- Email: [email protected]
TYPE 2 SEROTONIN RECEPTORS AND HEART FAILURE
307 fixed in the distal common bileduct (proximal to the ampulla to avoid duodenal reflux and cholangitis). The tube was also secured at the point of exit from the liver. Intraoperative X-rays confirmed the accurate position of the tube with adequate flow from the dilated ducts within the liver to the common bileduct. The proximal end of the tube was plugged and passed through the muscle and fascia to be secured in a subcutaneous pocket. The tube was readily palpable under the skin. All 4 patients are at home and free of jaundice though the tube dislodged and was replaced with a percutaneous drain in one patient. This technique offers benefits. As an alternative to the U-tube, there are no external devices which require daily management and may cause both psychological and physical discomfort. Exogenous infection should not occur. The lumen of the tube is larger than that of most current endoprostheses and may be less prone to blockage. However, should jaundice recur, the tube is readily accessible beneath the skin and can be brought to the surface by a minor procedure to be cleaned by a flexible bronchoscope brush or was
replaced over a guidewire.7 This technique has a role
in a clearly defined group of patients found to be non-resectable at laparotomy. Current investigations of the preoperative assessment of cholangiocarcinoma should allow delineation of cases which are neither resectable nor amenable to internal drainage by bypass and which may be best treated by percutaneously placed endoprostheses or
with
tumours
exo-endoprostheses. Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital,
L. H. BLUMGART C. R. VOYLES C. SMADJA
London W12 0HS
concentrations at least 4-fold greater than concentrations necessary for optimal growth with no evidence ofa30-50% decline. We agree that the mechanism by which the neutrophil derived inhibitor results in reduced CSF elaboration is of interest and this is over
being explored. Department of Therapeutics, City Hospital, Nottingham NG5 1PD
MEFENAMIC ACID OVERDOSE
SIR,-Information on self-poisoning and accidental overdosage with medicinal products is often very limited, so we welcome Dr Balali-Mood and colleagues’ informative article (June 20, p. 1354) on mefenamic acid overdosage. Recent information supplied to this company supports the finding that convulsions can occasionally occur in patients taking overdoses of mefenamic acid, but this has also been reported with overdoses of drugs in many therapeutic classes. Even drugs used in the treatment of seizures can produce convulsions in overdosage. Special care should always be exercised when prescribing drugs for epileptic patients. However, we cannot accept the suggestion that mefenamic acid should be-avoided in such patients since we have no evidence to suggest that, in therapeutic dosage, there is any increase in the incidence of convulsions. Warner-Lambert (U.K.) Ltd, Pontypool, Gwent NP4 0YH
SIR,-We thank Dr Baker and Dr Wilbur (June 27, p. 1425) for raising a problem which we did not discuss in our paper (April 18, p.
b
release of an inhibitor phagocytosing does appear to be inappropriate, particularly in the
866). At first sight the
of leucocytosis during chronic infections. However, the rate of granulopoiesis must be controlled by both positive and negative influences. We have found that endotoxin overrides the effect of the neutrophil derived inhibitory and this is in agreement with Broxmeyer’s observationthat the action of lactoferrin on granulopoiesis is also blocked by endotoxin. During infection the dominant drive to the bone marrow may be positive-from endotoxin and other antigens, both of which increase colony stimulating factor (CSF) production3,4-but this declines as phagocytes successfully ingest and digest the pathogens, so allowing the inhibitor released from normally functioning neutrophils to damp down marrow activity. The role of the neutrophil derived inhibitor in uninfected persons is not clear. To meet the challenge of potential infection a low level of phagocytic activity is likely, and this could limit granulopoietic activity. An imbalance of this steady state could explain the accumulation of neutrophils in chronic context
granulocytic leukaemia. We do not accept the
suggestion that the factor isolated from phagocytosing neutrophils reduces colony growth in maximally stimulated cultures only. In preliminary experiments, with feeder layer concentrations generating suboptimal levels of CSF, we still observed inhibitory activity and not stimulation. Furthermore, in our culture system the CSF dose-response curve shows a plateau
SIR,-In their article on 5- HT receptor blockade in the treatment of heart failure (May 30, p. 1186) Dr Demoulin and his colleagues infer that serotonin may play a part in the vasoconstriction found in heart failure and that the raised levels of circulating serotonin have a causative role when found in association with pulmonary arterial hypertension. There is little evidence to support the former hypothesis, and raised circulating levels of serotonin, when found in pulmonary hypertension, may well be the result rather than a cause of pulmonary hypertension. The lungs of mammals, including man, substantially inactivate serotonin.l-5 This uptake is a function of the pulmonary vascular endothelium,damage to which in association with pulmonary arterial hypertension decreases the uptake of another noradrenalineand possibly also the uptake of serotonin, allowing greater concentration of one or both to reach the systemic circulation. These increases in circulating monoamines might well further contribute to existing pulmonary hypertension, but as a secondary rather than primary effect. Thus it might not be correct to postulate that raised levels of circulating serotonin have a primary causative role in pulmonary hypertension. Selly Oak Hospital, Birmingham B29 6JD
use
of silastic transhepatic
2.
3.
stents in
benign and malignant biliary strictures. Ann Surg 1978; 188: 552. Philip MA, Standen G, Fletcher J. Phagocytosing neutrophils rapidly release a factor which inhibits granulopoiesis in vitro. Acta Haematol (in press) 2 Broxmeyer HE. Inhibition in vivo of mouse granulopoiesis by cell-free activity derived from human polymorphonuclear neutrophils. Blood 1978; 51: 889-901. 3 Mahmood T, Robinson WA. Granulocyte modulation of endotoxin-stimulated colonystimulating activity (CSA) production. Blood 1978; 51: 879-87. 4 Metalf D Acute antigen-induced elevation of serum colony stimulating factor (CSF) levels Immunology 1971, 21: 427-36.
R. M. JENKINS
DP, Vane JR. 5-hydroxytryptamine in the circulation of the dog Nature 1967; 216: 335-38. Alabater VA, Bakhle YS. Removal of 5-hydroxytryptamine in the pulmonary circulation of rat isolated lungs. Br J Pharmacol 1970; 40: 468-82. Gillis CM, Iwasawe Y. Technique for measurement of norepinephine and 5-hydroxytryptamine uptake by rabbit lung. J Appl Physiol 1972; 33: 404-06. Gillis CN, Greene NM, Cronan LH, Hammond GC. Pulmonary extraction of 5-hydroxytryptamine and norepinehphine before and after cardiopulmonary bypass in man. Circu Res 1972, 30: 666-674. A1-Ubaidi F, Bakhle YS. Metabolism of vasoactive hormones in human isolated lung. Clin Sci 1980; 58: 45-51 Strum JM, Junrod AF. Radioautographic demonstration of 5-hydroxytryptamine uptake by pulmonary endothelial cells. J Cell Biol 1972; 54: 456-67. Sole MJ, et al. The extraction of circulating cathecholamines by the lungs in normal man and in patients with pulmonary hypertension. Circulation 1979; 60: 160-63. Lande S, de la, et al. The interaction of serotonin and noradrenaline on the perfused artery. Br J Pharmac Chemother 1966, 28: 255-72.
1. Thomas
4.
Cameron JI., Gaylor BW, Zuidema GD. The
R. S. KINGSWELL
TYPE 2 SEROTONIN RECEPTORS AND HEART FAILURE
PHAGOCYTOSING NEUTROPHILS AND GRANULOPOIESIS
neutrophils
MARK A. PHILIP GRAHAM STANDEN JOHN FLETCHER
5. 6. 7.
8.
3H
replaced over a guidewire.7 This technique has a role
in a clearly defined group of patients found to be non-resectable at laparotomy. Current investigations of the preoperative assessment of cholangiocarcinoma should allow delineation of cases which are neither resectable nor amenable to internal drainage by bypass and which may be best treated by percutaneously placed endoprostheses or
with
tumours
exo-endoprostheses. Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital,
L. H. BLUMGART C. R. VOYLES C. SMADJA
London W12 0HS
concentrations at least 4-fold greater than concentrations necessary for optimal growth with no evidence ofa30-50% decline. We agree that the mechanism by which the neutrophil derived inhibitor results in reduced CSF elaboration is of interest and this is over
being explored. Department of Therapeutics, City Hospital, Nottingham NG5 1PD
MEFENAMIC ACID OVERDOSE
SIR,-Information on self-poisoning and accidental overdosage with medicinal products is often very limited, so we welcome Dr Balali-Mood and colleagues’ informative article (June 20, p. 1354) on mefenamic acid overdosage. Recent information supplied to this company supports the finding that convulsions can occasionally occur in patients taking overdoses of mefenamic acid, but this has also been reported with overdoses of drugs in many therapeutic classes. Even drugs used in the treatment of seizures can produce convulsions in overdosage. Special care should always be exercised when prescribing drugs for epileptic patients. However, we cannot accept the suggestion that mefenamic acid should be-avoided in such patients since we have no evidence to suggest that, in therapeutic dosage, there is any increase in the incidence of convulsions. Warner-Lambert (U.K.) Ltd, Pontypool, Gwent NP4 0YH
SIR,-We thank Dr Baker and Dr Wilbur (June 27, p. 1425) for raising a problem which we did not discuss in our paper (April 18, p.
b
release of an inhibitor phagocytosing does appear to be inappropriate, particularly in the
866). At first sight the
of leucocytosis during chronic infections. However, the rate of granulopoiesis must be controlled by both positive and negative influences. We have found that endotoxin overrides the effect of the neutrophil derived inhibitory and this is in agreement with Broxmeyer’s observationthat the action of lactoferrin on granulopoiesis is also blocked by endotoxin. During infection the dominant drive to the bone marrow may be positive-from endotoxin and other antigens, both of which increase colony stimulating factor (CSF) production3,4-but this declines as phagocytes successfully ingest and digest the pathogens, so allowing the inhibitor released from normally functioning neutrophils to damp down marrow activity. The role of the neutrophil derived inhibitor in uninfected persons is not clear. To meet the challenge of potential infection a low level of phagocytic activity is likely, and this could limit granulopoietic activity. An imbalance of this steady state could explain the accumulation of neutrophils in chronic context
granulocytic leukaemia. We do not accept the
suggestion that the factor isolated from phagocytosing neutrophils reduces colony growth in maximally stimulated cultures only. In preliminary experiments, with feeder layer concentrations generating suboptimal levels of CSF, we still observed inhibitory activity and not stimulation. Furthermore, in our culture system the CSF dose-response curve shows a plateau
SIR,-In their article on 5- HT receptor blockade in the treatment of heart failure (May 30, p. 1186) Dr Demoulin and his colleagues infer that serotonin may play a part in the vasoconstriction found in heart failure and that the raised levels of circulating serotonin have a causative role when found in association with pulmonary arterial hypertension. There is little evidence to support the former hypothesis, and raised circulating levels of serotonin, when found in pulmonary hypertension, may well be the result rather than a cause of pulmonary hypertension. The lungs of mammals, including man, substantially inactivate serotonin.l-5 This uptake is a function of the pulmonary vascular endothelium,damage to which in association with pulmonary arterial hypertension decreases the uptake of another noradrenalineand possibly also the uptake of serotonin, allowing greater concentration of one or both to reach the systemic circulation. These increases in circulating monoamines might well further contribute to existing pulmonary hypertension, but as a secondary rather than primary effect. Thus it might not be correct to postulate that raised levels of circulating serotonin have a primary causative role in pulmonary hypertension. Selly Oak Hospital, Birmingham B29 6JD
use
of silastic transhepatic
2.
3.
stents in
benign and malignant biliary strictures. Ann Surg 1978; 188: 552. Philip MA, Standen G, Fletcher J. Phagocytosing neutrophils rapidly release a factor which inhibits granulopoiesis in vitro. Acta Haematol (in press) 2 Broxmeyer HE. Inhibition in vivo of mouse granulopoiesis by cell-free activity derived from human polymorphonuclear neutrophils. Blood 1978; 51: 889-901. 3 Mahmood T, Robinson WA. Granulocyte modulation of endotoxin-stimulated colonystimulating activity (CSA) production. Blood 1978; 51: 879-87. 4 Metalf D Acute antigen-induced elevation of serum colony stimulating factor (CSF) levels Immunology 1971, 21: 427-36.
R. M. JENKINS
DP, Vane JR. 5-hydroxytryptamine in the circulation of the dog Nature 1967; 216: 335-38. Alabater VA, Bakhle YS. Removal of 5-hydroxytryptamine in the pulmonary circulation of rat isolated lungs. Br J Pharmacol 1970; 40: 468-82. Gillis CM, Iwasawe Y. Technique for measurement of norepinephine and 5-hydroxytryptamine uptake by rabbit lung. J Appl Physiol 1972; 33: 404-06. Gillis CN, Greene NM, Cronan LH, Hammond GC. Pulmonary extraction of 5-hydroxytryptamine and norepinehphine before and after cardiopulmonary bypass in man. Circu Res 1972, 30: 666-674. A1-Ubaidi F, Bakhle YS. Metabolism of vasoactive hormones in human isolated lung. Clin Sci 1980; 58: 45-51 Strum JM, Junrod AF. Radioautographic demonstration of 5-hydroxytryptamine uptake by pulmonary endothelial cells. J Cell Biol 1972; 54: 456-67. Sole MJ, et al. The extraction of circulating cathecholamines by the lungs in normal man and in patients with pulmonary hypertension. Circulation 1979; 60: 160-63. Lande S, de la, et al. The interaction of serotonin and noradrenaline on the perfused artery. Br J Pharmac Chemother 1966, 28: 255-72.
1. Thomas
4.
Cameron JI., Gaylor BW, Zuidema GD. The
R. S. KINGSWELL
TYPE 2 SEROTONIN RECEPTORS AND HEART FAILURE
PHAGOCYTOSING NEUTROPHILS AND GRANULOPOIESIS
neutrophils
MARK A. PHILIP GRAHAM STANDEN JOHN FLETCHER
5. 6. 7.
8.
3H