The other problem impairment of carbohydrate assimilation is typified by a deficiency of muscle phosphorylase (McArdle's syndrome) or phosphofructokinase. The first disorder prevents the utilization of glycogen in muscle but permits blood glucose to be used directly; the second prevents the utilization of carbohydrate altogether. In both disorders nearly all the muscle energy comes from the oxidation of fatty acids. Intense or anaerobic exercise, which absolutely requires carbohydrate metabolism, quickly uses up the stores of phosphocreatine, leading to cramp (an electrically silent contracture) and muscle damage, manifested by pain and sometimes by myoglobinuria. In contrast to carnitine palmitoyltransferase deficiency, however, these disorders are not marked by problems with fasting or prolonged lowintensity exercise, when fatty acid fuel can be used exclusively. Study of the inborn errors of muscle energy metabolism has taught us much about normal muscle physiology, and many of the insights summarized above originally came from research on human diseases. The article by Haller and Lewis7 in this issue of the Journal is another illustration of this fruitful interchange. The authors examined the role of plasma free fatty acids in sustaining exercise in patients with muscle phosphofructokinase deficiency as compared with patients with muscle phosphorylase deficiency described in earlier studies. In both disorders, exercise capacity is strikingly improved by raising, and worsened by lowering, the plasma levels of free fatty acids. The "second wind" occurs when muscle blood flow increases in response to gentle exercise, allowing greater delivery of fuel and oxygen to the muscles, hence an increased intensity of exercise.8 These observations suggest that blood glucose, available for use in phosphorylase deficiency but not in phosphofructokinase deficiency, does not serve as a major fuel even when glycogen metabolism is blocked; the symptoms of the two disorders are nearly identical. Nevertheless, the two disorders differ in one respect: a carbohydrate meal makes patients with phosphofructokinase deficiency worse by lowering their plasma fatty acid levels, but has little effect on patients with phosphorylase deficiency, in whom the lowered availability of fatty acids is offset by an increased entry of glucose into muscle. Haller and Lewis dubbed this feature of phosphofructokinase deficiency the "out-of-wind" phenomenon. The symptoms that limit exercise in patients with metabolic myopathies are poorly understood.9 The biochemical mechanisms of exercise-induced fatigue, muscle contracture, muscle pain, tachycardia, hyperventilation, and muscle necrosis are still being investigated, and it seems likely that this research will shed considerable light on the symptoms that limit exercise in normal persons. The study of these rare experiments of nature will continue to be rewarding for

REFERENCES

-

years to come. University of California, San Francisco San Francisco, CA 94143

Feb. 7, 1991

THE NEW ENGLAND JOURNAL OF MEDICINE

412

ROBERT B. LAYZER, M.D.

1. Astrand P-O. Diet and athletic performance. Fed Proc 1967; 26:1772-7. 2. Havel RJ. Influence of intensity and duration of exercise on supply and use of fuels. In: Pemow B, Saltin B, eds. Muscle metabolism during exercise: proceedings of a Karolinska Institutet Symposium held in Stockholm, Sweden, September 6-9, 1970. Vol. 11 of Advances in experimental medicine and biology. New York: Plenum Press, 1971:315-25. 3. Newsholme EA. Application of knowledge of metabolic integration to the problem of metabolic limitations in middle distance and marathon running. Acta Physiol Scand Suppl 1986; 556:93-7. 4. Ivy JL, Costili DL, Maxwell BD. Skeletal muscle determinants of maximum aerobic power in man. Eur J Appl Physiol 1980; 44:1-8. 5. Hultman E. Studies on muscle metabolism of glycogen and active phosphate in man with special reference to exercise and diet. Scand J Clin Lab Invest Suppl 1967; 94:1-63. 6. Layzer RB, Havel RJ, McIlroy MB. Partial deficiency of carnitine palmityltnsferase: physiologic and biochemical consequences. Neurology 1980; 30:627-33. 7. Haller RG, Lewis SF. Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. N Engl J Med 1991; 324:364-9. 8. Pemow BB, Havel RJ, Jennings DB. The second wind phenomenon in McArdle's syndrome. Acta Med Scand Suppl 1967; 472:294-307. 9. Layzer RB. Muscle metabolism during fatigue and work. Baillieres Clin Endocrinol Metab 1990; 4:441-59.

CORRESPONDENCE

LUNG CANCER AND EXPOSURE TO TOBACCO SMOKE IN THE HOUSEHOLD To

the

Editor: Dr. Janerich and his colleagues (Sept. 6 issue)1

report a significantly increased risk of lung cancer (odds ratio, 2.07; 95 percent confidence interval, 1.16 to 3.68) in men and women who had never smoked but were exposed to smoke for 25 or more smok-

during childhood and adolescence. Although there was no statistically significant increase in risk for all men and women who never smoked who were exposed during childhood and adolescence, the authors suggest that exposure to environmental tobacco smoke in early life increases the risk of lung cancer. This suggestion is unconvincing for a number of reasons. First, it ignores epidemiologic evidence, by now quite extensive, showing a complete absence of association between exposure to environmental

er-years

Letters to the Editor are considered for publication (subject to editing and abridgment), provided that they are submitted in duplicate, signed by all authors, typewritten in double spacing, and do not exceed 40 typewritten lines of manuscript text (excluding references). Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in theJournal's various editions (print, data base, and optical disk) in anthologies, revisions, and any other form or medium. Letters should not duplicate similar material being submitted or published elsewhere, and they should not contain abbreviations. Financial associations or other possible conflicts of interest should always be disclosed. Letters referring to a recentJournal article must be received within six weeks of the article's publication. We are unable to provide pre-publication proofs, and unpublished material will not be returned to authors unless a stamped, self-addressed envelope is enclosed. Receipt of letters is not acknowledged, but correspondents will be notified when a decision is made.

The New England Journal of Medicine Downloaded from nejm.org on October 10, 2015. For personal use only. No other uses without permission. Copyright © 1991 Massachusetts Medical Society. All rights reserved.

Vol. 324 No. 6

CORRESPONDENCE

413

Table 1. Relaton of Childhood Exposure to Environmental Tobacco Smoke and Risk of Lung Cancer among Persons Who Had Never Smoked, in 11 Skudies.* Souac oF ExsosuiE

STUDY

Janerich et al.

Kaa Sobue et al.3

SEX

Smoker in household Family member smoked Father smoked Motier smoked Other household member

No. OF BxpoE5D No. OF UNEXPOSED

ODDS RATIO

(95% Cl)

CASES

CONTROLS

134/57 21/15 73/47 18/102 25/95

123/68 69/36 77/61 375/144 46/473 103/416

1.30 (0.85-2.00) 0.73 (0.34-1.59) 1.68 (0.86-3.27) 0.60 (0.40-0.91) 1.71 (0.95-3.10) 1.13 (0.69-1.87)

F F

436 124

605 402

1.1 (0.7-1.7) 0.91 (0.74-1.12)

F

4/84 38/9 12V19 3/19 29 75

11/126

0.55 (0.17-1.77) 1.0 (0.4-2.3) 0.9 (0.4-2.3) 3.3 (0.5-18.8) 0.6 (0.2-1.7) "No associatione "No significant iscrease in risk"

M, F M

F F F F

36/17

smoked

Gao et al.4 Garfinkel et al.5

Lived with smoker Exposed to smoke of

Koo et aL.6 Pershagen et al.7 Svensson et al.'

At home Parents smoked Fatier smoked Modter smoked Parents smoked Parents smoked Paenta smoked

odiers F

F F F M, F M, F

76/18 71/98

10.

11.

Pershagen G, Hrubec Z, Svensson C. Passive smoking and lung cancer in Swedish women. Am J Epidemiol 1987; 125:17-24. Svensson C, Pershagen G, Klominek J. Smoking and passive smoking in relation to lung cancer in women. Acta Oncol 1989; 28:623-9. Wu AH, Henderson BE, Pike MC, Yu MC. Smoking and other risk factors for lung cancer in women. J Natl Cancer Inst 1985; 74:747-51. Akiba S, Kato H, Blot WJ. Passive smoking and lung cancer among Japanese women. Cancer Res 1986; 46:4804-7. Correa P, Pickle LW, Fontham E, Lin Y, Haenszel W. Passive smoking and lung cancer. Lancet 1983; 2:595-7. Varela LR. Assessment of the association between passive smoking and lung cancer. (Ph.D. thesis. New Haven, Conn.: Yale University, 1987.)

To the Editor: In interpreting the twofold risk of lung cancer associated with high levWu et asl9 els of exposure to tobacco smoke in the 250 Akiba et al 10 household during the first two decades of 313 30 life, Janerich et al. have made ample efforts Cor et al.I to discuss potential sources of bias. However, because /3-carotene and lung cancer *When numbers of exposed and unexposed case padents and controls were not separely available, the totl number of are inversely related,' this dietary constitucase patients and controls is given. Data for the studies by Akibs et al. and Pershagen et al. are approximate. Odds rtos for ent may be an important confounder, if it is and odher studies studies by Janench et al., Kabat, and Koo et al. adjusted for uiadjusted; thw for die decribed in thepap nsk factom, also associated with exposure to environresbictedtochildhoodexceptin the Persbagen Exposu topaatal smoking confidence intval. Cl mental tobacco smoke. Recently, Sidney et al.2 reported the estimated dietary intake of carotene to be lower in nonsmokers who had tobacco smoke in childhood and risk of lung cancer. As shown in been exposed to Fpassive smoking at home than in nonsmokers withTable 1, estimates of relative risk from 1 I studies, many involving out such exposurre. In an ongoin ig study of /3-carotene and DNA damage, we substantial numbers of case patients and controls, are all nonsignifimeasured plasm la levels of /3-carotene and cotinine in smokers, cant, with as many estimates below as above 1.0. Second, the significance of the association reported by Janerich et al. is not strong nonsmokers, andd passive smokers, which permits a biochemical validation of the association between ,B-carotene and passive smok(0.01