1104

about SAD. In our patient, exacerbation of panic attacks during thewinter and the attenuation of both panic and depressive symptomswith light therapy, suggest that seasonal panic disorder may be avariant of SAD, both conditions having a common underlyingpathophysiology. Indeed, panic disorder has been viewed as avariant of an affective illness.1,5 Since the depressive phase of SADarises regularly and predictably, investigation of panic disorder inpatients with SAD may be of value in the elucidation of the relationbetween depression and panic.We recommend that patients with panic disorder should be

assessed for seasonal variations in symptoms and that light therapyshould be considered in the management of patients with seasonaldisorders.

Department of Psychiatry,Albert Einstein College of Medicine,Bronx, NY 10461, USA

J. DANIEL KANOFSKYREUVEN SANDYK

Bio-Behavioral Psychiatry,Great Neck, NY

STEPHEN KAPLAN

JOSE A. YARYURA-TOBIAS

1. Blehar MC, Rosenthal NE. Seasonal affective disorders and phototherapy Arch GenPsychiatry 1989, 46: 469-74.

2. Wehr TA, Rosenthal NE Seasonality and affective illness. Am J Psychiatry 1989; 146:829-39.

3. Cameron OG Frequency of panic disorder in summer. Am J Psychiatry 1989; 146:123.

4. Coccaro EF. Panic attacks and depression Am J Psychiatry 1983; 140: 262.5. Breier A, Charney DS, Heninger GR. Major depression m patients with agoraphobia

and panic disorder. Arch Gen Psychiatry 1984; 41: 1129-35

Plasma endothelin-1 concentration duringcold exposure

SIR,-Dr Zamora and colleagues (Nov 10, p 1144), DrCimminiello and colleagues (Jan 12, p 114), and others havemeasured plasma endothelin (ET) concentrations after cold pressortests. Results are conflicting, with plasma ET concentrations beingeither increased or unchanged. The contribution of circulating ETin cold-induced vasoconstriction seems to be uncertain. To evaluatethe ET response to cold challenge, we measured plasma ET-1concentrations during whole-body exposure to low environmentaltemperature.

6 healthy males (mean [SD] age, 28[8] years) dressed in shortswere exposed in supine rest to a cold environment (+ 12°C, airvelocity 03 m/s, and 30% humidity) for 90 min. This cold challengewas preceded and followed by 90 min in a thermoneutralenvironment ( + 22°C, air velocity less than 0-2 m/s). In a

randomised order, at least one week apart, each subject also

participated in a control experiment by reclining for 270 min in athermoneutral environment. An indwelling catheter was insertedinto an antecubital vein for blood sampling, and both skin and core(rectal) temperatures as well as blood pressure and heart rate weremeasured. Plasma ET-1 concentration was measured by a

radioimmunoassay.lDuring cold exposure, antebrachial and dorsal hand

temperatures decreased significantly (p < 0001) from 33-5 [0’8] and314 [2’9]&deg;C to 24-5 [2.2] and 22.1 [3.5]&deg;C, respectively. Cold

PLASMA ET-1 CONCENTRATIONS AND BLOOD PRESSURE AFTER

COLD EXPOSURE

Results given as mean (SD).*p < 0 05 and tp < 0 001 between groups (treatment x time interaction m analysIs ofvariance) ET-endothehn, SAP=systolic arterial pressure, DAP=drastolic arterialpressure

exposure decreased rectal temperature slightly but significantly(p < 0.001 vs control experiment) from the pre-exposure value of36-5 [0.3]&deg;C to a minimum of 36-3 [0 4]&deg;C, 45 min after the end ofthe 90 min cold exposure. When compared with the controlexperiment, cold exposure did not affect plasma ET-1concentration (table). Blood pressure increased, while heart rate didnot change during the cold challenge.Zamora et al found that plasma ET-1 concentration increased

only after the water-bath temperature was cooled below 18&deg;C, andsuggested that cold-induced vasoconstriction at temperatures above18’C may not be causally linked to ET-1. Accordingly, we found nochange in plasma ET-1 concentration with mean antebrachial anddorsal hand skin temperatures of about 25&deg;C and 22&deg;C, respectively.An increase of plasma ET-1 concentration by total body coldexposure in normal subjects may require lower local temperaturesthan those achieved in our trial. ET-1 may not have a physiologicalrole in the initial vasoconstriction induced by cold.

Supported by both the Paulo Foundation and Yrjo Jahnsson Foundation.Department of Anaesthesia and

Fourth Department of Medicine,Helsinki University Central Hospital,SF-00290 Helsinki, Finland,Department of Physiology,Institute of Occupational Health,Helsinki,and Department of Physiology,

Minerva Institute for Medical Research,Helsinki

MARKKU HYNYNEN

RAIJA ILMARINENOUTI SAIJONMAAILKKA TIKKANEN

FREJ FYHRQUIST

1 Fyhrquist F, Saijonmaa O, Metsarinne K, Tikkanen I, Rosenlof K, Tikkanen TRaised plasma endothelin-1 concentration following cold pressor test. BiochemBiophys Res Commun 1990; 169: 217-21.

SIR,-Dr Zamora and colleagues reported raised serum

endothelin-1 (ET) levels in patients with Raynaud’s syndromeunder basal and cold-stimulated conditions. Although two

subsequent reports (Jan 12, p 114; Jan 26, p 236) present conflictingresults, your Jan 12 editorial states that "ET is clearly implicated" inRaynaud’s syndrome. All three research reports describe inabilityto establish a cause-and-effect relation between ET concentrationsand cold-induced vasospasm. We have analysed the direct effect ofcooling on ET-induced contractions in human subcutaneousresistance arteries. When these vessels are cooled, contractionsevoked by ET are severely diminished, which argues stronglyagainst a causal role for ET in Raynaud’s syndrome.At surgery, four patients donated 1 ml of inguinal subcutaneous

tissue. Resistance arteries ( < 500 um external diameter) weredissected and cut into rings 2 mm in length. The rings weresuspended in a wire myograph to record isometric contractions.This device is a miniaturised vesion of the classic organ chamber.’The myograph was fitted with peristaltic pumps and heat

exchangers, permitting rapid alteration of the temperature of therings between two preselected points. After equilibration vesselsegments were exposed to increasing concentrations of ET (01nmol/1 to 0’ 1 lunol/1) at 37&deg;C. When the contractile response to each

Contractile responses under influences of cooling and ETconcentration.

1105

concentration had stabilised at 37&deg;C, the temperature was reducedto 24&deg;C, this change being achieved in less than 90 s. When the effectof cooling had stabilised, the temperature was returned to 37&deg;C, andon stabilisation the next concentration was administered.

Contractile responses at 37&deg;C are presented as the mean increasein tension above basal before cooling and after rewarming to 37&deg;C.2The contractile response at 24&deg;C represents the nadir of the

response during cooling. Maximum contractile values were 1095(183) mg at 37&deg;C and 513 (120) mg at 24&deg;C. At every ET

concentration, contractions were inhibited by acute cooling andrestored upon rewarming (figure).As reported for other vessels, ET was a potent agonist in the

human resistance arteries. The effect of cooling was a profoundinhibition of the contractions. This does not reflect an overallinhibition of contractile processes by cooling because contractionsevoked by noradrenaline and potassium chloride are not similarlyaffected. Our data do not support a causal role for ET in thecold-induced vasospasm of Raynaud’s syndrome.

Divison of Vascular Surgery,Oregon Health Sciences University,Portland, Oregon 97201, USA

CHRISTIAN T. HARKER

JAMES M. EDWARDSLLOYD M. TAYLOR, JRJOHN M. PORTER

1. Aalkjaer C, Pederson EB, Heagerty AM, et al. Relaxation of isolated resistance vesselsfrom humans with vascular disease. Acta Med Scand 1986; 714 (suppl): 59-64.

2. Harker CT, Ousley PJ, Harris EJ, Edwards JM, Taylor LM, Porter JM. The effects ofcooling on human saphenous vein reactivity to adrenergic agonists. J Vasc Surgery1990; 12: 45-49.

Liver transplantation in severevon Willebrand disease

SIR,-von Willebrand factor (vWF), congenital deficiency ordysfunction of which results in the bleeding disorder von

Willebrand disease, is synthesised by vascular endothelial cells. 1The liver contains many endothelial cells but it is not certain if

specialised cells, such as those lining the hepatic sinusoids, alsocontain vWF.2-4A 44-year-old man with a history of frequent soft-tissue and

mucosal bleeding since childhood had had several treatments withwhole blood, cryoprecipitate, and factor VIII (FVIII) concentrates.His FVIII level was only 10%, with less than 6% ristocetin cofactoractivity of vWF, and only 0-04% vWF antigen. His bleeding timewas over 30 min, and he had antibodies to hepatitis B surface andcore antigens and hepatitis C virus, and a persistently raised alanineaminotransferase. He was HIV seronegative. Hepatic syntheticfunction had progressively deteriorated over the previous 10 yearsand he had episodes of variceal bleeding since 1985 and severalepisodes of hepatic encephalopathy. In 1990, a liver mass wasdiagnosed as hepatocellular carcinoma. Liver transplantation wasdone on Nov 29,1990, for which he was given 12 000 units of FVIIIconcentrate containing large amounts of vWF (’Hemate P’,Behring), 12 units of red blood cell concentrate, and 4 litres offresh-frozen plasma. Postoperatively the patient was treated withthe same concentrate until day 26 (total dose 10 000 units). The liveris functioning well, 5 months after the operation, and sincedischarge the patient has had no bleeding episodes or replacementtherapy.The table shows the results of FVIII and vWF measurements,

and bleeding time before the operation, and on day 45 and 5 monthsafterwards. FVIII levels increased 2-fold and vWF antigenincreased more than 20-fold, but was still very low. The bleedingtime remained abnormal. On day 45 the patient gave informedconsent to an infusion with desmopressin, but FVIII and vWFmeasurements did not change (table). Thus, when postoperativereplacement therapy had been stopped for at least 3 weeks vWFlevels, albeit remaining very low, were more than 20 times higherthan before transplantation. The precision and sensitivity of ourimmunoradiometric assay are such that an increase from 0-04% to1 02% cannot be due to experimental error, so there was probablyheightened production of vWF by the endothelial cells of the newliver. The post-transplantation increase in FVIII can perhaps beexplained by the fact that there was more vWF in plasma to carryand stabilise FVIII. No factor VIII nor vWF was stored, because

FVIII, vWF, AND BLEEDING TIME BEFORE AND AFTER LIVERTRANSPLANTATION*

*Factor assays expressed as % of reference plasma (calibrated against theInternational Standard for FVIII-related activities), with normal values of 50-150%.

desmopressin did not trigger any further increases. This naturalexperiment indicates that the liver produces only a small proportionof the plasma pool ofvWF, too small to correct the defect of primaryhaemostasis in severe von Willebrand disease. By contrast, incongenital deficiencies of haemostasis proteins synthesised by thehepatocytes (such as factor VIII and protein C), transplantationincreases plasma levels to a clinically relevant degree.

A Bianchi Bonomi Haemophiliaand Thrombosis Centre,and Liver Transplantation Unit,

IRCCS Maggiore Hospital,University of Milan,Milan, Italy

PIER MANNUCCIO MANNUCCIAUGUSTO FEDERICIMARCO CATTANEORANIERO FASSATIDINANGELO GALMARINI

1. Bowie EJW, Solberg LA, Fass DN, et al. Transplantation of normal bone marrow intoa pig with severe von Willebrand’s disease. J Clin Invest 1986; 78: 26-30.

2. Stel HV, van der Kwast Th H, Veerman ECI Detection of factor VIII/coagulantantigen in human liver tissue. Nature 1983; 309: 530-32.

3. Zelechowska MG, von Mourik JA, Brodniewicz-Proba T. Ultrastructural localizationof factor VIII procoagulant antigen in human liver hepatocytes. Nature 1985; 317:729-30.

4. Wion KL, Kelly D, Summerfield JA, Tuddenham EGD, Lawn RM. Distribution offactor VIII mRNA and antigen in liver and other tissues. Nature 1985; 317: 726-29.

Response of central nervous systemvasculitis to irradiation

SIR,-Isolated vasculitis of the central nervous system (IVCNS)is a rare entity confined to CNS vessels with few signs of systemicinvolvement. 1 If untreated, IVCNS is fatal. However,immunosuppressive therapy may lead to sustained remission. Wereport a child who failed to respond to this therapy, and who enteredtemporary remission on two occasions after cranial irradiation.A 11-year-old boy was admitted with signs of intracranial

hypertension of one month’s duration. Cranial computedtomography showed a low-density area in the left fronto-basalregion. A biopsy was completed which showed thrombosis andnecrosis of some vessel walls in the leptomeninges, and in corticaltissue and white matter. Arteriography showed lesions consistentwith the diagnosis of vasculitis, with multiple irregularities of theleft anterior choroid artery walls. An infectious cause and systemicvasculitis were excluded. IVCNS was diagnosed, and treatmentwith cyclophosphamide and prednisolone was started, but

neurological deterioration progressed with extension of the lesion tothe basal ganglia and brainstem. Irradiation of the affected area wasselected because of the patient’s critical condition. He received 2 Gyper day up to a total of 46 Gy, in the frontoparietal region. From thattime onwards, his symptoms remitted gradually and subsequentradiographic studies were normal. Despite this success, the patientpresented seven months later with cerebellar involvement thatresponded again to radiotherapy. Immunosuppressive drugs werenot continued in the interval between radiotherapy sessions.The patient deteriorated further, with left parietal involvement

fifteen months later. Since irradiation of previously irradiated areasis not possible, medical treatment with high doses of

cyclophosphamide and prednisone was restarted. This provedineffective, and the patient died fifteen days later. Permission fornecropsy was refused.

Satisfactory results of treatment of IVCNS with

cyclophosphamide and prednisone have been reported. However,irradiation has not been described previously. Our case is especiallyinteresting since, although diagnosed according to Moore’s