933

refractory to adrenergic agonists and unable to tolerate even suboptimaldoses of theophylline; the suppression of asthma unresponsive to mediator-release inhibitors, such as cromolyn sodium; and, importantly, the high level of acceptance and

compliance among people who do not comply with other stan-

therapeutic routines, either because of previous unforexperiences or the currently widespread fear-"pharmacophobla"-of ingested drugs.4 Many patients treated with inhaled beclomethasone diprodard

tunate

pionate or triamcinolone acetonide3,s have used the word "miracle" to describe their rehabilitation. Even though the term seem startling and unacceptable to a clinical scientist, it does, without much exaggeration, reflect the objective changes

may

produced exclusively by inhalational other known

treatment

corticosteroids and by no for the sustained control of chronic

ast

Allergy and Asthma Clinic, P.C., 1 55Cook Street

CONSTANTINE J. FALLIERS

Denver, Colorado 80206, U.S.A.

FIBRIN OCCLUSION OF A VESICOVAGINAL FISTULA

SIR,-Vesicovaginal fistulae usually develop as a result of gynaecological procedures such as hysterectomy or as a result of necrosis following radiotherapy for carcinoma of the cervix. Fistulae caused by obstetric trauma are rare in Sweden. The fistula can usually be successfully closed by a vaginal route or abdominal approach, with or without interposing an omental flap. Fistula; from radiation and/or surgery for cancer may be difficult to treat, and the patient often ends up with a supravesical urinary diversion. Plasma fractions containing mainly fibrinogen have been used for tissue adhesion,’ and it has long been known that inhibitors of fibrinolysis enhance formation of connective tissue, with increased tensile strength of wound tissue as a result.2 However, fibrin, protected by antifibrinolytics, has, as far as we know, not previously been used for closure of a vesicovaginal fistula. The patient, a 43-year-old woman, had a Wertheim operation for stage us carcinoma of the uterine cervix in April, 1973. Before the operation the patient was treated with intrauterine and intravaginal radium, and she was given supplementary postoperative external supervoltage radiation therapy to the left pelvic wall because of cancer involvement of one external liiac node. In March, 1978, abdominal colpectomy was done for recurrent carcinoma in the mid-vagina. 2 days after the operation urine leaked from the vaginal remnant. There was a ureterovaginal fistula on the left side and three vesicovaginal fistuke, one on the left and two on the right side of the trigone. In May, 1978, the nstulae were closed by an abdominal approach. The vaginal remnant and the posterior bladder wall were separated with a pedicled omental flap. Both ureters were re-implanted to the bladder. 6 weeks later urine again leaked from the vagina, and a fork-shaped vesicovaginal fistula 3 cm long, with three openings in the trigone and one in the vagina, was found. Surgical repair was this time thought unlikely to succeed. Diversion of urine by means of an ileal conduit was recommended but the patient refused this. We therefore tried a new way to occlude the fistula. In November, 1978, the fistulous tract was carefully excochleated with lised

sharp

epithelial lining. Lyophifibrinogen (Kabi) was dissolved according to the manufacturer’s instructions and calcium chloride was added to give the final concentration of calcium ions required for normal 4

a

curette to remove

any

Falliers, C J., Vrchota, J. A., Redding, M. A. Ann Allergy, 1977, 38, 155. 5. Falliers, J., C Kennedy, P. A., Petraco, A. J., Vrchota, J. A. ibid. 39, 71. 1 Rauchenwald, K , Urksberger, H., Henning, K., Braun, F., Sprängler, H. P., Holle, J.Aktuelle Urol. 1976, 7, 209. 2 kwaan, H. C., Astrup, T. Exp. mol. Path 1969, 11, 82.

cross-linking of fibrin. Thrombin (’Topostasin’, Roche) was added to part of the fibrinogen solution, giving a final concentration of 0.5 N.I.H. units/ml. The mixture was gently tilted in a syringe for about a minute until clotting began and viscosity increased. It was then rapidly injected into the fistula by a Chevassu technique. The fibrin was now viscous enough to stay in the fistula. Over the ensuing minutes the fibrin formed a firm plug in the fistula. To protect the plug, an indwelling urethral catheter was left in situ for 8 weeks, and to block the fibrinolytic activity (and thus stabilise and prolong the life of the fibrin plug) the patient was given tranexamic acid (’Cyklokapron’, Kabi) 4.55 g a day for 8 weeks. Fibrin forms a supporting framework for migrating fibroblasts and developing capillary buds. The fibrin is then removed by fibrinolysis and replaced by reparative connective tissue. Other substances, (e.g., factor xui, fibronectin, and plasminogen) may play a crucial role in this procedure. The fibrinogen used in our case was not completely pure, some of its contaminants in fact being factor xm, fibronectin, and plasminogen. We therefore thought that the conditions were suitable for physiological healing. 4 months after the occlusion, the patient still remains dry and has been able to resume her previous occupation as a secretary. The method represents a new approach to the treatment of urinary fistulx. The procedure is simple and can be repeated if the first attempt should fail. The indications and limitations of the method are not yet established but it is reasonable to assume that long, narrow fistula: will prove more suitable for this type of repair than short, wide ones. The method should, however, not be limited to urinary fistula:. Departments

of Urology,

Gynæcology and

Obstetrics

and Clinical Chemistry,

Sahlgren’s Hospital, University of Gothenburg, S-413 45 Gothenburg, Sweden

S. PETTERSSON H. HEDELIN

I. JANSSON A-C. TEGER-NILSSON

WHY CIRCULATING LEVELS OF TROPHOBLAST-SPECIFIC PROTEINS MAY BE

NORMAL IN ECTOPIC PREGNANCY

SIR,-Human chorionic gonadotrophin (H.C.G.), pregnancyspecific &bgr; 1-glycoprotein (SP1),’ and placental protein 5 (PP5)2.3 were measured in the peripheral and peritoneal blood in three women with ruptured tubal ectopic pregnancy. The concentrations of these proteins were much higher in peritoneal blood. Rupture in a tubal pregnancy should in theory be associated with an immediate and dramatic fall in the levels of trophoblast-specific proteins in maternal blood. For this reason several workers have proposed the measurement of H.C.G.,4.5 human placental lactogen,5 and SP 16 in the early diagnosis of this emergency. However, the results are inconsistent and apparently normal levels are sometimes seen in maternal blood-samples. We suggest that this ambiguity could be due to diffusion of trophoblast and proteins from peritoneal blood. Venous and intraperitoneal blood were obtained from three patients undergoing emergency surgery for ruptured tubal pregnancy (estimated gestation 6-8 weeks). The serum was separated within an hour of collection and stored at -20°C until assayed. Measurements of H.C.G., SP,, and p.p.5 were done by radioimmunoassay. 1,6,1 Peripheral-vein concentrations 1. Bohn, H. Arch. Gynäk. 1971, 210, 440. 2. Bohn, H Prot. Biol Fluids. 1976, 24, 117 3. Obiekwe, B. C., Grudzinskas, J. G., Gordon, Y B., Chard, T., Bohn, H. in Carcinoma Embryonic Proteins edited by F. Gunter Lehmann; vol II, p. 629. Amsterdam, 1979 4. Saxena, B. J., Landsman, R Fertil Steril 1975, 26, 397 5. Serreyn, R , Dhont, M., Vandekerckhove, D. Med. T. Geneesk. 1976, 120, 1103. 6. Grudzinskas, J. G., Gordon, Y. B , Jeffrey, D., Chard, T. Lancet, 1977, i, 333 7. Dhont, M., Serreyn, R., Vandekerckhove, D., Thiery, M. ibid. 1978, i. 559. 8 Crowther, M., Grudzinskas, J. H., Poulton, T., Gordon, Y B. Obstet

Gynec. 1979, 53, 59

934 CONCENTRATIONS OF TROPHOBLASTIC PROTEINS PERIPHERAL AND

(B)

(A)

bic

WITH RUPTURED TUBAL PREGNANCY

*Range for circulating PP5 undefined.

durmg early

normal pregnancy is

within the normal range in one patient, but low in the two. The peritoneal blood levels of H.C.G., SP and PP5 were consistently higher than circulating levels in each patient (table) and yielded inhibition parallel to the standard curve when assayed in dilution. The measurement of trophoblastic proteins in ectopic pregnancy has been described though there is disagreement about their diagnostic value. We have found that levels in peritoneal blood are consistently higher than those in the circulation. This is presumably due to direct release of trophoblastic products into this site, together with a clearance-rate much lower than that in the general circulation. Diffusion of molecules from peritoneal fluid may explain why circulating levels are often normal and why the tests are of less diagnostic value than would otherwise be the case.

were

other

Hospital,

areas

receptor

supersensitivitv.

J. G. GRUDZINSKAS T. CHARD

_

A. CLOW

University Department of Neurology,

Joint Academic Unit of Obstetrics, Gynecology and Reproductive Physiology, Medical College of St. Bartholomew’s London EC1A 7BE

with dopamine) in corpus striatum and mesohmafter continuous administration of trifluoperazine (2.5-3-5 mg/kg/day) or thioridazine (30-40 mg/kg/day) for a year and after drug withdrawal for up to 3 months. An agematched colony of control animals was reared under identical conditions. In rats given neuroleptic drugs we have seen most of the biochemical changes recorded in postmortem brains of schizophrenic patients-namely, increases in dopamine and DOPAC of between 25 to 35% in striatum and mesolimbic areas (but no change in H.V.A.), changes in 3H-spiperone receptor affinity (both an increase and a decrease at different times) and, perhaps the most significant, an increase in dopamine-receptor density as identified by specific 3H-spiperone binding and Scatchard analysis. An increase in receptor numbers (of up to 64S() noted after a year of drug exposure has persisted after drug withdrawal. Our results reinforce the need for caution in interpreting post-mortem biochemical data in schizophrenia. Those finding such abnormalities in human brain have to show that the changes are due to the disease and not to the drugs used to treat it. Inaccuracies in drug recording and the persistence of drugs and their metabolites for months after therapy has stopped make this a difficult task. However, even if changes in dopamine receptors are due to chronic drug intake, this at least provides firm evidence to support the hypothesis that tardive dyskinesias are due to the development of cerebral dopamine

displacement

IN

IN PERITONEAL BLOOD IN THREE PATIENTS

Institute of Psychiatry, and King’s College Hospital Medical School, London SE5 8AF

P. JENNER A. THEODOROU C. D. MARSDE

IMMUNE COMPLEXES IN NORMAL AND

PRE-ECLAMPTIC PREGNANCY

NEUROLEPTIC DRUGS AND THE DOPAMINE HYPOTHESIS

observation that antipsychotic drugs block cerebral dopamine receptors have led to the suggestion that overactivity of cerebral dopamine function causes schizophrenia. This "dopamine hypothesis" has been boosted by reports of dopamine biochemistry in post-mortem brains of schizophrenics. 1-4No consistent alteration of dopamine concentration in different brain areas has emerged,I-3 and the dopamine metabolites 3-4, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (H.V.A.) have been studied by only one group.3 However, two major contributors to this line of inquiry agree2,3 that there is an increase in the specific binding of tritiated neuroleptics to post-mortem brain homogenates from schizophrenic patients, probably due to an increase in receptor density;3 a third group4 initially was unable to demonstrate this change. Since few schizophrenics escape neuroleptic drugs we need to know what effect chronic neuroleptic drug administration has on the biochemistry of the brain. We can provide information for one year’s continuous treatment of rats with such drugs, an exposure that represents 30—40% of that animal’s life span. Details of the organisation and early results are given elsewhere.5,6 We concentrate here on changes in cerebral dopa-

mine,

H.V.A., DOPAC,

1. Bird, E

specific 3H-spiperone binding (defined by

D, Spokes, E. G., Barnes, J., Mackay, A.

Shepherd, M. Lancet, 1977, ii,

V

P., Iversen,

are contradictory reports concerning the ocof circulating immune complexes in normal and preeclamptic pregnancy. The differences seem to depend on the 1-3 type of assay used. We have therefore compared the Clq-binding assay of Zubler et a1.4 with the latex-agglutination assay of Levinsky and SoothilP in the same sera from twelve pairs of normal women and women matched for gestational maturity with preeclampsia as defined by Stirrat et al.’ No immune complexes were detected in any of the samples with the direct Clq-binding assay. In contrast, 9 of 12 and 10 of 12 pre-eclamptic sera had raised levels of IgG-containing and Clq-binding complexes, respectively (table). The data can be interpreted in two ways. Firstly, the direct Clq-binding assay could reflect the true state of affairs,-i.e., that immune complexes do not form in normal or pre-eclamptic pregnancy. The latex agglutination assay would therefore be detecting artefacts such as rheumatoid factor, native monomer IgG, or aggregated IgG. The first can be excluded because rheumatoid factor is removed by immunoadsorption in the initial stage of the assay. Monomer IgG is a poor inhibitor of agglutination in this assay, although abnormally high levels of circulating IgG could give rise to false positives. But maternal IgG levels in pregnancy are unchanged6 or significantly lower’ than those in normal controls and depression may be even more apparent if pregnancy is complicated by preeclampsia.7,8 So if abnormal IgG levels did have a significant

S!R,—There

SIR,-The production of a schizophreniform psychosis in man by the indirect dopamine agonist amphetamine, and the

L.

currence

L.,

1157.

2. Lee, T., Seeman, P, Tourtellotte, W W, Farley, I. J, Hornykerwicz, O. Nature, 1978, 274, 897. 3. Owen, F., Cross, A J., Crow, J. J., Longden, A., Poulter, M., Riley, G J. Lancet, 1978, 11, 223. 4 Mackay, A. V P, Doble, A , Bird, E D., Spokes, E. G., Quik, M., Iversen, I. L. Life Sci 1978, 23, 527. 5. Clow, A., Jenner, P., Marsden, C. D ibid 1978, 23, 421. 6 Clow, A., Jenner, P., Theodorou, A, Marsden, C. D. Nature, 1979, 278, 59.

1. Stirrat, G M, Redman, C. W. G., Levinsky, R J. Br. med. J. 1978, i, 1450 2. Gleicher, N., Theofilopoulos, A. N , Beers, P. Lancet, 1978, ii, 1108 3. Masson, P., Delire, M., Cambiaso, C. L. Nature, 1977, 266, 542. 4 Zubler, R H , I.ange, G., Lambert, P H., Miescher, P. A. J.Immun 1976,

116, 232. 5. Levinsky, R. J., Soothill, J. F. Clin. exp. Immun 1977, 29, 428 6. Gusten, J. P Jr Am J. Obstet. Gynec 1969, 103, 895. 7. Benster, B., Wood, E. J. J. Obstet. Gynœc Br Cwlth, 1970, 77, 8 Studd, J. W W. ibid 1973, 80, 872

518