1366 LUNG CANCER AND AIR POLLUTION
SIR,-As Dr Haack points out (May 27, p. 1154) in his commy paper of Feb. 11 respiratory cancer is more freand strongly linked with cigarette smoking than with industrial pollutants. However, it is highly unlikely that the high mortality from respiratory cancer in area E due west of the foundry in town V was wholly attributable to cigarettesmoking, although that activity may have played a part in the findings. In area E, the proportion of "non-and-light" smokers amongst the deceased was similar to that in the town as a whole. These numbers were small. The reliability of the relevant smoking histories was necessarily unproven, moreover. But it is doubtful if research into possible "clustering" of heavy smokers in town V on a retrospective basis could have yielded credible or relevant results in this context. I hope to publish additional information which will show that the temporal pattern of the annual mortality-rate from respiratory cancer in town V was bizarre, and probably inexplicable by the single mechanism of tobacco carcinogenesis, which is usually considered to have a latency of over twenty ment on
quently
malfunction of the gut. Its relationship to the disease is unknown. In two of our patients, classical malabsorption syndrome has been treated with antibiotics and partial reversal of clinical and laboratory data has occurred in one. Emphasis must also be placed upon the failure of routine vitamin BI2 levels to identify malabsorption of vitamin B12’ particularly in M.S. patients, who in many instances have had large doses of this drug for years. The gut in M.S. warrants increasing study. Department of Neuroscience, Long Island College Hospital, Brooklyn, N.Y. 11201, U.S.A.; and Downstate Medical Center, Brooklyn Department of Internal Medicine, Long Island College Hospital Department of Pathology, Downstate Medical Center Division of
ALBERT W. COOK
JAGDISH K. GUPTA LOUIS P. PERTSCHUK
Nursing,
Department of Neuroscience, Long Island College Hospital
FLORENCE NIDZGORSKI
years. Department of Community and Occupational Medicine, University of Dundee,
ÆTIOLOGY OF CROHN’S DISEASE
Medical School, Ninewells, Dundee DD1 9SY
O. LL. LLOYD
MULTIPLE SCLEROSIS AND MALABSORPTION
SIR_ Dr Fantelli and colleagues (May 13, p. 1039) provide additional evidence of functional and structural abnormalities in the gastrointestinal tract in multiple sclerosis (M.S.). We have reported the presence of measles viral protein and alteration of normal immunoglobulin ratios in the jejunum of M.S. patients.1-4 Our further observations have confirmed that this is a statistically valid finding. Others, with limited material, have not confirmed our findings.3 The importance of identification of an agent, which potentially may subtend a series of pathophysiological events leading to M.S., needs little emphasis. Lange and Shiner’s6 report also suggested that there may be abnormalities in the jejunum of M.S. patients. Unfortunately, we have not been able to dupli’
their findings exactly. In investigating fifty-two patients with M.S. for evidence of malabsorption’ we found low fivehour excretions of D-xylose in 27%, abnormal stool fat and undigested meat fibres in around 40%, and malabsorption of vitamin BI2 in 12%. One other patient, not in this series, has villous atrophy. Usually, the mucosa appears normal under light microscopy; in certain patients, increased inflammatory cells are present. Clinical tests for identifying functional capacity of the gut are poor. Similarly, it is a common experience in science for one group, at first, to be unable to reproduce the findings of another. Inappropriate methodological and statistical approaches are often the cause. In M.S. it is going to take a long time before we can be sure that certain associations are not just fortuitous. In the meantime, however, we should not disregard reports of possible changes in the gastrointestinal tract in patients with neurological disease. The report of Fantelli et al. supports our findings that in M.S. there may be a cate
1. 2. 3.
Pertschuk, L. P., Cook, A. W., Gupta, J. Life Sci. 1976, 19, 1603. Cook, A. W., Pertschuk, L. P., Gupta, J. Lancet, 1977, i, 434. Prasad, I., Pertschuk, L. P., Broom, J. D., Cook, A. W., Gupta, J. ibid. 1977, ii, 1188. 4. Pertschuk, L. P., Cook, A. W., Gupta, J. K., Broom, J. D., Vuletin, G. C., Kim, D. S., Brigati, D. G., Rainford, E. A., Nidsgorski, F. ibid. 1977, ii,
SIR,-Ward sought to explain the pathogenesis of Crohn’s by concentrating on the macrophage response.He sugthat the granulomatous nature of the tissue response gested was due to the limited ability of the macrophage to degrade ingested material. The pathogenesis of the disease probably results from multiple gut luminal and mucosal factors acting through a defective macrophage. The factors will be individual to each patient, which makes for continued pessimism for therapeutic innovations. The latest British Medical Bulletin2 (on mucus) suggests an extension of this hypothesis. The gel properties of mucus are important in protecting the mucosal barrier. These gel properties are due to the physical entanglement and probably hydrophobic interaction between very long, very extended molecules. These gel properties may be changed by cations and small molecules in solution or by other mucoproteins (e.g., bacterial or viral in nature). If the intestinal environment changes so that the mucus gel properties change, then flocculation may occur. Interaction between hydrophilic colloids (such as mucus) have been extensively studied. Mutual flocculation can occur between polymeric acids and bases. Flocculation occurs because of the electrostatic attraction between the oppositely Salts and ionic small molecules can have the charged polyions. 3 disease
same
effect.
Such flocculated enteric mucus may be engulfed by the macrophages, with the consequences described by Ward.’ Such coprecipitation would be difficult to demonstrate. Particularly as there are indications that the mucus in the ileum of patients with Crohn’s disease is indistinguishable from that of unaffected individuals. This concept of mucus flocculation by a variety of agents would fit with the range of aaiological factors described, bacterial, viral, chemical, and dietary. Treatment regimes which are modestly successful, steroids, salazopyrine (5-aminosalicylic acid and sulphapyridine) or azathioprine may act as gel stabilisers or inhibitors of mucus flocculation, not as "anti-inflammatory" agents. Altering the intestinal environment with elemental diets may also affect the gel properties of the mucus. A search for stabilisers of the appropriate gel properties may lead to a rational treament for this very confusing disease. Wolfson, Gastrointestinal Unit, Western General Hospital,
Edinburgh
EH4 2XU
MARTIN EASTWOOD
1119. 5. Woyciechowska, J., Madden, D. V. M., Sever, J. L. ibid. 1977, ii, 1046. 6. Lange, L. S., Shiner, M. ibid. 1976, ii, 1319. 7. Gupta, J., Ingegno, A. P., Cook, A. W., Pertschuk, L. P. Am. J. Gastroent.
1977, 68, 560.
1. Ward, M. Lancet, 1977, ii, 903. 2. Br. med. Bull. 1978, 34, no. 1. 3. Jirgensons, B. Straumanis, M. E. A Short Text Book of Colloid
Oxford, 1962.
Chemistry.
SIR,-As Dr Haack points out (May 27, p. 1154) in his commy paper of Feb. 11 respiratory cancer is more freand strongly linked with cigarette smoking than with industrial pollutants. However, it is highly unlikely that the high mortality from respiratory cancer in area E due west of the foundry in town V was wholly attributable to cigarettesmoking, although that activity may have played a part in the findings. In area E, the proportion of "non-and-light" smokers amongst the deceased was similar to that in the town as a whole. These numbers were small. The reliability of the relevant smoking histories was necessarily unproven, moreover. But it is doubtful if research into possible "clustering" of heavy smokers in town V on a retrospective basis could have yielded credible or relevant results in this context. I hope to publish additional information which will show that the temporal pattern of the annual mortality-rate from respiratory cancer in town V was bizarre, and probably inexplicable by the single mechanism of tobacco carcinogenesis, which is usually considered to have a latency of over twenty ment on
quently
malfunction of the gut. Its relationship to the disease is unknown. In two of our patients, classical malabsorption syndrome has been treated with antibiotics and partial reversal of clinical and laboratory data has occurred in one. Emphasis must also be placed upon the failure of routine vitamin BI2 levels to identify malabsorption of vitamin B12’ particularly in M.S. patients, who in many instances have had large doses of this drug for years. The gut in M.S. warrants increasing study. Department of Neuroscience, Long Island College Hospital, Brooklyn, N.Y. 11201, U.S.A.; and Downstate Medical Center, Brooklyn Department of Internal Medicine, Long Island College Hospital Department of Pathology, Downstate Medical Center Division of
ALBERT W. COOK
JAGDISH K. GUPTA LOUIS P. PERTSCHUK
Nursing,
Department of Neuroscience, Long Island College Hospital
FLORENCE NIDZGORSKI
years. Department of Community and Occupational Medicine, University of Dundee,
ÆTIOLOGY OF CROHN’S DISEASE
Medical School, Ninewells, Dundee DD1 9SY
O. LL. LLOYD
MULTIPLE SCLEROSIS AND MALABSORPTION
SIR_ Dr Fantelli and colleagues (May 13, p. 1039) provide additional evidence of functional and structural abnormalities in the gastrointestinal tract in multiple sclerosis (M.S.). We have reported the presence of measles viral protein and alteration of normal immunoglobulin ratios in the jejunum of M.S. patients.1-4 Our further observations have confirmed that this is a statistically valid finding. Others, with limited material, have not confirmed our findings.3 The importance of identification of an agent, which potentially may subtend a series of pathophysiological events leading to M.S., needs little emphasis. Lange and Shiner’s6 report also suggested that there may be abnormalities in the jejunum of M.S. patients. Unfortunately, we have not been able to dupli’
their findings exactly. In investigating fifty-two patients with M.S. for evidence of malabsorption’ we found low fivehour excretions of D-xylose in 27%, abnormal stool fat and undigested meat fibres in around 40%, and malabsorption of vitamin BI2 in 12%. One other patient, not in this series, has villous atrophy. Usually, the mucosa appears normal under light microscopy; in certain patients, increased inflammatory cells are present. Clinical tests for identifying functional capacity of the gut are poor. Similarly, it is a common experience in science for one group, at first, to be unable to reproduce the findings of another. Inappropriate methodological and statistical approaches are often the cause. In M.S. it is going to take a long time before we can be sure that certain associations are not just fortuitous. In the meantime, however, we should not disregard reports of possible changes in the gastrointestinal tract in patients with neurological disease. The report of Fantelli et al. supports our findings that in M.S. there may be a cate
1. 2. 3.
Pertschuk, L. P., Cook, A. W., Gupta, J. Life Sci. 1976, 19, 1603. Cook, A. W., Pertschuk, L. P., Gupta, J. Lancet, 1977, i, 434. Prasad, I., Pertschuk, L. P., Broom, J. D., Cook, A. W., Gupta, J. ibid. 1977, ii, 1188. 4. Pertschuk, L. P., Cook, A. W., Gupta, J. K., Broom, J. D., Vuletin, G. C., Kim, D. S., Brigati, D. G., Rainford, E. A., Nidsgorski, F. ibid. 1977, ii,
SIR,-Ward sought to explain the pathogenesis of Crohn’s by concentrating on the macrophage response.He sugthat the granulomatous nature of the tissue response gested was due to the limited ability of the macrophage to degrade ingested material. The pathogenesis of the disease probably results from multiple gut luminal and mucosal factors acting through a defective macrophage. The factors will be individual to each patient, which makes for continued pessimism for therapeutic innovations. The latest British Medical Bulletin2 (on mucus) suggests an extension of this hypothesis. The gel properties of mucus are important in protecting the mucosal barrier. These gel properties are due to the physical entanglement and probably hydrophobic interaction between very long, very extended molecules. These gel properties may be changed by cations and small molecules in solution or by other mucoproteins (e.g., bacterial or viral in nature). If the intestinal environment changes so that the mucus gel properties change, then flocculation may occur. Interaction between hydrophilic colloids (such as mucus) have been extensively studied. Mutual flocculation can occur between polymeric acids and bases. Flocculation occurs because of the electrostatic attraction between the oppositely Salts and ionic small molecules can have the charged polyions. 3 disease
same
effect.
Such flocculated enteric mucus may be engulfed by the macrophages, with the consequences described by Ward.’ Such coprecipitation would be difficult to demonstrate. Particularly as there are indications that the mucus in the ileum of patients with Crohn’s disease is indistinguishable from that of unaffected individuals. This concept of mucus flocculation by a variety of agents would fit with the range of aaiological factors described, bacterial, viral, chemical, and dietary. Treatment regimes which are modestly successful, steroids, salazopyrine (5-aminosalicylic acid and sulphapyridine) or azathioprine may act as gel stabilisers or inhibitors of mucus flocculation, not as "anti-inflammatory" agents. Altering the intestinal environment with elemental diets may also affect the gel properties of the mucus. A search for stabilisers of the appropriate gel properties may lead to a rational treament for this very confusing disease. Wolfson, Gastrointestinal Unit, Western General Hospital,
Edinburgh
EH4 2XU
MARTIN EASTWOOD
1119. 5. Woyciechowska, J., Madden, D. V. M., Sever, J. L. ibid. 1977, ii, 1046. 6. Lange, L. S., Shiner, M. ibid. 1976, ii, 1319. 7. Gupta, J., Ingegno, A. P., Cook, A. W., Pertschuk, L. P. Am. J. Gastroent.
1977, 68, 560.
1. Ward, M. Lancet, 1977, ii, 903. 2. Br. med. Bull. 1978, 34, no. 1. 3. Jirgensons, B. Straumanis, M. E. A Short Text Book of Colloid
Oxford, 1962.
Chemistry.
