194
Afflicted infants have hyperinsulinaemia, ketotic hypoglycEemia, various endocrine disorders (panhypopituitarism, isolated growth-hormone deficiencies, corticotrophin deficiency, Addison’s disease, hypothyroidism), or hepatic-enzyme deficiency (glycogen-storage diseases, disorders of
gluconeogenesis2). Inappropriate insulin secretion is present in 20-33% of all cases of persistent hypoglycaemia3.4 but diagnosis
is nonetheless difficult. The clinical symptoms are ataxia, somnolence, and coma (or seizures) before meals, starting in most cases before the age of 2. Some workers suggest that hyperinsulinsemic hypoglycarmia is a factor in sudden-infant-death syndrome.5,6 A characteristic finding is a high insulin/glucose ratio in blood, commonly with an associated leucine sensitivity.6,7 The primary goal of management is prevention of the repeated hypoglycxmic attacks, which can damage the brain. Sometimes this can be achieved by frequent feeding combined with cortisol therapy, or by glucose infusions. Alternatively, inappropriate insulin secretion can be controlled with diazoxide or, as lately reported,8 by subcutaneous injections of protamine zinc somatostatin. When medical treatment fails, surgical resection of the pancreas becomes necessary, and even then the patient may need long-term diazoxide therapy.9 Usually at least half the pancreas is resected: except in the rare cases of endocrine adenoma, gross morphological changes are absent. The underlying condition is known as nesidioblastosis-a term coined by Laidlawl° to describe diffuse proliferation of the islet cells, nesidioblasts being defined as "the cells that differentiate out of the duct epithelium to build islets". In the past precise histological diagnosis has been difficult: lack of normal islets, close contact between exocrine ducts and endocrine-cell clusters, and microadenomas have been regarded as hallmarks of the disorder. The process usually affects the entire pancreas. Classification had to await detailed structural analyses of the endocrine pancreas. Kloppel and his colleagues" did morphometric studies of a single case and Svik, Vidnes, and Falkmer9 analysed three cases, using special stains to delineate the A (glucagon) and B (insulin) cells. Useful as these investigations were, they could not properly distinguish the contribution of each individual endocrine cell type. This distinction can be made only by immunocytochemical procedures such as those employed by Heitz et al.,12 who examined seven surgical specimens of pancreas obtained at laparotomy from infants with persistent hyperinsulinaemic hypoglycaemia. They found that four types of endocrine cell invariably participate in the endocrine proliferation-namely, B, A, D (somatostatin), and P.P. (pancreatic polypeptide).Thecells Pagliara, A. S., Karl, I. E., Haymond, M., Kipnis, D. M. Pediatrics, 1973, 82, 365. 3. Kogut, M. D., Blaskovics, M., Donnell, G. N. ibid. 1969, 74, 853. 4. Dr George, A. M., Auerbach, V. H. Am. J. med. Sci. 1960, 240, 792. 5. Polak, J. M., Wigglesworth, J. Lancet, 1976, ii, 570. 6. Cox, J. N., Guelpa, G., Terrapon, M. ibid. p. 739. 7. Cochrane, W. A. Am. J. Dis. Child. 1960, 99, 476. 8. Hirsch, H. J., Loo, S, Evans, N., Crigler, J. F., Jr, Filler, R. M., Gabbay, K. H. New Engl J. Med. 1977, 296, 1323. 9. Søvik, O., Vidnes, J., Falkmer, S. Acta path. microbiol. scand. 1975, 83A, 2.
155. 10. 11.
Laidlaw, G. F. Am. J. Path. 1938, 14, 125. Klöppel, G., Altenähr, E., Reichel, W., Willig, R., Freytag, G. Diabetologia, 1974, 10, 245. 12. Heitz, Ph. U., Klöppel, G., Häcki, W. H., Polak, J. M., Pearse, A. G. E. Diabetes, 1977, 26, 632.
occurred in a ratio which was remarkably constant in the seven cases and for the B and A cells the ratio corresponded to that found in normal islets. On computerised image analysis the endocrine parenchyma proved to be increased almost fivefold in nesidioblastosis compared with age-matched controls, and Sovik et al. concluded that the pathogenesis of the different morphological patterns of endocrine proliferation-multifocal ductuloinsular proliferation, microadenomatosis, focal adenomatosis, and adenoma-are one and the same. Although the prime cause remains unknown, nesidioblastosis evidently represents a failure of the normal mechanisms controlling embryogenesis of the endocrine pancreas and its transition to the normal neonatal and infantile state. A systematic analysis of all hormones known to regulate pancreatic function may reveal the identity of the controlling factor whose excess (stimulation) or lack (failure of inhibition) is responsible for the uncontrolled expansion of the islet cells. WHAT HAPPENS TO CLOTS IN THE LUNGS? WHAT happens to patients with pulmonary emboli who survive to leave hospital? Do they have further pulmonary emboli, with pulmonary hypertension and poor long-term prognosis? There is surprisingly little information about these matters, and two papers from Hall and his co-workers are helpful. In one they report a 9-year follow-up of 72 patients who survived a massive pulmonary embolus after intensive but varied initial treatments.12 patients died within this period but in no case was death due to chronic pulmonary hypertension or to definite recurrence of pulmonary embolism. Of the 56 who were restudied none had clinical signs of pulmonary hypertension, either persistent or of later onset, and only 6% had a possible non-fatal recurrence of pulmonary embolism. Resolution of the embolus was complete in most cases although pulmonary arteriography 2-72 months later showed minor abnormalities in some, as did perfusion lung scans performed up to 8 years after the initial incident. The second paper looks at patients with less severe pulmonary emboli; they had a similar pattern of resolution and recurrence.2 These results are in accord with previous work. None of 58 patients initially studied by Paraskos3 and followed up died of pulmonary embolic disease: survival correlated with the presence or absence of pre-existing heartdisease. When 43 of these patients were restudied after 1-7 years, only 5 had evidence of unresolved embolism and only 1 had chronic cor pulmonale. Definite recurrent pulmonary embolism was recorded in only 1 patient, although 3 others had suspected embolism. Tow and Wagner4 did perfusion lung scans in 69 patients: within 4 months, between half and three-quarters had complete resolution or improvement irrespective of the severity of initial embolism. Others have made similar observations with both lung scans and arteriography, 3-7 1. Hall, R. J. C., Sutton, G. C., Kerr, I. H. Br. Heart J. 1977, 39, 1128. 2. Sutton, G. C., Hall, R. J. C., Kerr, I. H. ibid. p. 1135. 3. Paraskos, J. A., Adelstein, S. J., Smith, R. E., Rickman, F. D., Grossman, W, Dexter, L., Dalen, J. E. New Engl. J. Med. 1973, 289, 55. 4. Tow, D. E., Wagner, H. E. ibid. 1967, 276, 1053. 5. Sautter, R. D., Fletcher, F. W., Emanuel, D. A., Lawton, B. R., Olsen, T. G. J. Am. med. Ass. 1964, 189, 948. 6. Fred, H. L., Axelrad, M. A., Lewis, J. M., Alexander, J. K. ibid. 1966, 196, 1137. 7. Urokinase Pulmonary Embolism Trial. Circulation, 1973, 47, suppl. II, p. 1.
195
occurring within two weeks.8 disability in 10 of 68 patients but not employ lung scans or pulmonary
resolution sometimes
Phear9 reported early work did arteriography. Patients severe
this
disease present
a
with chronic thromboembolic different picture. Sutton’s patients
progressively worse with persistent pulmonary hypertension, increasing right-heart failure, and death.2 Others have also recorded cases of chronic cor pulmonale due to "silent" or recurrent untreated pulmoni became
ary thromboembolism. 10,11
What then
conclude about the late sequelae of is good evidence that resolution of the obstruction, whatever its size, occurs mainly in the first 4 months after the initial incident, and that most treated patients proceed to complete hxmodynamic and angiographic resolution.4-8 Chronic cor pulmonale is a very rare complication of pulmonary embolism, but may arise in patients who have repeated episodes that are undetected and therefore untreated. Treatment with anticoagulants reduces the incidence of recurrent pulmonary emboli.7 Provided that the initial episode is adequately treated and anticoagulants continued for at least 4 months, by which time the embolus will usually have resolved, the long-term prognosis of a pulmonary embolus, of any size, is excellent. can one
pulmonary embolism? There
CIRCADIAN DYSRHYTHMIAS DIURNAL variation of a hormone was first reported in 1943 by Pincus,’ who examined 17-ketosteroid excretion in normal subjects. Since then new techniques such as automatic blood-sampling devices, sensitive microchemical assays, and polygraphic sleep recorders have permitted the correlation of hormone secretion with sleep/waking rhythms. Application of these methods to conditions such as Cushing’s disease, acromegaly, anorexia nervosa, and affective disorders2 has provided new insights into patterns of hormone secretion. By manipulation of environmental conditions it should be possible to distinguish inherent rhythms from those influenced by the environment. Normal subjects isolated from time information tend to adopt sleep/activity cycles slightly longer than 24 hours3 and this has been generally attributed to an endogenous timing mechanism. Artificial prolongation of the day tends to lengthen the urinary electrolyte excretion cycle, but shortening of the day may result in two rhythms, both influencing excretion of the same electrolyte-one being persistently circadian and the other conforming to the artificially shortened sleep/activity cycle.4 Thus rhythms of urinary electrolyte excretion can be successfully entrained by days as long as 27 hours but not by days as short as 21 hours. Such studies of abnormal daylength may help to clarify the physiology of jet-lag and may be of importance in planning the sleep/activity programmes of astronauts.
Individuals with disturbed perception of important environmental cues might be expected to show disorders of circadian rhythm. This seems to happen in blind people without light perception, who may show abnormal periodicity of plasma-cortisol’ and urinary electrolyte excretion,6 suggesting that these diurnal rhythms are not correctly phased by light stimuli. Although impairment of growth-hormone release during sleep has been reported in blind subjects7 this has not been confirmed2 and defective secretion may have been caused by the abnormal sleep patterns of the subjects studied. Webb and Agnew8 suggested that disorders of circadian rhythm might become clinically manifest as sleep/wake disturbances,8and this effect has now been reported in a totally blind individual.9 For several weeks at a time he would experience insomnia and daytime sleepiness which interfered with his work and leisure. His body temperature, plasma-cortisol, urinary electrolyte excretion, and sleep/activity cycles all had a periodicity of 24-9 hours and could not be entrained to 24 hours by a strict sleep/activity schedule. Such symptomatic disturbances of circadian rhythm may also arise in people with normal vision,3 so loss of light cues from the environment is not the sole cause. Possibly, circadian dysrhythmias are common in milder form, causing insomnia, fatigue, poor performance, and various non-specific symptoms. Without elaborate long-term monitoring1O they are likely to remain undiagnosed.
A GROUP of American scientists who recently visited the People’s Republic of China were impressed by work there on cancer, discovering what one member described as an "etiologic wonderland". 11 Two features contributed to this feeling. Firstly, the Chinese allow many of their domestic animals to live out their full lives, well beyond the best years for breeding or egg-laying; so they are well acquainted with diseases of later life such as cancers, some of which resemble those prevalent in the human population. Secondly, the Chinese have constructed maps showing cancer mortality rates, and with some of them (as in the United States) the distribution is nonrandom. The hepatocellular-carcinoma map, for instance, shows distinct areas of high incidence. This cancer is common not only in human beings but also in the local ducks. Poultry may have something to say, too, about oesophageal cancer. When a water reservoir was needed, 50 000 people had to be moved to new homes, from a high oesophageal cancer area to a low one. They took with them one lone chicken; otherwise they started afresh with local birds. Yet the chickens of the relocated people are now getting oesophageal cancer; so the cause must be somewhere in their narrow environment. Table scraps form part of the chicken diet, and a nitrosaminerich pickled-vegetable mix is under suspicion.
8. Crane,
C., Hartsuck, J., Birtch, A., Couch, N. P., Zollinger, R., Matloff, J., Dalen, J., Dexter, L. Surgery Gynec. Obstet. 1969, 128, 27. 9. Phear, D. Lancet, 1960, ii, 832. 10. Davison, P. H., Armitage, G. H., Mcllveen, D. J. S. ibid. 1956, ii, 224. 11. De Soyza, N. D. R., Murphy, M. L. Chest, 1972, 62, 665. 1. Pincus, G. J.J. clin Endocr. Metab 1943, 3, 195. 2. Weitzman, E. D. A. Rev. Med. 1976, 27, 225. 3. Mills, J. N., Minors, D. S., Waterhouse, J. M. J. Physiol. 1974, 240, 567. 4 Mills, J. N., Minors, D. S., Waterhouse, J. M. ibid. 1977, 268, 803.
5. Orth, D. N., Island, D. P., J. clin Endocr. Metab. 1969, 29, 479. 6. Simenhoff, M. L. J. appl. Physiol. 1974, 37, 374. 7. Krieger, D. T., Glick, S. J. clin. Endocr. Metab. 1971, 33, 847. 8. Webb, W. B., Agnew, H. W. Sleep Res. 1972, 1, 179. 9. Miles, L. E. M., Raynal, D. M., Wilson, M. A. Science, 1977, 198, 421. 10. Halberg, F., Lauro, R., Carandente, F. Ric. Clin. Lab. 1976, 6, 207. 11. Miller, R. W. Childhood Cancer Etiology Newsletter, no. 44. Washington,
D.C., 1977.
Afflicted infants have hyperinsulinaemia, ketotic hypoglycEemia, various endocrine disorders (panhypopituitarism, isolated growth-hormone deficiencies, corticotrophin deficiency, Addison’s disease, hypothyroidism), or hepatic-enzyme deficiency (glycogen-storage diseases, disorders of
gluconeogenesis2). Inappropriate insulin secretion is present in 20-33% of all cases of persistent hypoglycaemia3.4 but diagnosis
is nonetheless difficult. The clinical symptoms are ataxia, somnolence, and coma (or seizures) before meals, starting in most cases before the age of 2. Some workers suggest that hyperinsulinsemic hypoglycarmia is a factor in sudden-infant-death syndrome.5,6 A characteristic finding is a high insulin/glucose ratio in blood, commonly with an associated leucine sensitivity.6,7 The primary goal of management is prevention of the repeated hypoglycxmic attacks, which can damage the brain. Sometimes this can be achieved by frequent feeding combined with cortisol therapy, or by glucose infusions. Alternatively, inappropriate insulin secretion can be controlled with diazoxide or, as lately reported,8 by subcutaneous injections of protamine zinc somatostatin. When medical treatment fails, surgical resection of the pancreas becomes necessary, and even then the patient may need long-term diazoxide therapy.9 Usually at least half the pancreas is resected: except in the rare cases of endocrine adenoma, gross morphological changes are absent. The underlying condition is known as nesidioblastosis-a term coined by Laidlawl° to describe diffuse proliferation of the islet cells, nesidioblasts being defined as "the cells that differentiate out of the duct epithelium to build islets". In the past precise histological diagnosis has been difficult: lack of normal islets, close contact between exocrine ducts and endocrine-cell clusters, and microadenomas have been regarded as hallmarks of the disorder. The process usually affects the entire pancreas. Classification had to await detailed structural analyses of the endocrine pancreas. Kloppel and his colleagues" did morphometric studies of a single case and Svik, Vidnes, and Falkmer9 analysed three cases, using special stains to delineate the A (glucagon) and B (insulin) cells. Useful as these investigations were, they could not properly distinguish the contribution of each individual endocrine cell type. This distinction can be made only by immunocytochemical procedures such as those employed by Heitz et al.,12 who examined seven surgical specimens of pancreas obtained at laparotomy from infants with persistent hyperinsulinaemic hypoglycaemia. They found that four types of endocrine cell invariably participate in the endocrine proliferation-namely, B, A, D (somatostatin), and P.P. (pancreatic polypeptide).Thecells Pagliara, A. S., Karl, I. E., Haymond, M., Kipnis, D. M. Pediatrics, 1973, 82, 365. 3. Kogut, M. D., Blaskovics, M., Donnell, G. N. ibid. 1969, 74, 853. 4. Dr George, A. M., Auerbach, V. H. Am. J. med. Sci. 1960, 240, 792. 5. Polak, J. M., Wigglesworth, J. Lancet, 1976, ii, 570. 6. Cox, J. N., Guelpa, G., Terrapon, M. ibid. p. 739. 7. Cochrane, W. A. Am. J. Dis. Child. 1960, 99, 476. 8. Hirsch, H. J., Loo, S, Evans, N., Crigler, J. F., Jr, Filler, R. M., Gabbay, K. H. New Engl J. Med. 1977, 296, 1323. 9. Søvik, O., Vidnes, J., Falkmer, S. Acta path. microbiol. scand. 1975, 83A, 2.
155. 10. 11.
Laidlaw, G. F. Am. J. Path. 1938, 14, 125. Klöppel, G., Altenähr, E., Reichel, W., Willig, R., Freytag, G. Diabetologia, 1974, 10, 245. 12. Heitz, Ph. U., Klöppel, G., Häcki, W. H., Polak, J. M., Pearse, A. G. E. Diabetes, 1977, 26, 632.
occurred in a ratio which was remarkably constant in the seven cases and for the B and A cells the ratio corresponded to that found in normal islets. On computerised image analysis the endocrine parenchyma proved to be increased almost fivefold in nesidioblastosis compared with age-matched controls, and Sovik et al. concluded that the pathogenesis of the different morphological patterns of endocrine proliferation-multifocal ductuloinsular proliferation, microadenomatosis, focal adenomatosis, and adenoma-are one and the same. Although the prime cause remains unknown, nesidioblastosis evidently represents a failure of the normal mechanisms controlling embryogenesis of the endocrine pancreas and its transition to the normal neonatal and infantile state. A systematic analysis of all hormones known to regulate pancreatic function may reveal the identity of the controlling factor whose excess (stimulation) or lack (failure of inhibition) is responsible for the uncontrolled expansion of the islet cells. WHAT HAPPENS TO CLOTS IN THE LUNGS? WHAT happens to patients with pulmonary emboli who survive to leave hospital? Do they have further pulmonary emboli, with pulmonary hypertension and poor long-term prognosis? There is surprisingly little information about these matters, and two papers from Hall and his co-workers are helpful. In one they report a 9-year follow-up of 72 patients who survived a massive pulmonary embolus after intensive but varied initial treatments.12 patients died within this period but in no case was death due to chronic pulmonary hypertension or to definite recurrence of pulmonary embolism. Of the 56 who were restudied none had clinical signs of pulmonary hypertension, either persistent or of later onset, and only 6% had a possible non-fatal recurrence of pulmonary embolism. Resolution of the embolus was complete in most cases although pulmonary arteriography 2-72 months later showed minor abnormalities in some, as did perfusion lung scans performed up to 8 years after the initial incident. The second paper looks at patients with less severe pulmonary emboli; they had a similar pattern of resolution and recurrence.2 These results are in accord with previous work. None of 58 patients initially studied by Paraskos3 and followed up died of pulmonary embolic disease: survival correlated with the presence or absence of pre-existing heartdisease. When 43 of these patients were restudied after 1-7 years, only 5 had evidence of unresolved embolism and only 1 had chronic cor pulmonale. Definite recurrent pulmonary embolism was recorded in only 1 patient, although 3 others had suspected embolism. Tow and Wagner4 did perfusion lung scans in 69 patients: within 4 months, between half and three-quarters had complete resolution or improvement irrespective of the severity of initial embolism. Others have made similar observations with both lung scans and arteriography, 3-7 1. Hall, R. J. C., Sutton, G. C., Kerr, I. H. Br. Heart J. 1977, 39, 1128. 2. Sutton, G. C., Hall, R. J. C., Kerr, I. H. ibid. p. 1135. 3. Paraskos, J. A., Adelstein, S. J., Smith, R. E., Rickman, F. D., Grossman, W, Dexter, L., Dalen, J. E. New Engl. J. Med. 1973, 289, 55. 4. Tow, D. E., Wagner, H. E. ibid. 1967, 276, 1053. 5. Sautter, R. D., Fletcher, F. W., Emanuel, D. A., Lawton, B. R., Olsen, T. G. J. Am. med. Ass. 1964, 189, 948. 6. Fred, H. L., Axelrad, M. A., Lewis, J. M., Alexander, J. K. ibid. 1966, 196, 1137. 7. Urokinase Pulmonary Embolism Trial. Circulation, 1973, 47, suppl. II, p. 1.
195
occurring within two weeks.8 disability in 10 of 68 patients but not employ lung scans or pulmonary
resolution sometimes
Phear9 reported early work did arteriography. Patients severe
this
disease present
a
with chronic thromboembolic different picture. Sutton’s patients
progressively worse with persistent pulmonary hypertension, increasing right-heart failure, and death.2 Others have also recorded cases of chronic cor pulmonale due to "silent" or recurrent untreated pulmoni became
ary thromboembolism. 10,11
What then
conclude about the late sequelae of is good evidence that resolution of the obstruction, whatever its size, occurs mainly in the first 4 months after the initial incident, and that most treated patients proceed to complete hxmodynamic and angiographic resolution.4-8 Chronic cor pulmonale is a very rare complication of pulmonary embolism, but may arise in patients who have repeated episodes that are undetected and therefore untreated. Treatment with anticoagulants reduces the incidence of recurrent pulmonary emboli.7 Provided that the initial episode is adequately treated and anticoagulants continued for at least 4 months, by which time the embolus will usually have resolved, the long-term prognosis of a pulmonary embolus, of any size, is excellent. can one
pulmonary embolism? There
CIRCADIAN DYSRHYTHMIAS DIURNAL variation of a hormone was first reported in 1943 by Pincus,’ who examined 17-ketosteroid excretion in normal subjects. Since then new techniques such as automatic blood-sampling devices, sensitive microchemical assays, and polygraphic sleep recorders have permitted the correlation of hormone secretion with sleep/waking rhythms. Application of these methods to conditions such as Cushing’s disease, acromegaly, anorexia nervosa, and affective disorders2 has provided new insights into patterns of hormone secretion. By manipulation of environmental conditions it should be possible to distinguish inherent rhythms from those influenced by the environment. Normal subjects isolated from time information tend to adopt sleep/activity cycles slightly longer than 24 hours3 and this has been generally attributed to an endogenous timing mechanism. Artificial prolongation of the day tends to lengthen the urinary electrolyte excretion cycle, but shortening of the day may result in two rhythms, both influencing excretion of the same electrolyte-one being persistently circadian and the other conforming to the artificially shortened sleep/activity cycle.4 Thus rhythms of urinary electrolyte excretion can be successfully entrained by days as long as 27 hours but not by days as short as 21 hours. Such studies of abnormal daylength may help to clarify the physiology of jet-lag and may be of importance in planning the sleep/activity programmes of astronauts.
Individuals with disturbed perception of important environmental cues might be expected to show disorders of circadian rhythm. This seems to happen in blind people without light perception, who may show abnormal periodicity of plasma-cortisol’ and urinary electrolyte excretion,6 suggesting that these diurnal rhythms are not correctly phased by light stimuli. Although impairment of growth-hormone release during sleep has been reported in blind subjects7 this has not been confirmed2 and defective secretion may have been caused by the abnormal sleep patterns of the subjects studied. Webb and Agnew8 suggested that disorders of circadian rhythm might become clinically manifest as sleep/wake disturbances,8and this effect has now been reported in a totally blind individual.9 For several weeks at a time he would experience insomnia and daytime sleepiness which interfered with his work and leisure. His body temperature, plasma-cortisol, urinary electrolyte excretion, and sleep/activity cycles all had a periodicity of 24-9 hours and could not be entrained to 24 hours by a strict sleep/activity schedule. Such symptomatic disturbances of circadian rhythm may also arise in people with normal vision,3 so loss of light cues from the environment is not the sole cause. Possibly, circadian dysrhythmias are common in milder form, causing insomnia, fatigue, poor performance, and various non-specific symptoms. Without elaborate long-term monitoring1O they are likely to remain undiagnosed.
A GROUP of American scientists who recently visited the People’s Republic of China were impressed by work there on cancer, discovering what one member described as an "etiologic wonderland". 11 Two features contributed to this feeling. Firstly, the Chinese allow many of their domestic animals to live out their full lives, well beyond the best years for breeding or egg-laying; so they are well acquainted with diseases of later life such as cancers, some of which resemble those prevalent in the human population. Secondly, the Chinese have constructed maps showing cancer mortality rates, and with some of them (as in the United States) the distribution is nonrandom. The hepatocellular-carcinoma map, for instance, shows distinct areas of high incidence. This cancer is common not only in human beings but also in the local ducks. Poultry may have something to say, too, about oesophageal cancer. When a water reservoir was needed, 50 000 people had to be moved to new homes, from a high oesophageal cancer area to a low one. They took with them one lone chicken; otherwise they started afresh with local birds. Yet the chickens of the relocated people are now getting oesophageal cancer; so the cause must be somewhere in their narrow environment. Table scraps form part of the chicken diet, and a nitrosaminerich pickled-vegetable mix is under suspicion.
8. Crane,
C., Hartsuck, J., Birtch, A., Couch, N. P., Zollinger, R., Matloff, J., Dalen, J., Dexter, L. Surgery Gynec. Obstet. 1969, 128, 27. 9. Phear, D. Lancet, 1960, ii, 832. 10. Davison, P. H., Armitage, G. H., Mcllveen, D. J. S. ibid. 1956, ii, 224. 11. De Soyza, N. D. R., Murphy, M. L. Chest, 1972, 62, 665. 1. Pincus, G. J.J. clin Endocr. Metab 1943, 3, 195. 2. Weitzman, E. D. A. Rev. Med. 1976, 27, 225. 3. Mills, J. N., Minors, D. S., Waterhouse, J. M. J. Physiol. 1974, 240, 567. 4 Mills, J. N., Minors, D. S., Waterhouse, J. M. ibid. 1977, 268, 803.
5. Orth, D. N., Island, D. P., J. clin Endocr. Metab. 1969, 29, 479. 6. Simenhoff, M. L. J. appl. Physiol. 1974, 37, 374. 7. Krieger, D. T., Glick, S. J. clin. Endocr. Metab. 1971, 33, 847. 8. Webb, W. B., Agnew, H. W. Sleep Res. 1972, 1, 179. 9. Miles, L. E. M., Raynal, D. M., Wilson, M. A. Science, 1977, 198, 421. 10. Halberg, F., Lauro, R., Carandente, F. Ric. Clin. Lab. 1976, 6, 207. 11. Miller, R. W. Childhood Cancer Etiology Newsletter, no. 44. Washington,
D.C., 1977.
