- Email: [email protected]
ASEPTIC NECROSIS AND STEROID THERAPY
1135
well et al.3 lately suggested that Whipple’s disease is caused by infection in patients with an immunological deficit; and Taylor 4 proposed that in regional enteritis, as in sarcoidosis, some disturbance of normal immunological response of anergic type may be concerned. Though the evidence yet is far from conclusive, Golde’s hypothesis deserves further investigation to try to identify a bacterial origin which perhaps initiates a particular tissue response in which immunological factors may play an important role. Clinicians might well consider his suggestion of a controlled trial of sulphones and related compounds in this disease.
WATSON’S HELIX
might have subtitled his bookÓ " Science", for his intention was to correct a widespread ignorance of what goes on inside a scientist’s laboratory-the clashes of personality that sometimes hinder progress; ambitions tempered by a sense of fair play; false trails (never hinted at in the crisp published scientific paper) that may waste months or years of time and effort before the right answer is reached. But Professor Watson has, of course, another very important reason for writing this book: his own particular bit of science-the discovery, in 1953, of the double helical structure of D.N.A.-was acclaimed as the most important contribution to biological science since Darwin propounded his theory of natural selection, and won for him, together with Francis Crick and Maurice Wilkins, a Nobel prize in 1962. Since his college days Watson had been driven by an Professor Watson Taking the Lid off
urge to discover the essential nature of the gene, and
postgraduate research fellowship
at
Indiana
a
University,
where he worked under Salvador Luria, gave him the opportunity to follow up his interest. While others hoped that genetic tricks would provide the answer, Luria, who had already spent some years working on bacteriophage genetics, was convinced that the mechanism of gene control would not be elucidated until the chemical structure of D.N.A. was known. Watson feared that Luria was right, but he shied away from chemistry (he had always preferred birds, he says). Nevertheless, he set out for Copenhagen, hoping to learn some biochemistry from his new mentor, Herman Kalckar. But he found Kalckar incomprehensible and the atmosphere unstimulating, so he soon returned to conventional phage work (though this was a violation of the terms of his fellowship). A two-month trip with Kalckar to the Stazione Zoologica at Naples was also unfruitful, but at a scientific meeting there he heard Wilkins describe his recent X-ray diffraction studies, which showed that D.N.A. was a crystalline substance. Watson was fired with a sudden enthusiasm to learn chemistry: if D.N.A. could crystallise it must have a regular structure, and its solution should be straightforward. Watson returned to Copenhagen just after Pauling had announced his discovery of the protein helix. This news made Watson even more anxious to learn something about structural chemistry, for Pauling would surely turn soon to D.N.A. So, with Luria’s help, he secured a position in 3.
Maxwell, J. D., Ferguson, A., McKay, A. M., Imrie, R. C., Watson, W. C. Lancet, April 27, 1968, p. 887. 4. Taylor, K. in Recent Advances in Gastroenterology (edited by J. Badenoch and B. N. Brooke). London, 1965. 5. The Double Helix. By JAMES D. WATSON. London: Weidenfeld Nicolson. 1968. Pp. 226. 35s.
laboratory at Cambridge. Within a few days of meeting Crick (" finding someone ... who knew that D.N.A. was more important than proteins was real luck ") they decided to follow Pauling’s example and experiment with molecular models-and, if possible, beat him at his own game. This they did, but only just. The latest X-ray pictures could be interpreted as a helical structure, and the chemical composition of the nucleotides was Perutz’s
known. But how many helices
there ? Was the outside the coil? Watson that a two-
were
backbone inside
sugar-phosphate Inspired guesswork suggested to stranded helix was the right one (" important biological objects come in pairs "), and a good deal of fiddling with the molecular models finally showed how two irregular sequences of nucleotide bases could be arranged in a regular fashion within the double helix. Pauling had lately published his own interpretation of D.N.A. structure as a three-chain helix with the sugar-phosphate backbone in the centre, but Crick had quickly pointed out that he had made some elementary mistakes in basic chemistry. or
This was the final spur to Watson and Crick’s efforts-the fear that Pauling would very soon discover his mistakes and immediately come up with the right answer. It is not easy to believe that so momentous a discovery was the result of anything but carefully planned, logical experiment. Watson’s record that it was not will save us a lot of fictitious dialogue from future popularisers of scientific history. He has, at times, been uncomfortably truthful:not all his colleagues appear in an entirely favourable light, and some have been offended by his frankness. But this book is not an attack on the people with whom he worked. It is a recollection of a young man’s reactions both to those who helped him and to those who thwarted his plans. It portrays his own youthful arrogance and his impatience with his elders and seniors; but these are part of the D.N.A. story. Had Watson been more restrained his story would have been less vivid-and, indeed, less honest.
ASEPTIC NECROSIS AND STEROID THERAPY
ASEPTIC bone necrosis, most often in the femoral head, is a complication of corticosteroid therapy. Although the condition may appear abruptly, symptoms are usually slowly progressive, starting with pain in the hip and limitation of movement. In 8 male patients with this necrosis,! the range of steroid dose was from 25 to 120 mg. per day of cortisone, and the necrosis manifested itself between three and twenty-nine months after the start of treatment. 5 patients had bilateral signs and 1 also had a destructive process in the head of the humerus. Patients who survive renal homotransplantation often have bone changes. Cruess et awl.3 studied 27 patients who were alive for six months or more after transplantation, and 10 patients had some bony lesion. Aseptic necrosis of the femoral heads was found in 9 (in 5 the hips alone were affected), and around the knee-joint in 5 and the humeral heads in 2. The average time after transplantation when symptoms arose was seven months and the X-ray changes appeared about two months later. Radiological investigation showed that the first change in the Sutton, R. D., Benedek, T. G., Edwards, G. A. Archs intern. Med. 1963, 112, 594. 2. Boksenbaum, M., Mendelson, C. G. J. Am. med. Ass. 1963, 184, 262. 3. Cruess, R. L., Blennerhassett, J., MacDonald, F. R., MacLean, L. D., Dossitor, J. Annual meeting of the American Academy of Orthopædic Surgeons, Chicago, January, 1968. 1.
1136
femoral and humeral heads was demineralisation in the subchondral area, extending to more and more bone, always distally from the subchondral area. The bone then collapsed and the lesion looked more sclerotic. Histological examination in 4 patients did not provide any definite clue to the cause of the condition. Discussing the possible factors in the production of aseptic necrosis in their patients, Cruess et al. do not think that actinomycin was responsible, and azathioprine and its related compounds have not been shown to produce changes in adult bones or joints in experimental animals. The amount of postoperative irradiation was insufficient to produce such lesions, and in any case they were often outside the irradiated field. The most likely cause is the high doses of corticosteroids given after the operation. Cortisone, it has been suggested, may induce a vasculitis which would lead to bone death, for it is known that such lesions arise in post-transplant patients, 45 but no histological evidence of this was found in the bone specimens Steroid-induced osteoporosis may be the examined. but the lesions are well localised and do not affect cause, all patients. Cruess et al. suggest that the most likely cause was fatty embolisation. Long-continued corticosteroid therapy may produce severe fatty changes in the liver, and fatty embolism from the liver may be bad enough to cause death. A 9-year-old girl treated with high doses of steroids was found at necropsy to have a large fatty liver with fat emboli in the lungs, kidneys, spleen, 6 Fat embolism is a pancreas, meninges, and brain. complication of renal transplantation; Jones et al.,’ in the first reported case, found that the probable source was a fatty liver and they suggested that this was due to corticosteroid therapy. Intravenous fat emboli are known to concentrate in the subchondral area of the femoral head and in the metaphysis of the femur and tibia next to the knee.8 The absence of visible fat emboli in histological sections of the bone involved could be the result of changes following bone collapse. Cruess et al. do not seem to have any evidence about the state of the livers of their patients. In keeping with their hypothesis is their later experience with a small group of patients who have been treated with anti-lymphocyte serum and much lower doses of steroids; no bony changes have been observed in these patients.
URINARY INFECTION
in London last month discussed advances understanding of urinary infection. A new and interesting finding is the powerful antibacterial activity of the prostatic fluid, and this observation suggests that the difference between the incidence of urinary infection in males and females may not be entirely due to difference in urethral length. The prostatic fluid, which is continually secreted into the urethra may also be an important barrier to ascending infection. But even when bacteria do reach the bladder urine,which is an excellent culture medium, they are by no means certain to establish an infection. The efficacy of dilution and displacement of infected urine from the bladder by emptying, as a defence mechanism, has been studied in mechanical and computer models. A
SYMPOSIUM
in the
Dunea, G., Hazard, J. B., Kolff, W. J. J. Am. med. Ass. 1964, 190, 199. Porter, K. A., Thomson, W. B., Owen, K., Kenyon, J. R., Mowbray, J. F., Peart, W. S. Br. med. J. 1963, ii, 639. 6. Hill, R. B. New Engl. J. Med. 1961, 265, 318. 7. Jones, J. P., Engleman, E. P., Najarian, J. S. ibid. 1965, 273, 1453. 8. Jones, J. P., Sakovich, L. J. Bone Jt Surg. 1965, 48A, 149.
4. 5.
ability to diagnose silent infection in the kidney is undoubtedly important. Approaches to this problem include examination of the serum for specific antibody against the urinary organism, the ability of the kidney to concentrate after deprivation of fluid, and the use of ureteric catheters. There seems to be good agreement The
between these methods when all are carried out on the same patient, but their value is confined to active infection and to showing that such infections have been eradicated. Renal biopsy with subsequent culture for bacteria and viruses has been used in an attempt to detect persistent infection in chronic pyelonephritis; but the results were negative. If bacteria or viruses are continually present in the chronic pyelonephritic kidney, they must lie in small foci which are missed by the biopsy needle. A large study of domiciliary patients who had had urinary infections showed that the bowel was the reservoir. The Escherichia coli causing infections were those which generally predominate in the faeces, and no evidence emerged that bacteria present in the bowel in small numbers had special pathogenicity for the urinary tract, as had often been suggested. Important developments in the study of urinary infections in children suggest that they are often the precursor of the adult disease. Diagnosis depends on testing the urine, and the care needed to collect adequate specimens was again emphasised. Suprapubic puncture had been shown to be a simple procedure in the infant or child, and it should be used when there was doubt. (The use of this method in pregnancy is the subject of an article on p. 1112.) The relative importance of infection of the kidney and vesico-ureteric reflux, which often accompanies infection in the child, in producing renal scarring But impressive evidence was remained in doubt.1 to show that control of infection permitted presented renewed growth of a damaged kidney in spite of persistent reflux. Treatment of urinary infection in pregnancy defines a group of patients who fail to respond and they are later shown to have urinary-tract abnormalities, although the risk of abnormality is apparently not as great as that reported in other countries. Nevertheless, the postpartum radiological study of such patients is of great importance, and an account of the radiological changes in the urinary tract in pregnancy illustrated that they persisted for much longer than had previously been realised. Although a good deal is known about blood and urinary levels of antibiotics, the intrarenal concentration of these substances is in doubt. Since asymptomatic renal infection is known to be far more common than was previously supposed, such information has an important bearing on the choice of therapy. Attempts to demonstrate renal levels by cannulation of the renal lymphatics indicated that intrarenal levels were more closely related to antibiotic concentrations in the plasma than to those in the urine. Urinary concentrations are obviously also vital for the elimination of urinary organisms. Contrary to previous recommendations, a case was made for administrations of antibiotic with fluid loading, the justification being that the antibacterial effect was prolonged and that the diuresis helped to eradicate the bacteria by mechanical cleansing. A disappointing note at the meeting was the poor prognosis given to chronic bacteriuria. In spite of lengthy treatment, reinfection was common, and the need for early diagnosis and treatment was re-emphasised. 1. See
Lancet, May 18, 1968, p. 1072.
well et al.3 lately suggested that Whipple’s disease is caused by infection in patients with an immunological deficit; and Taylor 4 proposed that in regional enteritis, as in sarcoidosis, some disturbance of normal immunological response of anergic type may be concerned. Though the evidence yet is far from conclusive, Golde’s hypothesis deserves further investigation to try to identify a bacterial origin which perhaps initiates a particular tissue response in which immunological factors may play an important role. Clinicians might well consider his suggestion of a controlled trial of sulphones and related compounds in this disease.
WATSON’S HELIX
might have subtitled his bookÓ " Science", for his intention was to correct a widespread ignorance of what goes on inside a scientist’s laboratory-the clashes of personality that sometimes hinder progress; ambitions tempered by a sense of fair play; false trails (never hinted at in the crisp published scientific paper) that may waste months or years of time and effort before the right answer is reached. But Professor Watson has, of course, another very important reason for writing this book: his own particular bit of science-the discovery, in 1953, of the double helical structure of D.N.A.-was acclaimed as the most important contribution to biological science since Darwin propounded his theory of natural selection, and won for him, together with Francis Crick and Maurice Wilkins, a Nobel prize in 1962. Since his college days Watson had been driven by an Professor Watson Taking the Lid off
urge to discover the essential nature of the gene, and
postgraduate research fellowship
at
Indiana
a
University,
where he worked under Salvador Luria, gave him the opportunity to follow up his interest. While others hoped that genetic tricks would provide the answer, Luria, who had already spent some years working on bacteriophage genetics, was convinced that the mechanism of gene control would not be elucidated until the chemical structure of D.N.A. was known. Watson feared that Luria was right, but he shied away from chemistry (he had always preferred birds, he says). Nevertheless, he set out for Copenhagen, hoping to learn some biochemistry from his new mentor, Herman Kalckar. But he found Kalckar incomprehensible and the atmosphere unstimulating, so he soon returned to conventional phage work (though this was a violation of the terms of his fellowship). A two-month trip with Kalckar to the Stazione Zoologica at Naples was also unfruitful, but at a scientific meeting there he heard Wilkins describe his recent X-ray diffraction studies, which showed that D.N.A. was a crystalline substance. Watson was fired with a sudden enthusiasm to learn chemistry: if D.N.A. could crystallise it must have a regular structure, and its solution should be straightforward. Watson returned to Copenhagen just after Pauling had announced his discovery of the protein helix. This news made Watson even more anxious to learn something about structural chemistry, for Pauling would surely turn soon to D.N.A. So, with Luria’s help, he secured a position in 3.
Maxwell, J. D., Ferguson, A., McKay, A. M., Imrie, R. C., Watson, W. C. Lancet, April 27, 1968, p. 887. 4. Taylor, K. in Recent Advances in Gastroenterology (edited by J. Badenoch and B. N. Brooke). London, 1965. 5. The Double Helix. By JAMES D. WATSON. London: Weidenfeld Nicolson. 1968. Pp. 226. 35s.
laboratory at Cambridge. Within a few days of meeting Crick (" finding someone ... who knew that D.N.A. was more important than proteins was real luck ") they decided to follow Pauling’s example and experiment with molecular models-and, if possible, beat him at his own game. This they did, but only just. The latest X-ray pictures could be interpreted as a helical structure, and the chemical composition of the nucleotides was Perutz’s
known. But how many helices
there ? Was the outside the coil? Watson that a two-
were
backbone inside
sugar-phosphate Inspired guesswork suggested to stranded helix was the right one (" important biological objects come in pairs "), and a good deal of fiddling with the molecular models finally showed how two irregular sequences of nucleotide bases could be arranged in a regular fashion within the double helix. Pauling had lately published his own interpretation of D.N.A. structure as a three-chain helix with the sugar-phosphate backbone in the centre, but Crick had quickly pointed out that he had made some elementary mistakes in basic chemistry. or
This was the final spur to Watson and Crick’s efforts-the fear that Pauling would very soon discover his mistakes and immediately come up with the right answer. It is not easy to believe that so momentous a discovery was the result of anything but carefully planned, logical experiment. Watson’s record that it was not will save us a lot of fictitious dialogue from future popularisers of scientific history. He has, at times, been uncomfortably truthful:not all his colleagues appear in an entirely favourable light, and some have been offended by his frankness. But this book is not an attack on the people with whom he worked. It is a recollection of a young man’s reactions both to those who helped him and to those who thwarted his plans. It portrays his own youthful arrogance and his impatience with his elders and seniors; but these are part of the D.N.A. story. Had Watson been more restrained his story would have been less vivid-and, indeed, less honest.
ASEPTIC NECROSIS AND STEROID THERAPY
ASEPTIC bone necrosis, most often in the femoral head, is a complication of corticosteroid therapy. Although the condition may appear abruptly, symptoms are usually slowly progressive, starting with pain in the hip and limitation of movement. In 8 male patients with this necrosis,! the range of steroid dose was from 25 to 120 mg. per day of cortisone, and the necrosis manifested itself between three and twenty-nine months after the start of treatment. 5 patients had bilateral signs and 1 also had a destructive process in the head of the humerus. Patients who survive renal homotransplantation often have bone changes. Cruess et awl.3 studied 27 patients who were alive for six months or more after transplantation, and 10 patients had some bony lesion. Aseptic necrosis of the femoral heads was found in 9 (in 5 the hips alone were affected), and around the knee-joint in 5 and the humeral heads in 2. The average time after transplantation when symptoms arose was seven months and the X-ray changes appeared about two months later. Radiological investigation showed that the first change in the Sutton, R. D., Benedek, T. G., Edwards, G. A. Archs intern. Med. 1963, 112, 594. 2. Boksenbaum, M., Mendelson, C. G. J. Am. med. Ass. 1963, 184, 262. 3. Cruess, R. L., Blennerhassett, J., MacDonald, F. R., MacLean, L. D., Dossitor, J. Annual meeting of the American Academy of Orthopædic Surgeons, Chicago, January, 1968. 1.
1136
femoral and humeral heads was demineralisation in the subchondral area, extending to more and more bone, always distally from the subchondral area. The bone then collapsed and the lesion looked more sclerotic. Histological examination in 4 patients did not provide any definite clue to the cause of the condition. Discussing the possible factors in the production of aseptic necrosis in their patients, Cruess et al. do not think that actinomycin was responsible, and azathioprine and its related compounds have not been shown to produce changes in adult bones or joints in experimental animals. The amount of postoperative irradiation was insufficient to produce such lesions, and in any case they were often outside the irradiated field. The most likely cause is the high doses of corticosteroids given after the operation. Cortisone, it has been suggested, may induce a vasculitis which would lead to bone death, for it is known that such lesions arise in post-transplant patients, 45 but no histological evidence of this was found in the bone specimens Steroid-induced osteoporosis may be the examined. but the lesions are well localised and do not affect cause, all patients. Cruess et al. suggest that the most likely cause was fatty embolisation. Long-continued corticosteroid therapy may produce severe fatty changes in the liver, and fatty embolism from the liver may be bad enough to cause death. A 9-year-old girl treated with high doses of steroids was found at necropsy to have a large fatty liver with fat emboli in the lungs, kidneys, spleen, 6 Fat embolism is a pancreas, meninges, and brain. complication of renal transplantation; Jones et al.,’ in the first reported case, found that the probable source was a fatty liver and they suggested that this was due to corticosteroid therapy. Intravenous fat emboli are known to concentrate in the subchondral area of the femoral head and in the metaphysis of the femur and tibia next to the knee.8 The absence of visible fat emboli in histological sections of the bone involved could be the result of changes following bone collapse. Cruess et al. do not seem to have any evidence about the state of the livers of their patients. In keeping with their hypothesis is their later experience with a small group of patients who have been treated with anti-lymphocyte serum and much lower doses of steroids; no bony changes have been observed in these patients.
URINARY INFECTION
in London last month discussed advances understanding of urinary infection. A new and interesting finding is the powerful antibacterial activity of the prostatic fluid, and this observation suggests that the difference between the incidence of urinary infection in males and females may not be entirely due to difference in urethral length. The prostatic fluid, which is continually secreted into the urethra may also be an important barrier to ascending infection. But even when bacteria do reach the bladder urine,which is an excellent culture medium, they are by no means certain to establish an infection. The efficacy of dilution and displacement of infected urine from the bladder by emptying, as a defence mechanism, has been studied in mechanical and computer models. A
SYMPOSIUM
in the
Dunea, G., Hazard, J. B., Kolff, W. J. J. Am. med. Ass. 1964, 190, 199. Porter, K. A., Thomson, W. B., Owen, K., Kenyon, J. R., Mowbray, J. F., Peart, W. S. Br. med. J. 1963, ii, 639. 6. Hill, R. B. New Engl. J. Med. 1961, 265, 318. 7. Jones, J. P., Engleman, E. P., Najarian, J. S. ibid. 1965, 273, 1453. 8. Jones, J. P., Sakovich, L. J. Bone Jt Surg. 1965, 48A, 149.
4. 5.
ability to diagnose silent infection in the kidney is undoubtedly important. Approaches to this problem include examination of the serum for specific antibody against the urinary organism, the ability of the kidney to concentrate after deprivation of fluid, and the use of ureteric catheters. There seems to be good agreement The
between these methods when all are carried out on the same patient, but their value is confined to active infection and to showing that such infections have been eradicated. Renal biopsy with subsequent culture for bacteria and viruses has been used in an attempt to detect persistent infection in chronic pyelonephritis; but the results were negative. If bacteria or viruses are continually present in the chronic pyelonephritic kidney, they must lie in small foci which are missed by the biopsy needle. A large study of domiciliary patients who had had urinary infections showed that the bowel was the reservoir. The Escherichia coli causing infections were those which generally predominate in the faeces, and no evidence emerged that bacteria present in the bowel in small numbers had special pathogenicity for the urinary tract, as had often been suggested. Important developments in the study of urinary infections in children suggest that they are often the precursor of the adult disease. Diagnosis depends on testing the urine, and the care needed to collect adequate specimens was again emphasised. Suprapubic puncture had been shown to be a simple procedure in the infant or child, and it should be used when there was doubt. (The use of this method in pregnancy is the subject of an article on p. 1112.) The relative importance of infection of the kidney and vesico-ureteric reflux, which often accompanies infection in the child, in producing renal scarring But impressive evidence was remained in doubt.1 to show that control of infection permitted presented renewed growth of a damaged kidney in spite of persistent reflux. Treatment of urinary infection in pregnancy defines a group of patients who fail to respond and they are later shown to have urinary-tract abnormalities, although the risk of abnormality is apparently not as great as that reported in other countries. Nevertheless, the postpartum radiological study of such patients is of great importance, and an account of the radiological changes in the urinary tract in pregnancy illustrated that they persisted for much longer than had previously been realised. Although a good deal is known about blood and urinary levels of antibiotics, the intrarenal concentration of these substances is in doubt. Since asymptomatic renal infection is known to be far more common than was previously supposed, such information has an important bearing on the choice of therapy. Attempts to demonstrate renal levels by cannulation of the renal lymphatics indicated that intrarenal levels were more closely related to antibiotic concentrations in the plasma than to those in the urine. Urinary concentrations are obviously also vital for the elimination of urinary organisms. Contrary to previous recommendations, a case was made for administrations of antibiotic with fluid loading, the justification being that the antibacterial effect was prolonged and that the diuresis helped to eradicate the bacteria by mechanical cleansing. A disappointing note at the meeting was the poor prognosis given to chronic bacteriuria. In spite of lengthy treatment, reinfection was common, and the need for early diagnosis and treatment was re-emphasised. 1. See
Lancet, May 18, 1968, p. 1072.