Inflammation: nutritional, botanical, and mind-body influences.

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

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The Invention of Partially Hydrogenated Trans-fatty Acids

It 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 (C[H.sub.3]) 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, chances are you will see partially hydrogenated oil in the ingredients (chips, crackers, granola bars, frosted cupcakes).

[FIGURE 1 OMITTED]

We have now realized the potential dangers of these partially hydrogenated trans-fatty acids.

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 profiles (2) and elevated markers of inflammation. (3,4) Research from 823 women from the Nurse's 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 fast-paced 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).

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.

Benefits of Omega-3 Fatty Acids on Inflammation

The potential benefit of omega-3 fatty acids was first documented by Dyerberg et al (9) and Bang et al (10) 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 hydrogenated oils and saturated fats), have proinflammatory and tumor growth-enhancing properties. (11-14)

[FIGURE 2 OMITTED]

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 (PG[E.sub.2]), 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-[alpha]. (17,18) In summary, omega-3 fatty acids lead to the production of less inflammatory prostaglandins of the one- and three-families (PG[E.sub.1] and PG[E.sub.3]) and less inflammatory leukotrienes while also reducing proinflammatory AA within the cell membrane and reducing enzymes needed to promote inflammation.

[FIGURE 3 OMITTED]

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.

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 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 food's 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 food's 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 food's 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, characterized by increased levels of IL-1-[beta] 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 phase-reactant production increases in hyperglycemia, perhaps in response to TNF-a levels. Liu et al, using prospective data from the Women's 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 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 tract (31) cancers. A slightly increased risk of endometrial cancer (32) and pancreatic cancer (33) 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.

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 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 6 1/2 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 al (40) 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 of CRP (41) 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 fatigue (46) 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 reducing 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.

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

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: 70-100
  ** Medium: 50-70
  ** Low: <50
* Glycemic load ranges
  ** High: >20
  ** Medium: 11-19
  ** 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 other's 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 X 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.

Table 2. Foods likely to promote inflammation

Characteristic            Example foods             Link to inflammation

High saturated fat        * Animal products         Increase production
  content                   (except cold water        of arachidonic
                            fish)                     acid,
                          * Dairy products            prostaglandin),
                                                      and leukotrienes.
High omega-6 fatty acid   * Partially hydrogenated  Increase production
  content                   oils                      of arachidonic
                          * Margarine                 acid,
                          * Corn, cottonseed,         prostaglandin
                            grapeseed, peanut,        [E.sub.2], and
                            safflower, sesame,        leukotrienes.
                            soybean, and sunflower
                            oils
                          * Any food with a long
                            shelf life (pastries,
                            chips, crackers)
Foods with a high         * Bagels                  Exact mechanism
  glycemic load           * English muffins           unclear. More
                          * Baked potatoes            pronounced insulin
                          * Instant rice              surges are linked
                          * Rice and corn cereals     to increased
                          See Table 1 [glycemic       production of
                            index table]              tumor necrosis
                                                      factor-[alpha],
                                                      C-reactive
                                                      protein, and free
                                                      radicals.
High-allergenicity foods  * Dairy products          Possible relation
                          * Wheat                     to immunoglobulin
                          * Eggs                      G release. May be
                          Varies among                associated with
                            individuals.              increased
                                                      intestinal
                                                      permeability to
                                                      larger, allergenic
                                                      proteins.

Information from References 38 and 39.

Table 3. Foods that may have a beneficial influence on inflammation (a)

Characteristic            Example foods             Mechanism

Foods with high omega-3   * Cold water fish         Essential fatty acid
  fatty acid content        (salmon, mackerel,        metabolism shifted
                            sardines, herring)        to creating less
                          * Flax seeds or oil         inflammatory
                          * Walnuts                   PG[E.sub.1] and
                          * Green leafy vegetables    PG[E.sub.3] and
                                                      leukotrienes
Foods containing high     * Yellow/orange/red       Decrease levels of
  levels of antioxidants    vegetables                free radicals in
                          * Red/purple/blue           the bloodstream
                            vegetables                which could
                          * Dark leafy greens         trigger the
                                                      inflammatory
                                                      response. Low
                                                      antioxidant levels
                                                      tied to higher
                                                      levels of some
                                                      inflammatory
                                                      cytokines
                          * Cruciferous vegetables  (Allium vegetables
                            (broccoli,                release sulfur-
                            cauliflower, Brussels     containing
                            sprouts)                  compounds which
                          * Citrus fruits             alter platelet
                          * Black teas                aggregation and
                          * Allium vegetables         lipid metabolism)
                            (onions, garlic)
Spices containing         * Ginger                  * Inhibits cyclo-
  particular                                          and lipooxygenase
  antiinflammatory                                    pathways
  chemical compounds      * Rosemary                * Rosmarinic acid in
                                                      rosemary decreases
                                                      inflammatory
                                                      cytokines,
                                                      chemokines, and
                                                      allergen-specific
                                                      antibody
                          * Turmeric                * Curcumin from
                                                      turmeric
                                                      suppresses COX-2
                                                      expression
                          * Oregano                 * Contains compounds
                                                      with
                                                      antimicrobial,
                                                      antioxidant
                                                      antimutagenic
                                                      properties. Alters
                                                      lipid metabolism.
                          * Cayenne                 * Capsaicin lowers
                                                      levels of acidic
                                                      glycoproteins
                                                      which precede
                                                      inflammation,
                                                      affects pain
                                                      transmission
                          * Clove                   * COX-2 inhibition
                          * Nutmeg                  * Myristicin
                                                      inhibits TNF-
                                                      [alpha] release in
                                                      animal studies
Herbs containing          * Feverfew                * Prostaglandin
  antiinflammatory                                    inhibition
  chemical components     * Boswellia               * Inhibition of both
                                                      lipooxygenase and
                                                      cyclooxygenase
                                                      pathways

(a) PGE, prostaglandin E; COX cyclooxygenase; TNF, tumor necrosis
factor.
Information from References 38 and 39.

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

Accepted December 13, 2004.

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RELATED ARTICLE: Key Points

* Foods rich in partially hydrogenated oils and trans-fatty 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.

David P. Rakel, MD, and Adam Rindfleisch, MD, MPHIL 

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-R25-ATO 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: [e-mail].