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LETTERS: Richard Smith Passive smoking: Comment from the editor BMJ 2003; 327: 505-a [Full text]

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Rapid Responses published:

An inquiry is still needed

Martin McKee, Pascal Diethelm, OxyGenève, Geneva   (29 August 2003)

Thak you for publishing this paper

Michel Beaufils, 75020 Paris, France   (29 August 2003)

Smoking, weight loss, obesity and type 2 diabetes

Richard G Fiddian-Green   (29 August 2003)

Opthalmic motes or specks of dust?

Andy Ashworth   (30 August 2003)

An inquiry is still needed 29 August 2003
Martin McKee, Professor of european public health London School of Hygiene and Tropical Medicine, Pascal Diethelm, OxyGenève, Geneva Send response to journal: Re: An inquiry is still needed	Dear editor, In one of our earler rapid responses we listed a series of quite specific questions about Dr Enstrom's links with the tobacco industry that demanded answers (bmj.com/cgi/eletters/326/7398/1057#32472). We are sorry that Drs Enstrom and Kabat felt unable to use their right of reply to address our concerns. Specifically, if the tobacco industry did not know the paper was being published can we be told more about what was discussed at the meeting in Washington on June 7-8, 2000 that Dr Enstrom and various industry representatives attended and where Dr Enstrom spoke about ETS and lung cancer and why Dr Enstrom felt it appropriate to share editorial responses to his earlier papers using these data with industry scientists. Furthermore, Dr Enstrom might help us to understand why a Philip Morris executive, in a 11 July 2000 memo, felt it appropriate to organise a 2 day seminar with Dr Peter Lee, a researcher with acknowledged links to the tobacco industry to "discuss CPS-I and CPS-II results and develop possible approaches to analyzing the data". Given the statement that they would not have accepted funding from the industry had other funds been available, can Dr Enstrom help us to understand why his proposal to CIAR was considered within its "Directed "research" programme, a mechanisms at the heart of the industry campaign to undermine the evidence of health effects of passive smoking? And while he may not have testified on behalf of the industry, can he say more about his consulting and research on passive smoking for Jeffrey Furr of the law firm Womble Carlyle, acting on behalf of Philip Morris and RJ Reynolds, which he admited to in a letter of July 15, 1996? Competing interests:   See bmj.com/cgi/eletters/326/7398/1057#32472
Thak you for publishing this paper 29 August 2003
Michel Beaufils, MD Hôpital Tenon, 75020 Paris, France Send response to journal: Re: Thak you for publishing this paper	Sir, I would like to warmly congratulate the Editors of the BMJ for publishing this paper. I suspect it had been previously rejected by major american Journals. I don't intend to discuss on the ground, since my knowledge of the topic is not sufficient. Nevertheless, my knowledge is sufficient to know that the study was done in conformity with the best rules of art, and that it probably has no equivalent in terms of methodology and duration. Therefore it was worth to be published in a major Journal, that's the honour of BMJ. I am horrified by the number of responses and their content. This clearly indicates that good science is of so little value for so many "scientists" involved (blinded) in ideology and lobbies rather than in honest knowledge. Anyone knows that one study does not make a definitive truth. Anyone also knows that rejecting papers and excluding studies (even excellent) just because they are not in accordance with the current claims of lobbies is the worst publication bias, and the best way to maintain fallacies. Michel Beaufils, MD Hôpital Tenon Paris, France PS this letter is in no way intended to be published (although I would not refuse) but only to express my appreciation to you. I would be grateful if it is transmitted to the paper's authors. Competing interests:   None declared
Smoking, weight loss, obesity and type 2 diabetes 29 August 2003
Richard G Fiddian-Green, None None Send response to journal: Re: Smoking, weight loss, obesity and type 2 diabetes	Have the effects of passive or active smoking been standarised for their effects upon weight and potentially upon the complications of obesity and type 2 diabetes? Might the agggressive anti-smoking lobby have contributed to the costly epidemic in obesity and type 2 diabtes that Professor Sir George Alberti have warned us about? More importantly do the effects of smoking on weight provide any clues to how we might manage obesity and prevent type 2 diabetes more effectively. In his recent review on obesity Professor Steven Bloom observed that obesity may be treated by decreasing intake, decreasing absorption of nutirents or by increasing the basal metabolic rate by exercise or with thyroxine. Investigators and pharmaceutical companies have concentrated upon the first two but neglected the third. Professor Bloom considers increasing basal metabolic rate with thyroxine dangerous because of its potential to cause thyrotoxicosis. He does not consider other ways in which the metabolic or rather catabolic rate of of adipose tissue might be increased. There appear to be several very simple ways in which this might be accomplished. The first is exercise and the second is smoking. There may, however, be other simpler, safer and more effective ways of increasing catabolic rate and inducing controllable weight loss. The onset of strenuous exercise has been estimated to increase glycolytic rate as much as 1000 fold (1). ATP and creatine phosphate pools are depleted within seconds and the resynthesis of ATP depends first upon the adenylate kinase reaction and then upon glycolysis. Contrary to popular perceptions glycolysis alone is the preferred means of replenishing ATP in dynamic cellular circumstances such as those existing in glial cells, healing wounds, embryos and neoplasms. This is presumably because far fewer metabolic steps are required to resynthesise ATP by anaerobic than by aerobic means. Indeed the generation of lactate buys time by shifting the metabolic burden from muscles to other tissues, notably liver, heart, brain and kidney. The continued generation of significant amounts of ATP by glycolysis alone is, however, possible only so long as the transport of oxygen and nutrient to these other organs allows oxidative phosphorylation in them to proceed. The Cori, alanine and ornithine cycles are intimately involved in the shifting of the metabolic burden from exercising muscles. The principle difference between ATP resynthesis by glycolysis alone and that by glyoclysis and oxidative phosphorylation is that it requires some 19 times more nutrient to resynthesize one mole ATP by glycolysis alone than by glycolysis and oxidative phosphorylation. This increased need for nutrient is provided by muscle glycogen stores intially and then by fatty acids released by the lipolysis of adipose stores to form fatty acids and glycerol. Beta oxidation of the fatty acids and metabolism of the glycerol in the glycolytic pathway causes the weight loss in exercising subjects. In other words the rate of adipose tissue catabolism appears to be increased by depriving muscles of their ability to resynthesise ATP by oxidative phosphorylation. It is, therefore, not just the increase in workload but also the shift in ATP resynthesis from dependence upon glycolysis and oxidative phosphorylation to dependence upon glyocolysis alone that accounts for the weight loss. It is common knowledge that people who smoke are likely to gain weight when they stop smoking. The weight gain is not caused by a decrease in exercise. Tobacco smoking is also known to reduce appetite and body weight. Cessation of smoking leads to hyperphagia and weight gain (2). An intravenous infusion of nicotine causes hypophagia in rats, that is a significant decrease in the number of meals and a smaller decrease in the size of meals. These changes are accompanied by a reduction in weight. Stopping the nicotine infusion results in hyperphagia by a significant increase in meal sizes. Body weight normalized. Nictotine has also been shown to cause a dose-dependent decrease in oxygen consumption in the brain (3). Nicotine does this by binding to complex I of the respiratory chain and inhibiting the NADH-Ubiquinone reductase activity. The nicotine and NADH are competitive on complex I. In decreasing oxygen consumption by its action on complex I nicotine also decreases free radical generation. In other words nicotine appears to do in animals what exercise does in man without the need for an increase in exercise. Smoking also exposes subjects to carbon monoxide. In carbon monoxide (CO) poisoning, the mortality and morbidity risk do not always correlate with the level of carboxyhemoglobin (COHb)(4). Recent studies have established that the mitochondrial cytochrome portion of the respiratory chain is susceptible to CO toxicity at concentrations traditionally considered nontoxic. These laboratory findings correlate with subtle neurologic symptoms detected by psychometric studies in individuals many days from the time of acute intoxication. Smoking for weight control is prevalent across many race/ethnic groups and both genders among adolescents (5). The increase in weight after the cessation of smoking may, therefore, be due to los of the inhibition of oxidative phoshorylation by nicotine and/or the carbon monoxide in inhaled smoke. Conversely the loss of weight apparently caused by taking up smoking might be due to these effects. Weight loss also occurs at high altitude and in patients with obstructive lung disease(6,7). The pathophysiology behind changes in body composition at extreme altitude is still not fully understood. Proper acclimatization to altitude and high caloric intake minimizes, but cannot completely prevent significant weight loss under the influence of hypobaric hypoxia. Intermittent hypoxic training has evoked considerable investigative interest. There are two different strategies: (1) providing hypoxia at rest with the primary goal being to stimulate altitude acclimatization and (2) providing hypoxia during exercise, with the primary goal being to enhance the training stimulus. Each approach has many different possible application strategies, with the essential variable among them being the "dose" of hypoxia necessary to achieve the desired effect. One approach, called living high-training low, has been shown to improve sea-level endurance performance (8). This strategy combines altitude acclimatization (2500 m) with low altitude training to ensure high-quality training. The opposite strategy, living low-training high, has also been proposed by some investigators. Rather than intensifying the training stimulus, training at altitude or under hypoxia leads to the opposite effect and is unlikely to provide any advantage for a well- trained athlete"(8). But living high (also causes a significant decrease in food and water intake, and body weight(9). Carbohydrate supplements do not ameliorate this loss in body weight. The implication is that if living high-training low can cause weight loss it may do so despite consuming additional carbohydrates. Although the effects of hypoxia and smoking upon weight loss have been attributed to a loss of appetite and decreased intake the mechanism might be the same as that causing pyloric reflux the volume of which increases as the number of cigarettes smoked each day increases (10). Excessive amounts of pyloric reflux may in occasions, in our experience, cause nausea and vomiting(11). Loss of appetite, heart burn from gastro- oesophageal reflux [which often accompanies large amounts of pyloric reflux], nausea and vomiting are the sequential symptoms and signs of obstructed gut or retrograde gastroduodenal peristaltic activity. It has been proposed, therefore, that the reflux might be due to motor disturbances caused by the unreversed ATP hydrolysis and its accompanying fall in pH and rise in [Ca++] in smooth muscle cells, changes that occur in hypoxic tissues (12). Might the smoking of cigarettes, possibly enhanced to yield higher doses of nicotine and carbon monoxide, be used to prevent weight gain or manage obesity and type 2 diabetes? What then of the increased risk of cancers and other diseases? The manner in which smoking causes cancer and these other diseases is not known. One possibility is that smoking might cause these diseases by precipitating intermittent episodes in which there is an anaerobic or glyoclytic shift in ATP resynthesis. Weight loss is a common feature of carcinoma of the lung and often precedes the development of any clinical evidence of malignant diseases (13). Indeed cachexia, as the profound weight loss in malignant dieases is called, often develops before there has been any loss in nutrient intake and before there is significant tumour burden. It has been proposed, therefore, that whatever it is that causes cachexia might also be the cause of the cancers(14). If indeed inhibiting oxidative phosphorylation intermittently increases the rate of lipolysis and fatty acid catabolism and induces weight loss, as these data suggest, then smoking enhanced cigarettes and especially intermittent hypobaric hypoxia are appealing strategies for controlling weight, preventing type 2 diabetes without increasing unacceptably the risk of other diseases. Pharmocological means of achieving the same objectives are not as appealing because the therapeutic effect could be much more difficult to manage and especially to reverse. is more difficult to control. Careful monitoring of the subjects during their hypoxic stress would, however, be advisable to limit the risk of acute cardiovascular events as it is for exercise. It would, however, be much easier to manage the risks with hypobaric hypoxia than with exercise unless conducted in an hypobaric chanmer. 1. Berg JM, Tymoczko JL, Stryer L. Biochemistry 5th edition. WH Freeman, NY 2002. 2. Miyata G, Meguid MM, Fetissov SO, Torelli GF, Kim HJ. Nicotine's effect on hypothalamic neurotransmitters and appetite regulation. Surgery. 1999 Aug;126(2):255-63. 3. Cormier A, Morin C, Zini R, Tillement JP, Lagrue G. In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation. Brain Res. 2001 May 4;900(1):72-9. 4. Gabrielli A, Layon AJ. Carbon monoxide intoxication during pregnancy: a case presentation and pathophysiologic discussion, with emphasis on molecular mechanisms. J Clin Anesth. 1995 Feb;7(1):82-7. 5. Fulkerson JA, French SA. Cigarette smoking for weight loss or control among adolescents: gender and racial/ethnic differences. J Adolesc Health. 2003 Apr;32(4):306-13. 6. Tschop M, Morrison KM. Weight loss at high altitude. Adv Exp Med Biol. 2001;502:237-47. 7. Berry JK, Baum CL. Malnutrition in chronic obstructive pulmonary disease: adding insult to injury. AACN Clin Issues. 2001 May;12(2):210-9. 8. Levine BD. Intermittent hypoxic training: fact and fancy. High Alt Med Biol. 2002 Summer;3(2):177-93. 9. Sharma A, Singh SB, Panjwani U, Yadav DK, Amitabh K, Singh S, Selvamurthy W. Effect of a carbohydrate supplement on feeding behaviour and exercise in rats exposed to hypobaric hypoxia. Appetite. 2002 Oct;39(2):127-35 10. Fiddian-Green R, Russell RC, Hobsley M. Pyloric reflux in duodenal ulceration and its relationship to smoking. Br J Surg. 1973 Apr;60(4):321. 11. Fiddian-Green RG, Russell RC, Hobsley M. Secretin-induced pyloric reflux: verification of the mathematical formula for eliminating reflux in gastric aspirate. Br J Surg. 1972 Nov;59(11):903. 12. Richard G Fiddian-Green<br>Oesophageal reflux: also a metabolic disorder?http://bmj.com/cgi/eletters/325/7370/945#26621, 30 Oct 2002 13. Richard G Fiddian-Green Omega-3 fatty acids and brown fat.http://bmj.com/cgi/eletters/326/7404/1419#35863, 19 Aug 2003 14. Richard G Fiddian-Green A common denominator in cancer and thromboembolism?Pathophysiological considerations in http://bmj.com/cgi/eletters/326/7379/37#29394, 4 Feb 2003 Competing interests:   None declared
Opthalmic motes or specks of dust? 30 August 2003
Andy Ashworth, GP Non-principal Bonhard House, Bo'ness, EH51 9RR Send response to journal: Re: Opthalmic motes or specks of dust?	Editor, I note that in the paper journal it is impossible to identify the smoking (passive and/or active) status of the various contributors. Will we ever get the hang of admitting, let alone declaring "Politically Correct conflicts of interest"? Competing interests:   A lifetime non-smoker who hates passive smoking and who would love to have a medical excuse to achieve the aesthetic objective of breathing clean air. I am developing a website to assist smokers to overcome their addiction.