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III
Discussion

RICHARD JANSEN: Dr. Vallerand, could you comment on the mechanism of action of ephedrine and xanthines in their role as stimulants, as well as their metabolic effects? Is the mechanism similar? In other words, is there any rationale for combining these substances as opposed to giving a higher dose of, for example, caffeine? Also, how does the potency of the various xanthines like theophylline and caffeine compare?

ANDRÉ VALLERAND: At the moment, this mixtures of ephedrine/xanthines seem to be favored by many authors in the field of thermogenesis. With respect to the mechanism of action, it appears that the key is the combination of the sympathomimetic effects. For instance, with respect to ephedrine, there is an effect on α- and β-adrenergic receptors. In many cases, an increase in catecholamine levels.

With respect to the xanthines, there is possibly an effect on the inhibition of phosphodiesterase activity, possibly translocation of calcium, and possibly an antagonistic effect on adenosine receptors. It appears to be a combination of these effects that is the key to enhanced thermogenesis, not only from an acute point of view but also in chronic studies. I am also suggesting that they [the subjects] were not able to document a tolerance to this particular drug. So the effect appears to persist over time.



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--> III Discussion RICHARD JANSEN: Dr. Vallerand, could you comment on the mechanism of action of ephedrine and xanthines in their role as stimulants, as well as their metabolic effects? Is the mechanism similar? In other words, is there any rationale for combining these substances as opposed to giving a higher dose of, for example, caffeine? Also, how does the potency of the various xanthines like theophylline and caffeine compare? ANDRÉ VALLERAND: At the moment, this mixtures of ephedrine/xanthines seem to be favored by many authors in the field of thermogenesis. With respect to the mechanism of action, it appears that the key is the combination of the sympathomimetic effects. For instance, with respect to ephedrine, there is an effect on α- and β-adrenergic receptors. In many cases, an increase in catecholamine levels. With respect to the xanthines, there is possibly an effect on the inhibition of phosphodiesterase activity, possibly translocation of calcium, and possibly an antagonistic effect on adenosine receptors. It appears to be a combination of these effects that is the key to enhanced thermogenesis, not only from an acute point of view but also in chronic studies. I am also suggesting that they [the subjects] were not able to document a tolerance to this particular drug. So the effect appears to persist over time.

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--> ELDON W. ASKEW: Dr. Vallerand, I was impressed with the success on increasing tolerance you had with the individual pharmaceutical agents. Why didn't you have the same success with the Cold Buster™ bar? Was the dose not high enough? Was it the combination? What is your opinion? ANDRÉ VALLERAND: This is a good and a tough question at the same time. We have analyzed the Cold Buster™ bar independently. It is a high-carbohydrate sports bar that is loaded with cocoa. We have analyzed the bar, and it appears, like most other cocoa-containing products, to be 2 percent theobromine. Theobromine is another xanthine, probably less potent than caffeine and definitely less potent than caffeine and theophylline. In this particular application, we were not able to confirm the cold-tolerance enhancement that has been found by the inventor of the bar. We have tried to do so in two different trials, and we have looked at the possibility that perhaps the metabolic rate was not high enough to confirm the theory, but that did not appear to be the case. Then we looked at dose levels. We went to almost 717 kcal (3,000 kJ). Again, we did not observe an enhancement effect. I do not have a good explanation except that perhaps one needs a bit more punch to enhance thermoregulatory thermogenesis. I would like to return the question maybe to you and also to Dr. LeBlanc. We were also not sure why we were not able to observe a thermic effect of the food. It is a high-carbohydrate compound. Perhaps the thermic effect of food in those various trials is too small to be detected at those metabolic rates. We do not know. It is also possible, and this is one area where we would like to focus our research, to switch to survival-like conditions, meaning longer trials and possibly energy-deficient states. Maybe we could see an effect there. At the moment, I do not have a very good answer for you. ROBERT POZOS: In terms of the sympathomimetic effects you are getting, what do you think are the proposed effects on the neuromuscular system? Because if you are increasing norepinephrine rather than total catecholamines, you might be increasing neuromuscular activity, which might compromise other functions. Have you studied that at all? ANDRÉ VALLERAND: We have not looked at that. Perhaps we should look deeper into the various mechanisms of action. We tried to stay one step lower or higher, one step, say, above that. We wanted to concentrate more on what would be the best means, either pharmacological and/or dietary, to enhance cold tolerance, and then possibly look at the mechanisms afterward. HARRIS LIEBERMAN: We have also given sympathomimetic drugs to animals and exposed them to cold stress. We have seen increased activity in

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--> what we interpret as positive behavior. I will report on this tomorrow. The drug we used was phenylpropanolamine. IRA JACOBS: I would like to take Dr. Wang's stance for a minute, because I have worked with him closely in the past. Why does the Cold Buster™ work for him and not for us? He has not published human data with the Cold Buster™ per se. His data, which Dr. Vallerand showed you, were based on theobromine administration. Most of those studies were on animals, but animals, to my mind, have proven to be very poor models of human body temperature regulation in environmental extremes for a number of reasons. Dr. Wang would also suggest, perhaps, that the cold stresses that were employed in our experiments were significantly different than his, and that might have an effect. His experiments were done at a range of temperatures, for example, -15°, -10°, and -20°C (5°, 14°, and -4°F). ANDRÉ VALLERAND: The animal experiments? IRA JACOBS: No, the human experiments. He titrated his individual temperature exposures for each subject. He wanted to be sure that within 2 or 3 hours, each subject in the placebo situation experienced a 2°C (35.6°F) drop in rectal temperature. Then he used that same temperature for his experimental trial. Dr. Wang would suggest that our cold stress was not significant enough. That is his stance, but we tend to disagree with him for a number of reasons. I would like to ask a question of Dr. Beard. I thought it was almost oxymoronic to say that there is evidence that highly trained athletes are iron deficient. By their very nature, their performance is high. They are not suffering, or their performance is not. They are able to perform at extremely high levels, certainly higher than most military personnel would be required to perform. I found that a little confusing, and I began to wonder if perhaps the index used to determine iron status is valid? Does a measure of serum ferritin concentration or the concentration of anything else in serum really reflect the changes in intramuscular levels of substances that are supposed to be under the influence of those serum levels? JOHN BEARD: I think your first question is a reasonable one. We have a large anecdotal body of information in which people argue that adolescent athletes are at especially high risk for being iron deficient. As an athlete becomes more advanced in terms of national caliber or ranking, the likelihood of iron deficiency goes down quite dramatically, because people are paying more and more attention to the balance between requirements and intake. So if you look at elite-caliber athletes—people who run in the Boston Marathon or whatever—you are absolutely right. You do not see much iron

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--> deficiency. But of the overall population who exercise habitually, not many are of that caliber. So my comment was that there is a large group of people who exercise a significant amount and who may have a change in iron metabolism because of that exercise. In terms of the elite-caliber athletes, I think more recent data would argue quite the opposite, that one doesn't find iron deficiency anymore. This is because elite-caliber athletes who are on the national teams have trainers and dietitians who are paying attention to such things. ALLISON YATES: What is the total amount of theobromine in the Cold Buster™ bar? ANDRÉ VALLERAND: It is 2 g per 100 g. PARTICIPANT: I think the bar was 38 g. ALLISON YATES: At this point, has anyone tested theobromine by itself, other than knowing that it is not as active perhaps in humans as theophylline? ANDRÉ VALLERAND: We have not done similar tests with theobromine by itself. The inventor of the bar, I am sure, has data to match that, but I do not want to speculate or discuss those results here for him. GAIL BUTTERFIELD: I had some questions for Dr. Beard about the study on young women at Penn State. What was their iron status before you started, and did you keep track of diet? JOHN BEARD: Yes. We screened over 1,000 people in order to identify about 30 subjects who were matched for body fatness but could be divided into anemic, tissue iron deficient, and iron sufficient categories. Thus, they came into the study iron-deficient or not. We did nothing to intervene in their dietary patterns other than to provide supplements at the end of the study. The objectives did not include a dietary assessment. GAIL BUTTERFIELD: So you had this really dramatic improvement in 70 percent of the women, but was that related to where they started? JOHN BEARD: The supplement was able to correct the anemia in 12 weeks. So as a group, they had hemoglobins between 11 and 12. After 12 weeks of 125 mg of ferrous sulfate, they all were above 12, but their serum ferritin concentrations, to go back to Dr. Jacobs' question, were still low. So they actually took on the appearance of the tissue-depleted but no longer anemic group. So the model that we still have to work with shows the

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--> potential for a functional defect due to tissue iron deficiency that we do not understand. The largest effect is anemia. GAIL BUTTERFIELD: To say that the exercise had an effect seems to me to be pushing the point. JOHN BEARD: I was planning to come back to Bob Reynolds' point about additional iron. It is something that we faced in changing the U.S. recommendation for iron for women in pregnancy, a panel I was on last year. Do you work prophylactically, or do you wait for a situation to occur? My point in raising the iron and exercise issue is that I think there is reasonable evidence now to say that if you are exercising someone hard, there is a good chance their iron status is going to change. It is going to go down, and that has been demonstrated well for women. A very short study was published in the American Journal of Clinical Nutrition a couple of years ago on some Navy SEALs. During 1 week of very hard physical activity and mental stress, their plasma concentrations of iron went down 60 or 70 percent in 2 days. Zinc went down. Selenium went down. I do not remember if copper changed very much. These are labile indicators. There are no strong data indicating that if you are not anemic but you are tissue iron deficient, there is going to be an effect. But, we may need to act prophylactically and make recommendations accordingly. Now, back to Dr. Jacobs' question: I do not know if we have a better indicator of iron stores. We have some new indicators that are becoming available. We can now measure the transferrin receptor, which is sloughed off into the plasma pool. Part of the transferrin receptor molecule that sits on the plasma membrane is cut off, and that other fragment now floats around in the plasma pool. There are antibodies now available for measuring that. It turns out that there is an inverse relationship of iron status to receptor in that individual. The more iron deficient you are, the more receptors you have. You are trying to up-regulate iron movement into tissue. So as somebody becomes iron deficient, you see more and more of these transferrin receptors floating around. IRA JACOBS: I know of one study where, in fact, cytochrome oxidase activity was measured in skeletal muscle of iron-deficient people. Iron-deficient was defined in clinical terms. He found no impairment of muscle cytochrome oxidase activity. JOHN BEARD: There are several different approaches that people have used. One has been to take people who naturally became iron-deficient, which is what we did with cold stress. The other uses a paradigm that some people in Seattle actually were the forerunners of, which is to phlebotomize people. Bob

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--> Woodson phlebotomized a group of people and looked at exercise performance after phlebotomy. Phlebotomy creates a different experimental paradigm, which we do not understand. Biologically, the subjects are different if they are phlebotomized to make them anemic and iron deficient. Somehow the body is reacting differently than if it develops naturally over a longer period of time. We do not understand what the difference is, but I think Celsing's data are at odds with some of the other data about what occurs when there is naturally developing iron deficiency. ORVILLE LEVANDER: I have two comments, one to Dr. Beard and one to Dr. Reynolds. John, I sat here for quite a while wringing my hands and wondering whether you were going to say anything about selenium. I am glad that you did. Do I conclude from your presentation that it is really selenium that is important and not iron in this thermogenesis problem? JOHN BEARD: Well, Orville, iron is still more important than selenium. I think selenium's proximal site of action is very likely, at the thyroid Type I deiodinase and at glutathione peroxidase (GPX), to have an effect on selenium. If we can understand how selenium moves around and gets put into tissues, then we have some chance of understanding how iron is affecting that process. I think we may see some sort of effect of iron on both GPX and this deiodinase activities by affecting selenium incorporation into tissue. ORVILLE LEVANDER: Are you aware of the work that John Arthur did on the cold adaptation of rats on selenium-deficient diets and the fact that the iodinase is induced in the selenium-depleted but not in the selenium-deficient animals. JOHN BEARD: That is right. ORVILLE LEVANDER: That is very interesting and very pertinent to the discussion today. Moving on to my old-time friend, Bob Reynolds, the approach that you are advocating to go with this supplement for military personnel, of course, is not without its hazards. If you increase the intake of riboflavin as much as you say, for example, and the squad leaders are instructed to go out and take a look where the men have been urinating to see if they are dehydrated or not, they are going to see all that B2 on the ground and possibly be misled.

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--> ROBERT REYNOLDS: I don't think that amount of riboflavin is sufficient to color the urine that much. It is a valid point you raise. But, I do not think that is enough to give it an enhanced yellow color. It may be. ORVILLE LEVANDER: It was meant as a semiserious comment, anyway. As a follow up, I tried to look for some kind of unifying rationale for the approach that you have taken for the different supplements. You have sort of tailor-made each recommendation for different reasons, ranging from vegetarians in the Armed Forces to lack of fresh vegetables in the diet. If you take a look, for example, at the different rations and their composition on the sheets that we were provided today, it would appear that many of these supplement levels are already supplied. Thus it may be a nonissue for the military. Even the levels of the ones that you mentioned as being difficult to obtain by dietary means, like vitamin C and magnesium, are pretty well satisfied by the rations as currently formulated. I do not know how they are getting that much vitamin C in there, maybe Tang or something of that sort, but that brings us to vitamin E. ROBERT REYNOLDS: Can I respond to that? I was very interested in that handout that contained the composition of the rations that came around this morning. That was the reason I raised the question of what percentage of those rations are actually consumed, to see how that actually meshed with what I was talking about. I agree, and as stated in my presentation, most of these levels can be achieved in the current military rations. If 80 percent of these rations are consumed, that would reduce what I am recommending. But that still does not meet the vitamin E, vitamin C, and magnesium requirements. It comes close. I also said that as more data are generated—and I consider the handout today as more data—I am willing to change my recommendations on these, and I do not own a vitamin-mineral supplement company. ORVILLE LEVANDER: Even for magnesium, if 80 percent of rations were consumed, you would still be getting your 350 mg. I do not know why in your expedition those folks were getting only half the RDAs. ROBERT REYNOLDS: It is a very good question. I don't know, either. Virtually all of our food items were commercially available. ORVILLE LEVANDER: The vitamin E question is a difficult one to tackle. It is based, I guess, on one study, or perhaps two studies. We have also heard recommendations in some areas to decrease iron intakes on the basis of one study linking high iron intake to cardiovascular disease.

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--> I think that until we have more data, it might be premature to go to the supplement levels that you are recommending. If this group did that, it would find itself pretty far away from the mainstream of nutrition thought. ROBERT NESHEIM: One of the things the committee has to do is to take a look at all of the available information and decide where the information leads. That is why your papers are published as presented; they are not peer reviewed. They are your opinions, which our committee takes as part of the information. The other part we take from other resources and ultimately end up with recommendations that we are willing to make to the Surgeon General about ration composition. ROBERT REYNOLDS: I would like to make one quick response to Orville about the vitamin E level. Until September of this past year, I did not take any supplements. I now take 400 mg of vitamin E per day based on the Harvard studies that looked at the several hundred thousand man-years. It has turned me from a scoffer into a believer. So perhaps the mainstream will follow. ORVILLE LEVANDER: Well, Dan Steinberg, whose work led to the hypothesis of antioxidants and atherosclerosis, testified at a recent Food and Drug Administration hearing here in Washington that he is still advocating holding the vitamin E recommendation. ROBERT REYNOLDS: Right. There has been much more use documented for the safety of vitamin E than for any drug that has ever been prescribed. I do not adhere to his position. That is why we have these differences. WILLIAM BEISEL: I want to comment on the iron question. We have to think of any acute changes in iron and zinc as possible cytokine-mediated sequestrations. So acute data, that is data gathered during infections, after trauma, or after severe stress and exercise should not be included in our thinking about long-term iron needs. JOHN BEARD: The only exception to that may be that some of these proteins—deiodinase protein may be one of them—turn over relatively rapidly. The half-life of the protein is only 18 hours. If you have acute muscle trauma due to a forced march in which you have IL-2 being released as a normal response to that, and you have iron being sequestered; it is likely this deprivation of iron in the plasma pool leads to a decrease in deiodinase activity. This results in a decline in circulating T3 concentrations. WILLIAM BEISEL: Certainly a decrease in the production of hemoglobin or red cells is possible.

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--> JOËL GRINKER: This is a question for either John Beard or Robert Reynolds. Can you partition out the effects of either altitude or strenuous exercise from long-term chronic exposure to cold for some of your recommendations, particularly the iron? ROBERT REYNOLDS: In coming up with this hypothetical recommended vitamin-mineral supplement, I tried to do that. It is very difficult for the simple reason that when you have extreme altitude, you also simultaneously have very cold temperatures. The resulting energy expenditure can be quite high. For example, we saw during the On Top Everest '89 expedition that one man was burning on average approximately 9,000 kcal/d for a 3-wk period. This was measured by doubly labeled water. Thus at high altitude, you have the altitude, the cold, and the exercise. I find it almost impossible to separate them out. JOËL GRINKER: I was thinking about the cold without necessarily the altitude. ROBERT NESHEIM: We will be talking about altitude tomorrow, and then we have a panel discussion later in the afternoon to try to integrate some of the data we have discussed on cold and altitude. I think we can probably hold that particular discussion until then. PETER JONES: Dr. Reynolds, based on your rationale, are you saying then that the MRDAs should be elevated in terms of your suggested supplements? ROBERT REYNOLDS: I really would have to spend more time thinking about what the different T Rations and the Rations, Cold Weather provide, how much is actually consumed, and the massive interaction of the B vitamins in controlling energy production. PETER JONES: The reason I am bringing it up is because an RDA, I think, is defined as the level of a specific nutrient consumed which, based on the best available information, meet the needs of the majority of individuals. When you talked about folate, I remember you mentioned that it is a problem in northern climes. If we go by the strict definition of the RDAs or the MRDAs, which are based on the same rationale, we are looking at recommended intakes. The issue of availability may be something quite distinct. So in terms of supplements, it may well be that troops in the cold or at high altitude require supplementation. However, whether we should change the RDAs or MRDAs may be a separate issue that is based more on requirement, as you point out, for some nutrients, perhaps increased energy levels. Because they are not getting enough of the nutrient does not necessarily mean we should increase the MRDAs.

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--> ROBERT REYNOLDS: I agree, and this is something I need to spend some more time thinking about. What should be changed? Maybe my goal should be to say what I think is a reasonable goal for each of these nutrients and then see how the MRDA or the RDA meets that goal. JOHN BEARD: These are open questions to any of the people who have presented data here today. It is a scientific issue that gnaws at me a little bit. What do we know about biologic variance within our subjects—not between but within our subjects—and in terms of a research design question, how many subjects do you need to show a significant difference in the treatment group? This is a question about basic biology. I have not heard it mentioned at all, other than the mention this morning of rhythms and the timing of events. First question: If Dr. Jacobs repeats the same exact study in the same exact subject, will he get the same exact number out of that subject? Probably not. How much variability exists? Second question: How much of that variability has to do with genetic diversity among population groups? Let me give you an example. We know in the iron field that our indices for anemia for blacks are different than they are for whites. It is very clear now, and it is a huge controversy, because nobody wanted to admit that there is a genetically different circulating hemoglobin concentration in blacks and whites that defines anemia differently in the two groups. We will likely have at some time in the near future a different requirement for public health officials to define anemia in a black population versus a white population. My main question is, do we know of similar sorts of differences for these biologic outcome variables related to temperature regulation? ANDREW YOUNG: I want to respond to the within-subject variability question. In my lab, we have done cold acclimation studies in which I have required subjects to be immersed in cold water, 5 d/wk for 5 consecutive weeks. So we have a lot of opportunities to watch each subject each day respond to the cold. In a just-completed training study we have the same subjects over an 8-wk period perform 5 d/wk of cold-water immersions. We have a lot of experience with repeated cold exposure. I have not done a systematic data analysis, but it is my impression that a given subject repeats his or her characteristic responses, to the point where you can predict that certain people show a rise in temperature within the first 10 minutes of cold exposure due to their intense shivering; they will always increase their metabolic rate very rapidly. Someone else will take 30 or 40 minutes. You can characterize it and bet on it. Therefore I think that given individuals are very reliable in terms of their metabolic response and their change in core temperature. Over the long term, say a year, then we see changes for a given individual. There are big

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--> differences among individuals, so big that it makes doing research on human physiology difficult, as we said earlier. JOHN BEARD: So you would say coefficients of variations of 5 or 7 percent? ANDREW YOUNG: It depends on the parameter. I think that body temperatures are probably tighter than that, but if we were to look at norepinephrine response to cold, we would see coefficients of variation greater than that. So it depends on the parameter. But I think body temperature response and at least the spirometry-measured changes in metabolic rate are fairly reliable, probably 5 percent or less. ORVILLE LEVANDER: I have a couple of comments. First, I do not have any answer to the variability question, but I think it might be of interest to this group that there will be a conference at the Human Nutrition Research Center here in Washington. I think it is February 22 and 23, and one of the themes will be diversity of human nutritional requirements. Perhaps some of these topics will be discussed there. I want to react to something that Peter Jones said. I thought I heard him use the term ''requirements" for these numbers. These are not requirements. These are allowances, and allowances are requirements plus safety factors, so that things like bioavailability and other matters are theoretically all taken into account to come up with this final number. I think you have to keep that in mind. The other comment I would make is that, if the decision were to make some sort of recommendation such as this, particularly for vitamin C, magnesium, and vitamin E, we would have to change the name. We could not call it MRDA any longer, because it is a dietary allowance, and there is no way you can meet these levels of nutrients with a diet. ROBERT REYNOLDS: That is a very good point that Orville makes. It is not dietary any longer. JOËL GRINKER: I have a question about the nature of the supplements. Does it matter, for example, the kind of fat or carbohydrate that is being supplemented, or is everybody using relatively the same kinds of basic supplements? We know that even in temperate situations it is going to make a difference in terms of long-term metabolism. How much difference does that add to the experimental paradigms, if any? I do not know. Maybe Dr. Jones or somebody can comment. ROBERT NESHEIM: Joël, some people could not hear your question. Could you please repeat it?

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--> JOËL GRINKER: My question was whether or not the nature of the fat, for example, Eskimo blubber, makes a difference in supplementation. Has that been explored in any detail in terms of improvement of performance issues? PETER JONES: I think the answer is yes. Polyunsaturated fats and fish oil have been shown by a number of groups, including our own recently in the Journal of Nutrition, to tend to up-regulate energy metabolism. JACQUES LeBLANC: I have a comment on the practical remark that was made this morning by COL Schumacher of the Marine Corps regarding meal frequency. He suggested that instead of feeding the soldier three large meals a day, they might be fed snacks, because this is what they want anyway. I did an experiment recently where we fed one large meal to subjects, and on another occasion, we fed the same number of calories in five or six small meals. We found that when they ate more frequently, they were more thermogenic, and they were using their fat. Measuring the respiratory quotient indicated that the extra energy they were producing came from the fat. We made insulin measurements at the same time. When you take a large meal, whether it is carbohydrate or protein, the insulin goes up a great deal, whereas with a small meal, there is an almost insignificant increase in insulin. Because insulin blocks lipid utilization, we conclude that possibly by eating more frequently, the ability to use fat reserves is increased. I wonder whether anyone has done experiments on meal frequency. ROBERT NESHEIM: There have been. Bob, you have done some work on meal frequency. ROBERT REYNOLDS: No, we have not done that, but I think that frequent meals are now highly recommended in weight-loss clinics as a means of utilizing stored fat. Eating smaller, more uniform, more frequent meals results in a more rapid utilization of fat. It is not just the colder altitude. ANDRÉ VALLERAND: Was this research done in humans or in dogs? JACQUES LeBLANC: It was done in humans. ANDRÉ VALLERAND: Okay. What percentage difference are we talking about in comparing the large meal and many small meals? JACQUES LeBLANC: Feeding the large meal, the increase was about 15 percent over a period of time, whereas with the many small meals, it was about 25 percent. That makes a significant difference.

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--> JOHN VANDERVEEN: Several times today we have heard information about adaptation being a very significant factor, certainly for persons at high altitudes and perhaps under cold stress. I would like to know if researchers involved in these areas would make different recommendations for acute situations like you saw in the airplane crash versus a more long-term operation where there would be some preparation involved prior to the initiation of the activities. ANDREW YOUNG: I think the point there is the one Ira Jacobs raised. You have your emergency survival situations and then all the other situations. Cold acclimatization or cold acclimation or cold habituation—whatever process we are measuring—can be seen by physiologists, measured in the lab, and written about. But the reality is that in terms of gross temperature, gross defense of body heat stores and nutritional requirements, cold acclimation or acclimatization probably has no effect on the nutrient requirements, be they the macro energy requirement or the micro. These factors are physiologically curious and it is interesting for scientists to study Ama diving women and the people who repeatedly immerse themselves in cold water for weeks at a time. We are not sure what to make of cold acclimatization physiologically, but I do not think that cold acclimatization has an effect on the nutritional requirements. The other question concerned the difference between the emergency or survival situation and operational environments. I think that the situations are greatly different. JOHN BEARD: I am not sure you can say that, because as Bob Reynolds pointed out before, we do not have the data. I mean, you talk about requirements. You are making static measurements in concentration or appearance of urine. These are kinetic and dynamic processes. ANDREW YOUNG: Well, we do have measurements on metabolic heat production. JOHN BEARD: No, I am talking about nutrients, micronutrients, more specifically. You cannot tell me that we have any information whatsoever about ascorbate metabolism in cold or even at high altitude. ANDREW YOUNG: My point is that acclimation or acclimatization is not going to make much difference in your requirements. Cold may or may not, but humans just do not exhibit that large a spectrum of physiological change with chronic or repeated cold exposure. It is not the same as adaptations to chronic heat stress or exposure to high altitudes. We do not have the same capacity to adjust ourselves to cold exposure as we do with chronic heat exposure.

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--> IRA JACOBS: I agree entirely with what Andy just said. Furthermore, we do have evidence that troops are operationally effective and have been for a long time in the cold and seem to be able to cope with it without a problem nutritionally. We do not have any medical evidence or reports that the cold, per se, is causing health risks other than peripheral cold injury. JOHN BEARD: Do we have any information that ascorbate turnover or utilization has changed? Do we have any information that selenium has changed? IRA JACOBS: I do not know. ANDREW YOUNG: What are the medical symptoms of changes in utilization of ascorbate or selenium? I would turn it around. JOHN BEARD: No, it is a different question. One is that you may have intakes that are 5, 8, 10 times the requirement for these micronutrients, and you can double or triple the utilization rate, and you are not going to see anything because you are still well above some sort of balance point. That is not the same thing as saying that there is not an effect. IRA JACOBS: From an operational point—the colonel should be standing up and saying this—so what? ELDON W. ASKEW: The old literature with regard to ascorbate was based largely on animal studies. It got people excited, and they found resistance to cold injury in animals with high levels of ascorbate. But it never seemed to go past that point. It never made the transition to humans, as far as I know. RICHARD JANSEN: Well, we know there are many vegetarians out there. Number one, they are not consuming any heme iron at all, and their intake of nonheme iron is not great. Now, of course, they may consume a larger amount of nonheme iron, but when you compare their performance, they perform very well. I mean, a lot of athletes are consuming very little heme iron. I find it very puzzling then to see an aerobic dance causing an iron deficiency by your definition. JOHN BEARD: No, I am saying it is causing an iron depletion. The amount of storage iron that is there is going down. They are not adapting. It may be because they are in a study. These are free-living subjects who are participating in a study. It is not the same thing as somebody who is not in a study and has several other options available. The body does not care where iron comes from once it gets in there. It does not care if it is from meat or from a supplement or from wherever.

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--> RICHARD JANSEN: But the absorption of heme iron is so much more. JOHN BEARD: Absolutely. RICHARD JANSEN: Okay, so you are talking about these subjects. I mean, you are saying it is not a deficiency, but in fact you are suggesting that it is a deficiency. JOHN BEARD: I am saying that you need to be cautious. RICHARD JANSEN: I am saying that real-world experience does not seem to track with that in terms of vegetarians performing over many years and consuming diets that are lower than the RDA in iron. DAVID SCHNAKENBERG: Dr. Ira Jacobs, in looking at a food bar that might enhance survival, for instance in that downed aircraft, I have a question. Most of those supplements have been carbohydrate to date. Has someone tried using a primarily protein supplement? I think the data indicate that you get a greater thermic heat rise from consuming 100 g of protein than you would from 100 g of carbohydrate. Is that a possibility for exploration? Of course fluid intake becomes a concern with higher a protein bar, but if the issue is overnight survival perhaps the heat is more important. Maintaining the heat is more important than the fluids. ANDRÉ VALLERAND: I would like to answer that question. I believe the thermogenic effect of food (TEF) for protein ingestion is about 25 percent of the energy intake. So it is the highest of the three macronutrients with respect to the TEF. As far as I'm aware, little data exist that bears directly on this issue. If others have additional data, please provide it, but I seem to recall there are only a few studies in the 1950s where they have tried protein supplements during the night. I think they were able to show slight improvement in core temperatures or mean skin temperature, but I could be wrong. ELDON W. ASKEW: Mitchell and coworkers1, in their work from the late 1940s at the University of Illinois with thermoregulation and nutrients, were interested in the same thing. They were aware of the potential of protein to increase thermoregulation because of its high specific dynamic action, but they could not find this effect when they conducted long-term dietary studies with human subjects. They found that, given the same caloric dose, carbohydrate 1   H.H. Mitchell, N. Glickman, E.G. Lambert, R.W. Keeton, and M.K. Fahnestock. 1946. The tolerance of man to cold as affected by dietary modification: Carbohydrate versus fat and the effect of the frequency of meals. Am. J. Physiol. 146:85–96.

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--> maintained a higher core temperature during cold exposure than did fat or protein. Protein was the worst, and no one has really been able to explain that. PATRICK DUNNE: As a biochemist who likes to know about mechanisms, I would like to stimulate a little discussion. We are really interested at Natick in different forms of carbohydrates, such as those that stimulate insulin release and those that do not. So looking at the mechanisms of nonshivering thermogenesis, are there unifying themes? There seem to be some that work on carbohydrates and the futile cycles. I do not know how viable that is in human beings, because animal enzymes that participate in the futile cycles are induced in response to cold. Human beings seem not to do that. Therefore, some of your animal models are out because different levels of enzymes are induced. Then we can go to fats and look at mitochondria. Something we are not hearing enough about is where the thyroxine loop is coming in. I think there might be a role for the right kind of fat-based supplement. Looking at uncouplers of oxidative phosphorylation and at your chocolate bar, if you have ever overdosed on chocolate you do get a hot flush. I think there may be something to these things, but you have to really look at them at a mechanistic level and sort them out. I hope the committee can help guide us. ANDRÉ VALLERAND: I will try to answer that to the best of my capability. With respect to futile cycling in humans in the cold, we are in the process of studying that right now with stable isotopes. We hope to be able to report something to the committee in the future. With respect to different carbohydrates in the cold, there really has not been much done. Perhaps more should be performed on this particular point of view. With respect to uncouplers of oxidative phosphorylation, I think that would be the next Nobel Prize. If one could localize uncouplers in a particular tissue, you could solve obesity problems and survival in the cold overnight with a hypermetabolic approach. MURRAY HAMLET: Although I was not impressed over the years with the quality of the Soviet doctrine and their science, they have for a long time used vitamin supplements—fairly high vitamin supplements—in cold exposure. Whether there are data in the former Soviet Union on vitamins that might be useful is up for grabs. There may be a mechanism in the future to get that data; for example, paying them to do literature searches on various subjects. This might be something for this committee to pursue. They use megadose vitamins in Antarctica, in Vladivostok, and their other stations daily. They have long used them for their oil-drilling rigs in Siberia. So they are proponents of heavy vitamin supplementation, and even more for cold weather exposure. But again, I do not know the scientific basis.

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--> ROBERT REYNOLDS: Yes, what is the basis for it? MURRAY HAMLET: No idea. ANDRÉ VALLERAND: I have a question for Dr. Young. I enjoyed your presentation this morning. One of the slides that you showed described thermal modifying factors. It summarized the effect of age, fitness, hydration, diet, and acclimation. I must have been out for a few seconds. I missed your comments with respect to the effects of diet on cold tolerance. Could you summarize? ANDREW YOUNG: No, I did not say anything about diet. The only things I have done in our lab with cold were the studies that I reported, in which we manipulated the carbohydrate content. You have heard something about that from both Ira and myself. DAVID SCHNAKENBERG: Along that line is the observation that a lot of our soldiers who go to the field and who are eating our rations do not obtain enough calories to meet their energy demands. They do begin to lose weight. In that situation where they are perhaps doing heavy work, they might be at a 1,500 to 2,000 kcal/d deficit relative to expenditure. Does the literature give us any clue as to the point at which they might be at greater risk of a cold injury if they are exposed? For example, does it require 5 days of total starvation before you have a loss of body fat insulation that would contribute to an increased risk of injury? Or is there some intermediate point at which insufficient calories to meet energy expenditures might increase the risk of suffering a cold injury or becoming hypothermic? ROBERT NESHEIM: That is an interesting question. As I recall, some of the data we were looking at in ration consumption showed there was an increase in the consumption of rations in cold weather, but it still did not meet their energy expenditure. It was around 1,000 or 1,200 kcal/d less intake than what estimated expenditure was. That is about what we tend to see in more moderate temperatures. Even though they ate more, they still did not meet their energy requirements. PETER JONES: Studies that were conducted in noncold situations—actually, it was with the Irish hunger strikers some years ago—showed that they did not actually start to show ill effects until they had nearly exhausted their fat reserves and reached a critical mass in terms of lean body fat-free mass. Once you reach the end of your fat reserves and begin to deplete your lean mass reserves, it is at that point that you become much more susceptible to disease. The hunger strikers, I think, were able to go between 30 and 60 days.

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--> DAVID SCHNAKENBERG: I know about disease. I was wondering about reduced capability to thermoregulate in the cold. JOHN VANDERVEEN: I think the prisoners of war returning from Vietnam had a terrible time when it got down to the near-freezing temperatures in some of those camps, despite the fact that they had what we would consider reasonable blanket capability. They shivered all night long. New recruits coming in to the country at the same time were able to maintain body temperature, and were comfortable, but those who were down to 4 to 5 percent body fat just were not capable of thermoregulation. Quite a bit of documentation was collected on that. DAVID SCHNAKENBERG: In fact, in some of the earlier Ranger studies, they were forcing a 2,000 or 2,500 kcal/d deficit on people and were expecting them to do field maneuvers in the mountains in the cold weather. Were they at any greater risk of cold injury within that 8-wk scenario? ANDREW YOUNG: If you remember the slide that I showed that plotted the thermal conductance or the insulation as a function of subcutaneous fat thickness, I believe that about a 5-mm change in subcutaneous fat thickness would be a very physiologically significant reduction in insulation. I do not know what would be required dietarily to produce a 5-mm reduction in subcutaneous fat over the entire body. Maybe somebody else could comment on that. But at approximately 5-mm and beyond, there is a much greater risk of hypothermia. JAMES DeLANY: But on that same slide you had the Eskimos, and they were the leanest. ANDREW YOUNG: That is absolutely correct. That slide was drawn for another purpose, which was to show that the Eskimos were not particularly protected. In the particular database we were looking at, the differences in thermal conductance between the Eskimos and the Caucasians or the Inuits and the Caucasians was simply due to the fact that the population of Inuit was leaner. But once we plotted the data on the same graph, we found they had the same slope. In other words, fat is fat. It does not really matter whose fat it is. JAMES DeLANY: No. The Eskimos are the native people. They do not freeze. ANDREW YOUNG: Well, they also do not get exposed to the cold, because they traditionally wear excellent clothing.

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--> JAMES DeLANY: Better than our soldiers? ANDREW YOUNG: I would say probably equivalent, or certainly it protected them more. MURRAY HAMLET: The clothing? Functional Eskimo clothing has significantly higher insulation values than any… ANDREW YOUNG: Their hands also sleep in warm shelters. The Eskimos are probably not particularly adapted. They are a very poor example of natural cold acclimatization. ANDRÉ VALLERAND: What about local adaptation with respect to the Eskimos? What about, for instance, the hands, face, and feet? ANDREW YOUNG: The hands are different. ANDRÉ VALLERAND: Their hands look like really thick leather. I think you have done some work, Dr. LeBlanc, with respect to this? JACQUES LeBLANC: I would agree that, systemically, they are not exposed to cold any more than anyone else. ANDRÉ VALLERAND: Yes. MURRAY HAMLET: Their hands will acclimatize. Their cold-induced vasodilatory responses (CIVDs), will be more frequent and heightened, as you have shown many times. That is a trainable response, but essentially, they are not exposed. ROBERT NESHEIM: One of the things this committee was interested in doing when reviewing two of the Ranger studies was looking beyond mean data. We would like at some point to see some more definitive analysis done on the outliers with regard to body weight, because some of these people lost a large amount of body weight. It would be interesting to see what problems they experienced in terms of illness or injury, more than what was observed for the mean or the ones who maintained higher body weight. I think a comparison of the outliers would be a useful thing to do sometime. ROBERT SCHOENE: It is interesting to look at regional geographic differences. The Sherpas who we measured 12 years ago or so had 4 percent body fat, and they tolerated cold very well.

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--> JOHN VANDERVEEN: I forgot to mention that most of the returned prisoners of war were very low in thiamin, so that also created a problem with regulation. KARL FRIEDL: There is more to it than just the body fat layer. The Rangers certainly feel more cold sensitive. At different phases of the study, they are naked, and one area of the room has a bit of air conditioning. We actually felt warm, and they were all shivering and felt cold. So they were definitely more susceptible to cold. The question is whether this is due to their fat insulation or if there is something else going on here, like the drop in thiamin, which was 50 percent of normal. Remember that Dr. John Kinney was particularly interested in the cold sensitivity question. That is something that still has to be followed up. ELSWORTH BUSKIRK: One of factors here is the persistent vasoconstriction that goes on in all the chronic cold exposures. In World War II we had the trenchfoot phenomenon. We had it in Korea, and then in the chamber studies at Natick with just exposure to cold air. Where there is persistent vasoconstriction, you get chronic injury. Of course, with frostbite and the other things associated with actual freezing, that is a different situation. Those people who were very thin were more susceptible to chronic vasoconstriction than were those who had a larger body burden of fat. But the differences were not all that great. They were subtle, and it took something like 8 or 9 days to get to that stage where there was a cold injury. MICHAEL SAWKA: I have a question to follow Dave Schnakenberg's question to either André or Ira. We have talked about the different nutritional modifiers of thermoregulation as well as whole body heat balance. Might there be a nutritional impact on cold-induced vasodilation that can alter susceptibility to cold injury? Has this been studied apart from whole-body balance? Is there any reason to believe that there might be dissociations between whole-body thermal balance and specific effects on limbs or fingers, making people more susceptible? IRA JACOBS: From what I have read and from our own database, I believe there is no relationship between CIVD response—in other words, peripheral response to cold—and whole-body metabolic response to cold. Someone who may have more of a prophylactic effect peripherally because of what might be called a good CIVD response is not necessarily someone who is going to be more resistant to decreases in body temperature in reaction to a given cold stress, everything else being equal. There does not seem to be any relationship at all. In terms of whether or not there have been studies of nutritional supplements, I think that some of the older studies—military studies that were

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--> done here and in Canada and some of the proceedings that COL Askew alluded to at the beginning—did include CIVD tests as a peripheral indicator for responses. There were nutritional manipulations, but I do not remember the data. ROBERT REYNOLDS: High doses of niacin in the range of 1 g will create tremendous vasodilation, which is commonly used to bring cholesterol down. That is one nutritional example.

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