- Email: [email protected]
IMMUNISATION
554 Sheiham does not indicate the place of preventive therapy in modern dental practice. In citing the findings of Suomi and co-workers which suggest that increasing the frequency of cleaning and polishing teeth from once to two or three times a year gives little or no additional benefit to gingival health,’ Sheiham omits to report their conclusion that daily removal of plaque by the individual patient is the single most important step for good periodontal health. Suomi et al. advocate that additional sessions might be better spent giving patients intensive instruction in oral hygiene and in attempting to motivate them to practise thorough plaque-removal procedures at home on a daily basis,I.2 a procedure for which the dentist is not adequately remunerated
bytheN.H.S. Clinical studies in children have shown that prevention of both gingival disease and caries is possible,3-s and we await the results of further research to indicate what programme will achieve maximum prevention with minimum frequency of visits and duration of treatment-time. Surely we need to define the future role the dentist will play in the prevention of dental disease before recommending that patients should attend the dentist less often. D. A. M. GEDDES K. W. STEPHEN Department of Oral Medicine and Pathology, E. E. MACFADYEN Glasgow Dental Hospital and School, D. K. MASON Glasgow G2 3JZ
SIR,-I agree with much of Dr Sheiham’s article on dental examinations but I think that, as in so many papers based on statistics, there are too many generalisations and assumptions. Thus he assumes that at a dental examination all carious lesions are noted, and this is far from the case. He does not take into account those patients who have rampant caries and certainly require examinations and treatment every 6 months. Surely the general dental practitioner should be the arbiter of how often he requires -to see his patients for a dental inspection: Sheiham implies that there is evidence of overprescribing by the general dental practitioners. As a consultant who sees a large number of adolescents each year I have no evidence of overtreatment-indeed in some cases quite the opposite. Royal Hampshire County Hospital, R. T. BROADWAY
Winchester
ACCEPTANCE OF MEASLES VACCINE
SIR,-You rightly draw attention (Aug. 20, p. 387) to the low acceptance-rate of measles vaccination in infancy. We have lately completed a study of immunisation in a cohort of some 1200 children born in 1974, drawn from a random sample of sixteen general practices in Leeds. Preliminary analysis (of 826 children) showed an immunisation-rate for measles of 48%. However, with regard to the factors which you associate with this low take-up rate, our own findings differ in some important respects: "... all immunisation-rates have fallen as a result of adverse publicity about whooping-cough vaccine". While the uptake of whooping-cough vaccine in Leeds has fallen dramathe corresponding tically between 1972 (75%) and 1974 fall in diphtheria/tetanus and poliomyelitis vaccination has been from 76% (1972) to 70% (1974). The effect of publicity about whooping-cough vaccine on rates of uptake of other vaccines should not be overestimated.
(42%),
1.
Suomi, J. D., Smith, L. W., Chang, J. J., Barbano, J. P. J. Periodont. 1973, 44, 406. 2. Suomi, J. D., Greene, J. C., Vermillion, J. R., Doyle, J., Chang, J. J., Leatherwood, E. C. ibid. 1971, 42, 152. 3. Axelsson, P., Lindhe, J. J. clin. Periodont. 1974, 1, 126. 4. Englander, H. R., Keyes, P. H., Gestwicki, M., Sultz, H. A. J. Am. dent. Ass. 5.
1967, 75, 638. Stephen, K. W., MacFadyen, E. E.
Br. dent.
J. 1977, 143, 111.
In urban communities "The problems are greater than in the rural areas since population turnover is high and change of names and addresses ... are frequent". Amongst 826 children, we found evidence of previous registration with a different doctor or different family practitioner in 167 (20%). Amongst these socially mobile children, 14% were unknown to the area health authority’s computer (as against 9% of the socially static children); and the rates of uptake for all five principal vaccines were marginally lower than those of their peers. But in neither respect were these differences significant at the 1% level. Again, therefore, this factor should not be overestimated. "... some doctors regard childhood measles as a generally mild infection not worth preventing". Only 5 out of 33 doctors rated measles immunisation as of little value. These 5 doctors were concerned with 228 children, but 91 of them (40%) had been immunised for measles. "... no doubt the computer makes high acceptance-rates easier to achieve". Yes, but the computer itself does not determine vaccine acceptance levels. In Leeds the computer file proved to be more efficient at registering children than we had anticipated; it identified and recorded the immunisation state of all but 10% of the children registered with these practitioners. (And this level of efficiency might be compared with the 28% of measles-immunised children whose immunisation was not recorded in the practitioners’ files.) Yet in this city the uptake of measles vaccine remains low. Bacon remarked that "it is from ignorance of causes that operations fail". It seems that we must look elsewhere for the causes of low uptake of measles vaccine. At the time of preliminary analysis 352mothers of these 826 children had been interviewed about a wide range of antenatal, natal, postnatal, family, and attitudinal factors. The findings showed a statistically significant association (P<0-1) between the uptake-rate of all vaccines and the position of the child in the family (uptake rates dropping dramatically in the fifth and later child), attendance/non-attendance at a baby clinic (wherever held), and the mother’s perception of the protective value of immunisation. For measles vaccine there was also evidence of a significantly reduced uptake (p<0.05) with a history of any major sibling illness and with mothers who rated the hazards of measles vaccine to be high. In contrast with other vaccines, however, no association was found between the uptake of measles vaccine and social class, breast feeding, or mother’s education. Amongst the thirteen practices included in the preliminary analysis, the take-up rate of measles vaccine varied between 36% and 61%. No statistically significant associations were evident between a spectrum of professional and practice characteristics of the practitioners, and the uptake-rate of measles vaccine they achieved. However, there was evidence of misunderstanding about the contraindications to all types of immunisation (including measles); and the rank correlation between the uptake-rates achieved for measles and for diphtheria/tetanus vaccine was significant at the 3% level. These preliminary findings suggest some practical priorities for any attempt to improve the uptake of measles vaccine; but we would wish to await the completed analysis before crystallising these. of Community Medicine and General Practice,
Department St
James’s Hospital, University of Leeds,
H.
Leeds LS9 7TF
J. WRIGHT
IMMUNISATION
SIR,-You praise (Aug. 20, p. 387) the high acceptance ratios achieved by a growing number of health authorities "with the aid of computers" and mention the success sustained by West Sussex in those computer-related activities. I find it hard to reconcile this truth with the advocacy (6
555
later) by Dr Alberman and her colleagues that this responsibility (for maintaining good immunisation performances) should "now rest squarely with the G.P. and his nursing colleagues". pages
It is of
course
the clinician who decides whether
or not a
child should receive an indicated inoculation, but the organisation of services like this must continue (for some time at least) to be the business of computer-equipped authorities who are alive to changing schedules of immunisation, have the authority to act on them, and, most importantly, facilitate the work of the family doctor and his nurses by acting as his memory, his record-keeper, and arranger of appointments. However conscientious and systematic general practice may become, it will be some time before the health administrations can safely rely on that, and this is certainly not "what reorganisation is all about".
Hampshire Area Health Authority, Kings Walk, Silver Hill, Winchester SO23 8AF
T. MCL. GALLOWAY
S.M.O.N. IN ITALY
SIR,-S.M.O.N. (subacute myelo-optic neuropathy) has been rarely reported in Western countries.’ We have seen, in Italy, a patient with S.M.O.N. type disease. An Italian woman aged 28 had had chronic diarrhoea since 1967. Clinical and laboratory investigations revealed a colonic Crohn’s disease. In 1971 she underwent a total colectomy with ileorectal anastomosis. Despite this operation the diarrhoea persisted. The patient could obtain relief only with continuous clioquinol therapy at a very high dosage-800 mg daily for 4 years (300 g/year) and 2 g daily in the last year (800 g). The total dosage has been 2 kg in 5 years. While on clioquinol, during the late summer months of 1976, she experienced painful dysaesthesias in distal segments of the legs. Slowly she lost strength in her legs and walking became unsteady. In August, 1976, the patient was admitted to the S. Camillo Hospital in Rome, and examination showed a spastic paraplegia with decreased sensitivity to touch, pain, and heat but no micturition troubles, and visual symptoms (transitory dimness of vision with unchanged fundi). Her general condition (state of nutrition and so on) was good, except for slight hyposideraemic anaemia. Other organs and body systems were not affected except that the patient had granulomatous ulcers of the rectal mucosa and continuous diarrhoea.
Laboratory investigations were largely negative. Her cerebrospinal fluid was completely normal; serological investigations for influenza A and B, parainfluenza 1, 2, and 3; adenovirus, Coxsackie B 1, 2, 3, 4, and 5, herpes, and parotitis viruses were negative (<1/4). Opaque myelography was also normal. The disease stabilised with a slight recovery from neurological disability; the motor symptoms and signs remained unaltered, while the sensory troubles got a little better. Clioquinol treatment was immediately stopped, and the diarrhoea was successfully treated with salicylazosulphapyridine. One year after the start of the neurological symptoms the patient is still para-
plegic. In this
subacute myeloneuropathy developed in had had a colectomy for Crohn’s disease and who had been treated with prolonged, high doses of clioquinol a
case severe
in
diploid cells from human embryonic lung have been negative. Now we are looking for neutralising antibody against the Inoue s.M.o.N.-associated virus;2 this approach has permitted an s.r.t.o.rt. developing after pneumonitis to be associated ture
with the Inoue virus.’ III Divisione Medicina Marchiafava Divisione di Neurologia Medica Lancisi, Ospedale San Camillo de Lellis,
Rome, Italy
F. FABIANI L. SINIBALDI
DOPAMINE-INDUCED ISCHÆMIA
(July 30, p. 231) that the only nonof intravenous dopamine are nausea cardiac adverse effects and vomiting is incorrect. Dopamine has been implicated as the causative factor of ischaemia and gangrene in extremities in several cases.4-8 This side-effect is related to peripheral vasoconstriction from alpha-adrenergic stimulation by dopamine. Gangrene developed within 48 h in patients receiving doses of 1-55 .g/kg/min up to 14 p.g/kg/min. Most patients in whom gangrene developed already had vascular disease; one had tissue necrosis and gangrene secondary to dopamine infiltration.8 Of the drugs used to treat dopamine-induced ischaemia only alpha-adrenergic blocking agents had any therapeutic benefit.4,7 Phentolamine gave relief from the ischaemia in one case, but failed in another where the patient’s finger had to be amputated4g Chlorpromazine was effective in one patient and allowed continued use of dopamine without recurrence of ischa;mia7 These case-reports suggest that caution should be used in the administration of dopamine to elderly patients with pre-existing vascular disease, diabetes, Raynaud’s disease, and frostbite. Indwelling venous catheters for administration should reduce the risk of infiltration. SIR,-Your
statement
Holy Cross Hospital, Fort Lauderdale, Florida 33308, U.S.A.
CAL W. GREENLAW LARRY W. NULL, II
CIMETIDINE AND BONE-MARROW TOXICITY
SiR,-The report by Dr Craven and Dr Whittington (Aug. p. 294) of agranulocytosis after therapy with cimetidine raises new concern over the potential dangers associated with the clinical use of H2-receptor-blocking agents. I have suggested9 that the bone-marrow toxicity of metiamide might be related to the compound’s ability to block the histamine H2-receptor associated with the pluripotent bone-marrow stem cell rather than to the presence of a thiourea group in its structure. Recent findings in my laboratory demonstrate that cimetidine, in vitro, is more potent than metiamide as an antagonist of the histamine H2 receptor of bone-marrow. Bone-marrow effects might well be expected of all histamine He antagonists that attain adequate concentrations in hsematopoietic tissues. Compensatory mechanisms in bone-marrow could easily shield a stem-cell effect. Hence, decreased differentiation from the pluripotent stem-cell population into the populations of committed (unipotent) progenitor cells would not be immediately reflected by peripheral-blood counts. Accordingly, the delayed bone-marrow effect observed by Craven and Whittington for a drug acting at the level of the pluripotent stem cell is not surprising. They report the day when severe neutropenia was
6,
patient who
for diarrhoea.
Common, alternative neurological diagnoses
by the clinical
are
ruled
out
and laboratory findings. We think that this patient had S.M.O.N. Possible causes are the massive doses of.clioquinol or a virus. Attempts to isolate a virus from faeces by cul1. Wadia, N. H. J. Neurol. Neurosurg. Psych. 1977, 40, 268.
2. Inoue, Y. K., Nishibe, Y., Kimura, T., Shimada, Y., Yamada, G. Lancet, 1972, ii, 705. 3. Chambers, C. H., Straumfjord, J. V., Clowry, L. J., Nishibe, Y., Inoue, Y. K. Am. J. clin. Path. 1976, 66, 531. 4. Alexander, C. S., Sako, Y., Mikulie, E. New Engl. J. Med. 1975, 293, 591. 5. Green, S. I., Smith, J. W. ibid. 1976, 294, 114. 6. Julka, N. K., Nora, J. R. J. Am. med., Ass. 1976, 235, 2812. 7. Valdes, M. E. New Engl. J. Med. 1976, 295, 1081. 8. Boltax, R. S. ibid. 1977, 296, 823. 9. Byron; J. W. Lancet, 1976, ii, 1350.
bytheN.H.S. Clinical studies in children have shown that prevention of both gingival disease and caries is possible,3-s and we await the results of further research to indicate what programme will achieve maximum prevention with minimum frequency of visits and duration of treatment-time. Surely we need to define the future role the dentist will play in the prevention of dental disease before recommending that patients should attend the dentist less often. D. A. M. GEDDES K. W. STEPHEN Department of Oral Medicine and Pathology, E. E. MACFADYEN Glasgow Dental Hospital and School, D. K. MASON Glasgow G2 3JZ
SIR,-I agree with much of Dr Sheiham’s article on dental examinations but I think that, as in so many papers based on statistics, there are too many generalisations and assumptions. Thus he assumes that at a dental examination all carious lesions are noted, and this is far from the case. He does not take into account those patients who have rampant caries and certainly require examinations and treatment every 6 months. Surely the general dental practitioner should be the arbiter of how often he requires -to see his patients for a dental inspection: Sheiham implies that there is evidence of overprescribing by the general dental practitioners. As a consultant who sees a large number of adolescents each year I have no evidence of overtreatment-indeed in some cases quite the opposite. Royal Hampshire County Hospital, R. T. BROADWAY
Winchester
ACCEPTANCE OF MEASLES VACCINE
SIR,-You rightly draw attention (Aug. 20, p. 387) to the low acceptance-rate of measles vaccination in infancy. We have lately completed a study of immunisation in a cohort of some 1200 children born in 1974, drawn from a random sample of sixteen general practices in Leeds. Preliminary analysis (of 826 children) showed an immunisation-rate for measles of 48%. However, with regard to the factors which you associate with this low take-up rate, our own findings differ in some important respects: "... all immunisation-rates have fallen as a result of adverse publicity about whooping-cough vaccine". While the uptake of whooping-cough vaccine in Leeds has fallen dramathe corresponding tically between 1972 (75%) and 1974 fall in diphtheria/tetanus and poliomyelitis vaccination has been from 76% (1972) to 70% (1974). The effect of publicity about whooping-cough vaccine on rates of uptake of other vaccines should not be overestimated.
(42%),
1.
Suomi, J. D., Smith, L. W., Chang, J. J., Barbano, J. P. J. Periodont. 1973, 44, 406. 2. Suomi, J. D., Greene, J. C., Vermillion, J. R., Doyle, J., Chang, J. J., Leatherwood, E. C. ibid. 1971, 42, 152. 3. Axelsson, P., Lindhe, J. J. clin. Periodont. 1974, 1, 126. 4. Englander, H. R., Keyes, P. H., Gestwicki, M., Sultz, H. A. J. Am. dent. Ass. 5.
1967, 75, 638. Stephen, K. W., MacFadyen, E. E.
Br. dent.
J. 1977, 143, 111.
In urban communities "The problems are greater than in the rural areas since population turnover is high and change of names and addresses ... are frequent". Amongst 826 children, we found evidence of previous registration with a different doctor or different family practitioner in 167 (20%). Amongst these socially mobile children, 14% were unknown to the area health authority’s computer (as against 9% of the socially static children); and the rates of uptake for all five principal vaccines were marginally lower than those of their peers. But in neither respect were these differences significant at the 1% level. Again, therefore, this factor should not be overestimated. "... some doctors regard childhood measles as a generally mild infection not worth preventing". Only 5 out of 33 doctors rated measles immunisation as of little value. These 5 doctors were concerned with 228 children, but 91 of them (40%) had been immunised for measles. "... no doubt the computer makes high acceptance-rates easier to achieve". Yes, but the computer itself does not determine vaccine acceptance levels. In Leeds the computer file proved to be more efficient at registering children than we had anticipated; it identified and recorded the immunisation state of all but 10% of the children registered with these practitioners. (And this level of efficiency might be compared with the 28% of measles-immunised children whose immunisation was not recorded in the practitioners’ files.) Yet in this city the uptake of measles vaccine remains low. Bacon remarked that "it is from ignorance of causes that operations fail". It seems that we must look elsewhere for the causes of low uptake of measles vaccine. At the time of preliminary analysis 352mothers of these 826 children had been interviewed about a wide range of antenatal, natal, postnatal, family, and attitudinal factors. The findings showed a statistically significant association (P<0-1) between the uptake-rate of all vaccines and the position of the child in the family (uptake rates dropping dramatically in the fifth and later child), attendance/non-attendance at a baby clinic (wherever held), and the mother’s perception of the protective value of immunisation. For measles vaccine there was also evidence of a significantly reduced uptake (p<0.05) with a history of any major sibling illness and with mothers who rated the hazards of measles vaccine to be high. In contrast with other vaccines, however, no association was found between the uptake of measles vaccine and social class, breast feeding, or mother’s education. Amongst the thirteen practices included in the preliminary analysis, the take-up rate of measles vaccine varied between 36% and 61%. No statistically significant associations were evident between a spectrum of professional and practice characteristics of the practitioners, and the uptake-rate of measles vaccine they achieved. However, there was evidence of misunderstanding about the contraindications to all types of immunisation (including measles); and the rank correlation between the uptake-rates achieved for measles and for diphtheria/tetanus vaccine was significant at the 3% level. These preliminary findings suggest some practical priorities for any attempt to improve the uptake of measles vaccine; but we would wish to await the completed analysis before crystallising these. of Community Medicine and General Practice,
Department St
James’s Hospital, University of Leeds,
H.
Leeds LS9 7TF
J. WRIGHT
IMMUNISATION
SIR,-You praise (Aug. 20, p. 387) the high acceptance ratios achieved by a growing number of health authorities "with the aid of computers" and mention the success sustained by West Sussex in those computer-related activities. I find it hard to reconcile this truth with the advocacy (6
555
later) by Dr Alberman and her colleagues that this responsibility (for maintaining good immunisation performances) should "now rest squarely with the G.P. and his nursing colleagues". pages
It is of
course
the clinician who decides whether
or not a
child should receive an indicated inoculation, but the organisation of services like this must continue (for some time at least) to be the business of computer-equipped authorities who are alive to changing schedules of immunisation, have the authority to act on them, and, most importantly, facilitate the work of the family doctor and his nurses by acting as his memory, his record-keeper, and arranger of appointments. However conscientious and systematic general practice may become, it will be some time before the health administrations can safely rely on that, and this is certainly not "what reorganisation is all about".
Hampshire Area Health Authority, Kings Walk, Silver Hill, Winchester SO23 8AF
T. MCL. GALLOWAY
S.M.O.N. IN ITALY
SIR,-S.M.O.N. (subacute myelo-optic neuropathy) has been rarely reported in Western countries.’ We have seen, in Italy, a patient with S.M.O.N. type disease. An Italian woman aged 28 had had chronic diarrhoea since 1967. Clinical and laboratory investigations revealed a colonic Crohn’s disease. In 1971 she underwent a total colectomy with ileorectal anastomosis. Despite this operation the diarrhoea persisted. The patient could obtain relief only with continuous clioquinol therapy at a very high dosage-800 mg daily for 4 years (300 g/year) and 2 g daily in the last year (800 g). The total dosage has been 2 kg in 5 years. While on clioquinol, during the late summer months of 1976, she experienced painful dysaesthesias in distal segments of the legs. Slowly she lost strength in her legs and walking became unsteady. In August, 1976, the patient was admitted to the S. Camillo Hospital in Rome, and examination showed a spastic paraplegia with decreased sensitivity to touch, pain, and heat but no micturition troubles, and visual symptoms (transitory dimness of vision with unchanged fundi). Her general condition (state of nutrition and so on) was good, except for slight hyposideraemic anaemia. Other organs and body systems were not affected except that the patient had granulomatous ulcers of the rectal mucosa and continuous diarrhoea.
Laboratory investigations were largely negative. Her cerebrospinal fluid was completely normal; serological investigations for influenza A and B, parainfluenza 1, 2, and 3; adenovirus, Coxsackie B 1, 2, 3, 4, and 5, herpes, and parotitis viruses were negative (<1/4). Opaque myelography was also normal. The disease stabilised with a slight recovery from neurological disability; the motor symptoms and signs remained unaltered, while the sensory troubles got a little better. Clioquinol treatment was immediately stopped, and the diarrhoea was successfully treated with salicylazosulphapyridine. One year after the start of the neurological symptoms the patient is still para-
plegic. In this
subacute myeloneuropathy developed in had had a colectomy for Crohn’s disease and who had been treated with prolonged, high doses of clioquinol a
case severe
in
diploid cells from human embryonic lung have been negative. Now we are looking for neutralising antibody against the Inoue s.M.o.N.-associated virus;2 this approach has permitted an s.r.t.o.rt. developing after pneumonitis to be associated ture
with the Inoue virus.’ III Divisione Medicina Marchiafava Divisione di Neurologia Medica Lancisi, Ospedale San Camillo de Lellis,
Rome, Italy
F. FABIANI L. SINIBALDI
DOPAMINE-INDUCED ISCHÆMIA
(July 30, p. 231) that the only nonof intravenous dopamine are nausea cardiac adverse effects and vomiting is incorrect. Dopamine has been implicated as the causative factor of ischaemia and gangrene in extremities in several cases.4-8 This side-effect is related to peripheral vasoconstriction from alpha-adrenergic stimulation by dopamine. Gangrene developed within 48 h in patients receiving doses of 1-55 .g/kg/min up to 14 p.g/kg/min. Most patients in whom gangrene developed already had vascular disease; one had tissue necrosis and gangrene secondary to dopamine infiltration.8 Of the drugs used to treat dopamine-induced ischaemia only alpha-adrenergic blocking agents had any therapeutic benefit.4,7 Phentolamine gave relief from the ischaemia in one case, but failed in another where the patient’s finger had to be amputated4g Chlorpromazine was effective in one patient and allowed continued use of dopamine without recurrence of ischa;mia7 These case-reports suggest that caution should be used in the administration of dopamine to elderly patients with pre-existing vascular disease, diabetes, Raynaud’s disease, and frostbite. Indwelling venous catheters for administration should reduce the risk of infiltration. SIR,-Your
statement
Holy Cross Hospital, Fort Lauderdale, Florida 33308, U.S.A.
CAL W. GREENLAW LARRY W. NULL, II
CIMETIDINE AND BONE-MARROW TOXICITY
SiR,-The report by Dr Craven and Dr Whittington (Aug. p. 294) of agranulocytosis after therapy with cimetidine raises new concern over the potential dangers associated with the clinical use of H2-receptor-blocking agents. I have suggested9 that the bone-marrow toxicity of metiamide might be related to the compound’s ability to block the histamine H2-receptor associated with the pluripotent bone-marrow stem cell rather than to the presence of a thiourea group in its structure. Recent findings in my laboratory demonstrate that cimetidine, in vitro, is more potent than metiamide as an antagonist of the histamine H2 receptor of bone-marrow. Bone-marrow effects might well be expected of all histamine He antagonists that attain adequate concentrations in hsematopoietic tissues. Compensatory mechanisms in bone-marrow could easily shield a stem-cell effect. Hence, decreased differentiation from the pluripotent stem-cell population into the populations of committed (unipotent) progenitor cells would not be immediately reflected by peripheral-blood counts. Accordingly, the delayed bone-marrow effect observed by Craven and Whittington for a drug acting at the level of the pluripotent stem cell is not surprising. They report the day when severe neutropenia was
6,
patient who
for diarrhoea.
Common, alternative neurological diagnoses
by the clinical
are
ruled
out
and laboratory findings. We think that this patient had S.M.O.N. Possible causes are the massive doses of.clioquinol or a virus. Attempts to isolate a virus from faeces by cul1. Wadia, N. H. J. Neurol. Neurosurg. Psych. 1977, 40, 268.
2. Inoue, Y. K., Nishibe, Y., Kimura, T., Shimada, Y., Yamada, G. Lancet, 1972, ii, 705. 3. Chambers, C. H., Straumfjord, J. V., Clowry, L. J., Nishibe, Y., Inoue, Y. K. Am. J. clin. Path. 1976, 66, 531. 4. Alexander, C. S., Sako, Y., Mikulie, E. New Engl. J. Med. 1975, 293, 591. 5. Green, S. I., Smith, J. W. ibid. 1976, 294, 114. 6. Julka, N. K., Nora, J. R. J. Am. med., Ass. 1976, 235, 2812. 7. Valdes, M. E. New Engl. J. Med. 1976, 295, 1081. 8. Boltax, R. S. ibid. 1977, 296, 823. 9. Byron; J. W. Lancet, 1976, ii, 1350.