549
LETTERS to the EDITOR
Clinical
use
of intravascular
oxygenation
SIR,-During the weekend of Jan 26/27 the first clinical use of intravascular oxygenation (IVOX) was publicised on television and in newspapers in Britain. We write to report the background and clinical details. The intravascular oxygenator is based on the same technology as the hollow-fibre membrane oxygenators in regular use for cardiopulmonary bypass. However, if extracorporeal membrane oxygenation (ECMO) is used beyond a few hours there are major complications due to platelet consumption, activation of clotting cascades, and other consequences of exposure of blood to pumps and plastic tubes. These create a clinical state that often becomes irretrievable, and enthusiasm for this form of treatment, outside routine cardiac surgery, is very limited. Placement of the gasexchanging device in the venous side of the circulation offers a solution to some of these problems and obviates the need for round-the-clock supervision by a perfusionist. The device developed during ten years of research by Dr J. D. Mortensen! is designed to lie the length of the major venous structures from the confluence of the iliac veins, through the inferior vena cava, right atrium, and superior vena cava. It is configured so that 100% oxygen is drawn through the hollow fibres (under subatmospheric pressure for safety reasons) while venous blood anticoagulated to an ACT of 200 s flows through the interstices of the device, outside the hollow fibres. Oxygen can diffuse into the blood down its concentration gradient, while carbon dioxide and some water vapour diffuse out. The largest of the devices is capable of exchanging 150 ml of oxygen per min, which, unlike ECMO, provides only part of the patient’s total oxygen requirement. IVOX had been used in twenty patients in the United States and in Europe all with end-stage multiple organ failure, to satisfy US Food and Drug Administration product safety requirements. As a
an initiative by Mr Terence Lewis, funded by British Petroleum, Dr Mortensen and his research team gave a three-day practical training course for surgeons, intensive-care specialists, and perfusionists at the Royal London Hospital to prepare selected UK
result of
for use of the device. The first British patient is a 76-year-old man who had undergone femoropopliteal bypass grafting to save an ischaemic left leg. On the third postoperative day he became profoundly hypoxic (POz 7-4 kPa and PCOz 7-36 kPa) despite ventilation with 100% oxygen and 10 centres
HzO of positive end-expiratory pressure (PEEP). His cardiac index was 31 1/min/mz with a pulmonary artery wedge pressure of 12 mm Hg while he was on adrenaline infusion. Radiography supported the clinical diagnosis of the adult respiratory distress syndrome (ARDS). A size 9 Cardiopulmonics IVOX was inserted through the right common femoral vein under image intensifier screening. By the following day the patient’s blood gases improved in the face of declining Fi02 and PEEP (figure). The concomitant haemodynamic improvement enabled us to withdraw the adrenaline. When the IVOX was turned from "off’ to "on", to confirm satisfactory function, mixed venous saturation reproducibly increased from 61 % to 68%. This increase, with the haemoglobin level and cardiac output, yielded an estimate that the device was adding 80 ml oxygen/min. This figure was also confirmed by measuring the volume and concentration of the effluent gases, which also indicated that the device was removing 40 ml carbon dioxide/min. 6 days after insertion of the device, pulmonary gas exchange was adequate and the device was removed. 2 days later the patient was extubated and continues to make good progress. The place of this device is to provide temporary (6-20 days) augmentation of gas exchange. The lung problem causing hypoxia must be reversible and the likely indications are ARDS or severe acute lung infection. This device will replace neither the lungs nor the need for ventilation but may permit adequate oxygenation to be achieved with less than 100% FP2 (which is damaging to the lungs), and for ventilation at lower inspiratory and end-expiratory pressures to reduce the risk of barotrauma. IVOX has been shown to be safe but its efficacy remains to be assessed in a randomised, controlled clinical trial. cm
Intensive Care and Cardiothoracic Units, St George’s Hospital, London SW17 0QT, UK
PANNY KALLIS NAAB M. AL-SAADY DAVID BENNETT TOM TREASURE
JD, Barry G. Conceptual and design features of a practical, clinically effective, intravenous, mechanical blood oxygen/carbon dioxide device (IVOX). Int J Artif Organs 1989; 12: 384-89.
1. Mortensen
Hantavirus infection and renal failure
Blood gases and ventilation requirements in patient before and during IVOX therapy.
SIR,-Dr Zeier and colleagues (Dec 8, p 1441) report a case of hantavirus infection in Germany presenting as acute renal failure. The symptoms (dizziness, vomiting, low back pain, macroscopic haematuria) are well-known features of hantavirus infection (nephropathia epidemica) in Scandinavia, whence most European cases have been reported.!) In Scandinavia hantavirus infection varies widely in clinical presentation from mild influenza-like disease with only slight renal dysfunction to severe disease with acute renal failure and shock. Encephalitis and "acute abdomen" are other clinical presentations.3’ We have seen hantavirus infection complicated by severe bleeding from the renal and gastrointestinal
550
tract, disseminated intravascular coagulationand fatal shock. Hantavirus infection in Europe can easily be confused with various other infectious diseases, including septicaemia. I agree that hantavirus serology should be done in cases with acute renal failure but in endemic regions this investigation should also be done liberally for acute febrile illnesses of unknown aetiology with only slightly or moderately impaired renal function and/or thrombocytopenia and raised serum transferase or lactate dehydrogenase activities. Department of Infectious Diseases, University of Umeå, Regionsjukhuset, S-901 85 Umeå, Sweden
poisoning are being reported world wide,2 especially associated with imported ceramic pottery, should we not follow Food and Drug Administration recommendations3 and give high inspection priority to ceramics and make suppliers more accountable for their products? Finally, urinary delta-amino laevulinic acid, measured spectrophotometrically,4 may serve as a simple screening test if techniques to measure blood lead concentration are not readily available. Department of Medical Microbiology, Royal London Hospital London E1 2AD, UK
M. A. ZUCKERMAN
BO SETTERGREN Zuckerman MA, Savory D, Rayman G. Lead encephalopathy from an imported Toby mug Postgrad MedJ 1989, 65: 307-09. 2. Anonymous. Lead poisoning from ceramics. Lancet 1988; ii: 1358 3. US Department of Health, Education and Welfare. FDA consumer memo "glazes and decals on dinnerware". Washington, DC: Food and Drug Administration, 1979. 4. Tomokmi K, Ogata M. Simple method for the rapid determination of lead in blood by atomic absorption spectrophotometry. Analyst 1970; 18: 1534-36. 1.
J. Nephropathia epidemica in Finland: a clinical, histological and epidemiological study. Ann Clin Res 1971; 3 (suppl 8): 1-154. 2. Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR. Hemorrhagic complications and other clinical findings m nephropathia epidemica in Sweden: a study of 355 serologically venfied cases. J Infect Dis 1988; 157: 380-82. 3. Launes J, Hautanen A. Nephropathia epidemica encephalitis. Acta Neurol Scand 1988; 78: 234-35. 4. Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989; 11: 921-27. 1. Lahdevirta
Anticardiolipin antibody cofactor SIR,-In
Lancet paper last year! we did not adequately the work of Dr Steven Krilis and colleagues in
our
acknowledge
Australia. Before the 4th International Meeting on Antiphospholipid Antibodies, held in Sirmione, Italy, from April 9 to 11,1990, we had considered the possibility that ACA-cofactor was identical to &bgr;2-glycoprotein I, but important discrepancies made us decide that we might be dealing with two different proteins. Discussions with Krilis at Sirmione prompted me to re-evaluate some of our earlier data and do some new experiments. After my return from Sirmione my group did find support for ACA-cofactor being identical to &bgr;2-g1ycoprotein I, but two uncertainties on the anticoagulant properties of both proteins and on the binding of affinity-purified ACA to cofactor in the absence of lipid remained. When we amended our Lancet paper at proof stage we stated that ACAcofactor has properties "very similar" to those of &bgr;2-glycoprotein I, leaving room for alternatives. The Sirmione meeting and discussions there with Krilis thus stimulated a change in our opinion on the protein’s identity. I very much regret that I did not take the opportunity, when altering our paper, to give credit to Krilis and his team. In our letter of Oct 13 (p 952) we indicated that the Australian group were the first to establish the identity of ACA-cofactor; we now wish to state this explicitly. Biochemistry Department, Rijksuniversiteit Limburg, Maastricht, The Netherlands
E. M. BEVERS
1. Galli
M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anneardiolipin antibodies (ACA) directed not to cardiolipm but to a plasma protein cofactor. Lancet 1990, 335: 1544-47.
Lead exposure from lead
crystal
SIR,-Dr Graziano and Dr Blum describe the elution of lead from crystal decanters and glasses (Jan 19, p 141) and highlight the potential health hazard associated with lead compounds in glassware and ceramics. With my colleagues, I reported a 33-year-old woman who was admitted with lead encephalopathy after drinking cider over a 4 month period from a partly lead glazed mug made in Italy in 1976.1 A lead concentration of 130 pg/1 was recorded after leaving cider in the mug for 12 h (the European Community maximum is 50 Lg/1). In the UK the Pottery (Health) Special Regulations 1942 apply to both the manufacture and importation of pottery, but there are no guidelines about personal use. In addition, the Consumer Protection Act 1987 and General Safety Requirements include lead glaze recommendations but the onus is on the supplier to ensure that goods are safe. Since an increasing number of cases of lead
Spread of HIV-2 in India SIR,-in 1987, the year when HIV-1 was isolated for the first time in India, the reported number of HIV-1 infections was 145, and only 1 case of AIDS was seen. However, the detection of HIV antibodies in samples of anti-rhesus(Rh) immunoglobulin and other products derived from donated blood in 1989 indicated that HIV infection was a severe problem for the Asian subcontinent.’ Blood samples and blood products of Indian origin were screened and as a result all locally made blood products were withdrawn and destroyed. The prevalence of HIV infection in the population of India appears very low according to some reports,2,3 but the number of HIV infections in the big cities has been increasing sharply.’ So far, HIV-2 has not been observed. In December, 1990, and January, 1991, 22 serum samples from patients at the G.T. Hospital and STD Clinic (Municipal), Bombay, which had been prescreened for HIV-1 by ELISA and found to be HIV positive were analysed further at the GeorgSpeyer-Haus, Frankfurt. 1 sample could not be confirmed by western blot or immunofluorescence and must be regarded as a false positive. 16 samples were confirmed as HIV-1 positive by immunofluorescence and western blot. 4 sera (A, CE in table) showed a double reaction to HIV-1 and HIV-2 in all tests andI other sample (not shown) demonstrated clear reaction to HIV-1 but only a weak reaction to HIV-2. Further study is need to reveal whether these results are due to double infections or to doubly reactive virus types. 1 sample (B) was HIV-2 positive, this being confirmed by western blot and immunofluorescence. The patient, a 25-year-old pregnant prostitute, had inguinal lymphadenopathy, fever, jaundice, and vulvaloedema, but no neurological symptoms. All 21 HIV-positive patients were born and raised in India. Only 1 man had been abroad (Uganda), so all others must have acquired the infection locally. 1 was a 3-year-old girl, probably infected through her mother. Of the 20 adults 7 were male (18-43 years old, average 26) 13 were female (20-50 years old, average 33). 12 of the females were prostitutes; the other woman had had a blood transfusion. Only 1 of the men was homosexual; the others were heterosexual. The finding of sera doubly reactive to HIV-1 and HIV-2 and the 1 case of HIV-2 infection in this small sample is reminiscent of the situation in the Ivory Coast and AngolaS.6 and indicates that HIV-2 has probably existed for some time in India. One explanation could be the old connections between India and Africa. A high degree of variation can be expected between Indian strains and strains from other parts of the world, and possibly even among Indian strains. More HIV-2 infections are probably present than have so far been identified. That the spread of HIV-2 in India is substantial is indicated by other data. Out of 46 additional sera from the same STD clinic in Bombay not prescreened with ELISA we found 15 HIV-1 positive, 3 HIV-2 positive, and 7 doubly reactive (confirmed by western blot and immunofluorescence). Also, A. Shanmugasundararaj and colleagues have recorded HIV-2 ELISA positivity in Madurai, Tamil Nadu, though without confirmatory tests (Virus Information Exchange Newsletter, vol 5 [no 4], p 132).
LETTERS to the EDITOR
Clinical
use
of intravascular
oxygenation
SIR,-During the weekend of Jan 26/27 the first clinical use of intravascular oxygenation (IVOX) was publicised on television and in newspapers in Britain. We write to report the background and clinical details. The intravascular oxygenator is based on the same technology as the hollow-fibre membrane oxygenators in regular use for cardiopulmonary bypass. However, if extracorporeal membrane oxygenation (ECMO) is used beyond a few hours there are major complications due to platelet consumption, activation of clotting cascades, and other consequences of exposure of blood to pumps and plastic tubes. These create a clinical state that often becomes irretrievable, and enthusiasm for this form of treatment, outside routine cardiac surgery, is very limited. Placement of the gasexchanging device in the venous side of the circulation offers a solution to some of these problems and obviates the need for round-the-clock supervision by a perfusionist. The device developed during ten years of research by Dr J. D. Mortensen! is designed to lie the length of the major venous structures from the confluence of the iliac veins, through the inferior vena cava, right atrium, and superior vena cava. It is configured so that 100% oxygen is drawn through the hollow fibres (under subatmospheric pressure for safety reasons) while venous blood anticoagulated to an ACT of 200 s flows through the interstices of the device, outside the hollow fibres. Oxygen can diffuse into the blood down its concentration gradient, while carbon dioxide and some water vapour diffuse out. The largest of the devices is capable of exchanging 150 ml of oxygen per min, which, unlike ECMO, provides only part of the patient’s total oxygen requirement. IVOX had been used in twenty patients in the United States and in Europe all with end-stage multiple organ failure, to satisfy US Food and Drug Administration product safety requirements. As a
an initiative by Mr Terence Lewis, funded by British Petroleum, Dr Mortensen and his research team gave a three-day practical training course for surgeons, intensive-care specialists, and perfusionists at the Royal London Hospital to prepare selected UK
result of
for use of the device. The first British patient is a 76-year-old man who had undergone femoropopliteal bypass grafting to save an ischaemic left leg. On the third postoperative day he became profoundly hypoxic (POz 7-4 kPa and PCOz 7-36 kPa) despite ventilation with 100% oxygen and 10 centres
HzO of positive end-expiratory pressure (PEEP). His cardiac index was 31 1/min/mz with a pulmonary artery wedge pressure of 12 mm Hg while he was on adrenaline infusion. Radiography supported the clinical diagnosis of the adult respiratory distress syndrome (ARDS). A size 9 Cardiopulmonics IVOX was inserted through the right common femoral vein under image intensifier screening. By the following day the patient’s blood gases improved in the face of declining Fi02 and PEEP (figure). The concomitant haemodynamic improvement enabled us to withdraw the adrenaline. When the IVOX was turned from "off’ to "on", to confirm satisfactory function, mixed venous saturation reproducibly increased from 61 % to 68%. This increase, with the haemoglobin level and cardiac output, yielded an estimate that the device was adding 80 ml oxygen/min. This figure was also confirmed by measuring the volume and concentration of the effluent gases, which also indicated that the device was removing 40 ml carbon dioxide/min. 6 days after insertion of the device, pulmonary gas exchange was adequate and the device was removed. 2 days later the patient was extubated and continues to make good progress. The place of this device is to provide temporary (6-20 days) augmentation of gas exchange. The lung problem causing hypoxia must be reversible and the likely indications are ARDS or severe acute lung infection. This device will replace neither the lungs nor the need for ventilation but may permit adequate oxygenation to be achieved with less than 100% FP2 (which is damaging to the lungs), and for ventilation at lower inspiratory and end-expiratory pressures to reduce the risk of barotrauma. IVOX has been shown to be safe but its efficacy remains to be assessed in a randomised, controlled clinical trial. cm
Intensive Care and Cardiothoracic Units, St George’s Hospital, London SW17 0QT, UK
PANNY KALLIS NAAB M. AL-SAADY DAVID BENNETT TOM TREASURE
JD, Barry G. Conceptual and design features of a practical, clinically effective, intravenous, mechanical blood oxygen/carbon dioxide device (IVOX). Int J Artif Organs 1989; 12: 384-89.
1. Mortensen
Hantavirus infection and renal failure
Blood gases and ventilation requirements in patient before and during IVOX therapy.
SIR,-Dr Zeier and colleagues (Dec 8, p 1441) report a case of hantavirus infection in Germany presenting as acute renal failure. The symptoms (dizziness, vomiting, low back pain, macroscopic haematuria) are well-known features of hantavirus infection (nephropathia epidemica) in Scandinavia, whence most European cases have been reported.!) In Scandinavia hantavirus infection varies widely in clinical presentation from mild influenza-like disease with only slight renal dysfunction to severe disease with acute renal failure and shock. Encephalitis and "acute abdomen" are other clinical presentations.3’ We have seen hantavirus infection complicated by severe bleeding from the renal and gastrointestinal
550
tract, disseminated intravascular coagulationand fatal shock. Hantavirus infection in Europe can easily be confused with various other infectious diseases, including septicaemia. I agree that hantavirus serology should be done in cases with acute renal failure but in endemic regions this investigation should also be done liberally for acute febrile illnesses of unknown aetiology with only slightly or moderately impaired renal function and/or thrombocytopenia and raised serum transferase or lactate dehydrogenase activities. Department of Infectious Diseases, University of Umeå, Regionsjukhuset, S-901 85 Umeå, Sweden
poisoning are being reported world wide,2 especially associated with imported ceramic pottery, should we not follow Food and Drug Administration recommendations3 and give high inspection priority to ceramics and make suppliers more accountable for their products? Finally, urinary delta-amino laevulinic acid, measured spectrophotometrically,4 may serve as a simple screening test if techniques to measure blood lead concentration are not readily available. Department of Medical Microbiology, Royal London Hospital London E1 2AD, UK
M. A. ZUCKERMAN
BO SETTERGREN Zuckerman MA, Savory D, Rayman G. Lead encephalopathy from an imported Toby mug Postgrad MedJ 1989, 65: 307-09. 2. Anonymous. Lead poisoning from ceramics. Lancet 1988; ii: 1358 3. US Department of Health, Education and Welfare. FDA consumer memo "glazes and decals on dinnerware". Washington, DC: Food and Drug Administration, 1979. 4. Tomokmi K, Ogata M. Simple method for the rapid determination of lead in blood by atomic absorption spectrophotometry. Analyst 1970; 18: 1534-36. 1.
J. Nephropathia epidemica in Finland: a clinical, histological and epidemiological study. Ann Clin Res 1971; 3 (suppl 8): 1-154. 2. Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR. Hemorrhagic complications and other clinical findings m nephropathia epidemica in Sweden: a study of 355 serologically venfied cases. J Infect Dis 1988; 157: 380-82. 3. Launes J, Hautanen A. Nephropathia epidemica encephalitis. Acta Neurol Scand 1988; 78: 234-35. 4. Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989; 11: 921-27. 1. Lahdevirta
Anticardiolipin antibody cofactor SIR,-In
Lancet paper last year! we did not adequately the work of Dr Steven Krilis and colleagues in
our
acknowledge
Australia. Before the 4th International Meeting on Antiphospholipid Antibodies, held in Sirmione, Italy, from April 9 to 11,1990, we had considered the possibility that ACA-cofactor was identical to &bgr;2-glycoprotein I, but important discrepancies made us decide that we might be dealing with two different proteins. Discussions with Krilis at Sirmione prompted me to re-evaluate some of our earlier data and do some new experiments. After my return from Sirmione my group did find support for ACA-cofactor being identical to &bgr;2-g1ycoprotein I, but two uncertainties on the anticoagulant properties of both proteins and on the binding of affinity-purified ACA to cofactor in the absence of lipid remained. When we amended our Lancet paper at proof stage we stated that ACAcofactor has properties "very similar" to those of &bgr;2-glycoprotein I, leaving room for alternatives. The Sirmione meeting and discussions there with Krilis thus stimulated a change in our opinion on the protein’s identity. I very much regret that I did not take the opportunity, when altering our paper, to give credit to Krilis and his team. In our letter of Oct 13 (p 952) we indicated that the Australian group were the first to establish the identity of ACA-cofactor; we now wish to state this explicitly. Biochemistry Department, Rijksuniversiteit Limburg, Maastricht, The Netherlands
E. M. BEVERS
1. Galli
M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anneardiolipin antibodies (ACA) directed not to cardiolipm but to a plasma protein cofactor. Lancet 1990, 335: 1544-47.
Lead exposure from lead
crystal
SIR,-Dr Graziano and Dr Blum describe the elution of lead from crystal decanters and glasses (Jan 19, p 141) and highlight the potential health hazard associated with lead compounds in glassware and ceramics. With my colleagues, I reported a 33-year-old woman who was admitted with lead encephalopathy after drinking cider over a 4 month period from a partly lead glazed mug made in Italy in 1976.1 A lead concentration of 130 pg/1 was recorded after leaving cider in the mug for 12 h (the European Community maximum is 50 Lg/1). In the UK the Pottery (Health) Special Regulations 1942 apply to both the manufacture and importation of pottery, but there are no guidelines about personal use. In addition, the Consumer Protection Act 1987 and General Safety Requirements include lead glaze recommendations but the onus is on the supplier to ensure that goods are safe. Since an increasing number of cases of lead
Spread of HIV-2 in India SIR,-in 1987, the year when HIV-1 was isolated for the first time in India, the reported number of HIV-1 infections was 145, and only 1 case of AIDS was seen. However, the detection of HIV antibodies in samples of anti-rhesus(Rh) immunoglobulin and other products derived from donated blood in 1989 indicated that HIV infection was a severe problem for the Asian subcontinent.’ Blood samples and blood products of Indian origin were screened and as a result all locally made blood products were withdrawn and destroyed. The prevalence of HIV infection in the population of India appears very low according to some reports,2,3 but the number of HIV infections in the big cities has been increasing sharply.’ So far, HIV-2 has not been observed. In December, 1990, and January, 1991, 22 serum samples from patients at the G.T. Hospital and STD Clinic (Municipal), Bombay, which had been prescreened for HIV-1 by ELISA and found to be HIV positive were analysed further at the GeorgSpeyer-Haus, Frankfurt. 1 sample could not be confirmed by western blot or immunofluorescence and must be regarded as a false positive. 16 samples were confirmed as HIV-1 positive by immunofluorescence and western blot. 4 sera (A, CE in table) showed a double reaction to HIV-1 and HIV-2 in all tests andI other sample (not shown) demonstrated clear reaction to HIV-1 but only a weak reaction to HIV-2. Further study is need to reveal whether these results are due to double infections or to doubly reactive virus types. 1 sample (B) was HIV-2 positive, this being confirmed by western blot and immunofluorescence. The patient, a 25-year-old pregnant prostitute, had inguinal lymphadenopathy, fever, jaundice, and vulvaloedema, but no neurological symptoms. All 21 HIV-positive patients were born and raised in India. Only 1 man had been abroad (Uganda), so all others must have acquired the infection locally. 1 was a 3-year-old girl, probably infected through her mother. Of the 20 adults 7 were male (18-43 years old, average 26) 13 were female (20-50 years old, average 33). 12 of the females were prostitutes; the other woman had had a blood transfusion. Only 1 of the men was homosexual; the others were heterosexual. The finding of sera doubly reactive to HIV-1 and HIV-2 and the 1 case of HIV-2 infection in this small sample is reminiscent of the situation in the Ivory Coast and AngolaS.6 and indicates that HIV-2 has probably existed for some time in India. One explanation could be the old connections between India and Africa. A high degree of variation can be expected between Indian strains and strains from other parts of the world, and possibly even among Indian strains. More HIV-2 infections are probably present than have so far been identified. That the spread of HIV-2 in India is substantial is indicated by other data. Out of 46 additional sera from the same STD clinic in Bombay not prescreened with ELISA we found 15 HIV-1 positive, 3 HIV-2 positive, and 7 doubly reactive (confirmed by western blot and immunofluorescence). Also, A. Shanmugasundararaj and colleagues have recorded HIV-2 ELISA positivity in Madurai, Tamil Nadu, though without confirmatory tests (Virus Information Exchange Newsletter, vol 5 [no 4], p 132).
