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DIABETIC RETINOPATHY
31 a
blood-bank and
should,
a
haemophilia centre; and the trainee
if necessary, go
to centres
other than his main
gain this experience. At the end of this time, his capabilities should be assessed. " The standard aimed at should be equivalent to that currently demanded by the final examination for membership of the Royal College of Pathologists. The Royal College of Pathologists and the Royal Colleges of Physicians should discuss and agree how this assessone to
should be made." This is a realistic scheme of training and the final three years would fit well into a training programme at the senior-registrar level, so that, when it was successfully completed, the trainee would be ready for a consultant post. Some action should certainly be taken along the lines suggested by the Society. No doubt many of the younger doctors attracted to haematology wish to include more clinical activities in their programme. And, with increasing mechanisation in the laboratory and the acceptance by skilled scientists and technicians of much of the " hand work" in the laboratory, the consultant hxmatologist of the future will wish to spend more of his time in clinical work. Already boards appointing consultant haematologists are often willing and indeed anxious to offer clinical resources, and candidates who have had good clinical medical experience during their training therefore have a stronger hand. ment
TWO WAYS TO PROTEIN
THE past few weeks have
seen
three reports sug-
gesting that the classic sequence of protein synthesis (D.N.A.-R.N.A.- protein) may not, after all, be a oneway street. If confirmed these findings would upset the near-sacred " central dogma " of molecular biology ; they could provide a new direction for cancer research; and they have already vindicated the perseverance of H. M. Temin who, six years ago,! suggested that the R.N.A. of some tumour viruses can act as a template for D.N.A. The very existence of R.N.A. viruses had necessitated some modification of the central dogma, for such viruses seemed to possess a blueprint but to lack the machinery for its replication; but this was resolved by the finding in R.N.A. bacteriophages of an enzyme which enables R.N.A. to replicate itself-the central dogma was shortened but not reversed. Temin’s idea was much more radical, but the evidence for it (inhibition of transformation by compounds which inhibit D.N.A. synthesis, hybridisation experiments, and the sensitivity of virion replication to actinomycin D) was insufficient for most biologists to conclude that the pathway to protein was not unidirectional. Now all this has changed: workers in the United States have reported evidence for the existence, in R.N.A. tumour viruses (Rauscher mouse leukaemia,2Rous sarcoma,2,a and other viruses 4) of an R.N.A.-dependent D.N.A. polymerase capable of making D.N.A. from nucleotides and an R.N.A. temolate. The role of R.N.A. viruses in human 1. 2. 3. 4.
Temin, H. M. Natn. Cancer Inst. Monogr. 1964, 17, 557. Baltimore, D. Nature, 1970, 226, 1209. Temin, H. M., Mizutani, S. ibid. p. 1211. Spiegelman, S. Paper read at a Royal Society meeting on Animal Viruses as Genetic Modifiers of the Cell, held in London, on June 18.
clear; but if the enzyme is unique to R.N.A. tumour viruses, then it might be possible to develop agents with the property of blocking the step between viral R.N.A. and D.N.A. (and so preventing viral replication) without damaging the host cell. cancer
is far from
With the first step in the classic sequence shown to be unnecessary or reversible, it is tempting to speculate mischievously that the second part might also be wrong -that protein might code for R.N.A. But this would be altogether too much: Prof. S. Spiegelman has remarked that, if that happened, "I would become a theologian ".5
DIABETIC RETINOPATHY
DIABETES is the most important systemic cause of blindness in Britain. It accounts for about 7% of new blind registrations each year (that is, 700 cases)-a figure likely to rise as life expectancy increases with improved treatment of diabetes, coupled with an inability to prevent retinal complications. Some recent investigations of diabetic retinopathy are examined in the latest issue of the British Medical Bulletin, which is devoted to research on the retina.6 Photographs of the human diabetic retina in vivo are now adding significantly to knowledge of this condition, by providing a detailed record of the natural history of the angiopathy and the response to treatment. The most important lesions of the retinopathy are to be found in channels not visible by ophthalmoscopy or by colour photography-that is, in the capillaries. Contrast angiography not only demonstrates capillaries but also reveals abnormal function in terms of altered dye-flow patterns, dye leakage, and staining of the vessel wall. The earliest lesions seen by fluorescein angiographyin diabetic retinopathy are in the capillary bed, and they include microaneurysms, generalised capillary dilatation, and areas of capillary closure. Microaneurysms, comare saccular, always associated with nonmonly In the earliest cases they have perfused capillaries. a focal distribution, but as the condition worsens they become distributed over the posterior pole. They appear as fluorescent dots of less than 30 ti diameter. Larger ones are commonly seen in association with cotton-wool spots. Confusion of microaneurysms with other fluorescent spots (such as those due to drusen or capillary loops) can be resolved by studying the angiographic sequence. Some microaneurysms do not perfuse with fluorescein and thus may be confused with dot haemorrhages. The generalised dilatation of retinal capillaries in advancing retinopathy enables these channels to be demonstrated by angiography earlier than in normal vessels. Capillary closure, the earliest sign of diabetic retinopathy according to some workers, is indicated by black (non-perfused) areas interrupting the capillary pattern. The absence of capillary perfusion in relation to retinal soft exudates is well recognised. Dilated channels around soft exudates can usually be seen; dye flows slowly through them and they generally leak. In more severe retino5. New Scientist, 1970, 46, 614. 6. Br. med. Bull. 1970, 26 (no. 2). 7. Kohner, E. M., Dollery, C. T. ibid.
p. 166.
32
pathies, occluded branch arterioles give rise to large areas of non-perfused capillaries. Arteriovenous communications across areas of capillary closure are often mistakenly termed shunt vessels, for they may follow longstanding capillary closure. Late revascularisation of non-perfused capillaries in small areas has been seen. In the wake of small-vessel abnormalities, changes in large vessels can be graphically demonstrated by fluorescein angiography. They include variations in the calibre of arterial lumen, focal narrowing of branch arterioles at their origins, with distal dilatations, and dilatation, tortuosity, and looping of retinal veins with a tendency to staining of the wall. New retinal vessels are either intraretinal or preretinal. Intraretinal new vessels appear as dilated channels on the venous side of the circulation. They do not always leak dye, in contrast to pre-retinal vessels, which are completely incontinent of fluorescein. According to angiographic evidence, new vessels on the optic disc may at least in part arise from the ciliary-choroidal circulation. A quantitative approach to the study of retinal angiograms should be of value in judging the response of retinopathies to treatment. Early attempts have included mapping specific areas of the fundus and counting microaneurysms in serial studies, to determine appearance and disappearance rates.
MEASLES
MEASLES seemed to be coming under control in Britain as a result of vaccination, but now there is a reversal of the trend and the number of cases in the first half of this year shows no reduction from that expected in a non-epidemic year. Contributory factors may include the withdrawal last year of the Beckenham31 strain of measles vaccine, the subsequent loss of confidence in measles vaccination, and the shortage of the Schwarz strain. The immediate reason for withdrawal was fears of an unacceptably high incidence of serious encephalitis following the use of Beckenham-31 vaccine. There is no evidence that the vaccine did cause encephalitis or that the association of encephalitis and the use of Beckenham-31 vaccine is higher than with other strains. This matter is subject to inquiry by the Committee on Safety of Drugs, but so far no information has been forthcoming. In the U.S.A. there have been 116 cases of encephalitis associated with the use of Enders B and Schwarz vaccines, but on epidemiological grounds the association was not thought to be causal because the incidence of encephalitis was not increased. What is certain, however, is that the Beckenham-31 strain causes more febrile convulsions than the Schwarz strain, and it is this fact which is probably decisive in preventing reintroduction of the vaccine into the U.K. measles-vaccination programme. It is clear, however, that the re-emergence of natural measles is likely to be associated with a higher incidence of all complications, including febrile convulsions. It is desirable, therefore, to establish the facts and, if they are reassuring, to try to increase confidence in measles vaccination. 1. See Lancet,
1969, i, 1198.
Measles has also increased in the U.S.A. after widespread use of vaccine had brought the disease under control. The exact reason is uncertain, but it seems to be a failure to use the vaccine widely among the lower socio-economic groups. There have been suggestions that the immunity conferred by more reaction-provoking vaccines, like Enders B or Beckenham 31, may
longer-lasting immunity because antibody higher, but so far there is no evidence for this suggestion. If, however, the vaccine giving a higher antibody response is to be used, then the incidence of febrile convulsions can be greatly reduced by giving
produce levels
a
are
vaccine at the age of 2 years instead of 1 year.
THE GIANT HOGWEED
THE hogweed or cow parsnip, Heracleum spondylum, has long been a familiar sight at British roadsides, but its giant cousin, H. mantegazzianum, has only lately established itself in some areas. Introduced from the Caucasus to Kew Gardens, it found a place amongst the more exotic garden plants, but it " escaped " about fifty or sixty years ago to become a frank weed at various places. It is found on the East Coast, particularly in Leith, the lower Tweed valley, the Thames estuary, and Lancashire, and it is now to be seen not only by the waterside but also on derelict sites. The giant hogweed grows to 12-15 ft. in three months and the stems can be 6 in. or more in diameter. This massive growthrate explains why it is usually found near water, and this in turn accounts for the fact that fishermen and bathers are those most often affected by its blistering properties. Summer camps produce a crop of unwary victims who learn of the giant’s irritation the unpleasant way. Several cases have lately been reported from
Edinburgh.! The aftermath of contact with the giant hogweed is phyto-photosensitivity, so that reactions appear on sunny summer days when bare skin is likely to be exposed to the sun and to the sap of the plant. The initial response is erythema within twenty-four hours and blistering within another twenty-four hours. The a
reaction follows the area of contact with the sap: in a linear pattern where stems have been brushed aside or used as staves on an opponent’s back; or around mouth or eye where the hollow stem has been used as a peashooter or a telescope. The bullse can be massive and very irritating, but they usually subside quickly. Brown pigmentation is left after healing-a feature which is said to have been valued by the ancient Egyptians. Scarring and pigmentation may be seen six years after the first reaction. Any bland lotion is suitable for firstaid treatment, and can be applied after the blisters have been snipped if necessary. No doubt corticosteroid creams or lotions would relieve irritation. The giant hogweed was once a gardener’s curiosity, but it is now a pest in many areas, having become much more widespread in the past five years. Cutting of accessible plants will help, but unfortunately the dried stems and heads float readily downstream in winter’s floods to seed the lower reaches. Perhaps a herbicide will become available, but meanwhile the advice must be to keep naked skin from contact with giant hogweed. 1.
Guardian, June 24.
blood-bank and
should,
a
haemophilia centre; and the trainee
if necessary, go
to centres
other than his main
gain this experience. At the end of this time, his capabilities should be assessed. " The standard aimed at should be equivalent to that currently demanded by the final examination for membership of the Royal College of Pathologists. The Royal College of Pathologists and the Royal Colleges of Physicians should discuss and agree how this assessone to
should be made." This is a realistic scheme of training and the final three years would fit well into a training programme at the senior-registrar level, so that, when it was successfully completed, the trainee would be ready for a consultant post. Some action should certainly be taken along the lines suggested by the Society. No doubt many of the younger doctors attracted to haematology wish to include more clinical activities in their programme. And, with increasing mechanisation in the laboratory and the acceptance by skilled scientists and technicians of much of the " hand work" in the laboratory, the consultant hxmatologist of the future will wish to spend more of his time in clinical work. Already boards appointing consultant haematologists are often willing and indeed anxious to offer clinical resources, and candidates who have had good clinical medical experience during their training therefore have a stronger hand. ment
TWO WAYS TO PROTEIN
THE past few weeks have
seen
three reports sug-
gesting that the classic sequence of protein synthesis (D.N.A.-R.N.A.- protein) may not, after all, be a oneway street. If confirmed these findings would upset the near-sacred " central dogma " of molecular biology ; they could provide a new direction for cancer research; and they have already vindicated the perseverance of H. M. Temin who, six years ago,! suggested that the R.N.A. of some tumour viruses can act as a template for D.N.A. The very existence of R.N.A. viruses had necessitated some modification of the central dogma, for such viruses seemed to possess a blueprint but to lack the machinery for its replication; but this was resolved by the finding in R.N.A. bacteriophages of an enzyme which enables R.N.A. to replicate itself-the central dogma was shortened but not reversed. Temin’s idea was much more radical, but the evidence for it (inhibition of transformation by compounds which inhibit D.N.A. synthesis, hybridisation experiments, and the sensitivity of virion replication to actinomycin D) was insufficient for most biologists to conclude that the pathway to protein was not unidirectional. Now all this has changed: workers in the United States have reported evidence for the existence, in R.N.A. tumour viruses (Rauscher mouse leukaemia,2Rous sarcoma,2,a and other viruses 4) of an R.N.A.-dependent D.N.A. polymerase capable of making D.N.A. from nucleotides and an R.N.A. temolate. The role of R.N.A. viruses in human 1. 2. 3. 4.
Temin, H. M. Natn. Cancer Inst. Monogr. 1964, 17, 557. Baltimore, D. Nature, 1970, 226, 1209. Temin, H. M., Mizutani, S. ibid. p. 1211. Spiegelman, S. Paper read at a Royal Society meeting on Animal Viruses as Genetic Modifiers of the Cell, held in London, on June 18.
clear; but if the enzyme is unique to R.N.A. tumour viruses, then it might be possible to develop agents with the property of blocking the step between viral R.N.A. and D.N.A. (and so preventing viral replication) without damaging the host cell. cancer
is far from
With the first step in the classic sequence shown to be unnecessary or reversible, it is tempting to speculate mischievously that the second part might also be wrong -that protein might code for R.N.A. But this would be altogether too much: Prof. S. Spiegelman has remarked that, if that happened, "I would become a theologian ".5
DIABETIC RETINOPATHY
DIABETES is the most important systemic cause of blindness in Britain. It accounts for about 7% of new blind registrations each year (that is, 700 cases)-a figure likely to rise as life expectancy increases with improved treatment of diabetes, coupled with an inability to prevent retinal complications. Some recent investigations of diabetic retinopathy are examined in the latest issue of the British Medical Bulletin, which is devoted to research on the retina.6 Photographs of the human diabetic retina in vivo are now adding significantly to knowledge of this condition, by providing a detailed record of the natural history of the angiopathy and the response to treatment. The most important lesions of the retinopathy are to be found in channels not visible by ophthalmoscopy or by colour photography-that is, in the capillaries. Contrast angiography not only demonstrates capillaries but also reveals abnormal function in terms of altered dye-flow patterns, dye leakage, and staining of the vessel wall. The earliest lesions seen by fluorescein angiographyin diabetic retinopathy are in the capillary bed, and they include microaneurysms, generalised capillary dilatation, and areas of capillary closure. Microaneurysms, comare saccular, always associated with nonmonly In the earliest cases they have perfused capillaries. a focal distribution, but as the condition worsens they become distributed over the posterior pole. They appear as fluorescent dots of less than 30 ti diameter. Larger ones are commonly seen in association with cotton-wool spots. Confusion of microaneurysms with other fluorescent spots (such as those due to drusen or capillary loops) can be resolved by studying the angiographic sequence. Some microaneurysms do not perfuse with fluorescein and thus may be confused with dot haemorrhages. The generalised dilatation of retinal capillaries in advancing retinopathy enables these channels to be demonstrated by angiography earlier than in normal vessels. Capillary closure, the earliest sign of diabetic retinopathy according to some workers, is indicated by black (non-perfused) areas interrupting the capillary pattern. The absence of capillary perfusion in relation to retinal soft exudates is well recognised. Dilated channels around soft exudates can usually be seen; dye flows slowly through them and they generally leak. In more severe retino5. New Scientist, 1970, 46, 614. 6. Br. med. Bull. 1970, 26 (no. 2). 7. Kohner, E. M., Dollery, C. T. ibid.
p. 166.
32
pathies, occluded branch arterioles give rise to large areas of non-perfused capillaries. Arteriovenous communications across areas of capillary closure are often mistakenly termed shunt vessels, for they may follow longstanding capillary closure. Late revascularisation of non-perfused capillaries in small areas has been seen. In the wake of small-vessel abnormalities, changes in large vessels can be graphically demonstrated by fluorescein angiography. They include variations in the calibre of arterial lumen, focal narrowing of branch arterioles at their origins, with distal dilatations, and dilatation, tortuosity, and looping of retinal veins with a tendency to staining of the wall. New retinal vessels are either intraretinal or preretinal. Intraretinal new vessels appear as dilated channels on the venous side of the circulation. They do not always leak dye, in contrast to pre-retinal vessels, which are completely incontinent of fluorescein. According to angiographic evidence, new vessels on the optic disc may at least in part arise from the ciliary-choroidal circulation. A quantitative approach to the study of retinal angiograms should be of value in judging the response of retinopathies to treatment. Early attempts have included mapping specific areas of the fundus and counting microaneurysms in serial studies, to determine appearance and disappearance rates.
MEASLES
MEASLES seemed to be coming under control in Britain as a result of vaccination, but now there is a reversal of the trend and the number of cases in the first half of this year shows no reduction from that expected in a non-epidemic year. Contributory factors may include the withdrawal last year of the Beckenham31 strain of measles vaccine, the subsequent loss of confidence in measles vaccination, and the shortage of the Schwarz strain. The immediate reason for withdrawal was fears of an unacceptably high incidence of serious encephalitis following the use of Beckenham-31 vaccine. There is no evidence that the vaccine did cause encephalitis or that the association of encephalitis and the use of Beckenham-31 vaccine is higher than with other strains. This matter is subject to inquiry by the Committee on Safety of Drugs, but so far no information has been forthcoming. In the U.S.A. there have been 116 cases of encephalitis associated with the use of Enders B and Schwarz vaccines, but on epidemiological grounds the association was not thought to be causal because the incidence of encephalitis was not increased. What is certain, however, is that the Beckenham-31 strain causes more febrile convulsions than the Schwarz strain, and it is this fact which is probably decisive in preventing reintroduction of the vaccine into the U.K. measles-vaccination programme. It is clear, however, that the re-emergence of natural measles is likely to be associated with a higher incidence of all complications, including febrile convulsions. It is desirable, therefore, to establish the facts and, if they are reassuring, to try to increase confidence in measles vaccination. 1. See Lancet,
1969, i, 1198.
Measles has also increased in the U.S.A. after widespread use of vaccine had brought the disease under control. The exact reason is uncertain, but it seems to be a failure to use the vaccine widely among the lower socio-economic groups. There have been suggestions that the immunity conferred by more reaction-provoking vaccines, like Enders B or Beckenham 31, may
longer-lasting immunity because antibody higher, but so far there is no evidence for this suggestion. If, however, the vaccine giving a higher antibody response is to be used, then the incidence of febrile convulsions can be greatly reduced by giving
produce levels
a
are
vaccine at the age of 2 years instead of 1 year.
THE GIANT HOGWEED
THE hogweed or cow parsnip, Heracleum spondylum, has long been a familiar sight at British roadsides, but its giant cousin, H. mantegazzianum, has only lately established itself in some areas. Introduced from the Caucasus to Kew Gardens, it found a place amongst the more exotic garden plants, but it " escaped " about fifty or sixty years ago to become a frank weed at various places. It is found on the East Coast, particularly in Leith, the lower Tweed valley, the Thames estuary, and Lancashire, and it is now to be seen not only by the waterside but also on derelict sites. The giant hogweed grows to 12-15 ft. in three months and the stems can be 6 in. or more in diameter. This massive growthrate explains why it is usually found near water, and this in turn accounts for the fact that fishermen and bathers are those most often affected by its blistering properties. Summer camps produce a crop of unwary victims who learn of the giant’s irritation the unpleasant way. Several cases have lately been reported from
Edinburgh.! The aftermath of contact with the giant hogweed is phyto-photosensitivity, so that reactions appear on sunny summer days when bare skin is likely to be exposed to the sun and to the sap of the plant. The initial response is erythema within twenty-four hours and blistering within another twenty-four hours. The a
reaction follows the area of contact with the sap: in a linear pattern where stems have been brushed aside or used as staves on an opponent’s back; or around mouth or eye where the hollow stem has been used as a peashooter or a telescope. The bullse can be massive and very irritating, but they usually subside quickly. Brown pigmentation is left after healing-a feature which is said to have been valued by the ancient Egyptians. Scarring and pigmentation may be seen six years after the first reaction. Any bland lotion is suitable for firstaid treatment, and can be applied after the blisters have been snipped if necessary. No doubt corticosteroid creams or lotions would relieve irritation. The giant hogweed was once a gardener’s curiosity, but it is now a pest in many areas, having become much more widespread in the past five years. Cutting of accessible plants will help, but unfortunately the dried stems and heads float readily downstream in winter’s floods to seed the lower reaches. Perhaps a herbicide will become available, but meanwhile the advice must be to keep naked skin from contact with giant hogweed. 1.
Guardian, June 24.