1022 LOPERAMIDE AND ACUTE INFECTIVE DIARRHŒA IN CHILDREN
SiR,-The observation by Dr Sandhu and colleagues (Sept. 29, p. 689) that the opiate analogue loperamide decreases cholera-induced secretion in rats is interesting and, as they suggest, it may be a useful research tool. However, we are concerned that their final
should not be interpreted as a therapeutic recommendation for the treatment of acute diarrhoea of infective aetiology in infants and children. "In the U.S.A. loperamide is not recommended in the pediatric age 1 group [under the age of 12]".’ The essential consequence of acute diarrhoea is dehydration, and the fundamental treatment is rehydration. An antisecretory substance should decrease subsequent loss, but nothing must obscure the fact that rehydration is the most important therapy. Antimotility drugs could divert from this basic therapy and may have other consequences. Active peristalsis may be important in ridding the intestines of some groups of pathogens. Diphenoxylate has adverse effects in human volunteers infected with shigellosis.2 Loperamide decreases transit time and helps to control chronic diarrhoea of various aetiologies.3 However, the manufacturer’s claim that loperamide, the most expensive drug in its class,4 is indicated for the "symptomatic control of acute and chronic diarrhoea of any xtiology"5 would not seem advisable without further evidence, particularly in children.
Such evidence, derived from the study of many patients over many years, is impressive, and in my opinion has not yet been outweighed by the more recent studies carried out. of Psychiatry, North Middlesex Hospital, London N18 1QX
Department
Ross Institute, London School of Hygiene and Tropical Medicine, London WC1E 7HT
W. A. M. CUTTING
Hospital for Sick Children, London WC1N 1EH
W. C. MARSHALL
PAGET’S DISEASE IN NORWAY
SIR,-Paget’s disease of bone is said to be rare in Scandinacompared with other countries,’ but there is no epidemiological support for this statement. In an attempt to register the incidence in Norway, all hospitals in an area of south-eastern Norway having medical, surgical, and/or orthopaedic departments were asked if they had had any contact with patients having symptomatic Paget’s disease during the years 1976-78. The population of the area was 1 236 577, at Dec. 31, 1977,2 constituting 30.5% of the total population of Norway. The request was answered by all forty-nine departments, and for the years in question 6 patients contacted these hospitals, 4 males and 2 females. Their mean age was 66.5years (range 50-84). This figure yields a yearly incidence of 0.16 per 100 000. Radiological signs of Paget’s disease are not too uncommon in Norway, according to our radiologists, but only when the disease becomes symptomatic is the patient referred to hospital. Incidences reported from other countries have been calculated differently,’ so the results are not directly comparable with ours. However, we can conclude that symptomatic Paget’s disease of bone is very rare in south-eastern Norway.
via
Medical Department Aker Hospital, Oslo 5, Norway
EFFICACY OF ECT have not been many inquiries into the efficacy of electroconvulsive therapy (ECT) in the past 15 years of ECT’s 40 year history (Oct. 27, p. 888) is that most of them were done in the preceding 25 years. Even then investigators were mostly concerned with assessing and reducing the unacceptable level of complications of the then unmodified
SiR,—The
reason
Two papers of almost 30 years ago,6,7 quoted in MayerGross, Slater, and Roth’s Clinical Psychiatry (1969) describe
the marked reduction in both morbidity and mortality in severe depressive illness following the introducton of ECT, not seen in untreated controls. The death rate in depressive patients was 16% in males and 14% in females during the years 1900-39, before ECT was available. In the years 1940-48, while the death-rate remained as high in untreated patients, in the patients treated by ECT it fell to 2% or less. The morbidity of the untreated depressive illness was severe, with, at times, starvation and hypermotility leading to cachexia and death from intercurrent disease.
1. Heel
RC, Brogden RN, Speight TM, Avery GS. Loperamide: A review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs 1978; 15: 33-52.
2. Du Pont HL, Hornick RB. Adverse effect of lomotil
therapy in shigellosis. JAMA 1973; 226: 1525. 3. Gough D, ed. The control of diarrhoea in clinical practice (Roy Soc Med Int Congr Symp Ser no 5). London: Royal Society of Medicine, 1978. 4. Department of Health and Social Security. Anti-diarrhæals: Comparative of treatment. ECL 106/69 serial no. 6/77. 5. Association of the British Pharmaceutical Industry. Data sheet compendium. 4th ed. London: A.B.P.I., 1978. 6. Karagulla S. Evaluation of electric convulsion therapy as compared with conservative methods of treatment in depressive states. J Ment Sci 1950; 96:1060. 7. Slater E. Evaluation of electric convulsion therapy as compared with conservative methods of treatment in depressive states. J Ment Sci 1951; 97: 567.
B,
J. A. FALCH
RADIONUCLIDE SCREENING FOR CHRONIC SUBDURAL HÆMATOMA
why there
treatment.
costs
M. G. REVILL
statement
SIR,-Between 1968 and 1973
did 5835 "radionuclide and static scintigraphic brain" scintillation cameras. Included were about 1000 patients in whom, among other neurological diagnoses, chronic subdural haematoma (CSH) was to be excluded. When CSH was diagnosed as highly probable in 17 patients having RN studies performed, all had CSH. CSH was "possible" in 36 patients who had abnormal RN studies, but only 6 had CSH. However, all 23 with proven CSH had abnormal RN imaging.’ The sensitivity of abnormal RN studies for detecting CSH was thus 1.0 (23/23). Because unsuspected CSH was occasionally detected by RN imaging and because atypically abnormal RN studies were often not specific for the diagnosis of CSH, their specificity could not be calculated precisely. Recently, we had our first false-negative RN study, so our current sensitivity figure is 0-98(40/41). Computerised tomography (CT) can diagnose CSH more accurately than can RN imaging and is therefore preferred. However, for screening to exclude CSH, negative contrast-enhanced CT is no better than properly done RN studies which are normal. Moreover, RN may be complementary to CT. Influential editorials (Sept. 1, p. 449) and a recent statistical analysis,. by comparing poor isotopic scanning data (derived from outdated, insensitive techniques) with modern CT, mistakenly discourwe
combined
dynamic angiographic (RN) studies using Anger
FR. Paget’s disease of bone. New York: Plenum Publishing, 1977: 23-26. 2 Vital statistics and migration statistics 1977. Oslo: Central Bureau of Statistics, 1978: 23. 3. Brown R, Weber PM, dos Remedios LV. Dynamic/static brain scintigraphy. An effective screening test for subdural hematoma. Radiology 1975; 117: 355-60. 4. Swets JA, Pickett RM, Whitehead SM, Getty DA, Schnur JA, Swets JB, Freeman BA. Assessment of diagnostic technologies. Science 1979; 205: 753-59. 1.
Singer
1023 our medical colleagues from ordering combined dynamic and static scintigraphy, which can effectively exclude CSH at reasonable cost when CT is not readily avaialble.
age
Division of Nuclear Medicine, Kaiser-Permanente Medical Center, Oakland, California 94611, U.S.A.
activity in SLE and disease activity, circulating immune complexes, natural thymocytotoxic antibody, and susceptibility to infection.
KAZUO OSHIMI MORITO SUMIYA NOBUYUKI GONDA SHOGO KANO FUMIMARO TAKAKU
L. V. DOS REMEDIOS Department of Medicine, Jichi Medical School, Tochigi 329-04, Japan
NATURAL KILLER CELL ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS
SIR,-Natural killer (NK) cells, defined as normal unprimed lymphocytes having the cytotoxic activity against target cells, are suspected as mediators of the first defence mechanism against cancer and viral infections.1,2 Most of their activities in T cells are found in Ty cells-i.e., IgG Fc receptor-bearing T cells in man.3 Since type-C viruses may play a possible pathogenetic role in systemic lupus erythematosus(SLE)’ and the number of T cells has been reported to be decreased in SLE, we have looked at NK cell activity in SLE. NK cell activity fluctuates from experiment to experiment in the same individual and activity may be influenced by age, sex, and treatment, so
IN-VITRO ACTIVITY OF CEFOTAXIME AGAINST GENTAMICIN AND MEZLOCILLIN RESISTANT STRAINS
SIR,-Vanhoof et al.1 have described the efficiency of cefotaxime against Enterobacteriacese: all strains tested were fully sensitive. We have determined minimum inhibitory concentrations (MIC) of cefotaxime, gentamicin, and mezlocillin by a microdilution procedure. 1112 clinical isolates of Staphylococcus aureus, Streptococcus faecalis, Pseudomonas ceruginosa, and Enterobacteriaceae were tested. Of 609 Enterobacteriaceae 31% were resistant to mezlocillin (MIC$: 32 mg/1), 15% to gentamicin (MIC 8 mg/1), and 2% to cefotaxime (MIC 16 mg/1). Amongst the 14 cefotaxime-resistant strains (2%) 10 SUSCEPTIBILITY OF GENTAMICIN
(G) AND MEZLOCILLIN (M)
RESISTANT STRAINS TO CEFOTAXIME
NK cell
activity in four female patients with (a) Age 18; (b) age 28; (c) age 18; (d) age 21.
=
Haller O. Natural killer cells in the mouse: an alternative imsurveillance mechanism? Contemp Topics Immunobiol 1978; 8: 171-201. 2. Santoli D, Koprowski H. Mechanisms of activation of human natural killer cells against tumor and virus-infected cells. Immunol Rev 1979; 44:
Kiesshng R, mune
125-63. Fernandes G, Nair M, Good RA. Spontaneous and antibody-dependent cell-mediated cytotoxicity by human T cell subpopulations. Proc Natl Acad Sci USA 1978; 75: 5137-41. 4. Phillips PE. The virus hypothesis in systemic lupus erythematosus. Ann InternMed 1975; 83: 709-15. 5. Gupta S, Good RA. Subpopulations of human T lymphocytes. I. Studies in immunodeficient patients. Clin Exp Immunol 1977; 30: 222-28. 3.
Gupta S,
I
I
I
SLE.
controls have to be matched for age and sex. With strictly selected controls, we have assayed the NK levels of four untreated patients with active SLE. The patients were all women aged 18-28. In every experiment five healthy female controls were used, matched for the patient’s age 13 years. 200 000 peripheral-blood lymphocytes separated from heparinised whole blood on ’Ficoll-Conray’ gradient were incubated in triplicate for 5 h with 10 000 51Crlabelled K562 or MOLT-4 target cells. % specific SICr release was calculated from the following formula and was considered as NK cell activity: % specific 5 ’Cr release [(E-S)/(M-S)]xlOO, where E was experimental 5’Cr release, S spontaneous 5 ’Cr release, and M maximum S 1Cr release. The results showed that NK levels against K562 and MOLT-4 cells were lower in the patients with SLE than in all normal controls. Santoli and Koprowski2 briefly mentioned similar findings of low NK cell activity in one patient with SLE. If others confirm that NK activity is definitely low in SLE the next step’would be to study the relation between NK 1.
I
were
Enterobactenaceae, 2 Citrobacter sp., and 2 Poteus vul-
garis. Cephalosporins
are less toxic than aminoglycosides, and the small percentage of resistant strains could make cefotaxime of value for the treatment of severe infections with multiresistant bacteria. For this reason, we investigated the susceptibility to cefotaxime of clinical isolates resistant to gentamicin and mezlocillin (table). Cefotaxime was especially effective against P. mirabilis: 100% inhibition was achieved at concentrations of 0-125 mg/1. For mezlocillin-resistant Escherichia coli 2 mgll was necessary, whereas gentamicin-resistant strains were fully inhibited at 0-25 mg/1. In these isolates Klebsiella posed problems : 60% were mezlocillin resistant, 38% gentamicin resistant. Cefotaxime inhibited all these isolates at 2 mg/1 concentration. The picture for Serratia was similar. However, less than 50% bf gentamicin or mezlocillin resistant Enterobacteriaceae could be inhibited with cefotaxime. Cefotaxime is a cephalosporin with some activity against Ps. a-ruginosa but the aminoglycosides, ticarcillin, azlocillin, and piperacillin are still
1. Vanhoof R, Butzler JP, Yourassowsky E. In-vitro activity of porin (HR 756) and cefazolin. Lancet 1978; ii: 209.
new
cephalos-
SiR,-The observation by Dr Sandhu and colleagues (Sept. 29, p. 689) that the opiate analogue loperamide decreases cholera-induced secretion in rats is interesting and, as they suggest, it may be a useful research tool. However, we are concerned that their final
should not be interpreted as a therapeutic recommendation for the treatment of acute diarrhoea of infective aetiology in infants and children. "In the U.S.A. loperamide is not recommended in the pediatric age 1 group [under the age of 12]".’ The essential consequence of acute diarrhoea is dehydration, and the fundamental treatment is rehydration. An antisecretory substance should decrease subsequent loss, but nothing must obscure the fact that rehydration is the most important therapy. Antimotility drugs could divert from this basic therapy and may have other consequences. Active peristalsis may be important in ridding the intestines of some groups of pathogens. Diphenoxylate has adverse effects in human volunteers infected with shigellosis.2 Loperamide decreases transit time and helps to control chronic diarrhoea of various aetiologies.3 However, the manufacturer’s claim that loperamide, the most expensive drug in its class,4 is indicated for the "symptomatic control of acute and chronic diarrhoea of any xtiology"5 would not seem advisable without further evidence, particularly in children.
Such evidence, derived from the study of many patients over many years, is impressive, and in my opinion has not yet been outweighed by the more recent studies carried out. of Psychiatry, North Middlesex Hospital, London N18 1QX
Department
Ross Institute, London School of Hygiene and Tropical Medicine, London WC1E 7HT
W. A. M. CUTTING
Hospital for Sick Children, London WC1N 1EH
W. C. MARSHALL
PAGET’S DISEASE IN NORWAY
SIR,-Paget’s disease of bone is said to be rare in Scandinacompared with other countries,’ but there is no epidemiological support for this statement. In an attempt to register the incidence in Norway, all hospitals in an area of south-eastern Norway having medical, surgical, and/or orthopaedic departments were asked if they had had any contact with patients having symptomatic Paget’s disease during the years 1976-78. The population of the area was 1 236 577, at Dec. 31, 1977,2 constituting 30.5% of the total population of Norway. The request was answered by all forty-nine departments, and for the years in question 6 patients contacted these hospitals, 4 males and 2 females. Their mean age was 66.5years (range 50-84). This figure yields a yearly incidence of 0.16 per 100 000. Radiological signs of Paget’s disease are not too uncommon in Norway, according to our radiologists, but only when the disease becomes symptomatic is the patient referred to hospital. Incidences reported from other countries have been calculated differently,’ so the results are not directly comparable with ours. However, we can conclude that symptomatic Paget’s disease of bone is very rare in south-eastern Norway.
via
Medical Department Aker Hospital, Oslo 5, Norway
EFFICACY OF ECT have not been many inquiries into the efficacy of electroconvulsive therapy (ECT) in the past 15 years of ECT’s 40 year history (Oct. 27, p. 888) is that most of them were done in the preceding 25 years. Even then investigators were mostly concerned with assessing and reducing the unacceptable level of complications of the then unmodified
SiR,—The
reason
Two papers of almost 30 years ago,6,7 quoted in MayerGross, Slater, and Roth’s Clinical Psychiatry (1969) describe
the marked reduction in both morbidity and mortality in severe depressive illness following the introducton of ECT, not seen in untreated controls. The death rate in depressive patients was 16% in males and 14% in females during the years 1900-39, before ECT was available. In the years 1940-48, while the death-rate remained as high in untreated patients, in the patients treated by ECT it fell to 2% or less. The morbidity of the untreated depressive illness was severe, with, at times, starvation and hypermotility leading to cachexia and death from intercurrent disease.
1. Heel
RC, Brogden RN, Speight TM, Avery GS. Loperamide: A review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs 1978; 15: 33-52.
2. Du Pont HL, Hornick RB. Adverse effect of lomotil
therapy in shigellosis. JAMA 1973; 226: 1525. 3. Gough D, ed. The control of diarrhoea in clinical practice (Roy Soc Med Int Congr Symp Ser no 5). London: Royal Society of Medicine, 1978. 4. Department of Health and Social Security. Anti-diarrhæals: Comparative of treatment. ECL 106/69 serial no. 6/77. 5. Association of the British Pharmaceutical Industry. Data sheet compendium. 4th ed. London: A.B.P.I., 1978. 6. Karagulla S. Evaluation of electric convulsion therapy as compared with conservative methods of treatment in depressive states. J Ment Sci 1950; 96:1060. 7. Slater E. Evaluation of electric convulsion therapy as compared with conservative methods of treatment in depressive states. J Ment Sci 1951; 97: 567.
B,
J. A. FALCH
RADIONUCLIDE SCREENING FOR CHRONIC SUBDURAL HÆMATOMA
why there
treatment.
costs
M. G. REVILL
statement
SIR,-Between 1968 and 1973
did 5835 "radionuclide and static scintigraphic brain" scintillation cameras. Included were about 1000 patients in whom, among other neurological diagnoses, chronic subdural haematoma (CSH) was to be excluded. When CSH was diagnosed as highly probable in 17 patients having RN studies performed, all had CSH. CSH was "possible" in 36 patients who had abnormal RN studies, but only 6 had CSH. However, all 23 with proven CSH had abnormal RN imaging.’ The sensitivity of abnormal RN studies for detecting CSH was thus 1.0 (23/23). Because unsuspected CSH was occasionally detected by RN imaging and because atypically abnormal RN studies were often not specific for the diagnosis of CSH, their specificity could not be calculated precisely. Recently, we had our first false-negative RN study, so our current sensitivity figure is 0-98(40/41). Computerised tomography (CT) can diagnose CSH more accurately than can RN imaging and is therefore preferred. However, for screening to exclude CSH, negative contrast-enhanced CT is no better than properly done RN studies which are normal. Moreover, RN may be complementary to CT. Influential editorials (Sept. 1, p. 449) and a recent statistical analysis,. by comparing poor isotopic scanning data (derived from outdated, insensitive techniques) with modern CT, mistakenly discourwe
combined
dynamic angiographic (RN) studies using Anger
FR. Paget’s disease of bone. New York: Plenum Publishing, 1977: 23-26. 2 Vital statistics and migration statistics 1977. Oslo: Central Bureau of Statistics, 1978: 23. 3. Brown R, Weber PM, dos Remedios LV. Dynamic/static brain scintigraphy. An effective screening test for subdural hematoma. Radiology 1975; 117: 355-60. 4. Swets JA, Pickett RM, Whitehead SM, Getty DA, Schnur JA, Swets JB, Freeman BA. Assessment of diagnostic technologies. Science 1979; 205: 753-59. 1.
Singer
1023 our medical colleagues from ordering combined dynamic and static scintigraphy, which can effectively exclude CSH at reasonable cost when CT is not readily avaialble.
age
Division of Nuclear Medicine, Kaiser-Permanente Medical Center, Oakland, California 94611, U.S.A.
activity in SLE and disease activity, circulating immune complexes, natural thymocytotoxic antibody, and susceptibility to infection.
KAZUO OSHIMI MORITO SUMIYA NOBUYUKI GONDA SHOGO KANO FUMIMARO TAKAKU
L. V. DOS REMEDIOS Department of Medicine, Jichi Medical School, Tochigi 329-04, Japan
NATURAL KILLER CELL ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS
SIR,-Natural killer (NK) cells, defined as normal unprimed lymphocytes having the cytotoxic activity against target cells, are suspected as mediators of the first defence mechanism against cancer and viral infections.1,2 Most of their activities in T cells are found in Ty cells-i.e., IgG Fc receptor-bearing T cells in man.3 Since type-C viruses may play a possible pathogenetic role in systemic lupus erythematosus(SLE)’ and the number of T cells has been reported to be decreased in SLE, we have looked at NK cell activity in SLE. NK cell activity fluctuates from experiment to experiment in the same individual and activity may be influenced by age, sex, and treatment, so
IN-VITRO ACTIVITY OF CEFOTAXIME AGAINST GENTAMICIN AND MEZLOCILLIN RESISTANT STRAINS
SIR,-Vanhoof et al.1 have described the efficiency of cefotaxime against Enterobacteriacese: all strains tested were fully sensitive. We have determined minimum inhibitory concentrations (MIC) of cefotaxime, gentamicin, and mezlocillin by a microdilution procedure. 1112 clinical isolates of Staphylococcus aureus, Streptococcus faecalis, Pseudomonas ceruginosa, and Enterobacteriaceae were tested. Of 609 Enterobacteriaceae 31% were resistant to mezlocillin (MIC$: 32 mg/1), 15% to gentamicin (MIC 8 mg/1), and 2% to cefotaxime (MIC 16 mg/1). Amongst the 14 cefotaxime-resistant strains (2%) 10 SUSCEPTIBILITY OF GENTAMICIN
(G) AND MEZLOCILLIN (M)
RESISTANT STRAINS TO CEFOTAXIME
NK cell
activity in four female patients with (a) Age 18; (b) age 28; (c) age 18; (d) age 21.
=
Haller O. Natural killer cells in the mouse: an alternative imsurveillance mechanism? Contemp Topics Immunobiol 1978; 8: 171-201. 2. Santoli D, Koprowski H. Mechanisms of activation of human natural killer cells against tumor and virus-infected cells. Immunol Rev 1979; 44:
Kiesshng R, mune
125-63. Fernandes G, Nair M, Good RA. Spontaneous and antibody-dependent cell-mediated cytotoxicity by human T cell subpopulations. Proc Natl Acad Sci USA 1978; 75: 5137-41. 4. Phillips PE. The virus hypothesis in systemic lupus erythematosus. Ann InternMed 1975; 83: 709-15. 5. Gupta S, Good RA. Subpopulations of human T lymphocytes. I. Studies in immunodeficient patients. Clin Exp Immunol 1977; 30: 222-28. 3.
Gupta S,
I
I
I
SLE.
controls have to be matched for age and sex. With strictly selected controls, we have assayed the NK levels of four untreated patients with active SLE. The patients were all women aged 18-28. In every experiment five healthy female controls were used, matched for the patient’s age 13 years. 200 000 peripheral-blood lymphocytes separated from heparinised whole blood on ’Ficoll-Conray’ gradient were incubated in triplicate for 5 h with 10 000 51Crlabelled K562 or MOLT-4 target cells. % specific SICr release was calculated from the following formula and was considered as NK cell activity: % specific 5 ’Cr release [(E-S)/(M-S)]xlOO, where E was experimental 5’Cr release, S spontaneous 5 ’Cr release, and M maximum S 1Cr release. The results showed that NK levels against K562 and MOLT-4 cells were lower in the patients with SLE than in all normal controls. Santoli and Koprowski2 briefly mentioned similar findings of low NK cell activity in one patient with SLE. If others confirm that NK activity is definitely low in SLE the next step’would be to study the relation between NK 1.
I
were
Enterobactenaceae, 2 Citrobacter sp., and 2 Poteus vul-
garis. Cephalosporins
are less toxic than aminoglycosides, and the small percentage of resistant strains could make cefotaxime of value for the treatment of severe infections with multiresistant bacteria. For this reason, we investigated the susceptibility to cefotaxime of clinical isolates resistant to gentamicin and mezlocillin (table). Cefotaxime was especially effective against P. mirabilis: 100% inhibition was achieved at concentrations of 0-125 mg/1. For mezlocillin-resistant Escherichia coli 2 mgll was necessary, whereas gentamicin-resistant strains were fully inhibited at 0-25 mg/1. In these isolates Klebsiella posed problems : 60% were mezlocillin resistant, 38% gentamicin resistant. Cefotaxime inhibited all these isolates at 2 mg/1 concentration. The picture for Serratia was similar. However, less than 50% bf gentamicin or mezlocillin resistant Enterobacteriaceae could be inhibited with cefotaxime. Cefotaxime is a cephalosporin with some activity against Ps. a-ruginosa but the aminoglycosides, ticarcillin, azlocillin, and piperacillin are still
1. Vanhoof R, Butzler JP, Yourassowsky E. In-vitro activity of porin (HR 756) and cefazolin. Lancet 1978; ii: 209.
new
cephalos-
