not be sold in Denmark.6 Despite the well-known negative health consequences of TFAs, our Western diet still consists of an excessive amount of these oils. Our dependence on convenience and a fastpaced lifestyle encourages continued consumption of these products. Fortunately, the Food and Drug Administration will require that trans-fatty acids be declared in the nutrition label of conventional foods and dietary supplements, effective January 1, 2006.7 Until then, we can educate our patients that any food that contains partially hydrogenated oils will be rich in TFAs. It is also important to realize that foods fried in vegetable oils that have been repeatedly reheated will also be rich in TFAs. Heating these oils increases the amount of TFAs in the oil. Excessive intake of these vegetable oils also increases the intake of omega-6 fatty acids, which can worsen the ratio of omega-6 to omega-3 fatty acids (discussed below).

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Fig. 3 Arachidonic acid leads to production of the main proponents of the inflammatory cascade, prostaglandins of the twofamily, and leukotrienes.

Fig. 2 Different types of fats and their molecular makeup (saturated, monounsaturated, and polyunsaturated).

and three-families (PGE1 and PGE3) and less inflammatory leukotrienes while also reducing proinflammatory AA within the cell membrane and reducing enzymes needed to promote inflammation. Both omega-3 and omega-6 fatty acids also compete for the same rate-limiting enzyme, delta-6 dehydrogenase. Certain situations influence this enzyme to shift toward the omega-6 pathway, resulting in more inflammatory mediators. These include excessive alcohol, diabetes, stress, and a high omega-6 to omega-3 ratio.

drogenated oils and saturated fats), have proinflammatory and tumor growth-enhancing properties.1114 To understand how these PUFAs influence inflammation, it is important to understand how they influence the inflammatory cascade, which includes the interaction of numerous inflammatory mediators in the form of cytokines, prostaglandins, leukotrienes, and many others that have not been defined or discovered. In an attempt to simplify a very complicated process, let us try and convey what we think we know. Omega-6 fatty acids and saturated fats result in more AA. AA leads to the production of the main proponents of the inflammatory cascade, prostaglandins of the two-family (PGE2), and leukotrienes (see Fig. 3). In contrast, omega-3 fatty acids have a more beneficial influence on inflammation. omega-3 fatty acids compete with AA in the cell membrane, reducing the amount available while also competing with the cyclooxygenase and lipoxygenase enzymes, which are upregulated in the inflammatory process.15,16 EPA also inhibits production of proinflammatory cytokines, including IL-1 and TNF- .17,18 In summary, omega-3 fatty acids lead to the production of less inflammatory prostaglandins of the oneSouthern Medical Journal Volume 98, Number 3, March 2005

Ratio of Omega-3 Fatty Acids to Omega-6 Fatty Acids

The ratio of omega-3 to omega-6 fatty acids in the diet matters because the more omega-6 fatty acids present in the body, the less we are able to utilize the beneficial influences of the omega-3 fatty acids. Before we manipulated our diet to contain more vegetable oils and processed food, the ratio of omega-6:3 fatty acids in the human body was 4:1. The ratio now is thought to be closer to 16:1. Current evidence supports a lower ratio for long-term health. A 4:1 ratio was associated with a 70% decrease in total mortality rate in the secondary prevention of cardiovascular disease. In asthmatic patients, a 5:1 ratio was associated with a benefit, whereas a 10:1 ratio had adverse consequences.19 It appears that we not only need to increase the intake of omega-3-rich foods in the West but also reduce the consumption of foods rich in omega-6 fatty acids.

Glycemic Index and Glycemic Load: An Inflammatory Role?

The optimal ratio of carbohydrates to fats and proteins in the diet is the subject of ongoing debate as certain fad diets continue to discourage carbohydrate consumption. Of no less

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importance is the question of what sources of carbohydrates are healthiest. Can some carbohydrate sources actually promote more inflammation than others? In guiding patients dietary choices, it is important to understand the concepts of glycemic index and glycemic load. Glycemic index is a measure of how rapidly a foods carbohydrates affect postprandial serum glucose levels over time. White bread and glucose cause the fastest and most dramatic rises in glucose levels, so one of them is typically assigned a value of 100, the highest index possible. All other foods are then assigned proportionately lower values, based on how they affect serum glucose in comparison.20 Glycemic load takes the concept of glycemic index a step farther, accounting not only for how rapidly a foods carbohydrates are converted to glucose but also the relative amounts of carbohydrate the food contains. Glycemic load is generally held to be a more accurate measure of a foods overall effect on pancreatic insulin release and serum glucose levels. In general, items with a low glycemic index tend to have a correspondingly low glycemic load. However, foods with a high glycemic index may vary as to whether their glycemic load will be low or high. For example, the carbohydrates in watermelon are rapidly converted to glucose, so the watermelon glycemic index is high, at 72. However, because watermelon is primarily made up of water and contains little absolute carbohydrate content, its glycemic load is relatively low, at a value of 4.21 Table 1 describes some guidelines for using glycemic index and glycemic load in clinical practice.22 Using glycemic load to guide dietary choices has been found to have several benefits. High-load foods can often lead to rapid release of large amounts of insulin, and this can ultimately cause blood glucose to fall below fasting levels a few hours after eating. This rebound hypoglycemia can be characterized by fatigue, which decreases substantially when high glycemic-load foods are removed from the diet. Interestingly, a low glycemic index meal will lead to a lower glycemic response to subsequent meals as well.23 On average, people who eat low glycemic load diets tend to eat smaller meals, and their food cravings diminish. Diets of predominantly high glycemic index foods have been associated with an increased risk of insulin resistance syndrome and type II diabetes.24 The degree to which dietary glycemic load can affect inflammation remains unclear, but a relationship does appear to exist. In both human and animal studies, hyperglycemia in the presence of diabetes has been linked to the production of reactive oxygen species, with consequent lipid peroxidation and resultant atherosclerosis. Hyperglycemia in nondiabetic patients has similarly been found to increase the production of reactive oxygen species in vitro, with resultant oxidative cellular damage and the ultimate triggering of inflammatory responses. Leukocyte movement, adherence, and movement from the bloodstream have also been noted in the presence of high glucose concentrations.25 Subclinical inflammation,

Table 1. Using glycemic index and glycemic load

Note whether an index is based on a value of glucose 100 or white bread 100. For a scale based on white bread, glucose has a value of 140. Index ranges (based on a glucose value of 100) High: 70100 Medium: 5070 Low: 50 Glycemic load ranges High: 20 Medium: 1119 Low: 10 Encourage patients to focus on eating foods that are in the medium or low ranges. Some overall rules to help with this include: Use beans as a side dish instead of rice or potatoes. The less pasta is cooked (the more el dente), the lower its glycemic index. If it is still slightly firm when bitten, that is better. If foods with a higher index are eaten, it is best to eat them in smaller quantities at the same time as foods with a lower index. Make cereal and fruit choices based on their glycemic index. Whole grains that have not been ground have lower indices. Tropical fruits tend to have higher indices. Encourage people to eat smaller, more frequent meals. Make lunch the main meal of the day. Remember that glycemic index does not correlate with nutrient content. Balanced nutrition must also be emphasized. When multiple foods are eaten, glycemic index can change based on how the foods affect each others digestion. It is reasonable to average the indices of the foods consumed, adjusting for the proportion of carbohydrate obtained from each food. This is glycemic load (glycemic index dietary carbohydrate content). Some patients are much more comfortable simply counting carbohydrate servings. Be careful not to make recommendations that are overly complicated. For those who monitor their own blood sugars, diet can be tailored to match their own personal glucose readings. Glycemic index can be used to normalize the blood sugars of people with type II diabetes, to decrease insulin resistance, to lower triglycerides, and to control hypoglycemia. Information from www.glycemicindex.com (accessed November 2, 2004) and from References 20 through 23.

characterized by increased levels of IL-1- and IL-6, have been noted to precede the development of type II diabetes in one large European study.26 The exact mechanisms by which elevated glucose levels might be associated with inflammation are unclear, but increased production of TNF-a may play a role. Acute phasereactant production increases in hyperglycemia, perhaps in response to TNF-a levels. Liu et al, using prospective data from the Womens Health Study, found a statistically significant association between dietary glycemic load and plasma levels of highly sensitive CRP, a marker for systemic inflammation associated with an increased risk of coronary artery and other inflammatory diseases. The risk was higher in women who had an elevated body mass index.27 This relation may partially explain why it has been concluded, based on
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epidemiologic data, that a diet with a high overall glycemic load was associated with increased coronary heart disease in women, independent of other known risk factors.28 A number of case-control and cohort studies suggest a link between glycemic load and various cancers. A positive association has been noted between glycemic load and the risk of developing gastric,29 colorectal,30 and upper aerodigestive tract31 cancers. A slightly increased risk of endometrial cancer32 and pancreatic cancer33 have been suggested as well. Studies of glycemic load and breast cancer have thus far not demonstrated a relation.34 Additional research is needed to fully elucidate the relation between glycemic load and inflammation. However, given the relatively low risks associated with using glycemic load or glycemic index to guide dietary carbohydrate choices, doing so may prove to be a useful part of an anti-inflammatory diet.

more than 11,000 Italian men, showed that those who ate the most Mediterranean-type foods, such as fish, fruit, raw and cooked vegetables, and olive oil, were 50% less likely to die over the 612 years of the study than those who did not follow these guidelines.36 Those men who supplemented with 1 g of fish oil had a significant reduction in death from all causes (-20%), cardiovascular-related death (-30%), and sudden cardiac death (-45%).37 Certain foods and spices can have a beneficial as well as harmful effect on inflammation (for a review, see Tables 2, 3, and 4).38,39

Mind-body Influences on Inflammation

To see if baseline omega-6 to omega-3 ratios influenced the production of inflammatory cytokines when an individual is exposed to stress, Maes et al40 studied 27 college students before and after a difficult examination. They found that those students who had an unfavorably high omega-6:3 ratio had greater production of inflammatory cytokines (TNF, interferon, IL-10 and IL-6) after the stressful test than those students with a more favorable low omega-6:3 ratio.40 This study supports that stress can worsen inflammation. But, more importantly, our baseline nutritional balance of essential fatty acids can influence how much inflammation our body produces when exposed to a psychologic stress. There are many cytokines, but we have identified only a handful: 15 interleukins, 2 interferons, and 2 tumor necrosis factors. The cytokines are messengers that directly communicate between the immune system and the brain. It is well documented that people with depression have elevated levels

The Mediterranean Diet and Inflammation

Of all the cultures and eating habits in the world, the Mediterranean diet appears to have the most positive influence on inflammation and the prevention of heart disease. The Mediterranean diet is rich in olive oil, fruits, vegetables, multigrain breads (with a low glycemic index), fish, and lean meat. In a study of more than 3,000 men and women in Greece, it was found that those who most strictly followed the Mediterranean diet had, on average, 20% lower CRP levels, 17% lower IL-6 levels, 15% lower homocysteine levels, and 6% lower fibrinogen levels as compared with those who did not follow the diet.35 The GISSI prevention trial, a study of

Table 2. Foods likely to promote inflammation Characteristic

High saturated fat content High omega-6 fatty acid content

Example foods
Animal products (except cold water fish) Dairy products Partially hydrogenated oils Margarine Corn, cottonseed, grapeseed, peanut, safflower, sesame, soybean, and sunflower oils Any food with a long shelf life (pastries, chips, crackers) Bagels English muffins Baked potatoes Instant rice Rice and corn cereals See Table 1 [glycemic index table] Dairy products Wheat Eggs Varies among individuals.

Link to inflammation
Increase production of arachidonic acid, prostaglandin), and leukotrienes. Increase production of arachidonic acid, prostaglandin E2, and leukotrienes.

Foods with a high glycemic load

Exact mechanism unclear. More pronounced insulin surges are linked to increased production of tumor necrosis factor- , C-reactive protein, and free radicals.

High-allergenicity foods

Possible relation to immunoglobulin G release. May be associated with increased intestinal permeability to larger, allergenic proteins.

Information from References 38 and 39.

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Table 3. Foods that may have a beneficial influence on inflammationa Characteristic

Foods with high omega-3 fatty acid content

Example foods
Cold water fish (salmon, mackerel, sardines, herring) Flax seeds or oil Walnuts Green leafy vegetables Yellow/orange/red vegetables Red/purple/blue vegetables Dark leafy greens Cruciferous vegetables (broccoli, cauliflower, Brussels sprouts) Citrus fruits Black teas Allium vegetables (onions, garlic) Ginger Rosemary Turmeric Oregano Cayenne Clove Nutmeg Feverfew Boswellia

Mechanism
Essential fatty acid metabolism shifted to creating less inflammatory PGE1 and PGE3 and leukotrienes

Foods containing high levels of antioxidants

Decrease levels of free radicals in the bloodstream which could trigger the inflammatory response. Low antioxidant levels tied to higher levels of some inflammatory cytokines (Allium vegetables release sulfur-containing compounds which alter platelet aggregation and lipid metabolism)

Spices containing particular antiinflammatory chemical compounds

Herbs containing antiinflammatory chemical components

a

Inhibits cyclo- and lipooxygenase pathways Rosmarinic acid in rosemary decreases inflammatory cytokines, chemokines, and allergen-specific antibody Curcumin from turmeric suppresses COX-2 expression Contains compounds with antimicrobial, antioxidant antimutagenic properties. Alters lipid metabolism. Capsaicin lowers levels of acidic glycoproteins which precede inflammation, affects pain transmission COX-2 inhibition Myristicin inhibits TNF- release in animal studies Prostaglandin inhibition Inhibition of both lipooxygenase and cyclooxygenase pathways

PGE, prostaglandin E; COX, cyclooxygenase; TNF, tumor necrosis factor.

Information from References 38 and 39.

of CRP41 and inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF.42 This probably helps explain the increased risk of cardiac events in depressed individuals.43,44 We also know that when we give cytokines as medicine, we can induce a state of depression. For example, when alpha-interferon is given for patients with hepatitis, the side effects that limit this therapy the most are depressed mood, fatigue, anhedonia, and hypersomnia.45 It makes sense that when our body produces these chemicals to fight infection that it would cause us to become fatigued and tired, so our body is able to conserve energy to help recover. We have established that depression is associated with elevated levels of inflammatory cytokines. When we give these cytokines as medicine, depression is a significant side effect. How can we influence this process in a positive way? We know that exercise is one of the best treatments for depression and fatigue46 and that it is inversely related to CRP levels.47 Exercise would also help with weight loss, which would have a beneficial influence on inflammation and its markers.48,49 We know that social support and connection is also needed to help treat and prevent depression. In fact, both exercise and social support have been found to reduce CRP.50 Common sense and medical experience support the use of exercise, weight loss, and social support for health.

We are also realizing that stimulation of the vagus nerve (or the parasympathetic nervous system) plays a positive role in reducing inflammation. Vagus nerve stimulation prevents the release of TNF, giving us a better understanding of how the mind can influence this inflammatory state through both positive and negative influences.51 Learning a simple abdominal breathing exercise stimulates relaxation in part by its vagal nerve influence. Understanding how this can also reduce inflammation will provide further incentive on how this inexpensive therapeutic technique can improve health. TNF inhibitors are the latest drugs to show benefit in chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Compare the cost of abdominal breath work with the cost of TNF inhibitors, with the potential risk of malignancy and opportunistic infection with the later,52 and the decision seems straightforward.

Conclusion
There is mounting evidence that too much inflammation over time can result in an elevated risk of chronic disease and its progression. Both the underlying causes and treatments for this condition are related to lifestyle choices. Improving nutrition, maintaining appropriate weight, exercising, and re 2005 Southern Medical Association

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Table 4. Summary of beneficial influences on inflammation Reducing inflammation

Exercise Weight loss Smoking cessation Mediterranean diet Low glycemic load foods Noncharred foods Omega-3 fatty acids Social support Treatment of depression Stress management Vagal nerve stimulation (abdominal breath work) Rx Aspirin Statins Fibrates Angiotensin receptor blockers Niacin Glitazones Multivitamin in diabetics

9. Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975;28:958 966. 10. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in northwestern Greenland. Am J Clin Nutr 1980;33:26572661. 11. Jho DH, Cole SM, Lee EM, et al. Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integr Cancer Ther 2004; 3:98 111. 12. Simopoulos AP. Omega-3 fatty acids in inflammation and auto-immune disease. J Am Coll Nutr 2002;21:495505. 13. Babcock T, Helton WS, Espat NJ. Eicosapentaenoic acid (EPA): an anti-inflammatory omega-3 fat with potential clinical applications. Nutrition 2000;16:1116 1118. 14. Jho DH, Babcock TA, Helton WS, et al. Omega-3 fatty acids: implication for the treatment of tumor associated inflammation. Am Surg 2003; 69:3236. 15. Obata T, Nagakura T, Masaki T, et al. Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells. Clin Exp Allergy 1999;29:1129 1135. 16. RingbomT, Huss U, Stenholm A, et al. Cox-2 inhibitory effects of naturally occurring and modified fatty acids. J Nat Prod 2001;64:745749. 17. Babcock TA, Helton WS, Hong D, et al. Omega-3 fatty acid lipid emulsion reduces LPS-stimulated macrophage TNF-alpha production. Surg Infect (Larchmt) 2002;3:145149. 18. Novak TE, Babcock TA, Jho DH, et al. NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol 2003;284:L84 L89. 19. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother 2002;56:365379. 20. Johnson K. The glycemic index, in Rakel D (ed): Integrative Medicine. Philadelphia, WB Saunders, 2003, pp 661 666.

ducing chronic stress and depression will result in a homeostasis that will require fewer medications to maintain health. The treatment and prevention of inflammation is a good example of the importance of empowering our patients to be active partners in their care. This collaboration will help us realize the greater importance of health-oriented care, so fewer resources are required to treat disease.

21. Foster-Powerll K, Holt SH, Barnd-Miller JC. International table of glycemic index and glycemic load values. Am J Clin Nutr 2002;76:5556. 22. Wolever TM, David JA, Jenkins, et al. The glycemic index: methodology and clinical applications. Am J Clin Nutr 1991;54:846 854. 23. Wolever TM. The glycemic index: aspects of some vitamins, minerals, and enzymes in health and disease. World Rev Nutr Diet 1990;62:120 185. 24. Schulze MB, Liu S, Rimm EB, et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle aged women. Am J Clin Nutr 2004;80:348 356. 25. Das UN. Is insulin an endogenous cardioprotector? Crit Care 2002;6: 389 393. 26. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective populationbased European Prospective Investigation into Cancer and Nutrition (EPIC): Potsdam Study. Diabetes 2003;52:812 817. 27. Liu S, Manson JE, Buring JE, et al. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr 2002;75:492 498. 28. Liu S, Willett WC, Stampfer MJ, et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2000;71:14551461. 29. Augustin LS, Gallus S, Negri E, et al. Glycemic index, glycemic load, and risk of gastric cancer. Ann Oncol 2004;15:581584. 30. Higginbotham S, Zhang ZF, Lee IM, et al. Dietary glycemic load and risk of colorectal cancer in the Womens Health Study. J Natl Cancer Inst 2004;96:229 233. 31. Augustin LS, Gallus S, Franceschi S, et al. Glycemic index and load and risk of upper aero-digestive tract neoplasms. Cancer Causes Control 2003;14:657 662. 32. Folsom AR, Demissie Z, Harnack L. Glycemic index, glycemic load, and incidence of endometrial cancer: the Iowa Womens Health Study. Nutr Cancer 2003;46:119 124.

References
1. Ascherio A, Katan MB, Zock PL, et al. Trans fatty acids and coronary heart disease. N Engl J Med 1999;340:1994 1998. 2. Lichtenstein AH. Trans fatty acids, plasma lipid levels, and risk of developing cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1997;95:2588 2590. 3. Lopez-Garcia E, Schulze MB, Manson JE, et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr 2004;134:1806 1811. 4. Baer DJ, Judd JT, Clevidence BA, et al. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. Am J Clin Nutr 2004;79:969 973. 5. Mozaffarian D, Pischon TT, Hankinson SE, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr 2004; 79:606 612. 6. Stender S, Dyerberg J. Influence of trans fatty acids on health. Ann Nutr Metab 2004;48:61 66. 7. Food and Drug Administration. Food Labeling: Trans Fatty Acids in Nutrition Labeling, Nutrient Content Claims, and Health Claims. Federal Register: 68 FR 41433 July 11, 2003. 8. Vlassara H, Cai W, Crandall J, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiography. Proc Natl Acad Sci 2002;99:15596 15601.

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It is part of the cure to wish to be cured.

Seneca

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2005 Southern Medical Association