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CYTOLOGICAL ASPECTS OF JOINT TISSUES
1105
of Surgeons and the Conjoint Board have arrangements for recognising overseas posts as appropriate for particular kinds of training. Some doctors dislike the idea of higher qualifications for anybody-physician, psychiatrist, or anyone else. Not without reason, these critics distrust all qualifications other than palpable merit, and they think that if we want to go on producing real doctors we must quickly put a stop to the compartmental elaboration of specialist training. Even to replace chaos by cosmos would give no pleasure to those who have come to feel that more could be done for Medicine by getting rid of fellowships and memberships than by improving them. At the meeting of the Royal Medico-Psychological Association reported on p. 1113, one speaker said that, as a measure of consultant status, the conception of a higher qualification is
Annotations A MILLION BLOOD DONORS
As
a
general
rule the clinician asks for
as
much blood
he thinks that he will need. This is provided without fuss and bother; and, if he needs more, it usually appears without delay. This sort of service is possible only because of highly efficient collection, distribution, and processing of the available blood. The attainment of the million mark by the active donor panel of the National Blood Transfusion Service is a reminder that the whole system would break down without an adequate supply of the raw material. On this occasion we should pay tribute to all those ordinary people who give their blood so readily and quietly, and who neither expect nor gain anything other than a sense of personal satisfaction. Who are these million ordinary people living in this land where affluence is so often equated with selfish materialism ? It is well to remember that the sort of person who is sometimes condemned as a poor citizen may have given many units of blood over the years; and this is not something that he or she would ever brag about. Next in line are the transfusion centres. Their directors, collecting teams, technicians, and drivers do a magnificent job; and a visit to one of these centres leaves one with an impression of efficiency unhampered by red tape. Lastly, the pathologists and technical staff of the laboratories all over the country who, day and night, see that compatible blood is always there when it is required. Blood is finally administered on the judgment of the clinician; and this is a time, too, for considering again the indications for transfusion. The wellbeing and esprit-decorps of the whole transfusion service depends on the correct use of blood. With a perishable commodity, some wastage is inevitable; and this we must accept. But we should not accept misuse of blood: the donor must be confident that his blood will be used correctly. The supply of blood is limited and the demand is always increasing. As we start on the second million, enrolment of each new donor becomes more difficult. What, then, are the indications for transfusion ? Nobody would question the two greatest-massive bloodloss associated with multiple injuries or hxmorrhage into the gastrointestinal tract, and major surgical procedures (sometimes of a severity undreamt of even in the recent past). Blood must be conserved for these purposes, and as
losing ground. Against this, it would be widely agreed that the average consultant (not necessarily the genius) gains competence from a planned course of trainingprovided the plan is stimulating rather than restrictive. Furthermore, under any medical system, posts have to be filled, and somebody has to say who is qualified to fill them. In determining whether a man is fully trained for his future work, the decisions of colleges should be more reliable than those of hospital appointments committees, which consist partly of laymen and usually decide by judging between competitors. The plan we have outlined is a natural development of present trends, and as such it needs to be faced and discussed. Once more it brings us up against the perils, for Medicine, of organisation or even order. Yet order is a necessity. this can be done most readily by avoiding unnecessary small transfusions. Criteria for transfusion must be stringent 1; when the sole purpose is to expand a moderately depleted bloodvolume, alternative infusions should be used. Brushing any cobwebs of unproven clinical impressions from our minds, we should recognise that blood in small quantities has no magical properties: dextran used with discretion is safe,2 and the hazards of small-pool plasma are hardly greater than those of blood itself. Accurate measurement of blood lost at operations may reveal that the pendulum has swung so that we now tend to overestimate the loss.3 Only by continual reappraisal of our blood-transfusion policy can we conserve blood. There are now a million reasons
why
we
should.
CYTOLOGICAL ASPECTS OF JOINT TISSUES
THE application of electron microscopy to the study of synovial tissues has already produced results of outstanding interest. The lining cells of the membrane of mammalian joints (exemplified by the rabbit and the guineapig) appear in two distinct forms, although some intermediate types also occur. The first type is characterised by a high degree of vacuolation of the cytoplasm and the presence of a complex arrangement of surface folds, several of which appear in section as finger-like processes. The second cell type lacks both vacuoles and surface folds, but its cytoplasm is rich in an endoplasmic reticulum liberally endowed with ribosomes. The features of the vacuolated cells suggest that they could be actively phagocytic-a suggestion borne out by the studies of J. A. Chapman, who described his findings at a symposium convened in London on Nov. 8 by the Empire Rheumatism Council. Chapman has shown that, shortly after an intra-articular injection of iron dextran, typical ferritin granules can be recognised in large numbers within the cytoplasmic vacuoles. Simultaneously the number and complexity of the cytoplasmic folds increase considerably. The second type of surface cells are apparently non-phagocytic and do not accumulate ferritin after intra-articular injection of iron dextran. The established relationship between endoplasmic reticulum and protein synthesis suggests that these cells are actively employed in some anabolic activity, and, since the most 1. Graham-Stewart, C. W. Lancet, 1960, ii, 421. Artz, C. P., Howard, J. M., Frawley, J. P. Surgery, 1955, 37, Gardiner, A. J. S., Dudley, H. A. F. Lancet, 1963, ii, 859.
2. 3.
612.
1106
obvious constituent of synovial fluid is hyaluronic, it is presumably in the synthesis of this polysaccharide that these cells are engaged. Also present in the synovial cells of both types are lysosomes, subcellular vesicles first shown by De Duve to consist of a lipoprotein membrane enclosing a mixture of several hydrolytic enzymes with little in common except optimal activity in the acid pH range of 3 to 5. Since these include powerful proteolytic enzymes which, in some tissues at least, can attack collagen and can certainly break down the protein-polysaccharide bond in chondromucoprotein, their participation in the pathogenesis of arthritis is extremely probable. In this context the studies of D. Hamerman with the electron microscope are especially significant. At the E.R.C. symposium he described finding in the lining cells of the synovium of rheumatic joints conspicuous electron-dense bodies much larger than lysosomes but probably derived from them, judging by their rich content of acid phosphatase. The precipitation of lead phosphate in the first stage of Gomori’s method for the display of this enzyme makes this a particularly suitable subject for electron microscopy. These studies of the ultra-structure of synovial cells suggest, therefore, that injury 10 joint structures may indeed be mediated by enzymes elaborated in the affected synovial cells. What leads in the first instance to the abnormality of these cells, as revealed by the electron microscope, is still obscure, but the results of Bitensky and her colleaguesI on the influence of antibodies to ascites tumour cells upon their lysosomal acid phosphatase imply that immune reactions on cell surfaces may be one method by which such lysosomal injury could arise. RENAL PAPILLARY NECROSIS AND PHENACETIN
THE frequency of renal papillary necrosis in Denmark is again emphasised by an account of 66 cases seen in four years in one department of medicine in Copenhagen. Harvald2 points out that only 5 of these were in patients with diabetes and only 8 in patients with obstruction of the urinary tract (his two " traditional " conditions associated with its occurrence). Of the other patients the largest group had had recurrent attacks of acute pyelonephritis, but of special interest was a group without any urological symptoms but with refractory anxmia found to be due to renal insufficiency from chronic pyelonephritis. Harvald was particularly concerned with the abuse of analgesic drugs, especially phenacetin : " most of our patients with papillary necrosis have consumed six tablets or more per day for over ten years". A few had reasonable grounds for this consumption (rheumatoid arthritis or osteoarthritis), but the majority gave vague explanations such as tiredness, feeling of insufficiency, over-exertion, or ill-defined headache. Harvald admits that the mechanism by which analgesics injure the kidneys remains obscuresLindwa113suggested that phenacetin may render the kidney more susceptible to infection. Papillary necrosis is less common in this country for perhaps two reasons. First, aspirin, and not phenacetin, is the main constituent of our headache powders 4 5; and, secondly, we may be more acutely aware of the minor 1. Bitensky, L. Brit. med. Bull. 1963, 19, 241. 2. Harvald, B. Amer. J. Med. 1963, 35, 481. 3. Lindwall, N. Acta radiol., Stockh. 1960, suppl. 192. 4. See Lancet, 1959, i, 84. 5. See ibid. 1960, ii, 858.
grades of pyelonephritis and the indefinite symptoms they produce. Thus the recognition of inapparent and subclinical pyelonephritis,6 and the purposeful investigation of indefinite symptoms possibly due to this or more overt chronic pyelonephritis,’ may lead to earlier recognition and treatment of infections, thus discouraging self-medication not only with phenacetin but with other analgesics too. It is surely too late to wait for the " comparatively unalarming symptomatology, either as attacks of acute pyelonephritis with excretion of papillary tissue or as a slowly progressing renal insufficiency."2 Lindwall3 found the changes of chronic pyelonephritis, often with acute exacerbations, in all the resected or postmortem kidneys of the phenacetin patients, while Harvald2 quotes Spuhler and Zollinger as finding a chronic interstitial nephritis which corresponds with Talbot’schronic interstitial infiltration in chronic ascendIt has already been shown4 how such a lesion can affect the blood-supply to the renal papillx.
ing pyelonephritis.
CHRONIC PANCREATITIS
THE
frequency of chronic pancreatitis may be much underestimated, because the main manifestations, such as a raised fasting level of serum-amylase or serumlipase, steatorrhoea, pancreatic calcification, and diabetes, are found only in well-established cases. Early, developing, mild, or atypical cases have been missed mainly through lack of specific tests of pancreatic function. Fitzgerald et awl. lay emphasis on the value of evocative enzyme tests in this connection. These workers investigated 53 patients with chronic pancreatitis by means of cholecystography, barium-meal examinations, tests for faecal occult blood, &bgr;-cell function tests (fasting bloodsugar levels and glucose tolerance), and straight X-rays to demonstrate pancreatic calculi. But they regard the secretin-pancreozymin test described by Howat 10 and elaborated by Burton et al. 11 as the most helpful of all tests in the diagnosis of early chronic pancreatitis, and as providing earlier information of pancreatic derangement than examination of the duodenal contents. 69 secretinpancreozymin tests were carried out on 40 patients with pancreatitis. The serum-amylase rose from fasting levels of 0-7-4-4 mg. per ml. (40-242 units) with a mean of 2-53 mg. per ml. (157 units) to 2-5-8-2 mg. per ml. (137-451 units) with a mean of 3-41 mg. per ml. (188 units). In normal control cases the serum-amylase rose from a fasting level of 0-5-1-9 mg. per ml. (28-105 units) with a mean of 1.3 mg. per ml. (72 units) to a peak post-stimulatory level varying from 0-6 to 2-6 mg. per ml. (38 to 137 units) with a mean of 1-5 mg. per ml. (84 units). In only 2 of Fitzgerald’s patients did the serum-amylase level fail to rise over 2-9 mg. per ml. (160 units) after stimulation-an accuracy of 95% for the test. This is an important finding, because fasting amylase and lipase levels are often normal in quiescent phases of pancreatitis, and may be raised in other diseases such as acute gallbladder disease and perforated duodenal ulcer and after
the administration of morphine-like narcotics.i2 Results from serum-lipase in the secretin-pancreo6. See ibid. 1959, i, 1265. 7. See ibid. 1961, ii, 89. 8. Talbot, H. S. J. Amer. med. Ass. 1958, 168, 1595. 9. Fitzgerald, O., Fitzgerald, P., Fennelly, J., McMullin,
J. P., Sylvester, J. B. Gut, 1963, 4, 193. Howat, H. T. Modern Trends in Gastro-enterology (edited by F. Avery Jones); p. 776. London, 1952. 11. Burton, P., Hammond, E. M., Harper, A. A., Howat, H. T., Scott, J. E., Varley, H. Gut, 1960, 1, 125. 12. Bogoch, A., Roth, J. L. A., Bockus, H. L. Gastroenterology, 1954, 26, 697. 10.
of Surgeons and the Conjoint Board have arrangements for recognising overseas posts as appropriate for particular kinds of training. Some doctors dislike the idea of higher qualifications for anybody-physician, psychiatrist, or anyone else. Not without reason, these critics distrust all qualifications other than palpable merit, and they think that if we want to go on producing real doctors we must quickly put a stop to the compartmental elaboration of specialist training. Even to replace chaos by cosmos would give no pleasure to those who have come to feel that more could be done for Medicine by getting rid of fellowships and memberships than by improving them. At the meeting of the Royal Medico-Psychological Association reported on p. 1113, one speaker said that, as a measure of consultant status, the conception of a higher qualification is
Annotations A MILLION BLOOD DONORS
As
a
general
rule the clinician asks for
as
much blood
he thinks that he will need. This is provided without fuss and bother; and, if he needs more, it usually appears without delay. This sort of service is possible only because of highly efficient collection, distribution, and processing of the available blood. The attainment of the million mark by the active donor panel of the National Blood Transfusion Service is a reminder that the whole system would break down without an adequate supply of the raw material. On this occasion we should pay tribute to all those ordinary people who give their blood so readily and quietly, and who neither expect nor gain anything other than a sense of personal satisfaction. Who are these million ordinary people living in this land where affluence is so often equated with selfish materialism ? It is well to remember that the sort of person who is sometimes condemned as a poor citizen may have given many units of blood over the years; and this is not something that he or she would ever brag about. Next in line are the transfusion centres. Their directors, collecting teams, technicians, and drivers do a magnificent job; and a visit to one of these centres leaves one with an impression of efficiency unhampered by red tape. Lastly, the pathologists and technical staff of the laboratories all over the country who, day and night, see that compatible blood is always there when it is required. Blood is finally administered on the judgment of the clinician; and this is a time, too, for considering again the indications for transfusion. The wellbeing and esprit-decorps of the whole transfusion service depends on the correct use of blood. With a perishable commodity, some wastage is inevitable; and this we must accept. But we should not accept misuse of blood: the donor must be confident that his blood will be used correctly. The supply of blood is limited and the demand is always increasing. As we start on the second million, enrolment of each new donor becomes more difficult. What, then, are the indications for transfusion ? Nobody would question the two greatest-massive bloodloss associated with multiple injuries or hxmorrhage into the gastrointestinal tract, and major surgical procedures (sometimes of a severity undreamt of even in the recent past). Blood must be conserved for these purposes, and as
losing ground. Against this, it would be widely agreed that the average consultant (not necessarily the genius) gains competence from a planned course of trainingprovided the plan is stimulating rather than restrictive. Furthermore, under any medical system, posts have to be filled, and somebody has to say who is qualified to fill them. In determining whether a man is fully trained for his future work, the decisions of colleges should be more reliable than those of hospital appointments committees, which consist partly of laymen and usually decide by judging between competitors. The plan we have outlined is a natural development of present trends, and as such it needs to be faced and discussed. Once more it brings us up against the perils, for Medicine, of organisation or even order. Yet order is a necessity. this can be done most readily by avoiding unnecessary small transfusions. Criteria for transfusion must be stringent 1; when the sole purpose is to expand a moderately depleted bloodvolume, alternative infusions should be used. Brushing any cobwebs of unproven clinical impressions from our minds, we should recognise that blood in small quantities has no magical properties: dextran used with discretion is safe,2 and the hazards of small-pool plasma are hardly greater than those of blood itself. Accurate measurement of blood lost at operations may reveal that the pendulum has swung so that we now tend to overestimate the loss.3 Only by continual reappraisal of our blood-transfusion policy can we conserve blood. There are now a million reasons
why
we
should.
CYTOLOGICAL ASPECTS OF JOINT TISSUES
THE application of electron microscopy to the study of synovial tissues has already produced results of outstanding interest. The lining cells of the membrane of mammalian joints (exemplified by the rabbit and the guineapig) appear in two distinct forms, although some intermediate types also occur. The first type is characterised by a high degree of vacuolation of the cytoplasm and the presence of a complex arrangement of surface folds, several of which appear in section as finger-like processes. The second cell type lacks both vacuoles and surface folds, but its cytoplasm is rich in an endoplasmic reticulum liberally endowed with ribosomes. The features of the vacuolated cells suggest that they could be actively phagocytic-a suggestion borne out by the studies of J. A. Chapman, who described his findings at a symposium convened in London on Nov. 8 by the Empire Rheumatism Council. Chapman has shown that, shortly after an intra-articular injection of iron dextran, typical ferritin granules can be recognised in large numbers within the cytoplasmic vacuoles. Simultaneously the number and complexity of the cytoplasmic folds increase considerably. The second type of surface cells are apparently non-phagocytic and do not accumulate ferritin after intra-articular injection of iron dextran. The established relationship between endoplasmic reticulum and protein synthesis suggests that these cells are actively employed in some anabolic activity, and, since the most 1. Graham-Stewart, C. W. Lancet, 1960, ii, 421. Artz, C. P., Howard, J. M., Frawley, J. P. Surgery, 1955, 37, Gardiner, A. J. S., Dudley, H. A. F. Lancet, 1963, ii, 859.
2. 3.
612.
1106
obvious constituent of synovial fluid is hyaluronic, it is presumably in the synthesis of this polysaccharide that these cells are engaged. Also present in the synovial cells of both types are lysosomes, subcellular vesicles first shown by De Duve to consist of a lipoprotein membrane enclosing a mixture of several hydrolytic enzymes with little in common except optimal activity in the acid pH range of 3 to 5. Since these include powerful proteolytic enzymes which, in some tissues at least, can attack collagen and can certainly break down the protein-polysaccharide bond in chondromucoprotein, their participation in the pathogenesis of arthritis is extremely probable. In this context the studies of D. Hamerman with the electron microscope are especially significant. At the E.R.C. symposium he described finding in the lining cells of the synovium of rheumatic joints conspicuous electron-dense bodies much larger than lysosomes but probably derived from them, judging by their rich content of acid phosphatase. The precipitation of lead phosphate in the first stage of Gomori’s method for the display of this enzyme makes this a particularly suitable subject for electron microscopy. These studies of the ultra-structure of synovial cells suggest, therefore, that injury 10 joint structures may indeed be mediated by enzymes elaborated in the affected synovial cells. What leads in the first instance to the abnormality of these cells, as revealed by the electron microscope, is still obscure, but the results of Bitensky and her colleaguesI on the influence of antibodies to ascites tumour cells upon their lysosomal acid phosphatase imply that immune reactions on cell surfaces may be one method by which such lysosomal injury could arise. RENAL PAPILLARY NECROSIS AND PHENACETIN
THE frequency of renal papillary necrosis in Denmark is again emphasised by an account of 66 cases seen in four years in one department of medicine in Copenhagen. Harvald2 points out that only 5 of these were in patients with diabetes and only 8 in patients with obstruction of the urinary tract (his two " traditional " conditions associated with its occurrence). Of the other patients the largest group had had recurrent attacks of acute pyelonephritis, but of special interest was a group without any urological symptoms but with refractory anxmia found to be due to renal insufficiency from chronic pyelonephritis. Harvald was particularly concerned with the abuse of analgesic drugs, especially phenacetin : " most of our patients with papillary necrosis have consumed six tablets or more per day for over ten years". A few had reasonable grounds for this consumption (rheumatoid arthritis or osteoarthritis), but the majority gave vague explanations such as tiredness, feeling of insufficiency, over-exertion, or ill-defined headache. Harvald admits that the mechanism by which analgesics injure the kidneys remains obscuresLindwa113suggested that phenacetin may render the kidney more susceptible to infection. Papillary necrosis is less common in this country for perhaps two reasons. First, aspirin, and not phenacetin, is the main constituent of our headache powders 4 5; and, secondly, we may be more acutely aware of the minor 1. Bitensky, L. Brit. med. Bull. 1963, 19, 241. 2. Harvald, B. Amer. J. Med. 1963, 35, 481. 3. Lindwall, N. Acta radiol., Stockh. 1960, suppl. 192. 4. See Lancet, 1959, i, 84. 5. See ibid. 1960, ii, 858.
grades of pyelonephritis and the indefinite symptoms they produce. Thus the recognition of inapparent and subclinical pyelonephritis,6 and the purposeful investigation of indefinite symptoms possibly due to this or more overt chronic pyelonephritis,’ may lead to earlier recognition and treatment of infections, thus discouraging self-medication not only with phenacetin but with other analgesics too. It is surely too late to wait for the " comparatively unalarming symptomatology, either as attacks of acute pyelonephritis with excretion of papillary tissue or as a slowly progressing renal insufficiency."2 Lindwall3 found the changes of chronic pyelonephritis, often with acute exacerbations, in all the resected or postmortem kidneys of the phenacetin patients, while Harvald2 quotes Spuhler and Zollinger as finding a chronic interstitial nephritis which corresponds with Talbot’schronic interstitial infiltration in chronic ascendIt has already been shown4 how such a lesion can affect the blood-supply to the renal papillx.
ing pyelonephritis.
CHRONIC PANCREATITIS
THE
frequency of chronic pancreatitis may be much underestimated, because the main manifestations, such as a raised fasting level of serum-amylase or serumlipase, steatorrhoea, pancreatic calcification, and diabetes, are found only in well-established cases. Early, developing, mild, or atypical cases have been missed mainly through lack of specific tests of pancreatic function. Fitzgerald et awl. lay emphasis on the value of evocative enzyme tests in this connection. These workers investigated 53 patients with chronic pancreatitis by means of cholecystography, barium-meal examinations, tests for faecal occult blood, &bgr;-cell function tests (fasting bloodsugar levels and glucose tolerance), and straight X-rays to demonstrate pancreatic calculi. But they regard the secretin-pancreozymin test described by Howat 10 and elaborated by Burton et al. 11 as the most helpful of all tests in the diagnosis of early chronic pancreatitis, and as providing earlier information of pancreatic derangement than examination of the duodenal contents. 69 secretinpancreozymin tests were carried out on 40 patients with pancreatitis. The serum-amylase rose from fasting levels of 0-7-4-4 mg. per ml. (40-242 units) with a mean of 2-53 mg. per ml. (157 units) to 2-5-8-2 mg. per ml. (137-451 units) with a mean of 3-41 mg. per ml. (188 units). In normal control cases the serum-amylase rose from a fasting level of 0-5-1-9 mg. per ml. (28-105 units) with a mean of 1.3 mg. per ml. (72 units) to a peak post-stimulatory level varying from 0-6 to 2-6 mg. per ml. (38 to 137 units) with a mean of 1-5 mg. per ml. (84 units). In only 2 of Fitzgerald’s patients did the serum-amylase level fail to rise over 2-9 mg. per ml. (160 units) after stimulation-an accuracy of 95% for the test. This is an important finding, because fasting amylase and lipase levels are often normal in quiescent phases of pancreatitis, and may be raised in other diseases such as acute gallbladder disease and perforated duodenal ulcer and after
the administration of morphine-like narcotics.i2 Results from serum-lipase in the secretin-pancreo6. See ibid. 1959, i, 1265. 7. See ibid. 1961, ii, 89. 8. Talbot, H. S. J. Amer. med. Ass. 1958, 168, 1595. 9. Fitzgerald, O., Fitzgerald, P., Fennelly, J., McMullin,
J. P., Sylvester, J. B. Gut, 1963, 4, 193. Howat, H. T. Modern Trends in Gastro-enterology (edited by F. Avery Jones); p. 776. London, 1952. 11. Burton, P., Hammond, E. M., Harper, A. A., Howat, H. T., Scott, J. E., Varley, H. Gut, 1960, 1, 125. 12. Bogoch, A., Roth, J. L. A., Bockus, H. L. Gastroenterology, 1954, 26, 697. 10.