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HYPERAMMONÆMIA AND URINARY ORGANIC ACIDS
371 TABLE II-PROPERTIES OF TEMPERATE PHAGES DETECTED IN THE GENTAMICIN-RESISTANT STRAINS STUDIED
sensitive derivatives of strains 8798 and 8801. These preliminary results suggest that a defective phage derived from the serological group F phage carried by strain 8799 can transfer resistance to gentamicin. This study demonstrates that phages other than those commonly used for in-vitro transduction experiments (i.e., serological group B phages), may play a significant part in the in-vivo transmission of resistance to gentamicin and - presumably-other antibiotics. Although transfer of resistance to gentamicin may be rare in vivo, the use of this antibiotic will tend to select resistant organisms and encourage their establishment in the hospital environment. Strain 57 was kindly 981 by Dr R. W. Lacey.
provided by
Prof. K. C.
Winkler,
strain RN
*
Strain 57 is fully sensitive at routine test dilution to the following phages: 29, 52, 52A, 80, 6, 42E, 47, 54, 75, 77, 84, 85, 81 and 95. to the typing phages, but also that least one of them can transmit resistance to this antibiotic. The strains showed linked and unstable resistance to gentamicin, kanamycin, tobramycin, and sisomycin. These linked resistances could be transduced, by serological group B phages propagated on the resistant strains, to gentamicin-sensitive strains that included PS47 (NCTC 8325) and its recombination-deficient mutant RN 981.4 The transduction frequency (10-5 to 10-6 per plaque-forming unit) depended on the particular phage/recipient system used and was reduced to approximately one-tenth after 2 min ultraviolet irradiation of the phage. Plasmid DNA (molecular weight 25 x 106) was isolated by Dr Henry Smith and Dr Geraldine Willshaw from the transductants from all three resistant strains, but was absent from the gentamicin-sensitive recipients. We considered these results strong evidence that the determinants for resistance to gentamicin were plasmid-born in these strains, and that the same plasmid was probably present in all three. Phages carried by the resistant strains were induced with mitomycin C, purified by serial, single-plaque isolation, identified serologically and used to lysogenise strain 57.5 Each phage produced a characteristic loss of phage-sensitivity in the "wide" typing pattern of strain 57 (table n). Attempts to transduce gentamicin-resistance to strain 57 with mitomycin-Cinduced lysates of the resistant strains have been unsuccessful. However, we have transferred resistance to gentamicin in mixed culture6 from all three resistant strains to a rifampicinresistant mutant of strain 57, although the number of colonies obtained on selective plates that contained both antibiotics was very low. No transfer of resistance to antibiotics other than gentamicin (and the linked aminoglycosides) occurred. All the resistant colonies ("transductants") tested appeared to be lysogenic for one of the phages carried by their respective donor strain (i.e., they were immune to the phage and showed the pattern of lysis characteristic of strain 57 lysogenised with it). Lysogenicity was confirmed for the transductants from strains 8798 and 8801 by phage production, but no phage could be demonstrated after induction of the transductant from strain 8799. However, this "lysate" could transfer gentamicin resistance to strain 57. In several controlled experiments (in which strain 57 was incubated overnight in the filtered lysate of the transductant from strain 8799) we obtained a frequency of conversion to gentamicin-resistance of up to 10-4 per colonyforming unit. Acquisition of resistance was inhibited by preincubation of the lysate with a specific antiserum against serological group-F phages but was unaffected by antisera against phages of serological groups A or B. Resistance could also be transferred-at a much lower frequency-to gentamicin-
Division of Hospital Infection, Central Public Health Laboratory, London NW9 5HT
MAUREEN DE SAXE AUDREY PORTHOUSE
mine patterns of sensitivity at
4. Wyman L, Goering RV, Novick RP. Genetic control of chromosomal and plasmid recombination in S. aureus. Genetics 1974; 76; 681-702. 5. Winkler KC, De Waarf J, Grootsen C, Zegers BJM, Tellier NF, Wertregt CD. Lysogenic conversion of staphylococci to loss of &bgr; toxin. J Gen Microbiol 1965; 39: 321—333. 6
Lacey RW. Transfer of tetracycline-resistance between strains of Staphylococcus aureus in mixed cultures. J Gen Microbiol 1971; 69: 229-237.
HYPERAMMONÆMIA AND URINARY ORGANIC ACIDS
SIR,-We have been following the debatel-3 about patients presenting with hyperammonsemia and excreting a leucine catabolite, 3-hydroxy-3-methylglutaric acid, in urine. We have studied another baby with such abnormal biochemistry. A girl aged 4 days was admitted to the Royal Alexandra Hospital for Children comatose and with a, high blood ammonia level (1200 .mol/1; normal, up to 100). Other biochemical findings included normal blood glucose, raised plasma glutamine, lysine, and alenine, and excretion of a number of unusual organic acids in urine. Analysis of urinary organic acids by combined gas chromatography-mass spectrometry revealed organic acids associated with leucine breakdown, namely 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-methylglutaric acids, together with lactic and 4-hydroxyphenylacetic acids and 2,3-butanediol.4 Despite vigorous attempts at resuscitation, including dialysis, the baby died on day 5. On the basis of the high levels of ammonia in the patient’s blood, an early urea cycle disorder was suspected. There was a moderate decrease in urea cycle enzymes carbamyl phosphate synthetase and ornithine transcarbamylase in liver tissue from our patient, a finding which has been reported for children with Reye’s syndrome.5 Both 3-hydroxy-3-methylglutaryl-CoA lyase and 3-methyl-glutaconyl-CoA hydratase acdemonstrated in cultured skin fibroblasts from the 1.9nmol/min/mg protein, respectively)4 and considered normal (controls 7-7and 4.9nmol/min/mg pro-
tivities
were
baby (5-6and
tein, respectively). When we first saw the data on organic acids in urine from the baby we were confident that we had another case of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. The original patient with this enzyme deficiency presented with symptoms of Reye’s syndrome but had normal levels of ammonia in blood.6 In a study of a second patient with this defect blood ammonia levels were not remarked on.7 As pointed out by Applegarth et al.2 hypoglycaemia is a feature of this disorder rather than hyperammonaEmia. All three patients excreted breakdown products of leucine in urine, although our patient differed in that 1. Leonard
JV,
et
al.
&bgr;-hydroxy-&bgr;-methylglutaricaciduria presenting
as
Reye’s
syndrome. Lancet, 1979; i: 680. 2. Applegarth DA, et al. Organic acids
and Reye’s syndrome. Lancet 1979; i: 1147. 3. Leonard JV, et al. &bgr;-hydroxy-&bgr;-methylglutaric-aciduria, Reye’s syndrome, and echovirus. 11. Lancet 1979; i:1147. 4. Truscott RJW, Halpern B, Wysocki et al. Clin Chim Acta (in press). 5. Brown T, Hug G, Lansky L. et al. Patient with defect in leucine metabolism.
N Engl J Med 1976; 294: 861, K, Bolton P, Halpern B et al. Patient with defect in leucine metabolism. N Engl J Med 1976; 294: 1013. Schutgens RBH, Heymans H, Ketel A, et al. Lethal hypoglycemia in a child with a deficiency of 3-hydroxy-3-methylglutarylcoenzyme-A-lyase. Pediat-
6. Faull 7.
rics 1979; 94: 89.
,
372
3-hydroxyisovaleric acid was not present in any quantity. Despite the similarities in the profiles of organic acids in urine, the activity of 3-hydroxy-3-methylglutaryl-CoA lyase in cultured skin fibroblasts from our patient was normal. Our data suggest that the excretion of abdominal organic acids in urine from patients with hyperammonaemia is a secondary effect, a possibility pointed out by Applegarth et al. An alternative explanation is that our patient had a defect in liver 3-hydroxy-3-methylglutaryl-CoA lyase but normal levels of this enzyme in peripheral tissues. Our experience has been that, while it is tempting to speculate about enzyme defects on the basis of metabolic profiles, such speculation must be tested by the measurement of enzyme levels in the patient’s tissues wherever possible. Department of Obstetrics and Gynæcology, King Edward Memorial Hospital for Women, Subiaco, Western Australia 6008.
S. J. WYSOCKI R. HÄHNEL
Department of Chemistry, University of Wollongong,
R. J. W. TRUSCOTT B. HALPERN
New South Wales 2500.
Health Commission, Olive Latham Laboratory, North Ryde, New South Wales 2113
B. WILCKEN
FOLLOW-UP OF WOMEN TREATED FOR CERVICAL PRECANCER Dr Kirkup and his colleagues (July 7, p. less intensive that 22) postoperative follow-up after treatment of cervical intraepithelial neoplasia (CIN) may be indicated. They suggest that three smears should be taken over the first 2 years after cervical biopsy, which is reasonable. I would suggest, however, that an annual smear should be taken thereafter rather than the 3 to 5 year follow-up that they suggest. We have followed up 286 cases of CIN treated in Leamington Spa since 1968. Repeat positive smears after cervical biopsy occurred in 44 patients (154%). 36 (82%) of the abnormal smears appeared within a year of cervical biopsy but this still left 8 patients producing abnormal smears between 1 and 6 years after the original cervical biopsy. In 177 patients treated before colposcopy became available there were 41 cases with a repeat positive smear, an incidence of 8.0per 100 women-years of follow up; in the 109 patients managed by colposcopy to date there have been only 3 cases with a repeat positive smear, 2.6per 100 women-years of follow up. Two cases are of interest: A 45-year-old para 2 woman underwent cone biopsy in 1968 because of a positive smear. The biopsy report was carcinomain-situ and "the lesion seems entirely excised". There were ten consecutive negative smears between 1969 and 1976. In April, 1976, she presented with suprapubic pain and vaginal discharge. Dilation of the cervix produced necrotic tissue reported as fragments of a squamous-cell carcinoma, doubtless arising from the cervix. The patient was treated by intracavitary csesium. She is alive and well 3 years later. A 44-year-old para 2 woman had a positive smear in 1968 and underwent a cone biopsy of the cervix. Multiple sections were examined and mild dysplasia with no carcinoma was reported. Four cervical smears were examined over the next 2 years and were negative. The patient was then lost to follow-up. In 1977 (9 years after the original biopsy) she presented with metrorrhagia and abdominal pain. Examination revealed a stage-in carcinoma of the cervix which was treated
SiR,-I agree with
National Health Service The difficulties of the Lambeth, Southwark, and Lewisham Area Health Authority were summarised in our last issue (p. 313). In the following article, Sir Francis Avery Jones discusses, in the light of the reportl of the Royal Commission, some wider aspects of resource allocation and health care in urban communities.
RAWP, THE ROYAL COMMISSION, AND THE "INNER CITIES" THE most important single issue now facing the Secretary of State for Social Services concerns the "inner cities". Largely as a result of the application of the resource-allocation policy (RAWP)2 at sub-regional level, to areas and districts in the largest conurbations, much hardship is being imposed on those who need help most; and, at the same time, many of the main academic and specialist centres are threatened and the survival of high standards-centres of excellence-is in jeopardy. Certainly, other factors are involved, particularly the policy of "area self-sufficiency", introduced by the N.H.S. reorganisation of 1974. Resource allocation is central to the terms of reference of the Royal Commission: "... the best use and management of the financial and manpower resources of the National Health Service." Research undertaken for the Commission by Buxton and Klein3led them to make penetrating comments on RAWP: "the problems of implementing RAWP therefore derive, largely if not exclusively, from the specific problems of the inner cities in both England and Scotland"; "given the complementarity and substitutability of the various social services, no formula designed in isolation for one service-on the assumption that there is no blurring of functions or overlapping of roles-will ever be satisfactory"; "if the country wants to keep pace, in the field of medical research and development, with other countries enjoying much higher per capita incomes, it cannot expect, or indeed realistically hope, to do so in the context of Regional equity." In spite of the known importance of the subject and the clarity of such warning signals, the Commission unhappily provides no real help. Its gives a brief historical review, a note of criticisms expressed, and a plea to the D.H.S.S. to sharpen the RAWP formula. What was needed was a critical look at the fundamental basis of RAWP. Can "need" really be defined and quantified? Is it sound in principle-as the Royal Commission maintains? The results of its application at sub-regional levels indicate that there is something very wrong with it. Where do we now stand with RAWP? It is not fundamental to the future of the N.H.S. It was the last of a series of steps taken towards the original objective of
Royal
report
by radiotherapy. Patients treated conservatively for CIN should be followed by smear and examination every year at least. Less frequent follow-up may lead to an increase in the group "lost to follow-up" with possibly serious consequences.
2.
Warneford
3.
1.
up
Hospital, Leamington Spa, Warwickshire
JOHN FRAMPTON.
Royal Commission on the National Health Service (chairman: Sir Alec Merrison). Cmnd 7615. H.M. Stationery Office. Pp. 491. £8. Chapter 22 (conclusions and recommendations) is available as a booklet entitled A Service for Patients (Pp. 42. £1.75). Sharing Resources for Health in England: report of the Resource Allocation Working Party. H.M. Stationery Office, 1976. Buxton MJ, Klein RE. Allocating health resources: a commentary on the report of the Resource Allocation Working Party. Royal Commission research paper no. 3. H.M. Stationery Office, 1978.
sensitive derivatives of strains 8798 and 8801. These preliminary results suggest that a defective phage derived from the serological group F phage carried by strain 8799 can transfer resistance to gentamicin. This study demonstrates that phages other than those commonly used for in-vitro transduction experiments (i.e., serological group B phages), may play a significant part in the in-vivo transmission of resistance to gentamicin and - presumably-other antibiotics. Although transfer of resistance to gentamicin may be rare in vivo, the use of this antibiotic will tend to select resistant organisms and encourage their establishment in the hospital environment. Strain 57 was kindly 981 by Dr R. W. Lacey.
provided by
Prof. K. C.
Winkler,
strain RN
*
Strain 57 is fully sensitive at routine test dilution to the following phages: 29, 52, 52A, 80, 6, 42E, 47, 54, 75, 77, 84, 85, 81 and 95. to the typing phages, but also that least one of them can transmit resistance to this antibiotic. The strains showed linked and unstable resistance to gentamicin, kanamycin, tobramycin, and sisomycin. These linked resistances could be transduced, by serological group B phages propagated on the resistant strains, to gentamicin-sensitive strains that included PS47 (NCTC 8325) and its recombination-deficient mutant RN 981.4 The transduction frequency (10-5 to 10-6 per plaque-forming unit) depended on the particular phage/recipient system used and was reduced to approximately one-tenth after 2 min ultraviolet irradiation of the phage. Plasmid DNA (molecular weight 25 x 106) was isolated by Dr Henry Smith and Dr Geraldine Willshaw from the transductants from all three resistant strains, but was absent from the gentamicin-sensitive recipients. We considered these results strong evidence that the determinants for resistance to gentamicin were plasmid-born in these strains, and that the same plasmid was probably present in all three. Phages carried by the resistant strains were induced with mitomycin C, purified by serial, single-plaque isolation, identified serologically and used to lysogenise strain 57.5 Each phage produced a characteristic loss of phage-sensitivity in the "wide" typing pattern of strain 57 (table n). Attempts to transduce gentamicin-resistance to strain 57 with mitomycin-Cinduced lysates of the resistant strains have been unsuccessful. However, we have transferred resistance to gentamicin in mixed culture6 from all three resistant strains to a rifampicinresistant mutant of strain 57, although the number of colonies obtained on selective plates that contained both antibiotics was very low. No transfer of resistance to antibiotics other than gentamicin (and the linked aminoglycosides) occurred. All the resistant colonies ("transductants") tested appeared to be lysogenic for one of the phages carried by their respective donor strain (i.e., they were immune to the phage and showed the pattern of lysis characteristic of strain 57 lysogenised with it). Lysogenicity was confirmed for the transductants from strains 8798 and 8801 by phage production, but no phage could be demonstrated after induction of the transductant from strain 8799. However, this "lysate" could transfer gentamicin resistance to strain 57. In several controlled experiments (in which strain 57 was incubated overnight in the filtered lysate of the transductant from strain 8799) we obtained a frequency of conversion to gentamicin-resistance of up to 10-4 per colonyforming unit. Acquisition of resistance was inhibited by preincubation of the lysate with a specific antiserum against serological group-F phages but was unaffected by antisera against phages of serological groups A or B. Resistance could also be transferred-at a much lower frequency-to gentamicin-
Division of Hospital Infection, Central Public Health Laboratory, London NW9 5HT
MAUREEN DE SAXE AUDREY PORTHOUSE
mine patterns of sensitivity at
4. Wyman L, Goering RV, Novick RP. Genetic control of chromosomal and plasmid recombination in S. aureus. Genetics 1974; 76; 681-702. 5. Winkler KC, De Waarf J, Grootsen C, Zegers BJM, Tellier NF, Wertregt CD. Lysogenic conversion of staphylococci to loss of &bgr; toxin. J Gen Microbiol 1965; 39: 321—333. 6
Lacey RW. Transfer of tetracycline-resistance between strains of Staphylococcus aureus in mixed cultures. J Gen Microbiol 1971; 69: 229-237.
HYPERAMMONÆMIA AND URINARY ORGANIC ACIDS
SIR,-We have been following the debatel-3 about patients presenting with hyperammonsemia and excreting a leucine catabolite, 3-hydroxy-3-methylglutaric acid, in urine. We have studied another baby with such abnormal biochemistry. A girl aged 4 days was admitted to the Royal Alexandra Hospital for Children comatose and with a, high blood ammonia level (1200 .mol/1; normal, up to 100). Other biochemical findings included normal blood glucose, raised plasma glutamine, lysine, and alenine, and excretion of a number of unusual organic acids in urine. Analysis of urinary organic acids by combined gas chromatography-mass spectrometry revealed organic acids associated with leucine breakdown, namely 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-methylglutaric acids, together with lactic and 4-hydroxyphenylacetic acids and 2,3-butanediol.4 Despite vigorous attempts at resuscitation, including dialysis, the baby died on day 5. On the basis of the high levels of ammonia in the patient’s blood, an early urea cycle disorder was suspected. There was a moderate decrease in urea cycle enzymes carbamyl phosphate synthetase and ornithine transcarbamylase in liver tissue from our patient, a finding which has been reported for children with Reye’s syndrome.5 Both 3-hydroxy-3-methylglutaryl-CoA lyase and 3-methyl-glutaconyl-CoA hydratase acdemonstrated in cultured skin fibroblasts from the 1.9nmol/min/mg protein, respectively)4 and considered normal (controls 7-7and 4.9nmol/min/mg pro-
tivities
were
baby (5-6and
tein, respectively). When we first saw the data on organic acids in urine from the baby we were confident that we had another case of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. The original patient with this enzyme deficiency presented with symptoms of Reye’s syndrome but had normal levels of ammonia in blood.6 In a study of a second patient with this defect blood ammonia levels were not remarked on.7 As pointed out by Applegarth et al.2 hypoglycaemia is a feature of this disorder rather than hyperammonaEmia. All three patients excreted breakdown products of leucine in urine, although our patient differed in that 1. Leonard
JV,
et
al.
&bgr;-hydroxy-&bgr;-methylglutaricaciduria presenting
as
Reye’s
syndrome. Lancet, 1979; i: 680. 2. Applegarth DA, et al. Organic acids
and Reye’s syndrome. Lancet 1979; i: 1147. 3. Leonard JV, et al. &bgr;-hydroxy-&bgr;-methylglutaric-aciduria, Reye’s syndrome, and echovirus. 11. Lancet 1979; i:1147. 4. Truscott RJW, Halpern B, Wysocki et al. Clin Chim Acta (in press). 5. Brown T, Hug G, Lansky L. et al. Patient with defect in leucine metabolism.
N Engl J Med 1976; 294: 861, K, Bolton P, Halpern B et al. Patient with defect in leucine metabolism. N Engl J Med 1976; 294: 1013. Schutgens RBH, Heymans H, Ketel A, et al. Lethal hypoglycemia in a child with a deficiency of 3-hydroxy-3-methylglutarylcoenzyme-A-lyase. Pediat-
6. Faull 7.
rics 1979; 94: 89.
,
372
3-hydroxyisovaleric acid was not present in any quantity. Despite the similarities in the profiles of organic acids in urine, the activity of 3-hydroxy-3-methylglutaryl-CoA lyase in cultured skin fibroblasts from our patient was normal. Our data suggest that the excretion of abdominal organic acids in urine from patients with hyperammonaemia is a secondary effect, a possibility pointed out by Applegarth et al. An alternative explanation is that our patient had a defect in liver 3-hydroxy-3-methylglutaryl-CoA lyase but normal levels of this enzyme in peripheral tissues. Our experience has been that, while it is tempting to speculate about enzyme defects on the basis of metabolic profiles, such speculation must be tested by the measurement of enzyme levels in the patient’s tissues wherever possible. Department of Obstetrics and Gynæcology, King Edward Memorial Hospital for Women, Subiaco, Western Australia 6008.
S. J. WYSOCKI R. HÄHNEL
Department of Chemistry, University of Wollongong,
R. J. W. TRUSCOTT B. HALPERN
New South Wales 2500.
Health Commission, Olive Latham Laboratory, North Ryde, New South Wales 2113
B. WILCKEN
FOLLOW-UP OF WOMEN TREATED FOR CERVICAL PRECANCER Dr Kirkup and his colleagues (July 7, p. less intensive that 22) postoperative follow-up after treatment of cervical intraepithelial neoplasia (CIN) may be indicated. They suggest that three smears should be taken over the first 2 years after cervical biopsy, which is reasonable. I would suggest, however, that an annual smear should be taken thereafter rather than the 3 to 5 year follow-up that they suggest. We have followed up 286 cases of CIN treated in Leamington Spa since 1968. Repeat positive smears after cervical biopsy occurred in 44 patients (154%). 36 (82%) of the abnormal smears appeared within a year of cervical biopsy but this still left 8 patients producing abnormal smears between 1 and 6 years after the original cervical biopsy. In 177 patients treated before colposcopy became available there were 41 cases with a repeat positive smear, an incidence of 8.0per 100 women-years of follow up; in the 109 patients managed by colposcopy to date there have been only 3 cases with a repeat positive smear, 2.6per 100 women-years of follow up. Two cases are of interest: A 45-year-old para 2 woman underwent cone biopsy in 1968 because of a positive smear. The biopsy report was carcinomain-situ and "the lesion seems entirely excised". There were ten consecutive negative smears between 1969 and 1976. In April, 1976, she presented with suprapubic pain and vaginal discharge. Dilation of the cervix produced necrotic tissue reported as fragments of a squamous-cell carcinoma, doubtless arising from the cervix. The patient was treated by intracavitary csesium. She is alive and well 3 years later. A 44-year-old para 2 woman had a positive smear in 1968 and underwent a cone biopsy of the cervix. Multiple sections were examined and mild dysplasia with no carcinoma was reported. Four cervical smears were examined over the next 2 years and were negative. The patient was then lost to follow-up. In 1977 (9 years after the original biopsy) she presented with metrorrhagia and abdominal pain. Examination revealed a stage-in carcinoma of the cervix which was treated
SiR,-I agree with
National Health Service The difficulties of the Lambeth, Southwark, and Lewisham Area Health Authority were summarised in our last issue (p. 313). In the following article, Sir Francis Avery Jones discusses, in the light of the reportl of the Royal Commission, some wider aspects of resource allocation and health care in urban communities.
RAWP, THE ROYAL COMMISSION, AND THE "INNER CITIES" THE most important single issue now facing the Secretary of State for Social Services concerns the "inner cities". Largely as a result of the application of the resource-allocation policy (RAWP)2 at sub-regional level, to areas and districts in the largest conurbations, much hardship is being imposed on those who need help most; and, at the same time, many of the main academic and specialist centres are threatened and the survival of high standards-centres of excellence-is in jeopardy. Certainly, other factors are involved, particularly the policy of "area self-sufficiency", introduced by the N.H.S. reorganisation of 1974. Resource allocation is central to the terms of reference of the Royal Commission: "... the best use and management of the financial and manpower resources of the National Health Service." Research undertaken for the Commission by Buxton and Klein3led them to make penetrating comments on RAWP: "the problems of implementing RAWP therefore derive, largely if not exclusively, from the specific problems of the inner cities in both England and Scotland"; "given the complementarity and substitutability of the various social services, no formula designed in isolation for one service-on the assumption that there is no blurring of functions or overlapping of roles-will ever be satisfactory"; "if the country wants to keep pace, in the field of medical research and development, with other countries enjoying much higher per capita incomes, it cannot expect, or indeed realistically hope, to do so in the context of Regional equity." In spite of the known importance of the subject and the clarity of such warning signals, the Commission unhappily provides no real help. Its gives a brief historical review, a note of criticisms expressed, and a plea to the D.H.S.S. to sharpen the RAWP formula. What was needed was a critical look at the fundamental basis of RAWP. Can "need" really be defined and quantified? Is it sound in principle-as the Royal Commission maintains? The results of its application at sub-regional levels indicate that there is something very wrong with it. Where do we now stand with RAWP? It is not fundamental to the future of the N.H.S. It was the last of a series of steps taken towards the original objective of
Royal
report
by radiotherapy. Patients treated conservatively for CIN should be followed by smear and examination every year at least. Less frequent follow-up may lead to an increase in the group "lost to follow-up" with possibly serious consequences.
2.
Warneford
3.
1.
up
Hospital, Leamington Spa, Warwickshire
JOHN FRAMPTON.
Royal Commission on the National Health Service (chairman: Sir Alec Merrison). Cmnd 7615. H.M. Stationery Office. Pp. 491. £8. Chapter 22 (conclusions and recommendations) is available as a booklet entitled A Service for Patients (Pp. 42. £1.75). Sharing Resources for Health in England: report of the Resource Allocation Working Party. H.M. Stationery Office, 1976. Buxton MJ, Klein RE. Allocating health resources: a commentary on the report of the Resource Allocation Working Party. Royal Commission research paper no. 3. H.M. Stationery Office, 1978.