The acromegalic rosary

860

acidosis was buffered. In the following days he had multifocal clonic seizures and brain oedema. The electroencephalogram showed a highly pathological pattern. The infant was discharged on the 28th postnatal day and at 6 months presented with pronounced neurological abnormalities. In contrast to earlier reports this case demonstrates that the fetus near term may not be protected against severe damage caused by anaphylaxis. Therefore drugs with the potential to produce anaphylactic reactions should be given with caution in pregnancies at term. Intensive fetal monitoring in anaphylactic reaction is necessary to allow rapid delivery of the infant. Department of Obstetrics and Gynaecology, Innsbruck University Clinic, A-6020-Innsbruck, Austria

K. HEIM A. ALGE C. MARTH

Sharpe O, Hall EG. Renal impairment, hypertension and encephalomalcia in an infant surviving severe intra-uterine anoxiy. Proc R Soc Med 1953; 46: 1063-67. 2. Baraka A, Sfeir S. Anaphylactic cardiac arest in a parturient. JAMA 1980; 243: 1745. 3. Entman SS, Moise KJ. Anaphylaxis in pregnancy. South Med J 1984; 77: 402-06. 4. Gallagher JS. Anaphylaxis in pregnancy. Obstet Gynecol 1988; 71: 491-93. 1.

Plasma D-dimer in suspected embolism

pulmonary

SIR,-Dr Bounameaux and colleagues (Jan 26, p 196) report the value of a normal plasma D-dimer in the investigation of patients with possible pulmonary thromboembolism (PTE). We have undertaken a similar prospective, consecutive study of 260 patients with suspected PTE, in which we based diagnosis on the results of ventilation-perfusion scans classified as high and low probability, or indeterminate. We undertook biochemical and other laboratory investigations on blood taken within four days of the onset of symptoms. We did not find the results of any investigation to be sufficiently reliable to exclude or confirm the diagnosis of PTE. However, only 2 of 123 (2%) of those in the low probability group had plasma cross-linked fibrin degradation products (XDP) greater than 500 µg/1, whereas 55 of 65 (85 %) in the high probability group, and 20 of 72 (28%) in the indeterminate group had such values. We therefore agree with Bounameaux et al that measurement of plasma cross-linked fibrin degradation products is of value in the exclusion of a diagnosis of PTE. Department of Medicine, University of Bristol, Southmead Hospital,

T. J. COOPER

Bristol BS10 5NB, UK

M. HARTOG

SIR,-Dr Bounameaux and co-workers prospectively measured plasma D-dimer (DD) concentrations in patients suspected clinically of having pulmonary embolism. They concluded that when the DD concentration is below 500 ng/ml pulmonary embolism can be ruled out. From November, 1989, to February, 1990, we prospectively studied 52 unselected patients (20 males, mean age 48 years) referred to our emergency department with a suspected diagnosis of pulmonary embolism. Ventilation perfusion (VQ) lung scans were used in the diagnostic work-up. 20 patients had high probability pulmonary embolism and 32 low probability. In the lowprobability group the diagnosis was confirmed in 14 patients (43%) by bilateral ascending venography. Blood was collected by clean venepuncture into tubes containing 3-8% trisodium citrate (9:1), and platelet-poor plasma was obtained by centrifuging at 3000 g for 15 min and stored at - 30°C. DD levels were measured, in samples taken on admission, by ELISA (Boehringer, Mannheim). In 6 patients with high-probability pulmonary embolism on admission, DD was measured again 7 days after admission, when the patients were on heparin. 30 healthy individuals were used as controls. Plasma DD levels were much higher in patients with pulmonary embolism than in controls (3592 [SD 3798] vs 241 [164] ng/ml; p < 0001 ). No differences were found between patients with high probability and those with low probability of pulmonary embolism, subsequently confirmed by bilateral ascending venography (3592 [3798] vs 2913 [1989] ng/ml). The sensitivity and specificity of a

DD cut-off set at the mean + 2 SD for the controls were 100% and 75%, respectively. In 10 patients with high-probability pulmonary embolism DD concentrations were lower on day 7, when they were on heparin, but were still significantly higher than control values

(p<0.01). The accurate and prompt diagnosis of pulmonary embolism remains a challenge to clinicians. Pulmonary angiography is not an ideal test because of its potential risks and logistic constraints, and the prevalence of pulmonary embolism with low or intermediate VQ lung scan results ranges from 4 to 46%.1 We agree with Bounameaux et al that plasma DD concentration has a role in the emergency diagnosis of pulmonary embolism. Important items yet to be addressed are the cut-off, which needs to be validated within each laboratory because some workers have published different values2,3 and the evolution, without anticoagulant therapy, of patients with suspected pulmonary embolism and DD levels below the cut-off. ANNA SUREDA

Haematology Department, Hospital Ramón y Cajal, 28034 Madrid, Spain

JULIO PASCUAL LUÍS J. GARCÍA FRADE

1. Alderson PO, Martin EC. Pulmonary embolism: diagnosis with multiple imaging modalities. Radiology 1987; 164: 297-312. 2. Goldhaber SZ, Vaughan DE, Tumeh SS, Loscalzo J. Utility of cross-linked fibrin

degradation products in the diagnosis of pulmonary embolism. Am J Heart J 1988; 116: 505-08. 3.

Bridey F, Philipotteau C, Dreyfus M, Siminneau G Plasma D-dimer and pulmonary embolism. Lancet 1989; 1: 791-92.

SIR,-Dr Bounameaux and colleagues used a complex method to diagnose pulmonary embolism, involving a combination of ventilation/perfusion (V/Q) scanning, pulmonary angiography, and clinical assessment. Only 17 of 55 patients with suspected pulmonary embolism had a pulmonary angiogram, the accepted "gold standard"." Hence, of the 23 patients diagnosed as having pulmonary embolism on a "high probability" V/Q scan without angiography, some may have represented false-positive results.2-4 More importantly, some of the 84 patients with inconclusive, but abnormal, V/Q scans diagnosed as not having an embolism may have had one (false negative); Bounameaux et al do not report the number of patients with inconclusive scans who had pulmonary angiography done or for that matter the total number of patients investigated in this way. Of the 31 patients with inconclusive scans but diagnosed as having a pulmonary embolism only 16 were proved by angiography, the rest being diagnosed by associated deep-vein thrombosis or on clinical evidence. While the D-dimer concentration may be increased in pulmonary embolism, it cannot, on the evidence presented, be used to exclude such embolism; only a negative perfusion scan or pulmonary angiogram should be used for that purpose. Department of Medicine, King’s College School of Medicine and Dentistry, London SE5 9PJ, UK

PHILIP M. W. BATH JOHN F. MARTIN

1. Alderson PO, Martin EC. Pulmonary embolism diagnosis with multiple imaging modalities. Radiology 1987; 164: 297-312. 2. Gray HW, McKillop JH, Bessent RG, Fogelman I, Smith ML, Moran F. Lung scanning for pulmonary embolism: clinical and pulmonary angiographic correlations. QJ Med 1990; 77: 1135-50. 3 Biello DR. Radiological (scintigraphic evaluation of patients with suspected pulmonary thromboembolism. JAMA 1987; 257: 3257-59. 4. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990; 263: 2753-59.

The

acromegalic rosary

SIR,-Dr Ibbertson and colleagues (Jan 19, p 154) found no correlation between costochondral enlargement and indices of growth hormone secretion. We have incubated serum with radiolabelled insulin-like growth factor-1 (IGF-1) and run the mixture on a ’Superose 12’ column to assess indirectly the quantity of the two main IGF binding proteins (designated IGFBP-3 and BPI) in serum.’ We applied this technique to serum samples from four acromegalic patients (3 fasting and 1 random) and the results are

861

probable mechanism is loss of the additional chromosome 21 during early development of the trophoblast ectoderm, although mosaicism resulting from a post-zygotic mitotic error cannot be

IGF-1 -labelled

0, normal controls

in

acromegaly. (n=10); 0, acromegalic patients (n=4). sera

shown in the figure. These data have been corrected for the free fraction to allow the binding proteins to be compared. The amount of IGFBP-3 is similar for both patients’ and pooled normal sera, but there is a decrease in available sites on IGFBP-1. Two explanations could account for this result. First, that the binding protein is fully saturated or second, and more likely, that the amount of binding protein is decreased. IGFBP-1 is inversely regulated by insulin,2 and insulin concentrations in active acromegaly are increased.3 IGFBP-1 has in-vitro inhibitory effects on basal and IGF-1stimulated costal-cartilage sulphation.4 We suggest that a reduction in this suppressive effect on cartilage growth may be a causal factor in the development of the acromegalic rosary. Further assessment of IGFBP-1 by radioimmunoassay would be of interest. K. D. HOPKINS Division of Medicine, St Thomas’ Hospital, London SE1 7EH, UK

R. H. JONES P. H. SÖNKSEN

Moore L, Napier JR, Davies SR, Bass JJ, Gluckman PD. Characterisation of insulin-like growth factor binding proteins in ovine tissue fluids. J Endocrinol 1989; 120: 429-38. 2. Holly JMP, Biddlecombe RA, Dunger DB, et al. Circadian variation of GH independent IGF binding protein in diabetes mellitus and its relationship to insulin: a new role for insulin. Clin Endocrinol 1988; 29: 667-75. 3. Roelfsema F, Frolich M. Glucose tolerance and plasma immunoreactive insulin levels m acromegalics before and after selective transphenoidal surgery. Clin Endocrinol

1.Hodgkinson SC,

1985; 22: 531-37. 4

Taylor AM, Dunger DB, Preece MA, et al. The growth hormone independent insulin-like growth factor-1 binding protein BP-28 is associated with serum insulin-like growth factor-1 inhibitory bioactivity in adolescent insulin-dependent diabetics. Clin Endocrinol 1990; 32: 229-39.

Short-term culture and false-negative results for Down’s syndrome on chorionic villus sampling SIR,-Short-term culture of chorion may give rise to falsenegative results for various chromosome abnormalities. 1-4 However, most women want prenatal cytogenetic diagnosis for Down’s syndrome, and the possibility that this condition might be missed on short-term culture (direct preparation) has not received much attention. We report such a case. A 38-year-old woman requested prenatal diagnosis on the basis of maternal age. Chorionic villus sampling (CVS) was done at thirteen weeks’ gestation by the transabdominal route.5 Short-term culture showed a normal male karyotype in all 100 cells counted but long-term culture showed trisomy 21 in all 100 cells examined from three separate cultures. After termination of the pregnancy, a placental sample was examined by short-term and long-term culture, which showed trisomy 21 in 75 and 100 cells, respectively. Cultures of amnion, fetal skin, and liver also showed trisomy 21 in all 300 cells examined. We concluded that this patient had mosaicism for chromosome 21, confined to trophoblast. The most

excluded. One of us (R. J. L.) has been asked for a medicolegal opinion on a further case, where birth of a child with non-disjunction Down’s syndrome followed a false-negative, short-term CVS culture. Long-term cultures were not attempted. Two further cases have been reported where short-term cultures produced a false-negative result for Down’s syndrome.6.7 In the first, long-term cultures were not established, and in the second a normal result on short-term culture was followed by subsequent detection of Down’s syndrome in long-term culture, with confirmation on fetal tissue. Thus, a total of four false-negative, short-term culture results for Down’s syndrome have been reported. It is difficult, however, to derive the false-negative rate since we do not know if our numerator is correct-ie, an unspecifiable number of cases might not have been reported-and nor do we know the denominator-ie, the number of CVS procedures that have been carried out for cytogenetic indications. On the improbable assumption that all false-negative Down’s syndrome results have been reported, and the further assumption that 400 000 CVS procedures have been done world wide for cytogenetic indications, one could conclude that the false-negative rate on a short-term culture is 0-001%. If we assume that the frequency of Down’s syndrome among women undergoing CVS for cytogenetic indications is 1 in 200, and that only half all false-negative results for Down’s syndrome have been reported, then the conditional probability of false reassurance given with an affected fetus would be nearly 1 in 200. Therefore, we think that CVS carried out for cytogenetic reasons should include a culture step (we are reluctant to dispose of the direct preparation, because of the risk that contaminating maternal cells may overgrow the culture). Since culture adds considerably to the cost of CVS,8 we anticipate that early amniocentesis may be more widely used in future, especially if it can be shown that any effects on fetal lung

development are not strongly gestational-age dependent. Departments of Obstetrics and Gynaecology and Cytogenetics, St James’s University Hospital, Leeds LS9 7TF, UK

R. J. LILFORD A. CAINE G. LINTON G. MASON

1. Eichenbaum SZ, Krumins EJ, Fortune DW, Duke J. False-negative finding on chorionic villus sampling. Lancet 1986; ii: 391. 2. Linton G, Lilford RJ. False-negative finding on chorionic villus sampling. Lancet 1986; ii: 630. 3. Martin AO, Elias S, Rosinsky B, Bombard AT, Simpson JL. False-negative finding on chorionic villus sampling. Lancet 1986; ii: 391-92. 4. Leschot NJ, Wolf H, Weenink GH. False-negative findings at third trimester chorionic villus sampling (CVS). Clin Genet 1988; 34: 204-05. 5. Lilford RJ, Linton G, Irving HC, Mason MK. Transabdominal chorion villas biopsy: 100 consecutive cases. Lancet 1987; i: 1415-17. 6. Bartels I, Hansmann I, Holland U, Zoll B, Rauskolb R. Down syndrome at birth not detected by first-trimester chorionic villus sampling. Am J Med Genet 1989; 34: 606-07. 7. Simoni G, Terzoli G, Rossella F. Direct chromosome preparation and culture using chorionic villi: an evaluation of the two techniques. Am J Med Genet 1990; 35: 181-83. 8. Lilford RJ, Irving H, Gupta JK, O’Donovan P, Lmton G. Transabdominal chorionic villus biopsy versus amniocentesis for diagnosis of aneuploidy: safety is not enough. In: Chapman M, Grudzinskas JG, Chard T, Maxwell D, eds. The embryo; normal and abnormal development and growth. London: Springer-Verlag, 1991: 91-100.

Peroperative t-PA thrombolysis SIR,—The embolectomy catheter, introduced in 1963, has more than proved its worth in the surgical management of arterial thromboembolism. However, the inability of the catheter to retrieve distal thrombus, with the continued occlusion of runoff vessels, leads to technical failures in some cases.2 Intra-arterial fibrinolytic therapy with streptokinase has been given, both alone and as an adjunct to catheter embolectomy, but long infusion times and systemic bleeding have limited its application.3 Tissue plasminogen activator (t-PA) is a more rapid thrombolytic agent than streptokinase, and has a shorter half-life;4 intra-arterial administration should be safer and more controlled. We have given t-PA on three occasions in addition to catheter