‘Internistendagen’, Veldhoven, Netherlands, 23–24 April 1998

The Netherlands

JOURNAL OF MEDICINE ELSEVIER

Netherlands

Journal

of Medicine

52 (1998)

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Abstracts of the ‘ ‘ Internistendagen’ ’ , Veldhoven, Netherlands, 23-24 April, 1998 Contents Connective tissue and joint diseases

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Haematological and oncological diseases

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III.

Blood coagulation

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IV.

Lung diseases

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Renal and urogenital diseases

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VI.

Endocrinological and metabolic diseases

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VII.

Cardiac diseases and circulatory disorders

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Gastrointestinal and liver diseases

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Infectious diseases

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Miscellaneous

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I. II.

V.

VIII. IX. X.

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Author index

0300-2977/98/$19.00

0 Elsevier

SSDIO300-2977(98)00026-7

Science

B.V.

All rights

reserved

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1998/Netherlands

I. Connective tissue and joint diseases 1. No increased risk of malignancies and mortality in cyclosporin A-treated rheumatoid arthritis patients. B.E.E.M. Landewe ‘, I. Houkes 3, F. Schild ‘. van den Borne ‘, R.B.M. P.C.W. van der Heyden 3, J.M.W. Hazes ‘. J.P. Vandenbroucke ‘, A.H. Zwinderman 5, H.S. Goei The ‘. F.C. Breedveld 3. H.J. Bemelot Moens ‘, Ph.M. Kluin 6, B.A.C. Dijkmans *. ’ Department of Internal Medicine, Catharina Hospital Eindhooen, ’ Department of Rheumatology, Wec>er Hospital, Heerlen, 3 Leiden lJniuersio/ Hospital, Departments of 4 Epidemiology, 5 Medical Statistics and 6 Pathology, l/nicer&y Hospital, L&den, ’ Medical Spectrum, Twente and a Free University Hospital, Amsterdam, Netherlands. Background: (1) The immunosuppressive drug cyclosporin A (CsA) is being used in organ transplant patients and in patients with autoimmune diseases such as rheumatoid arthritis (RA). (2) The use of CsA in transplant patients is associated with an increased incidence of malignant lymphoproliferative diseases (LPDs) and skin cancers, especially squamous cell carcinomas. (3) An increased risk of malignant LPDs has also been reported in patients with RA. (4) Mortality in RA patients is increased with cardiovascular disease being the primary cause of death. Purpose: To evaluate in RA patients: (1) the CsA-attributed risk of the development of malignancies in general and malignant LPDs and skin cancers in particular: and (2) the CsA-attributed mortality. Methods: In a retrospective controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 RA patients treated with CsA between 1984 and 1995 for various periods, and in 415 matched control RA patients. Patients were followed for a median duration of 5.0 years (range 1.4-12.0 years). Results: Forty-eight cases of malignancy (8 in the CsA group and 40 in the control group were identified (relative risk (RR) 0.40, 95% confidence interval (CI) 0.19-0.84)) including 8 malignant LPDs (2 vs. 6; RR 0.67, CI 0.14-3.27) and 14 skin cancers (2 vs. 12; RR 0.33, CI 0.08-l .47). Seventy-three patients had died (16 vs. 57; RR 0.56, CI 0.33-0.95): 24 primarily of cardiovascular diseases (4 vs. 22; RR 0.36, Cl 0.13-l ,041; and 11 primarily because of a malignancy (3 vs. 8; RR 0.67, Cl 0.18-2.43). Proportional hazard regression analysis with correction for potentially confounding factors did not significantly change the results. Conclusions: (1) CsA treatment in RA patients does not increase the risk of malignancies in general and malignant LPDs or skin cancers in particular; and (2) mortality in CsA-treated RA patients is comparable to mortality in matched control RA patients.

2. Combination therapy in recent-onset rheumatoid arthritis: a randomized double-blind trial of the addition of low-dose cyclosporin to patients treated with low-dose chloroquine. B.E.E.M. van den Borne ‘, R.B.M. Landewe ‘, H.S. Goei The *, J.H. Rietveld 3, A.H. Zwindermanh. G.A.W. Bruyn 4. F.C.

Journal

of Medicine

52 (1998)

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Breedveld ‘, B.A.C. Dijkmans ‘. ’ Department of Zntemal Medicine, Catharina Hospital, Eindhouen, 2 Department oj Rheumatology, Welver Hospital, Heerlen, ” Nourtis B.V., Arnhem, ’ Medical Centre, Leeuwarden, 5 Leiden University Hospital. ’ Department qf Medical Statistics, University Hospital, Leiden and 7 Free ChGersity Hospital, Amsterdam, Netherlanrls. Objectice: To investigate whether there is an interaction between chloroquine (CQ) and cyclosporin (CsA) at the level of efficacy and toxicity in recent-onset rheumatoid arthritis (RA) patients. Methods: Eighty-eight RA patients with recent-onset RA who had shown a suboptimal clinical response on low-dose CQ monotherapy, were randomly assigned to additional treatment with placebo, CsA 1.25 or 2.50 mg/kg/day (fixed doses) for another 24 weeks. The tender-joint count (TJC) was the primary outcome assessment of efficacy and the serum creatinine of toxicity. The 1995 preliminary ACR response criteria for improvement were applied to evaluate individual clinical responses. Results: Two patients in the placebo group (n = 29), 7 patients in the CsA 1.25 group (n = 29) and 8 patients in the CsA 2.50 group (n = 30) (P = 0.06) prematurely discontinued study medication for inefficacy or adverse effects. The intention-to-treat analysis disclosed that the TJC decreased 2.2 + 6. I (mean f SD) joints in the placebo group, 2.2 + 6.6 joints in the CsA I .25 group and 5.0+5.8 joints in the CsA 2.50 group (P = 0.04). The 1995 preliminary ACR response criteria for clinical improvement were met by 8 (28%) patients in the placebo group, 10 patients (34%) in the CsA 1.25 group and 15 patients (50%) in the CsA 2.50 group (P = 0.07). The serum creatinine increased with 2+7 ~mol/l in the placebo group, decreased with 1 + 8 pmol/l in the CsA 1.25 group and increased with lo* 15 kmol/l in the CsA 2.50 group (P < 0.00 1). Conclusions; The addition of low-dose CsA is moderately effective in early RA patients already treated with low-dose CQ. but results in statistically significant loss of renal function.

II. Haematological and oncological diseases 3. Antibody responses in patients with B-ceil chronic lymphocytic leukaemia. A. Hartkamp ‘, A.H.L. Mulder ‘, H. van Velzen-Blad *, D.H. Biesma ‘. Departments of Internal Medicine and 2 Medical Microbiology and Immunology. St. Antonius Hospital, Nieuwegein, Netherlands. Background: B-cell chronic lymphocytic leukaemia (B-CLL) is the most common type of leukaemia. Patients with B-CLL are highly susceptible to infections, especially bacterial infections of the respiratory tract. Infectious complications in patients with B-CLL are accompanied by relatively high morbidity and mortality. Hypogammaglobulinaemia and low specific antibody titres may be responsible for the increased susceptibility to infections. Aim: To assess antibody responses in patients with B-CLL who receive pneumococcal polysaccharide vaccine (Pneumovax 23) and conjugated Haemophilus inj7uenzae type B vaccine (ActHIB).

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Mefhods and patients: Specific antibody responses were mcasured in 25 patients with B-CLL before and 3 weeks after vaccination. Sufficient antibody responses were defined as a twofold or more increase in specific antibody titres with final levels > 20 U/ml. Antibody responses were correlated with clinical characteristics (Rai-classification) and laboratory parameters (white blood cell count, immunoglobulin levels, including IgG subclasses and soluble CD23 levels). Results: Respectively, five out of 20 (25%) and 6 out of 23 (26.1%) evaluable patients responded with specific antibody titres in the protective range ( > 20 U/ml) against tested pneumococcal serotypes and IgG levels, respectively, against H. infuenzae B. Patients with advanced-stage B-CLL (expressed as Rai-classification) had significantly less responses to Pneumovax 23 and Act-Hib vaccination (P < 0.001). Total IgG levels and IgG subclass 2 and 4 levels were significantly higher (P < 0.05) in B-CLL patients with adequate responses to both vaccinations. sCD23 levels were significantly lower in patients with adequate responses (P < 0.05). Conclusion: Response to vaccination and protection against encapsulated bacteria in B-CLL patients is poor, but correlates well with the stage of disease, immunoglobulin levels and soluble CD23 levels. Studies of more immunogenic vaccines (such as conjugated pneumococcal vaccines) in this category of patients is warranted.

4. Pyruvate kinase deficiency as a rare cause of jaundice. E.L.E. de Bruyne i, R.J.Th. Ouwendijk t, W.W. van Solinge ‘. ’ Department of Internal Medicine, lkazia Hospital, Rotterdam and 2 Department of Clinical Chemistry, Eemland Hospital. Amersfoort, Netherlands. A 33-year-old man presented with abdominal discomfort, nausea and vomiting. He had slightly red-brown coloured urine and normal stools. His previous medical history was unremarkable except for periodic asymptomatic jaundice since the age of 10 years. He was not taking medication. One week before admission he consumed 10 units of alcohol. On physical examination, he was jaundiced with no signs of chronic liver disease. Neither liver nor spleen were enlarged. Laboratory investigations showed a normal erythrocyte sedimentation rate (2 mm/h), a haemoglobin of 6.7 mmol/l (normal 8.5-l 1.0 mmol/l) with a normal MCV. The white blood count was 10.9X 109/1 (normal 4-10X 109/1) and the platelet count was 257 X 109/1 (normal 130-350X 109/ll. The reticulocyte count was 43%0 (normal 3-15%0). Total serum bilirubin was 289 pmol/l (normal < 20 pmol/l), indirect serum bilirubin was 108 pmol/l (normal < 15 pmol/l), alkaline phosphatase 42 IU/l (normal < 100 IU/l), y-glutamyltranspeptidase 339 IU/l (normal < 45 IU/l), ASAT 65 IU/l (normal < 25 IU/Il, ALAT 47 IU/l (normal < 30 IU/l), LDH 543 IU/l (normal 140-320 IU/l) with a haptoglobin of < 0.1 g/l (normal 0.4-2.2 g/l). Serological testing showed no signs of recent viral infections. Ultrasonography of the abdomen showed a normal liver without signs of bile duct obstruction or gallbladder stones, normal portal vessels, no ascites and a normal spleen. A presumptive diagnosis of a haemolytic anaemia was made. The diagnosis of pyruvate kinase deficiency was made by exclusion of the most common causes of haemolytic anaemia and by demonstration of a

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52 (1998)

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reduced pyruvate kinase activity in the red blood cells: 1.4 IV/g Hb (normal 4.8-9.6 IV/g Hb). Molecular analysis of the PKLR gene was performed. The proband was found to be a compound heterozygote. One allele exhibited a glycinel’targinine missense mutation caused by a G to A conversion at position 33 1. The other allele showed an arginine486tryptophan missense mutation due to a C to T conversion at position 1456. Both mutations are associated with PK deficiency. Conclusion: It is of interest that the diagnosis was made at adult age and that the phenotypic expression of the disease is relatively mild, despite two mutations in the PKLR gene. It is possible that the excessive alcohol intake induced the haemolysis in this patient.

5. Thromhopoietin accelerates thrombocyte recovery and multilineage bone marrow reconstitution after myelosuppressive treatment. S.C.C. Hartong, K.J. Neelis, G. Wagemaker. Institute of Haematology, Erasmus University, Rotterdam, Netherlands. Thrombocytopenia caused by chemo-/radiotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Platelet transfusions can prevent bleeding, but infectious and allergic complications and refractoriness due to alloimmunizations reduce their usefulness. Haemopoietic growth factors (HGF) may potentially counteract the severity and the duration of the pancytopenia and consequently may allow more effective high-dose regimens. Thrombopoietin (TPO), the ligand for the c-mpl receptor, has been cloned and characterized in 1994, is structurally related to EPO and has been shown to be the physiological regulator of megacaryopoiesis and platelet production. Peripheral blood TPO levels are inversely related to platelet numbers. In vitro studies have shown that TPO not only stimulated immature megacaryocyte progenitor cells, but also more immature CD34+ haemopoietic stem cells. We tested TPO in a preclinical rhesus monkey myelosuppression (5 Gy X-ray) model and have demonstrated that TPG stimulated thrombocyte and reticulocyte regeneration and accelerated immature bone marrow reconstitution, resulting in prevention of thrombocyte transfusions and accelerated recovery of thrombocytes to normal values. These effects could be further augmented by co-administration of GMCSF which also improved neutrophilic and bone marrow regeneration. However, high-dose radiation (8 Gy X-ray) followed by stem cell transplantation, resulted in a significantly reduced efficacy of TPO. These preclinical results will be compared with the initial clinical trials, such as those by Basser et al. and Fanucchi et al. who showed that TPO had stimulatory effects on platelet production in cancer patients with chemotherapy-induced thrombocytopenia, resulting in shorter thrombocytopenic periods which allow chemotherapy to be given at shorter intervals. Effects on haematocrit or leucocyte counts were not observed. Unfortunately, TPO did not have an effect on the number of thrombocyte transfusions in a high-dose chemotherapy setting with peripheral blood progenitor cell support in breast cancer patients (Glaspy et al.). Other potential applications of TPO include improvement of the ability of mobilized peripheral blood progenitor cell harvests to re-establish bone marrow function and/or an accelerated platelet recovery after transplantation.

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6. Co-administration of cyclosporin A enables oral therapy with paclitaxel. J.M. Meerum Terwogt ‘, J.H. Beijnen ‘, W.W. ten Bokkel Huinink i, H. Rosing ‘, 0. van Tellingen t, M. Swart ‘, K. Duchin 2, J.H.M. Schellens ‘. ’ Netherlands Cancer Institute, Amsterdam, Netherlands and ’ Baker Norton Pharm., Miami, FL, USA. Oral bioavailability (F) of paclitaxel (PAC) is very low, probably due to the high affinity of PAC for the efflux pump P-glycoprotein (P-gp). Based on our preclinical research, also with mdrla P-gp-deficient mice, oral administration of PAC plus the P-gp inhibitor cyclosporin A (CsA) should increase systemic exposure of PAC to therapeutic levels. To prove this, 5 patients received 60 mg/m2 oral PAC (Paxenel without CsA during course 1, and 3-h iv. PAC 175 mg/mz during all other courses. Nine other patients received oral PAC + 15 mg/kg oral CsA (Neoral oral solution) and all other courses i.v. PAC. The second course was randomized with the first course. CsA preceded PAC by 10 min. Oral drugs were taken with 100 ml tap water after an overnight fast. Standard PAC pretreatment was given all courses. The pharmacokinetics of PAC, Cremophor EL, CsA and ethanol were determined during courses 1 and 2. Patients (2 male, 12 female) had a median age of 56 years (range 34-69 years) and a median WHO PS of 1 (O-2). The most frequent tumours were of the ovary (n = 4), breast (n = 3) and carcinoma of unknown primary (n = 2). The median AUC in patients who received oral PAC+CsA was 1.45 pM * h (range 0.46-3.20 PM * h) which is 9-fold higher than without CsA (0.16 FM * h, range 0.12-0.36 FM * h; P < 0.001). In addition, using our published data (Huizing JCO 1997;15:317-329), F was 5% without CsA and 42% with CsA. The median T,,,, was 2.9 h. The median time above 0.05 FM was 0.8 h (range O-2.0 h) without CsA, 6.5 h (range 3.4-17.5 h) (P < 0.001) with CsA and 24.8 h (range 18.4-36.9 hl after i.v. PAC. CsA reached therapeutic concentrations. Oral Cremophor levels were undetectable. Ethanol concentrations were I 0.1%0. Besides a bitter taste, the oral combination was very well tolerated. A common PAC pattern of toxicity developed after 2-3 i.v. courses. In the other cohorts of, in total, 16 patients, an increase of the CsA dose to 30 or 2 X 15 mg/kg (the second dose 2 h after the first dose) did not further increase F. Dose escalation to 120 mg/m’ PAC + 15 mg/kg CsA was well tolerated. Further escalations and new drug formulations are currently being investigated. Oral PAC +CsA may be a realistic alternative to the current i.v. treatment.

7. Breast cancer in a male cirrhotic patient with hypogonadism. M.M.E. Krekels, B.J. Looij, L.G.J.B. Engels. Department of Internal Medicine, Maasland Hospital, Sittard, Netherlands. As common as breast cancer is in females, as rare it is in males. The occurrence of breast cancer in men seems to be associated with both gynaecomastia and Klinefelter syndrome, which suggests that hormonal imbalance is a predisposing factor. Our patient was admitted to hospital when he was 38 years old. He was known to have an alcohol intake of approximately 25 units/day. He presented with jaundice and ascites as a consequence of alcoholic liver disease. At that time, no testicular

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52 (I 998) Al&A67

atrophy was found, but many other features of liver failure besides jaundice and ascites were present (such as bilateral gynaecomastia). Over the next years he was admitted several times because of decompensated liver failure and variceal bleeding. At the age of 42 years he was seen at the out-patient clinic for a routine examination. At this time, modest testicular atrophy was present (left testicle 8 ml, right testicle 10 ml). He had no specific complaints except for a painful area under the right nipple. Bilateral gynaecomastia was again found, but the right disc had changed. On palpation it felt not only firm and irregular, but was also painful. Moreover, palpation of the right axilla was also painful. Enlarged lymph nodes, could not be found, however. An additional mammography showed gynaecomastia on both sides. but on the right side the glandular tissue was irregular and had the radiological appearance of a fibrous adenolipoma. All glandular tissue was removed on both sides under total anaesthesia. Histopathological investigation revealed an infiltrative carcinoma of 0.3 cm and a widespread area of 7 X2.5 cm with ductal carcinoma in the right breast. He subsequently underwent a modified radical mastectomy with removal of axillary lymph nodes. No proliferation of tumour could be found in this material, but one micrometastasis was present in one of the removed lymph nodes. The disease was labelled as stage II (TlNlMOl. To investigate whether a hormonal imbalance could have played a role in the development of breast cancer in this patient, additional hormonal data were obtained. Testosterone was in the lower normal range, but with relatively high luteinizing hormone levels. Oestrogen, progesterone and prolactin levels, on the other hand, were increased. Theoretically, therefore, when associated with hormonal imbalance, gynaecomastia, may be a premalignant state.

8. The association of pregnancy with severe aplastic anaemia: causal relationship or coincidence? H.M. Oosterkamp ‘, A. Brand ‘, J.C. Kluin-Nelemans ‘, J.P. Vandenbroucke ‘. Departments of' Clinical Epidemiology and 2 Haematology, Leiden Uniuersity Medical Centre, L&den, Netherlands The relationship between aplastic anaemia (AA) and pregnancy remains controversial. To assess whether an association between pregnancy and severe aplastic anaemia (SAA) exists, we compared the frequency of pregnancy in a series of women with SAA, aged 15-44 years, with the expected frequency in the general population. From a series of patients treated for SAA in the University Hospital Leiden between 1972 and 1996, we reviewed the charts of 35 women in this age group with newly diagnosed SAA and scored if they were pregnant at the time of diagnosis or relapse. The observed pregnancy rate in the SAA group is 3% (95% confidence interval (CI) O-8.4%)) when we only count the women who were pregnant at the time of diagnosis, or at a maximum of 6% (CI O-13.4%) when we also include a woman whose SAA was diagnosed 4 months postpartum. These percentages approximate the expected pregnancy rate of 4.4% in the general population, implicating no association between pregnancy and SAA. In addition, there was no relationship between a relapse of SAA and pregnancy, nor between oral contraceptive use and the development of SAA or a relapse. Based on these results and a review of the literature, there is no conclusive evidence to

Intemistendagen implicate pregnancy in the pathogenesis

or oral contraceptives of aplastic anaemia.

1998/Netherlands as aetiological

agents

9. Phase I and pharmacological study of water-soluble polymer-conjugated pa&axe1 (PNIJ 166945) administered as a l-h infusion in patients with advanced solid tumours. V.R. Namntn Panday, J.M. Meerum Terwogt, W.W. ten Bokkel Huinink, H. Rosing, M. &hot, M. Rocchetti, P. Liati, M.G. Zurlo, J.H.M. Schellens, J.H. Beijnen Departments of Medical Oncology and Pharmacy, Sloteruaart Hospital, Amsterdam and Netherlands Cancer Institute, Amsterdam, Netherlands. Due to its poor water solubility, paclitaxel (P) is currently formulated in a mixture of Cremophor EL and ethanol (1: 1, v/v). However, the vehicle Cremophor EL has been associated with hypersensitivity reactions (HSRS). An alternative formulation is a hydroxypropylmethacrylamide polymer-bound P (PNU 166945), which can easily be dissolved in water. Since PNU 166945 demonstrated activity in experimental models, we investigated this compound in a single-centre, single-arm study in patients with advanced resistant or refractory solid tumours. PNU 166945 80 mg/m’ as P equivalents was selected as starting dose and was administered as a l-h infusion every 3 weeks. To date, 13 patients were accrued with the following characteristics: median age 53 years (range 35-74 years), median WHO PS 1 (range O-2). Patients had adequate bone marrow, hepatic and renal functions. Fifty-one cycles were delivered (mean 4 cycles, range l-9). Haematological toxicity was mild. Neuropathy CTC grade I was pre-existent in 5 patients, and in 2 of these, 5 neuropathy CTC grade II was noted. One other patient developed CTC grade Ill neuropathy. Except for fatigue, nausea and alopecia, no other predominant toxicities 2 CTC grade II were observed. Furthermore, no HSRs were observed. One partial response was achieved in breast cancer. Pharmacokinetic (PK) studies revealed that the mean PNU 166945 AUC was 267 + 85 mg . h/l at 80 mg/m”, 219+45 mg * h/l at 100 mg/m’, 346+97 mg * h/l at 140 mg/m*, and 370+7 mg * h/l at 196 mg/m*. PNU 166945 displayed linear PK behaviour, and its mean clearance was 0.8 + 0.2 l/h. At these 4 dose levels, the free P AUCs were 2.9 f 0.6, 3.8 + 1.1, 8.0+ 3.7 and 7.1+ 1.0 mg . h/l, respectively. Free P concentrations above the threshold value of 0.1 PM were reached.

10. Outcome of patients with a haematological malignancy admitted to a medical intensive care unit. A.J. ten Hagen i, J.T.M. de Wolf ‘, T.S. van der Werf I, J.G. Zijlstra ‘. ’ Intensifie ana’ Respiratory Care Unit and 2 Division of Haematology, Department of Internal Medicine, University Hospital, Groningen, Netherlands. Patients with haematological malignancies can develop an indication for ICU admission related either to the underlying disease or to its treatment. However, whether these patients (or subgroups of these patients) benefit from intensive care treatment is subject to discussion. Therefore, we determined parameters associated with me survival of haematological patients admitted to our ICU. We retrospectively reviewed the records of 58 patients

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admitted to the intensive care unit who underwent chemotherapy for haematological malignancies. Patient characteristics were compared between survivors (n = 28; 48%) and non-survivors (n = 30; 52%). Twenty-seven patients required mechanical ventilation of whom 26% survived, whereas of the remaining 31 patients who were not mechanically ventilated, 68% survived (P < 0.001). Of the mechanically ventilated patients, 19 patients had a leucocyte count < 2.0 X 109/1. The remaining 8 patients had a higher leucocyte count. Of the latter, 75% survived, whereas only 5.3% (one patient) survived of the mechanically ventilated patients with a leucocyte count < 2.0 X 109/1 (P < 0.001). This survivor eventually died after being discharged from the ICU ward. Other patient characteristics (age, gender, underlying disease, documented sepsis) did not seem to determine survival to the same extent. In conclusion, patients with a haematological malignancy may benefit from treatment in an intensive care unit. However, those who were leucopenic ( < 2.0 X 109/1) in combination with requirement of mechanical ventilation had a 100% in-hospital mortality.

11. Intravenous gammaglobulin therapy for acquired von Willebrand’s disease. J. van den Bosch, M.J.A. Wolters-Geldof, W.L.E. Vasmel. Department of General Medicine, St. Lucas Andreas Hospital, Location Lucas, Amsterdam, Netherlands. In patients with acquired von Willebrand’s disease, bleeding may be difficult to manage. Intravenous infusion of desmopressin or factor VIII/van Willebrand’s concentrates is usually advised. We report a patient who did not respond to this regime. A 75-year-old male patient had been known since 1992 because of recurrent epistaxis. In 1970, he underwent a complete tooth extraction without problems. In 1980, he had had a severe haemorrhage after tonsillectomy and in 1985 the same occurred after haemorrhoidectomy. In 1992, laboratory tests showed normal values for the platelet count, prothrombin time and bleeding time. The cephalin time was slightly prolonged. vWF antigen and VW-ristocetin cofactor were absent, F VIII antigen and F VIIl activity were both lowered to 5%. A paraprotein IgG kappa, 5.5 g/l, was found in the blood. A diagnosis of acquired uon Willebrand’s disease was made. Prednisone, 1 mg/kg/day orally, had no effect on F VlII/von Willebrand’s values or the paraproteinaemia. In 1995, the patient developed a microcytic anaemia (Hb 6.9 mmol/l, MCV 74 fl). Colonoscopy showed a polyp in the caecum and a polypectomy was required. Desmopressin (0.3 pg/kg i.v.1 resulted in a minimal and short-lived rise of F VIII/van Willebrand’s values. A concentrate of F VIII/van Willebrand’s factor (50 U/kg i.v.1 also had only a marginal effect. In acquired von Willebrand’s disease, responses to highdose intravenous gammaglobulins have been occasionally described. We gave our patient gammaglobulins, 1 g/kg i.v., for 2 days. This had a tremendous effect on the values of F VIII antigen, F VIII activity, vWF antigen and VW-ristocetin cofactor. All values normalized. The effect appeared within 12 h, was maximal at 6 days and was still measurable after 3 weeks. Colonoscopy was performed after a second intravenous infusion of gammaglobulins. Biopsies could be taken without complications of bleeding. Histopathological investigation showed tubular

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adenoma with slight dysplasia. Acquired van Willebrand’s disease usually occurs in association with monoclonal gammopathies or lymphoproliferative disorders. For treatment of acquired von Willebrand’s disease, it is essential to treat the primary disorder. However, treatment with gammaglobulins can be considered in patients with acquired von Willebrand’s disease who do not respond to classical replacement therapy.

12. Feasibility study with paclitaxel, carboplatin and etoposide in the treatment of patients with adenocarcinoma of unknown primary. A.J. van de Wouw ‘. R.L.H. Jansen *. C. van der Heul i, H.F.P. Hillen ‘. ’ Departmentof Internal Medicine, St. Elisabeth Hospital, Tilburg and 2 Department of Internal Medicine, University Hospital, Maastricht, Netherlands. Carcinoma of unknown primary site (CUP) is defined as the presence of metastatic cancer documented in the absence of an identifiable primary tumour site. Depending on the definition used and the population of patients studied, between 0.5 and 10% of cancer patients will be diagnosed with this clinical entity. In the Netherlands, patients with CUP account for approximately 4% of all cancer diagnoses, i.e. 2400 patients per year. The prognosis of patients with a CUP is poor. Patients who are not treated or do not respond to therapy have a median survival of 2-3 months. Although some favourable subgroups of patients with better responsiveness to therapy can be recognized, over 70% of the patients with CUP, predominantly adenocarcinoma, do not tit into these subgroups. In a phase II study, Hainsworth et al. have demonstrated promising results in patients with CUP with combination chemotherapy of paclitaxel, carboplatin and etoposide. Before further use of this therapy in the advised dose, we performed a feasibility study in our hospitals. We treated 10 patients with metastatic adenocarcinoma, who had never received chemotherapy before, with 200 mg/m2 paclitaxel i.v. in 1 h and carboplatin 6 AUC iv. at day 1 and 10 days etoposide p.o. alternating 50 and 100 mg. The courses were given every 3 weeks, with a minimum of 2 and a maximum of 4 courses. Only the outcome of the first 2 courses was used. Toxicity was scored according to NCIC-CTC criteria. Leucopenia was the most common toxicity. Grade 2 was found in 4 patients, grade 3 in 5 patients and grade 4 in 1. One patient was admitted to the hospital because of neutropenic fever. In only 2 other patients, we noted grade 3/4 toxicity; grade 4 thrombocytopenia and grade 3 myalgia/arthralgia. We conclude that this therapy is feasible and initiated a randomized phase III study comparing paclitaxel, carboplatin and etoposide to 5.fluorouracil and folinic acid in the treatment of patients with ACUP.

13. Prevalence of co-morbidity and its impact on treatment in Hodgkin’s and non-Hodgkin’s lymphoma. D.J. van Spronsen I.‘, M.L.G. Janssen-Heijnen 3, W.P.M. Breed ‘, J.W.W. Coebergh s. ‘Catharina Hospital, Eindhouen, ’ University Hospital, Groningen and ’ The Comprehensive Cancer Centre South (I.K.Z.), Netherlands. Aim; Population-based series are likely to comprise more patients with serious co-morbidity than clinical trials with restrictive eligibility criteria. Since co-morbidity may influence treat-

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ment decisions and may also be an independent prognostic factor, we studied the age-specific prevalence of co-morbidity in lymphoma patients and its relationship with applied treatment in the general health-care environment. Methods: Data on all 191 Hodgkin’s and 885 non-Hodgkin’s patients diagnosed between 1993 and 1996 were derived from the Eindhoven Cancer Registry, that collected data from the medical records according to Charlson. Results; The prevalence of serious co-morbidity was 55% in the Hodgkin and 53% in the non-Hodgkin patients aged 60 years or more. Cardiovascular disease, hypertension, COPD and diabetes mellitus were the most frequent co-morbid conditions in both groups. There was no relationship between the existence of co-morbidity and detection (stage or grade). In the presence of co-morbidity, chemotherapy was applied twice less frequently in elderly patients with Hodgkin’s disease (P < 0.01) and 15% less frequently in elderly patients with intermediate/high-grade nonHodgkin’s lymphoma (P < 0.05). Conclusion; Serious co-morbidity was present in more than half of all lymphoma patients aged 60 years or more. In the presence of co-morbidity, elderly patients received chemotherapy less often. which is likely to adversely affect survival.

14. Life-threatening autoimmune haemolytic anaemia. I. Wauters, E. Monasch. Department of Internal Medicine, St. Lucas Andreas Hospital, Location Andreas, Amsterdam, Netherlands. Symptoms of autoimmune haemolytic anaemia are usually slow and insidious in onset over a period of several months, but cases of fulminant haemolysis have been reported. We saw a previously healthy 38.year-old Surinam woman, who presented with acute jaundice and haemodynamic instability. Physical examination showed a restless icteric women in shock. Respiratory failure developed within minutes which required prompt mechanical ventilation. Laboratory tests showed: haemoglobin 0.9 mmol/l. LDH 7095 UA, bilirubin 96 pmol/l, mainly unconjugated and undetectable haptoglobin levels. The Coombs’ test was positive: IgG-warm antibodies. A diagnosis of severe autoimmune haemolytic anaemia was made. In order to prevent ongoing haemolysis, we infused 1000 mg of methylprednisolone, after which careful transfusion, initially of two units of 0 Rh-negative followed by two units of B Rh-negative blood. was given, which resulted in an Hb of 4.5 mmol/l within 24 h. indeed suggesting prompt termination of haemolysis by methyl-prednisolone. Mechanical ventilation was discontinued and there was a rapid and complete recovery of the patient’s condition. In the serum, Rhesus anti-e autoantibodies and non-specific antibodies (Rhesus-related) were present. Despite careful investigation, we could not detect an underlying disorder. The patient was discharged after 1 week. During out-patient control, the dosage of prednisolone was lowered to a maintenance dose of 2.5 mg/day. At this time, the patient is well, the haemoglobin is 8.0 mmol/l, there are no demonstrable signs of haemolysis and the Coombs’ test has become negative. Our patient’s condition did not deteriorate further after mechanical ventilation. Mechanical ventilation seems to be a factor which may have saved our patient’s life. In this case, the physically soluted oxygen fraction is of utmost importance as

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it is almost equal to the haemoglobin-bound fraction. Only a few cases of nearly fatal autoimmune haemolysis of warm antibody type are described, and it seems that in these cases of life-threatening autoimmune haemolytic anaemia, one should not hesitate to administer high-dose corticosteroids as soon as possible in order to suppress haemolytic activity.

15. Castleman’s disease: benign or malignant? B.L.A.M. Weusten t, C.D. Kooijman 2, S. Wittebol ‘, Ph.M. Kluin 3, M.H.H. Kramer ‘. Departments of ’ Medicine and 2 Pathology, Eemland Hospital, Amersfoort and 3 Department of Pathology, Uniuersity Hospital, L&den, Netherlands. Background: Castleman’s disease is a rare disorder with a variable course. The possible benign or malignant nature of this disorder is subject to controversy. Associations between Castleman’s disease and malignant lymphoma have been described earlier, although scarcely. Case; A 49-year-old woman presented with fatigue, anorexia, and 10 kg of weight loss. Physical examination was grossly normal. Laboratory tests revealed a high erythrocyte sedimentation rate (125 mm/h) and a microcytic anaemia (Hb 5.4 mmol/l. MCV 70 fl). Extensive mediastinal lymphadenopathy and massive retroperitoneal lymph node enlargement was seen on CT scanning. Histological examination of the mediastinal lymph nodes revealed a Castleman’s lymphoma (plasma cell type), whereas the retroperitoneal lymph nodes consisted of a follicular CcCb nonHodgkin’s lymphoma. As expected, bcl-2 staining showed a strongly positive, homogeneous reaction of the lymphoid follicles in the abdominal lymphoid tissue. Within the mediastinal Castleman’s lymphoma, however, some parts of the follicle centres were also strongly positive for bcl-2. Clonal immunoglobulin heavychain (IgH) rearrangements were assessed using a polymerase chain reaction with primers specific for the CDR3 region. Clonal IgH rearrangement was found in the follicular lymphoma from the resected abdominal tissue. In the mediastinal Castleman tissue, a dominant clone was encountered as well. The dominant clone found in the Castleman tissue corresponded with the one encountered in the abdominal follicular lymphoma. Conclusion: We describe a patient with a plasma cell type Castleman’s disease with a concomitant follicular B-cell nonHodgkin’s lymphoma. The common monoclonal component of the B-cell non-Hodgkin’s lymphoma and Castleman’s lymphoma in our patient, in addition to tbe observation of fields of bcl-2-positive cells in the Castleman’s lymphoma, might be consistent with the view of Castleman’s disease as a premalignant disease.

III. Blood coagulation 16. Simplification of the diagnostic management of out-patients with symptomatic deep vein thrombosis with r4imer measurements. E.A.M. Beckers ‘, R.A. Kraaijenhagen 2, N. van der Laan ‘, B.J. Potter van Loon ‘, M.M.W. Koopman 2, L. Rossi 3, F. Verlato 3, F. Piovella 4, S. Siragusa 4, H.R. Biiller ‘.

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’ Department of Internal Medicine, Sint Lucas Andreas Hospital, 2 Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, 3 Institute of Medical Semeiotics, University Hospital, Padua and 4 Medicina Intema ed Oncologia Medica, University of Pauia, Italy. Background: Previous studies indicated that only 2-8% of patients with suspected deep vein thrombosis (DVT) and a normal compression ultrasonographic (CUS) result at referral, will have an abnormal test upon repeated testing. To detect this small subset of patients, it is necessary to repeat the ultrasound in all patients with an initial normal CUS result. Early identification of those patients, with serial normal CUS, would further simplify the diagnostic management. We hypothesized that a normal SimpliRED Ddimer assay, in combination with an initial normal CUS result, would exclude DVT at referral and make repeated testing unnecessary. An alternative strategy would be to use a clinical suspicion score. Patients and methods: All consecutive out-patients suspected of having DVT were prospectively and independently assessed by a standardized clinical decision rule (CDR) (Wells, 19951, a CUS test and a SimpliRED o-dimer test. Only patients with a normal CUS and an abnormal SimpliRED were seen for repeated CUS. All patients were followed-up for the occurrence of symptomatic venous thromboembolism over a 3-month period. Preliminary results: A total of 1201 patients were included; the prevalence of DVT was 21%. The sensitivity, specificity and negative predictive value of the SimpliRED compared to the CUS were 96, 62 and 98%, respectively. Of the 588 patients with a normal SimpliRED and a normal CUS result at baseline, three patients had an objectively confiied symptomatic venous thromboembolic event during follow-up (failure rate 0.5%). Interpretation: These preliminary data support the hypothesis that it is safe to withhold repeated testing in patients with suspected deep vein thrombosis with a normal CUS and a normal SimpliRED at presentation. Whether the CDR will be of additional help in predicting the risk of venous tbromboembolic complications in these patients needs to be determined.

17. Persistent thromhophilia despite disappearance of APC resistance. D.H. Biesma ‘, R.A. de Man 3, H.K. Nieuwenhuis 4, F.J.L.M. Haas 2. Departments of’ Internal Medicine and ’ Clinical Chemistry, St. Antonius Hospital, Nieuwegein, 3 University Hospital, Rotterdam and ’ University Hospital, Utrecht, Netherlands. Case: In January 1992, a 45-year-old female patient presented with deep venous thrombosis of her right leg and pulmonary embolism. In October 1992, while receiving only phenprocoumon therapy, jaundice became apparent. Laboratory investigations showed signs of severe cholestatic hepatitis, but serological tests for hepatitis A, B, C, and E and immunological tests for autoimmune hepatitis all remained negative. Despite discontinuation of phenprocoumon, her condition worsened with encephalopathy progressing to grade III, resulting in the need for an acute orthotopic liver transplantation. She received antirejection therapy with prednisone and cyclosporin. In August 1996, she was readmitted with thrombosis of the right popliteal vein. Activated

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protein C (APC) resistance was not detected. However, analysis of DNA extracted from lymphocytes showed that she was heterozygous for the factor V mutation (factor V Leiden). We performed a polymerase chain reaction @CR) for factor V Leiden on frozen biopsy materials of her own liver and of the transplant. PCR for factor V Leiden performed on her own liver was positive, whereas PCR did not detect factor V Leiden in the transplanted liver. The venous thrombosis was successfully treated with low molecular weight heparin. Discussion: Our patient showed phenotypic correction of APC resistance after liver transplantation, which was confirmed by a positive PCR for factor V Leiden on the patient’s own liver and by a negative PCR for factor V Leiden performed on specimens of the transplanted liver. Despite the inability to demonstrate APC resistance in the patient’s plasma after liver transplantation, a thrombotic event occurred 4 years later. This might be explained by the increased risk of thrombosis due to cyclosporin-induced hypercoagulability. A more intriguing explanation, however, can be the role of platelet factor V. Coagulation factor V is distributed in two fractions in blood. Approximately 80% circulates in plasma, whereas 20% is stored in the a-granules of platelets. Human megacaryocytes are able to synthesize factor V, which will be resistant to inactivation by APC in our patient, The attribution of platelet factor V Leiden to persistent thrombophilia in our patient may not be underestimated, because platelet factor V concentration exceeds over 600-fold the plasma factor V concentration within a platelet aggregate. Although liver transplantation led to disappearance of APC resistance in plasma, it is likely that factor V Leiden derived from platelets contributes largely to the persistent prothrombotic state in this patient.

18. Home-monitoring and self-management of oral anticoagulant therapy. M. Cromheecke, M. Levi, B.A.J.M. de Mol, E. Brie& M.H. Prins, J.W. ten Cate. Departments of Internal Medicine, Cardiovascular Surgery and Clinical Epidemiology, Academic Medical Centre, Amsterdam, Netherlands. Background and aim: Coumarin therapy is an effective modality for the prevention and treatment of thromboembolic events. However, the effect of coumarins is variable, necessitating frequent laboratory control and dose adjustments. Nevertheless, for a large number of patients, the intensity of anticoagulation is often not in the therapeutic range. In addition, the visits to the anticoagulation laboratory are, for some patients, inconvenient. Recently, small devices have become available, allowing the determination of the INR from capillary blood. Application of these devices may result in self-monitoring of anticoagulation and self-adjustment of the coumarin dose, potentially associated with improved control of anticoagulation. The aim of this study was to assess the feasibility, safety and reliability of self-management of oral anticoagulant therapy. Methods: Patients (n = 15) with a chronic indication for oral anticoagulation were educated to perform self-measurement of the INR and to adjust their coumarin dose. Hereafter, for a period of 6 weeks, patients determined their INR at weekly intervals and proposed a dosing scheme for the next period. On the same day of

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self-measurement, the INR was determined and a dosing scheme was established at the anticoagulation clinic. Results: All patients were able to perform home-monitoring of the INR. Home INR was less than 1 .O different from anticoagulation clinic INR in 945% of measurements. The mean + SD difference between home INR and anticoagulation clinic INR was 12.3 & lO.l%, with less variability in lower INR ranges and larger variability at INR values > 5.0. There was no significant difference in patients within or outside the therapeutic target range based on home INR vs. clinic INR. The total coumarin dose per week based on the home INR as compared with the clinic INR was less than 20% different in 95.6% of the weeks, and less than 10% different in 84.5% of the weeks. Patients were very well able to properly design coumarin dosing schedules (98.5% correct schemes). Conclusion; Home-monitoring of INR is feasible with an acceptable reliability of the test result as compared with an anticoagulation clinic setting. After proper education, patients are, in principle, able to self-manage their anticoagulation dose. Ongoing studies focus on the quality of anticoagulation control by self-management as compared with anticoagulation clinic-guided control and the effect on quality-of-life parameters.

19. The use of a rapid blood test in the diagnostic work-up for pulmonary embolism: preliminary results of a management study. M.R. de Groot ‘, H.R. Biiller 6. J.W. ten Cate ‘, A.H. Engelage 2, .I. Pouwels 3, A.F. Kuipers 4. E.P. Born 5, M. van Marwijk Kooy ‘. Departments of ’ Internal and 2 Nuclear Medicine, ’ Clinical Chemistry, 4 Pulmonary Disease and ’ Radiology, Sophia Hospital, Zwolle and 6 Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, Amsterdam, Netherlands. The SimpliRED (SR) whole blood D-dimer has been shown to be a simple and reliable method to exclude pulmonary embolism (PE) in the majority of patients. In an ongoing study, we test the safety and efficacy of incorporating the SR test in the diagnostic work-up of patients with suspected PE. Methods: The prospective study started in August 1996. An SR and ventilation/perfusion (V/Q) scan are done in all consecutive patients presenting with suspected PE. In the case of a normal or high probability V/Q scan, antithrombotic therapy is initiated or withheld, respectively, irrespective of the SR test result, When a non-diagnostic (ND) (not normal/high) V/Q scan is coupled with a negative SR, no additional diagnostic tests are performed, unless high clinical suspicion persists. In that case, as well as in patients with a ND V/Q scan and a positive SR, ultrasonography (US) of the legs and, if necessary, pulmonary angiography (PA) are performed to define a subgroup requiring long-term antithrombotic therapy. All patients are followed up for 3 months, Results: Follow-up has been completed in 161 patients. The V/Q scan was classified as normal in 44 (27%), and high-probability in 24 (15%) patients (2 negative SR test results occurred in the last group). The SR test was negative in 47 of 93 patients with an ND scan. Because of a persistent high clinical suspicion, US and PA were performed in 6 of those 47 patients yielding 1 PE. In

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9 of 46 patients with a positive SR and ND scan, PA was not done. Six because an alternative diagnosis clearly could explain the ND scan defects, the other 3 patients started with long-term anticoagulation without confirmation of PE by PA for various reasons. In the remaining 37 patients of the ND V/Q scan group and with positive SR, US yielded deep venous thrombosis in 5 patients (4 symptomatic) and PA pulmonary embolism in 3 patients. Thus, in 81 out of 93 patients in the ND group, long-term anticoagulation was not instituted. None of the 81 patients developed symptomatic venous thromboembolism during the follow-up period. Conclusion: The preliminary results support the hypothesis that incorporating the SR test in the diagnostic work-up for PE is safe and leads to a significant decrease in US and PA when used supplementary to the V/Q scan result.

20. Lack of association between von Willebrand’s disease phenotype and genotype in families identified in an epidemioIogical survey. J.C.J. Eikenboom ‘, G. Castaman ‘, R.M. Bertina I, F. Rodeghiero ‘. ’ Deparhn e n to f Haematology, L&den University Medical Centre, L.&den, Netherlands and ’ Department of Haematology, San Bortolo Hospital, Vicenza, Italy. In a previous epidemiological investigation, we found a prevalence of von Willebrand’s disease (VWD) of about 1% in the general population. This prevalence was much higher than expected. All patients fitted the criteria for VWD type 1. VWD is caused by defects at the von Willebrand’s factor (VWF) gene locus and the inheritance of type 1 is considered to be autosomal dominant. In the present study, we have investigated, in the families identified in the epidemiological survey, whether the VWD phenotype co-segregates with VWF gene polymorphisms. Eleven of the 14 previously identified VWD patients agreed to participate in the genetic study. In all patients and their family members, the bleeding history was evaluated and clinical records were reviewed; factor VIII procoagulant activity, VWF antigen, and VWF ristocetin cofactor activity were measured; and haplotype analysis was performed using two variable-number tandem repeat polymorphisms in intron 40 of the VWF gene and one RsaI dimorphism in exon 18. On retesting, the diagnosis of VWD was confirmed in 10 of the 11 previously identified patients. Clear co-segregation of the VWD phenotype and a specific VWF allele was only observed in one family. In five patients and their families, we observed a complete lack of association between the VWD phenotype and genotype. In the remaining five patients and their families, the data are inconclusive; linkage could not be rejected nor firmly established. The clinical records were reviewed to determine the relevance of the diagnosis VWD made in the population study. Over a 13-year period, four of the members of the family with clear co-segregation required treatment. Of the remaining ten families, only six individuals sought advice for prophylaxis or treatment for minor bleeding. In five families, none of the members needed treatment. This indicates that the prevalence of clinically relevant VWD is lower than the 1% estimated from population studies. We conclude, that in these families, which were identified by screening of a general population, there

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is lack of association between the VWD phenotype and markers at the VWF gene locus. This lack of linkage may be due to misdiagnosis or variability in expression of VWD, recessive rather than dominant inheritance, or to defects or modulating factors outside the VWF gene locus. Despite all shortcomings, phenotypic diagnosis still remains the only tool for VWD to identify patients at risk of bleeding.

21. Correction of the bleeding time by the infusion of fibtiogen-coated albumin microcapsules in severely thrombocytopenic rabbits. P. Friederich, M. Levi, S. Middleton, B. Biemond, J. Levin, J.W. ten Cate. Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands, Andan’s Ltd., Nottingham, UK and University of California School of Medicine, San Francisco, CA, USA. Background and aim: Severe thrombocytopenia, for example after chemotherapy or in patients with autoimmune thrombocytopenia, may result in potentially serious bleeding. Current treatment strategies may be effective, but are often associated with several drawbacks, such as the occurrence of antiplatelet antibodies in patients receiving allogeneic platelet transfusion. We have developed albumin microcapsules (0.d. 3.0 Frn) to which human fibrinogen has been linked (Synthocytes), and which may act to improve primary haemostasis. The aim of this study was to assess the effect of Synthocytes on the prolonged bleeding time in severely thrombocytopenic rabbits. Methods: Rabbits were anaesthetized and a catheter was installed into a jugular vein for administration of compounds. All rabbits received an i.v. bolus infusion of polyclonal goat antirabbit platelet antibody. At 60 min thereafter, the rabbits were randomized (n = 6 per group) to receive an i.v. bolus injection of: (1) Synthocytes (1.5 X lo9 microcapsules/kg); (2) Synthocytes (0.75 X lo9 microcapsules/kg); (3) control albumin microcapsules (1.5 X lo9 microcapsules/kg); or (4) saline. Bleeding time was measured in the ear using a standardized protocol and a Surgicutt device by an operator who was not aware of the treatment. Results: In all 4 experimental groups, the infusion of the antiplatelet antibody resulted in a drop in mean platelet count from 452 X 109/1 to 23 X 109/1, which was associated with a prolongation of the bleeding time from 1.77 + 0.4 to 21.65 + 4.4 min. The administration of Synthocytes resulted in a significant correction of this prolonged bleeding time: 15 min after the infusion of 1.5X109/kg or 0.75X109/kg Synthocytes, the bleeding time was 5.2+ 1.7 and 6.5* 1.7 min, respectively, whereas the bleeding time in the 2 control groups remained prolonged (20.6+ 2.6 min, P < 0.001 by ANOVA). At 75 min after the infusion of Synthocytes, the bleeding time was 4.25 + 0.8 and 8.75 +2.1 min in rabbits receiving Synthocytes (1.5 X 109/kg or 0.75 X 109/kg, respectively), as compared with 21 .l f 4.0 min in both control groups (P < 0.01). Conclusion: The administration of Synthocytes results in a reduction of the prolonged bleeding time in rabbits made thrombocytopenic with platelet antiserum. Studies in non-immune models of thrombocytopenia and with longer observation periods are currently ongoing.

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22. The prevalence of the 20210 G -+ A mutation of the protbrombin gene in patients with stroke, myocardial infarction and peripheral arterial disease. V.E.A. Gerdes ‘, D.P.M. Brandjes ‘, H.R. Bliller ‘, H. ten Cate ‘,4, V. Kwa ‘, P.H. Reitsma 4 on behalf of the Amsterdam Vascular Medicine Study Group. ’ Department of Internal Medicine, Sloteroaart Hospital, Amsterdam, Departments of 2 Vascular Medicine and -’ Neurology and 4 Laboratory of Experimental Internal Medicine, Academic Medical

Centre,

Amsterdam,

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discordance with the latter study, we did not find an association between the prothrombin mutation and clotting activation, possibly because of the high levels of activation in the whole study group. Further studies are needed to establish the factors that determine which individuals with the prothrombin mutation are at high risk of developing CVD, given the high prevalence in the general population.

Netherlunds.

Atherosclerosis is a multifactorial disease in which several inherited and acquired risk factors play a role. Probably other still unknown factors contribute to the disease. Recently, a mutation in the untranslated region of the prothrombin gene (nucleotide 20210 G -+ A) was identified as a novel risk factor for venous thrombosis (Poort et al. Blood 1996) In addition, this mutation appeared to be a risk factor for cardiovascular disease (CVD) in two separate cohorts of individuals with premature atherosclerosis (Roosendaal et al. Blood 1997;90:1747-1750; Franc0 et al. Blood 1997:abstr. 1126). The prevalence of the prothrombin mutation was examined in 277 patients from whom DNA samples were available for analysis, out of 307 consecutive patients with proven atherosclerosis. The patients were classified according to previous events: stroke (St, n = 103); myocardial infarction (MI, II = 97); and peripheral arterial disease (PAD, n = 107). The mean age was 61.8 years. For comparison, we utilized the prevalence data from a large cohort compiled from different regions in northwestern Europe (MalmG, Manchester, Sheffield, Amsterdam and Leiden), which comprised a total of 2756 healthy individuals. The frequency of the mutation in the patient group was 3.97% (11 out of 277) and 1.63% (45 out of 2756) in the control group, yielding an odds ratio for the mutation of 2.49 (95% CI 1.20-5.06, P = 0.006). Most mutations were confined to patients with either MI (5 out of 97), or PAD (4 out of 107). while only 2 stroke patients had the mutation (1.94%; OR 1.32, 95% CI 0.15-5.21). Odds ratios for MI (3.77, 95% CI 1.14-9.81, P = 0.01) and MI or PAD (3.12, 95% CI 1.40-6.75, P = 0.004) were moderately, but significantly, increased. Unexpectedly, all mutations were found in male patients, which may be partially explained by the high percentage of males in the MI (81.4%) and PAD (66.3%) groups. The presence of hypertension, hypercholesterolaemia, elevated homocysteine or smoking did not significantly influence the risk. None of the carriers had diabetes. The levels of prothrombin fragment 1+2 (Fl + 2) and thrombin-antithrombin complexes (TAT) were in the same range in carriers and non-carriers of the mutation in our study group (mean, respectively, 1.60 vs. 1.78 nmol/l for Fl + 2. 4.93 vs. 5.81 pg/ml for TAT). Because of the elevated levels of clotting activation in the whole group, we did not find support for the previous hypothesis that the mutation is associated with enhanced clotting activation. Our findings suggest that the 20210 G --t A mutation in the prothrombin gene is a moderate, but significant, risk factor for myocardial infarction and peripheral arterial disease, but not for stroke, in elderly individuals. The presence of other established risk factors did not significantly influence the risk. In our study, all carriers were male, which contrasts with a previous study in younger individuals ( < 50 years) in whom the relative risk of CVD and MI was greatest in females (Franc0 et al. Blood 1997:abstr. 1126). In addition, in

23. ICARVS: the incidence of venous thromboemboliim in asymptomatic carriers of the FV Leiden mutation: preliminary results of a prospective cohort study. S. Middeldorp, J.R. Meinardi, M.M.W. Koopman, E.C.M. van Pampus, K. Hamuly&k, J. van der Meer, M.H. Prim, H.R. Biiller. Academic Medical Centre,

Amsterdam,

University

Hospital,

Groningen

sity Hospital, Maastricht, Netherlands. Background: The FV Leiden @V:Q506)

and

Uniuer-

mutation is a common genetic defect associated with an increased risk of venous thromboembolism (VTE), but the annual incidence in asymptomatic carriers of the mutation is unknown. We are performing a multicentre prospective cohort study in asymptomatic carriers of the mutation to determine the annual incidence of VTE and the relationship with concomitant risk situations. Methods: Asymptomatic carriers of the FV:Q50h mutation were recruited by means of family studies of consecutive, unselected patients with venous thromboembolism and the mutation, Their first-degree relatives who were older than 15 years of age were asked to participate in the study; the heterozygous and homozygous subjects who had not had VTE previously were included. Whenever any symptom indicating the possible presence of VTE occurred, appropriate objective tests were performed. No anticoagulant prophylaxis was given, except during high-risk situations (according to the physician’s preference). The incidence of VTE was calculated. Results: A total of 314 subjects (144 male, 170 female) with a mean age at onset of the study of 43 years (range 15-88 years) were included in the study. A total of 421 observation years could be studied. The average duration of observation per subject was 16 months (range 0.5-30 months). Three thromboembolic events occurred in 3 male subjects, resulting in an overall annual incidence of VTE of 0.7% (95% CI 0.2-2.1). The incidences of VTE in relation to concomitant high-risk situations were calculated: spontaneous VTE, O.S%/yea.r (0. 1 - 1.7); surgery-related VTE, 14%/risk situation (0.4-57); pregnancy-related VIE, O%/pregnancy (o-70); VTE related to use of oral contraceptives, O%/year of use (O-7.0). Conclusions: Our preliminary results indicate a low risk of spontaneous VTE in carriers of the FV Leiden mutation. The observed incidence of VTE appears to be lower than the reported risk of major and fatal bleeding under adequate oral anticoagulant prophylaxis. This indicates that continuous anticoagulant prophylaxis is not warranted in asymptomatic subjects with the FV Leiden mutation. The optimal prophylactic approach in high-risk situations, however, remains unsure.

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24. Activation of clotting factor XI, without detectable contact activation in experimental human endotoxaemia. M.C. Minnema, D. Pajkrt, W.A. Wuillemin, W.K. Bleeker, M. Levi, S.J.H. van Deventer, C.E. Hack, H. ten Cate. Centre for Haemostasis and Thrombosis, Laboratory of Experimental Internal Medicine and Laboratory of Immunology, Academic Medical Centre, Amsterdam, Netherlands. According to the revised model of coagulation, factor Xl is activated by thrombin and is primarily involved in sustaining thrombin formation. However, there is no evidence for such a mechanism occurring in vivo. We investigated the activation of factor Xl in relation to thrombin formation and to activation of the contact system in 8 healthy volunteers after infusion of a low dose of endotoxin (4 rig/g of body weight). Previous studies have indicated that endotoxin-induced coagulation activation is solely dependent on the tissue factor-factor VIla complex (the extrinsic pathway). Activation of prekallikrein, factor XII, factor Xl and prothrombin was measured with sensitive ELISAs, and, in addition, factor Xl activation was measured with a novel enzyme-capture assay which detects non-complexed factor XIa. Activation of factor XI was apparent with a significant plasma peak level of non-complexed factor Xla of lo-11 pmol/l at 1 and 2 h, followed by a gradual increase in factor Xla-factor Xla inhibitor complexes, measured in the ELlSAs, with a summit of 1 l- 15 pmol/l at 6 and 24 h. The activation of factor Xl was accompanied by a significant decline in factor Xl antigen levels after 2 h of rfi lo%, which returned to baseline values at 24 h. In accordance with previous studies, thrombin generation was detected 1 h after the endotoxin infusion to be maximal after 3-4 h, while an increase of factor XlIaor kallikrein-Cl-inhibitor complexes was not detected. These data strongly suggest that during experimental endotoxaemia, factor XI is activated independently of factor XII by a thrombin-dependent mechanism.

25. Is home-treatment of deep venous thrombosis feasible in today’s primary care? W. Nieuwland i, C.H.M. Reker 2, L. Wijnja ’ I Department of Internal Medicine and 2 Department oj Health Care Management Consultancy, Martini Hospital, Groningen, Netherlands. Introduction: Home-treatment (HT) of deep venous thrombosis (DVT) has been demonstrated to be a safe therapeutic modality according to some recent studies. However, implementation of HT might be confronted with practical problems. Therefore, we evaluated implications for hospital and primary care, incidence of (short-term) complications and hurdles in HT of DVT. Patients and methods: A protocol for HT of DVT was developed in close cooperation between hospital and several care-givers in primary care (i.e. general practitioner (GP) and home-care nurses). Patients with suspected DVT were referred by their GP for diagnostic evaluation (clinical examination, compression ultrasonography or venography). After confirmation of the diagnosis of DVT, patients were treated with subcutaneous low molecular weight heparin (nadroparin) administered at home by home-care nurses; further treatment and follow-up was conducted by the GP. When HT was contraindicated, patients were treated as in-pa-

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tients. Patients younger than 40 years and without other risk factor for DVT were screened for inherited thrombophilia (IT). Results: During 7 months (April-November 19971, 104 patients (57.6 f 16.8 years) were referred for diagnostic evaluation. DVT was diagnosed in most patients (n = 62, 60%; 57.5 f 15.6 years; male:female 29:33 (47:53%)). In patients with no DVT (n = 42), we diagnosed, in particular, (ruptured) Baker’s cyst (24%), cellulitis/erysipelas (16%), or muscle or joint lesions (22%). Most DVT patients were treated at home (n = 36; 70%; 55.3 + 5.6) and no treatment-related complication was observed. IT was screened in 16 patients (26%); 8 were tested to have IT (i.e. antiprotein C resistance, protein C-, antithrombin Ill-, and protein S-deficiency; respectively, 5, 1, 1 and 1). The mean prevalence of DVT proved to be l-2 a year for a GP. This new HT protocol was implemented without great problems (only some minor problems; e.g. availability of nadroparin during the first day, or unfamiliarity with the treatment protocol of a few substituting GPs) and was welcomed with enthusiasm by patients, GPs and home-care nurses. Conclusion: Most patients with DVT ( > 60%) can be treated at home. This HT of DVT was implemented in primary care in our region without major problems or complications. The protocol proved to be a valuable tool for successful implementation and continuation of HT of DVT.

26. The incidence of venous thromboembolism in asymptomatic carriers of a marker of thrombophilia. B.J. Sanson, P. Simioni, M.H. Prins on behalf of the TACT study group. Department of Clinical Epidemiology and Biostatistics and Centre for Haemostasis, Thrombosis, Atherosclerosis and Injlammation Research, Academic Medical Centre, Amsterdam, Netherlands. Objectiue: To assess the incidence of venous thromboembolism (VTE) in asymptomatic subjects with a deficiency of either antithrombin (AT), protein C (PC) or protein S (PSI. Methods: Family members of unselected patients with documented VTE and one of the aforementioned deficiencies were asked to participate in this multicentre prospective cohort study. Only asymptomatic deficient subjects were included. The subjects were contacted every 6 months and instructed to present with any symptom indicating the possible presence of VTE. In such a situation, a clinical assessment was made and appropriate objective tests were performed. No continuous anticoagulant prophylaxis was given, except during high-risk periods (i.e. surgery, trauma, immobilization, pregnancy and puerpetium). The incidence of VTE, both spontaneous and risk-related, was calculated. Results: A total of 208 subjects (95 male, 113 female) from 94 families were included in the study. Of these, 45 were AT-deficient (21.6%), 93 were PC-deficient (44.7%) and 70 were PS-deficient (33.6%). The average age at onset of the study was 37.1 years (range 15-79 years). There was a total of 611 observation years. The average duration of observation per subject was 3 years (range 0.3-4.6 years). Five spontaneous venous thromboembolic events occurred, resulting in an annual incidence of 0.8%/year (95% Cl 0.3-1.9). Forty-two subjects experienced 48 risk periods (11 surgery, 11 trauma, 4 immobilization, 8 oral contraceptive treatments, 9 pregnancies and 5 others). Four risk-related throm-

A24

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1998/Netherlands

boembolic events occurred, one of which under adequate prophylactic treatment, resulting in an incidence of 8.3%/period (95% CI 2.3-21.3). Conclusion: The observed incidence of spontaneous venous thromboembolism is lower than the reported risk of major and fatal bleeding under adequate oral anticoagulant prophylaxis. This would indicate that anticoagulant prophylaxis is not warranted in asymptomatic deficient subjects, except during high-risk periods.

27. The half-lie of infused factor VIII in patients with haemophilia is influenced by ABO blood group. A.J. Vlot I.*, E.P. Mauser-Bunschoten’, A.G. Zarkova4. E. Haan ‘, C.L.J.J. Kruitwagen 3, J.J. Sixma ‘, H.M. van den Berg I 1 uan &weld Clinic and 2 Department of Haematology, Graduate School of Biomembranes, University Hospital, Utrecht, ’ Centre for Biostatistics, University of Utrecht, Utrecht, Netherlands and 4 National Centre of Haematology and Transjiuion, Sojia, Bulgaria. To investigate the large inter-individual variation in half-life of infused factor VIII, we infused a recombinant factor VIII concentrate in a group of 25 patients with haemophilia A: 18 brothers from 9 families, and 3 and 4 brothers from 2 families, respectively. Familial clustering was significant for ABO blood group (P < 0.0011, but could not be detected for factor VIII half-lives or preinfusion von Willebrand’s factor (vWF:Ag) levels. We subsequently analyzed pharmacokinetic data of a larger group of haemophiliacs, comprising a total of 39 pharmacokinetic studies performed in 32 patients with either monoclonally purified or recombinant factor VIII concentrates. The mean factor VIII halflives of both concentrates were similar (18.2k5.0 vs. 17.6k4.1 h). Factor VIII half-lives were normally distributed, whereas vWF:Ag levels were skewed to the right. vWF:Ag levels were positively correlated with factor VIII half-life (r = 0.52, P = 0.002), i.e. each variable is associated with about 27% of the variance of the other. ABO blood group frequencies of the 32 patients were: group A, 23 (72%); group 0, 8 (25%); and group B, 1 (3%). The median vWF:Ag level in patients of blood group A (1.25 U/ml) did not differ from blood group 0 (1.29 U/ml) (P = 0.84). Patients with blood group 0 exhibited a statistically significant shorter factor VIII half-life (15.3 + 2.6 h) than patients with blood group A (19.7 +4.5 h) (P = 0.003). The relationship of the variables age, length, body weight, factor VIII gene inversion, vWF:Ag level, ABO blood group, and Rhesus phenotype to the dependent variable factor VIII half-life was assessed by multiple linear regression analysis. vWF:Ag level (P = 0.001) and ABO blood group (P = 0.003) were the only significant predictors of factor VIII half-life, both independent of each other. These data indicate that the factor VIII half-life in patients with haemophilia A is influenced by ABO blood group. A possible mechanism might be that the presence of ABO blood group determinants on vWF affects the clearance of vWF. and subsequently the half-life of infused factor VIII.

28. Me&analysis of studies evaluating once daily subcutaneous low molecular weight heparins versus unfractionated heparin in the treatment of deep-vein thrombosis. M.I.E. van

Journal

of Medicine

52 (1998)

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Poelgeest, M.V. Huisman. Department of General Internal Medicine, Leiden University Medical Centre, Leiden, Netherlands. Background: Low molecular weight heparins (LMWH) have the potential to improve the initial treatment of patients with deep-vein thrombosis (DVT) because they can be administered by subcutaneous injection once or twice daily without laboratory monitoring. Recent pharmacological studies have shown that a once daily regimen of LMWH might exhibit a sustained effect during 24 h, making such an approach attractive for the treatment of DVT on an out-patient basis. Several studies evaluating a once daily S.C. LMWH regimen have been published. Methods: We performed a meta-analysis of all randomized clinical studies comparing a once daily regimen of subcutaneous LMWH with standard intravenous unfractionated heparin (UFH), in order to evaluate the efficacy and safety of once daily S.C. LMWH in the treatment of patients with DVT. Only studies were eligible for analysis which had objective outcome parameters of recurrent venous thromboembolism (VIE) and major bleeding during 3 months of anticoagulant treatment. Odds ratios (OR) and their 95% confidence intervals (CD were calculated using the modified Mantel-Haenzel method. Results: Three studies evaluating Dalteparin (all three had an identical design and could therefore be pooled), one evaluating Tinzaparin and one evaluating Enoxaparin were included. All patients were initially treated in hospital. Recurrent VTE occurred in 31 of 849 (3.7%) LMWH-treated patients and in 32 of 876 (3.7%) UFH-treated patients (OR 1.0, 95% CI 0.60-I .65). The studies showed heterogeneous results with regard to the number of recurrences of VIE. Major bleeding was observed in 6 (0.7%) of the 849 LMWH-treated patients and in 25 (2.9%) of the 876 UFH-treated patients (OR 0.24, 95% CI 0.10-0.59). Conclusions: This analysis shows that for treatment of deepvein thrombosis, a once daily regimen of S.C. LMWH is as effective and significantly safer than standard i.v. UFH, although the studies showed heterogeneous results with regard to effectiveness. This practical treatment regimen with its ease to the patient is thus potentially the treatment of choice for home treatment of DVT. To prove this hypothesis, studies are necessary that compare standard in-hospital treatment using continuous i.v. UFH vs. LMWH administered once daily by S.C. injection on an out-patient basis.

IV. Lung diseases 29. Eosinopbilia in active tuberculosis. A.A.M. Zandbergen, F.H.J. Wolthagen, J.C.E. Meek, A. Dees. Departments of Internal and Pulmonary Medicine, Ikazia Ho,spital, Rotterdam. Netherlands. Background: Eosinophilia is usually observed in patients with autoimmune or tropical disease. Its presence in chronic tuberculosis has been described incidentally. In a survey of patients treated for active tuberculosis in our departments, the incidence of eosinophilia was investigated. The data of 60 consecutive patients were analyzed. Severe eosinophilia was found in one patient (l/60, < 2%).

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Case: A 36-year-old Pakistani woman complained of weak ness and a painful neck. Her medical history was unremarkable and revealed no specific environmental conditions. Physical examination demonstrated submandibular and supraclavicular lymphadenopathy. Laboratory investigation showed eosinophilia, the total blood eosinophil level was 1290X 106/1 (normal 50-400) and white blood cell differential count showed 18% eosinophils. The chest X-ray showed a few nodular opacities in the right lung and hilus, suspect of previous pulmonary tuberculosis. Histological examination of a lymph node revealed gmnulomar inflammation with necrosis. Tuberculosis was diagnosed and treatment was started (isoniazid, pyrazinamide, rifampicin and ethambutol). Initially, a slight increase in lymphadenopathy and eosinophilia was noted (up to an eosinophil level of 2500X 106/1 and 30% eosinophils in the cell count). An extensive serological and pamsitological work-up was performed: repeated stool, sputum and serum examination and serological tests remained negative. After 9 months of antituberculous therapy, the lymphadenopathy had resolved completely, and the eosinophil level had dropped to normal. Mechanism: It has been suggested that a hypersensitivity reaction to mycobacterial antigens can cause eosinophilia in patients with active tuberculosis. A transient deterioration of the eosinophilia during the initial period of drug treatment is occasionally seen. This phenomenon is explained by the same mechanism. Conclusion: Eosinophilia might be present in tuberculosis. There is evidence in the literature that this is more commonly observed in chronic disease, as demonstrated here in a female who presented with an extrapulmonary type of tuberculosis.

30. Idiopathic chylopnemnothorax? J.A.E. Somers, P.M. v.d. Berg. Department of Pulmonary Diseases, Menvede Hospital, Dordrecht, Netherlands. A 77.year-old, previously healthy male complained of dyspnoea, weight loss and difficulty in swallowing. A right-sided chylopneumothorax was diagnosed. Extensive additional examinations did not show a causal disease, although bronchoscopy revealed a very small tumourous process in the right lower lobe, histologically believed to be a carcinoid. Mycobacterium was cultured from the chylus; 6 weeks later, determination proved it to be a Mycobacterium auium. He was treated in a conservative way with continuous tube drainage, total parenteral nutrition and tuberculostatics. Because symptoms did not improve, surgical intervention with transthoracic ligation of the thoracic duct took place. During surgery, no malignancy could be detected. After surgery, respiratory failure developed; the patient died several days later. Postmortem examination showed a severe bronchopneumonia; macroscopic examination gave no suspicion of malignancy. At microscopic examination a diffuse growing malignant mesothelioma of the epithelial type was found, localized in the lungs, mediastinum, diaphragm and retroperitoneum. Pneumothorax is a rare first manifestation of a malignant mesothelioma. To our knowledge, presentation with chylopneumothorax has not previously been described. In addition, such a diffuse infiltrating growth is very uncommon for a malignant mesothelioma.

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V. Renal and urogenital diseases 31. Continuous arterioor venovenous haemodiafiltration and amino acid balance. M.J. Blans ‘, H.J.L.M Uhlencate *, C. Bogaers 3, M.J.E. van Puyenbroek ‘, B. Speelberg ‘. Departments of ’ Internal Medicine, ’ Clinical Chemistry and 3 Dietetics, St. Elisabeth Hospital, Tilburg. Netherlands. Introduction: Continuous renal replacement therapy (CRRT) has become an established therapy of renal failure in the critically ill patient. The nutritional impact of this therapy is unclear. We investigated amino acid (AA) balances in patients treated with CRRT. Methods: Twenty patients with acute renal failure due to multi-organ failure were investigated, two patients were studied twice leading to 22 observations. Eighteen patients (20 cases) were treated with continuous arteriovenous haemodiafiltration (CAVHD), and two patients were treated with continuous venovenous haemodiafiltration (CVVHD). The same hollow fibre filter (AN 69, Hospal, Lyon, France) was used in CAVHD as in CVVHD. The nutritional support provided was total parenteral (n = 41, enteral (n = 7), a combination of both (n = 6) or no nutritional support (n = 2). Of three patients, no history of nutritional intake was known. The AA profile of plasma specimens and of dialysate specimens was analyzed by ion-exchange chromatography and subsequent spectrophotometry, using ninhydrin as an indicator. Results: Nineteen case records were studied. The mean&SD age was 62f 19 years, the Apache II score was 28k7, males 16 (84%), females 3 (16%), survivors 4 (21%), deaths 15 (79%). The mean+SD AA concentration in plasma was 3774.5 k3164 kmol/l, the AA concentration in the dialysate was 2954.1 f 2514.1 pmol/l. The AA profiles in the dialysate closely resembled the profile in plasma. The concentrations of AA in plasma and in dialysate correlated significantly (r = 0.98, P < 0.0001). Of the patients receiving nutritional support, there was a considerable loss of AA/24 h. We calculated the% AA loss compared to the amount provided by nutrition. In the group receiving TPN, combination and enteral nutrition losses were, respectively, 2Ok 11.5%, 8.9 f 6.9% and 8.8 + 1.9% and were not statistically different. In the 2 patients not receiving nutritional support, there was a considerable loss of AA (71,837.4 and 45,300 pmo1/24 h). Compared to the amounts of AA losses in the groups receiving enteral and/or parenteral nutrition this was not significantly different. Conclusion: We conclude that continuous haemodiafiltration therapy results in a considerable loss of AA. The way in which patients received nutritional support seems to be of little influence. A higher plasma concentration means a higher sieving from plasma to dialysate. In providing nutritional support in the critically ill patient, one has to consider the huge loss of AA.

32. The antihypertensive pared to nifedipine in A.J.W. Branten I, F.Th.M.

and renal effects of mibefradii compatients with chronic renal failure. Huysmans ’ , A J J Woittiez ‘. ’ Diui-

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I998

/ Netherlands

sion of Nephrology, Uniuersiry Hospital, Nijmegen and ’ Department of Internal Medicine, Twenteborg Hospital, Almelo, Netherlands.

Effective blood pressure lowering may decrease the rate of loss of renal function in patients with renal hypertension. This effect is generally parallelled by a reduction in proteinuria. Since dihydropyridines do not lower, or even may increase urinary protein excretion, their role in renal protection is debated. Therefore, we compared antihypertensive and renal effects as well as tolerability of the dihydropyridine nifedipine (Nif) with mibefradil (Mib), a new type of calcium antagonist that selectively blocks T-type calcium channels, in 143 hypertensive patients with chronic renal failure (ECC lo-60 ml/min) in a parallel, randomized, double-blind multicentre trial. After a 2-week placebo run-in period, patients were randomized to receive 25 mg Mib once daily (baseline BP 171 + 19/103 k6 mmHg) or 10 mg Nif b.i.d. (baseline BP 166 *22/103 +7 mmHg). At l- to 2-week intervals, patients could be titrated up to 50-100 mg Mib once daily or 20-40 mg Nif b.i.d. when the diastolic blood pressure (DBP) was > 90 mmHg. At the end of a 12-week treatment period, DBP had decreased more during Mib compared to Nif (- 12.8 vs. - 9.1 mmHg, respectively, P = 0.014). Of the Mib-treated patients. 62% finally achieved normalization of DBP compared to only 37% of the Nif-treated patients (P < 0.01). In both treatment groups a slight and identical decrease in creatinine clearance of 2.5 ml/min was observed during the study period. The increase in proteinuria (+ 780 mg/24 h) at 12 weeks was comparable during Mib and Nif. Adverse effects (ankle oedema, headache and flushing) were recorded in 51.4% of the patients during Mib treatment and in 58.9% of the patients during Nif. Conclusion: In patients with chronic renal failure and hypertension, the antihypertensive effect of Mib is superior to that of Nif. This effect is particularly expressed in a significant larger decrease in DBP during Mib. Both drugs did have similar effects on creatinine clearance and proteinuria, and were comparable in tolerability.

33. Icodextrin with nitroprusside increases ultrafiltration peritoneal transport during long CAPD dwells. C.E. J.K Hiralall, D.R. de Waart, D.G. Struijk, R.T. Krediet. ment of Nephrology, Netherlands.

Academic

Medical

Centre,

and Douma, Depart-

Amsterdam,

Addition of the nitric oxide (NO) donor nitroprusside to 1.36% glucose dialysate enlarges the effective peritoneal surface area during 4-h dwells. The theoretical positive effect on ultrafiltration is, however, counteracted by an increase in glucose absorption. The absorption of the glucose polymer icodextrin is much lower compared to glucose dialysate, due to its high molecular weight. In the present study, 7.5% icodextrin with and without the addition of 4.5 mg/l nitroprusside was studied during 8-h CAPD dwells. Two standard peritoneal permeability analyses, adapted for 8-b dwells, were performed in 10 stable CAPD patients, Nitrate and cGMP were measured as parameters of NO synthesis. The transcapillary ultrafiltration increased in a linear way with icodextrin (ICO) and was even higher after the addition of nitroprusside (NP): 666 (ICO) vs. 834 (NP) ml/8 h, P = 0.03. The

Journal

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52 ( 1998)

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effective lymphatic absorption rate was not different. The resulting net ultrafiltration increased with nitroprusside: 344 (ICO) vs. 540 (NP) ml/8 h, P < 0.01. The mass transfer area coefficient of urea increased 15% and of creatinine 26% with nitroprusside, consistent with the expected enlargement of the vascular surface area. The increase in protein clearances was more pronounced the larger the protein: P,-microglobulin, 19%; albumin, 47%; IgG, 63%; and cY,-macroglobulin 95%. D/P ratios of nitrate were not higher than expected values on the basis of its molecular weight (P < 0.001). They increased 19% with nitroprusside. In addition, the D/P ratio cGMP after 4 h increased with nitroprusside: 0.39. range 0.13-0.55 (ICO); and 0.82, range 0.36-l .39 (NP), P = 0.01. With nitroprusside, the D/P ratio cGMP was higher than expected after 4 and 8 h. P < 0.001. This points to local generation of NO after the addition of nitroprusside. The nitroprusside-induced increase in the MTAC of creatinine and in the ultrafiltration caused an increase in the creatinine clearance from 4.2 to 5.0 ml/min This means that daily administration of nitroprusside will add 3 l/week to the peritoneal clearance of creatinine. The adequacy of peritoneal dialysis can therefore be improved by the addition of nitroprusside to 7.5% icodextrin, used for the long exchange.

34. Granulomatous interstitial nephritis and hypercalcaemia in a patient with tuberculosis. C.V. Elzo Kraemer ‘, C. Baur ‘, of I Internal Medicine, J.B. Rosman I, P. Blok 3. Departments ’ Pulmonology

and

’ Pathology,

Westeinde

Hospital,

The Hague,

Netherlands.

Granulomatous interstitial nephritis remains a rare condition attributed to drugs, infections (including tuberculosis) and especially sarcoidosis. The combination of hypercalcaemia/hypercalciuria and granulomatous interstitial nephritis has almost exclusively been associated with sarcoidosis. We present a case of hypercalcaemia and granulomatous interstitial nephritis in a patient with Mycobacterium tuberculosis infection. A 31 -year-old African male was admitted with general malaise, night sweats and a positive sputum test for tuberculosis. Six months prior to admission, the patient was treated in Zaire for tuberculosis. At physical examination, no abnormalities were found. Relevant laboratory tests showed an elevated ESR (102 mm), normal white cell counts, hypercalcaemia (3.35 mmol/l). normal serum albumin (34.5 g/l), elevated serum creatinine (162 pmol/l; reference 70-l 10 pmol/l), plasma alkaline phosphatase (409 U/l; reference 40-120 U/l) and ACE (102 U/l; reference 12-54 U/l). PTH was non-detectable (reference 1.3-7.6 pmol/l), 25-OH-D3 (calcitriol) was normal (39 nmol/l; reference 25-100 nmol/l) and 1 (r-25di(OH)-D3 (calcitriol) elevated (498 pmol/l). Urine analysis revealed microaibuminuria, sterile leucocyturia, microhaematuria and hypercalciuria (15 g/24 h; reference 2.5-7.5 g/24 h). Chest X-ray showed bilateral infiltrates. Microscopy and culture for M. tuberculosis was positive in sputum and bronchoalveolar lavage, both negative in urine. Bronchial granulomaa were present in biopsied tissue. Percutaneous renal biopsy revealed non-caseous interstitial granulomas and an interstitial infitrate. Immunofluorescence study was negative. The patient was treated with fluid replacement and a combination of isoniazid. rifampin, pyrazinamide and ethambutol. After renal biopsy, pred-

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nisolone 20 mg was started. Serum creatinine (86 pmol/l) and calcium (2.39 mmol/l) normalized. The patient was erroneously discharged without prednisone. At out-patient follow-up, serum creatinine (107 pmol/l) and calcium (2.48 mmol/l) remained normal. This case demonstrates the necessity to exclude M. tuberculosis infection in any patient with hypercalcaernia or granulomatous interstitial nephritis, especially when both are present,

35. Pentosidine in patients with ultrafiltration failure: effect of non-glucose dialysis solutions. M.M. Ho-dac-Pannekeet ‘, M.A. Friedlander ‘, P. Erhard *, R.T. Krediet ‘. ’ Academic Medical Centre, Amsterdam, Netherlands and 2 Case Western Reserve University, Cleveland, OH, USA Glucose-containing dialysis solutions in peritoneal dialysis patients (PD patients) induce non-enzymatic glycosylation within the peritoneal cavity. Advanced glycosylation end-products may be implicated in the functional deterioration of the peritoneal membrane in long-term PD patients. In the present study, glycosylation of peritoneal membrane proteins was studied by the determination of pentosidine in 4-h effluents and plasma of nine patients with clinically severe ultrafiltration failure CUFF) (UF < 400 ml/4 h with 3.86% glucose). They were compared to a group of patients treated with PD for 1 month. Six of the patients with UFF were subsequently treated with non-glucose dialysis solutions and studied again after 6 weeks. In addition, in 5 patients each, pentosidine content of dialysate proteins after dwells with 3.86% glucose was compared to 1.36% glucose and icodextrin. No significant difference was present between effluent pentosidine comparing 3.86% glucose to either 1.36% glucose or icodextrin. Both effluent and serum pentosidine were higher in the UFF patients than in the recently started patients (effluent 22.6 + ,4 vs. 12.4+ 2, P = 0.02; serum 16.8 +3 vs. 9.0+2 pmol/mg protein, P = 0.03). As a consequence, dialysate to plasma (D/P) ratios of pentosidine also tended to be higher in the UFF patients (1.35 vs. 1.21, P = 0.11). Effluent pentosidine was related to duration of PD (r = 0.67, P = 0.04). In 5 out of the 6 patients who were treated with non-glucose dialysate, effluent pentosidine decreased (25.2+5 to 20.2* 6 pmol/mg protein, P = 0.06, n == 6). Serum pentosidine did not change 18.6+5 vs. 12.7 + 4 pmol/mg protein, P = 0.29, n = 6). These data show that 4-h effluent pentosidine contents are not influenced by glucose concentration or osmolality. Together with D/P ratios Z+ 1.0, this indicates that effluent pentosidine reflects glycosylation of pentoneal membrane proteins. The correlation between effluent pentosidine and duration of PD, and the decrease in effluent pentosidine after 6 weeks non-glucose dialysate, suggests that glucose exposure is an important determinator of membrane glycosylation. Wash-out of glycosylated proteins from the peritoneal membrane probably occurs during treatment with non-glucose dialysis solutions. However, serum pentosidine was unaffected.

36. Rapidly progressive glomerulonephritis, nephrotic syndrome and hypertensive retinopathy associated with Mycoplasma pneumoniae infection. C.V. Elzo Kraemer ‘, G.W.

Journal

of Medicine

52 (1998)

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A27

Erkelens ‘, J.B. Rosman t, L.D.M. van Osch *, P. Blok 3, C.L. Jansen 4. Departments of ’ Internal Medicine, 2 Ophthalmology, 3 Pathology and 4 Microbiology, Westeinde Hospital, The Hague, Netherlands. Mycoplasma pneumoniae infection has been described in association with a wide range of extrapulmonary manifestations. Its association with glomerulonephritis has only sporadically been reported. We present a case of (mesangiocapillary) glomerulonephritis, nephrotic syndrome and severe hypertensive retinopathy, in a patient with M. pneumoniae infection. A 34-year-old intravenous drug addict visited the ophthalmologic department complaining of l-month history of bilateral visual loss, retro-ocular pain, photophobia, malaise and dry cough. Fundoscopy revealed retinal exudates, haemorrhages, severe optic disc oedema and extensive choroidal detachments. On admission, systemic hypertension (200/ 110 mmHg), periorbital and peripheral oedema was noticed. No murmurs were present at cardiac examination. Lungs were clear except for pleural effusion. Relevant laboratory examination demonstrated an elevated ESR (99 mm), anaemia (Hb 4.8 mmol/l), normal white cell count, hypoalbuminaemia (19 g/l, reference 33-49 g/l) and renal failure (creatinine 301 pmol/l, reference 70-l 10 pmol/l). Urinalysis showed 3 + protein, 3 + erythrocytes but no casts. Proteinuria was quantitated at 13.5 g/24 h. A serum agglutinin test for M. pneumoniae was positive (titre 1:160). IgM and IgG were positive in immunofluorescence, suggesting recent infection. Cold agglutinins were absent. Tests for ANCA, anti-GBM, ANA, cryoglobulinaemia, hepatitis B and C, HIV, toxoplasmosis, Chlamydia and syphilis were negative. AS0 titre was normal. Chest X-ray was normal except for bilateral pleural effusion. CT-thorax demonstrated bilateral upper-lobe grown-glass opacities. Transthoracic echocardiography (performed twice), revealed no vegetations. Bacteriological cultures were sterile. In view of the deteriorating renal function, a percutaneous renal biopsy was performed on day 6 (creatinine 598 Fmol/l). Light microscopy showed a diffuse proliferative (mesangiocapillary) glomerulonephritis with crescent formation ( > 50%). lmmunoperoxidase studies showed scattered (granular) deposition of C3. immunosuppressive therapy was started with methylprednisolone (1 g i.v. X 3) followed by oral prednisolone (initially 60 mg/day) and a 14-day treatment with erythromycin (4 g/day). The general condition, serum creatinine (130 pmol/l) and fundoscopic findings all improved. M. pneumoniae infection should be considered in any patient with rapidly progressive glomerulonephritis and nephrotic syndrome.

37. Prognosis of renal cholesterol embolic disease: retrospective report of 13 cases. A.J. Kooter, B.J. Potter van Loon. Department of Internal Medicine, Sint Lucas Andreas Hospital, Amsterdam, Netherlands. Background: Cholesterol crystal embolization is a multisystem disorder commonly presenting with renal failure. The literature on cholesterol crystal embolization (CCE) largely represents CCE diagnosed at autopsy. This makes statements concerning prognosis unclear. The purpose of this study is to evaluate both renal prognosis and mortality in renal CCE.

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1998/Netherlands

Methods: We carried out a retrospective review of all cases with renal cholesterol embolic disease in vivo from 1986 to 1997 in our nephrology unit. Thirteen patients were found: 10 men and 3 women. They had an average age of 67 years (50-81 years). Ten patients had histologically proven cholesterol embolism, in 1 patient, retinal plaques gave clue to diagnosis, and in 2 patients, diagnosis was made on clinical grounds. Result: Renal failure developed in all patients, necessitating renal replacement therapy (RRT) in 70%. Eventually, 44% of patients on RRT recovered renal function after a median of 6 months (0.5-20 months). During follow-up (3-120 months) median survival was 33 months. Six patients died, respectively, 3, 8. 14, 33, 48 and 72 months after diagnosis. Conclusion: Cholesterol embolic disease, presenting with renal failure does not always lead to irreversible function loss (renal damage), but can have a favourable prognosis, even in patients who require dialysis. However, the prognosis regarding survival is poor.

38. Safety and effkacy of intravenous sedation during placement of intravascular catheters for haemodialysis. S.K.L. Schiltmans, F. Bosch. Department of Nephrology, Rijnstate Hospital, Arnhem, Netherlands. The purpose of this study is to investigate the results of sedation during the placement of Tesio and dual-lumen catheters. Using a standardized list, the placement procedure was scored by the following variables: age, gender, type of catheter, location, dosage of sedative, 0, saturation, blood pressure and heart frequency, movements, simplicity of the procedure, complications, recollection and pain afterwards. Between July 1996 and November 1997, 48 procedures were performed on 38 consecutive patients: 36 Tesio catheters (75%), 11 dual-lumen catheters (23%) and 1 single-lumen catheter (2%). Mean dosages of midazolam and fentanyl were, respectively, 6.3 cc (range O-23 cc) and 1.4 cc (range O-12 cc). Blood pressure and heart frequency remained stable during the procedure. If saturation dropped below 85%, oxygen was given (n = 9). In 88% of the cases, it was a simple procedure with no or few movements by the patient (92%). We noticed two minor complications, namely an arterial puncture and a local haemorrhage. In general, the patient had no recollection (73%) or only slight recollection (14%) of the procedure. Most patients felt no pain (55%) or mild pain (34%). Sedation during placement of catheters is a safe and patient-friendly method and simplifies the procedure.

39. Peritoneal permeability characteristics using glycerol-based dialysate in CAPD. W. Smit, D.G. Struijk, R.T. Krediet. Department of Nephrology, Academic Medical Centre, Unitiersity of Amsterdam, Netherlands. Glycerol is a low-weight molecule (MW 92 Da), that can be used as an osmotic agent in CAPD. Due to its low molecular weight, the osmotic gradient disappears rapidly and despite the higher osmolality at the beginning of a dwell, ultrafiltration has

Journal

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been found lower for glycerol compared to glucose (MW 1801, when equimolar concentrations were used. Former studies showed glycerol to be safe for long-term use, but some discrepancies have been reported on the transport of small solutes and protein loss. In the present study, we used the standard peritoneal permeability analysis (SPA) to assess permeability characteristics for a glycerol 1.4% solution compared to glucose 1.36% in six stable CAPD patients. An SPA consists of a 4-h dwell using dialysate to which dextran 70 is added to calculate fluid kinetics. Median values for the glycerol SPA were: net ultrafiltration rate 1.18 ml/min, which was higher than for glucose 1.36% (0.05 ml/min, P = 0.036). The effective lymphatic absorption rate was 1.01 ml/min, which was not different from the glucose-based solution. Mass transfer area coefficients for urea, creatinine and “rate were similar for both solutions (18.6, 9.2 and 6.4 ml/min for glycerol vs. 19.7, 10.3 and 7.2 ml/min for glucose). Clearances of µglobulin, albumin, IgG and a,-macroglobulin were not different for the two osmotic agents (1090, 100, 65 and 27 pl/min, for glycerol vs. 1130, 100, 70 and 28 pl/min for glucose). The median absorption was higher for glycerol, 74% compared to 56% for glucose (P = 0.0361, as can be expected from the low molecular weight. The use of a 1.4% glycerol solution in a 4-h dwell caused a median rise in plasma glycerol from 0.16 to 0.43 mmol/l, but since this rise was only seen in 3 out of 6 patients, it did not reach significance. Plasma osmolality remained constant (308 vs. 309 mOsm/kg). These findings show that glycerol is an effective osmotic agent, with the same adequacy as glucose. The fact that (despite earlier publications) no higher protein loss was found using glycerol, makes it unlikely that the nutritional status of the patient will be influenced in a negative way. In the present study, we could not confirm the lower ultrafiltration for glycerol. This can be explained by the higher initial osmolality of the glycerol solution (410 mOsm/kg for 1.4% glycerol vs. 347 mOsm/kg for 1.36% glucose) and the fact that none of the six patients had very high transport rates, preventing a very rapid disappearance of the osmotic gradient.

40. Does renovascular hypertension in atherosclerotic patients really exist? P.J. Stassen, F. Tuynman, J.H. Kouwenberg, A.J.J. Woittiez. Departments of Internal Medicine and Radiology, Twenteborg Hospital, Almelo, Netherlands. Objectiue: In the diagnostic work-up of established and/or therapy-resistant hypertension, renal angiography is advocated. In the case of a demonstration of a renal artery stenosis, the diagnosis renovascular hypertension (RVHT) is made and a dilatory procedure is undertaken. Bearing the 50% success rate of percutaneous renal angioplasty (PTRA) in mind, we performed a prospective study to correlate the technical and clinical success in so-called ‘renovascular hypertension’. Methods: Forty patients (21 men, 19 women, mean age 63 years) with hypertension related to atherosclerotic lesions ( > 50% stenosis) underwent PTRA. and a control angiography after I year, irrespective of the blood pressure response (Am. Sot. RVHT Criteria).

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Results: Sixty stenoses out of 88 renal artery lesions (24 unilateral) were studied. Immediate technical success was 98%; l-year patency was 59% (recurrent and de novo stenosis). Blood pressure response (cure plus improvement) was 58% after 3 months and 43% after 1 year. We could not demonstrate any correlation between acute and long-term technical success and blood pressure response after 3 and 12 months ( ,$-tests). Conclusions: (1) PTRA in atherosclerotic renal artery stenosis is clinically successful in 58% and is not related to the acute and l-year patency of the vessel. (2) A minority of the lack of response is explained by recurrent stenosis. (3) It is doubtful if the clinical entity ‘renovascular hypertension’ in patients with atherosclerotic stenosis really exists. (4) It is less doubtful that the renal atherosclerotic lesions are more often an effect than a cause of the hypertension.

41. Should aortocoronary bypass surgery he performed in patients with end-stage renal disease? R.P.L.M. van der Aa, E.F.H. van Bommel. Department of Internal Medicine, Drechtsteden Hospital, Dordrecht, Netherlands. Introduction: Ischaemic heart disease causes great morbidity and is the leading cause of death in end-stage renal disease (ESRD) patients. While in the general population, coronary bypass surgery is performed with low operative mortality and longterm symptomatic improvement, it is not clear whether this is achieved in chronic dialysis patients. We sought to address this issue by critically reviewing relevant data from the literature. Methods: An extensive literature search was performed using the Medline, cross references and cumulative Index Medicus. We identified a total of 28 articles published from 1974 to November 1997. We reviewed all articles, but a substantial number could not be used for final analysis because of mixed data (i.e. cardiac surgery also included (concomitant) valvular surgery) (n = 8) or reports included < 10 patients (n = 12). These latter studies were excluded for reasons of potential selection or publication bias. Results: Data from a total of 247 patients from 8 studies were available for final analysis (mean age 58.2 years (range 27-79 years); male sex 79% (68-85%)); diabetes 23% (S-35%)). Mean duration of dialysis prior to surgery was 34.2 (15.8-56) months. Most patients had previous myocardial infarction (MI; 61% (50-80%)) and 3-vessel or left major artery disease (68% (63-81%)). A large variability was seen in the use of arterial grafts in these studies (20% (O-91%)). Thirty-day mortality was 6.5% (O-20%). There was no correlation between the use of arterial grafts and survival. Perioperative MI occurred in 6.2% (O-25%). Postoperative complications included infections (15% (6-23%)) and stroke (4.1% (O-8%)). Even from studies included for final analysis. insufficient data were available to assess l- and 5-year symp tomatic improvement and I- and 5-year survival, respectively. Conclusion: Thirty-day mortality of coronary bypass surgery in ESRD patients seems twice as high as compared with the general population (6.5 vs. 3% (Circulation 1989;79(Sl):Sl-88: Eur Heart J 1995;16:1200-1206)). This difference may even be greater because our selection probably still does not exclude the potential of publication bias with some studies reporting zero

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perioperative mortality and very low infection rates in this population at risk. Of major concern is the lack of data concerning long-term symptomatic improvement and survival. A detailed study on this subject with sufficient patients is urgently needed.

42. Morbidity and mortality daring renal replacement therapy: transplantable versus transplanted patients. L. StraathofGalema ‘, J.L.C.M. van Saase ‘, CA. Verburgh 3, J. de Fijter 3, W.Th. van Dorp ‘. I Kennemer Hospital, Location EG, Haarlem, 2 St. Clara Hospital, Rotterdam and 3 University Hospital, kiden, Netherlands. Many patients with end-stage renal failure who are undergoing dialysis are eligible for renal transplantation. To enable a patient to choose between transplantation or continued dialysis, information about difference in morbidity and mortality between the two options should be available. In the present study, we compared the morbidity and mortality of patients on the waiting list for transplantation and transplanted patients by studying the number and length of hospital admissions in both groups. Data were collected retrospectively from the medical records of all patients who were either on the waiting list or underwent transplantation between January 1990 and January 1997. All patients were dialyzed in the Kennemer Hospital and renal transplantation was performed at the University Hospital in Leiden. After transplantation, the patient switched from group I to II in the study. During the study period, 102 patients have been on the waiting list (group I) and 53 patients have been transplanted (group II). The mean age was 48.1 vs. 49.8 years in groups I and II, respectively; 38.2 vs. 38.9% of the patients were female. Hospital admissions were studied during two periods, i.e. during and after the first 6 months on the waiting list for transplantation. In group I, 11 patients died, 10 patients became permanently non-transplantable, 56 patients underwent transplantation (3 patients underwent transplantation elsewhere) and 25 patients are still on the waiting list. In group II, 6 patients died and 7 patients had a transplant failure, after which they returned to dialysis and were excluded from further follow-up in our study. Patient survival of groups I and II was 100 vs. 96 (at 1 year) and 82 vs. 74 (at 5 years), respectively. During the first 6 months, the number of hospital admissions in groups I and II was 1.23 + 1.24 (mean* SD; range O-5) vs. 2.46* 1.38 (range l-6); the duration of hospital stay was 13.0+ 18.3 (range O-132) vs. 20.1 + 16.6 (range 3-76). After the first 6 months, the number of admissions was 3.13k3.45 (range O-17) vs. 1.41+2.35 (range O-13) and the duration was 32.4k40.4, range O-202) vs. 13.1+ 10.99 (range l-48). All differences were significant (P C 0.05). During the study period, the time spent in hospital in group I is 4.7% of the total treatment time and in group II, 5.6%. In the first 6 months, this is 7.3 and 23.7% in groups I and Il. respectively and after 6 months, 3.8 and 2.16%. In conclusion, we revealed that mortality does not differ between transplantable and transplanted patients. Secondly, we showed that morbidity, as defined by hospitalization, is increased in the group of transplanted patients during the first 6 months. This can easily be explained by the procedure itself. After the first 6 months, morbidity is less in the transplanted group.

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VI. Endocrinological and metabolic diseases 43. The vasopressin precursor is not processed in the hypothalamus of Wolfram patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2. B.A.Th.F. Gabreels I,*, D.F. Swaab ‘, F.W. van Leeuwen ‘. ’ Netherlands Institute ,for Brain Research, Amsterdam and ’ Department of Internal Medicine, Rode Kruis Hospital, Beuenvijk, Netherlands. Wolfram syndrome (WS) is characterized by optic atrophy, insulin-dependent diabetes mellitus. vasopressin-sensitive diabetes insipidus (DI), neurosensory hearing loss, urinary tract abnormalities and neurological dysfunctions. It is an autosomal recessive syndrome, the gene of which is located on chromosome 4~16. Here we report a disturbance in vasopressin (VP) precursor processing in the supraoptic (SON) and paraventricular nucleus (PVN) of clinically diagnosed WS patients. In two of the WS patients with DI, we could hardly detect any cellular immunoreactivity for VP in the SON and PVN. On the other hand, in the PVN, a considerable number of cells immunoreactive for VP precursor were present, although the cells were clearly too small. In one WS patient, with a mild form of DI, only a partial absence of VP was found. WS patients seem to have an unaffected expression of oxytocin in the SON and PVN. In the two VP-negative WS patients, the proprotein convertase PC2 and the molecular chaperone 7B2 were also absent, whereas the expression of the proprotein convertase PC 1 was slightly diminished. Since expression of PC2 and 7B2 was detected in the nearby nucleus basalis of Meynert of one WS patient and in the anterior lobe of the other WS patient, the absence of the two proteins in the PVN was not due to mutations in their genes. These results indicate that in WS patients with DI, not only VP neurone loss occurs in the SON, but also a defect in VP precursor processing.

44. Weight loss normalizes growth hormone concentrations in obese women due to both higher secretion and lower clearance. J.G. Langendonk, H. Pijl, J. Burggraaf, M. Friilich, R. Schoemaker, A.F. Cohen, A.E. Meinders. Department of General Intern& Medicine and Centre for Human Drug Research, Leiden Uniuersiry Medical Centre, L&den, Netherlands. Reduced plasma growth hormone (GH) levels in obesity normalize after weight loss due to an unknown mechanism. It is also unknown whether body fat distribution influences GH levels during obesity or during GH normalization following weight loss. Therefore, differences in 24-h GH levels, GH clearance and 24-h GH secretion were studied in obese women, before and after weight loss. The study was performed in 8 normal weight (NW). 7 lower body obese (LBO) and 8 upper body obese women (UBO). UBO had a waist-to-hip ratio (WHR) of 0.96 +0.05 (mean + SD) and LB0 had a WHR of 0.76 +0.03. The obese subjects were similar for body mass index (NW 22 f 2 kg/m’, LB0 3454, UBO 34+3) and all 3 groups were similar in age (NW 38k8 years, LB0 35+5. UBO 38 +8). GH clearance (CL) was determined after an iv. bolus of exogenous rhGH, during a continuous infusion of somatostatin to suppress endogenous GH secretion.

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Obese women had lower 24-h GH-AUC compared to NW women (LB0 2.6k1.6 U/l*min, UBO 2.4i2.1, NW 5.2k2.5). The lower 24-h GH-AUC in obese women was caused by higher CL and lower GH secretion compared to NW (LB0 680+ 140 ml/mitt, UBO 6191126 vs. 470+ 105 in NW and LB0 1.9+ 1.4 U/day, UBO 1.5 f 1.3 vs: 2.4& 1.3 in NW). All GH parameters were similar in UBO and LB0 women. After weight loss (mean weight loss of 14 kg in both obese groups), 24-h AUC and secretion increased (LB0 5.0 + 2.4 U/l * min and 2.9 + 2.1 U/day, UBO 5.0 k 3.5 and 2.8 f 1.9), and CL diminished in both groups (LB0 573 f 199 ml/mitt, UBO 567 + 120). The increase in 24-h GH-AUC was due to higher average peak amplitudes, while the number of peaks remained unchanged. This study shows that low plasma GH levels in obese women are due to a dual change in GH clearance and production. Weight loss appears to restore GH levels through an increase of production and a decrease of clearance. Body fat distribution did not influence GH clearance nor production.

45. Preoperative localization of enlarged parathyroids by ultrasound: a significant examination? M.J.M. Groenen ‘, P.C. Smit a, M.G.A. Baggen ‘, H.F. Veen *. Departments of’ Inter& Medicine and 2 Surgery, Ikazia Hospital, Rotterdam and ’ Department of Surgery, Academic Hospital, Utrecht, Netherlands. Introduction: If a patient presents with hypercalcaemia caused by a primary hyperparathyroidism (PHP), preoperative localizing examination, usually by ultrasound, is performed in many centres. The sensitivity of this non-invasive method for enlarged parathyroids ranges from 34 to 77%. A primary surgical exploration of the neck for PHP is, when performed by an experienced surgeon, successful in at least 95% of the patients. Aim: To determine the predictable value of ultrasound as a localizing procedure for enlarged parathyroids in a representative peripheral hospital. Patients and methods: Over a period of IO years, prior to a primary bilateral surgical exploration of the neck for PHP, a preoperative localizing ultrasound of the neck was performed in 20 patients. The preoperative findings were compared to the peroperative and histological findings and the postoperative calcium values. A correct prediction was defined as an enlarged parathyroid found in the predicted quadrant of the neck. Results: All patients were preoperatively examined by ultra sound of the neck, performed by different radiologists. Subsequently, all patients underwent a primary bilateral systematic exploration of the neck by the same surgeon. In 18 patients, a total of 20 enlarged parathyroids were identified and removed. According to histological examination, there were 16 adenomas and 4 hyperplastic parathyroids diagnosed. Two explorations remained negative. Postoperative serum calcium normalized in 19 patients, one after a negative exploration. In one patient, the hypercalcaemia persisted after negative exploration. In only 5 parathyroid adenomas (25%) had the correct location been predicted preoperatively, in three cases, the correct side was predicted, on twelve occasions, the localization was falsely predicted. Conclusion: On account of the small predictive value of this preoperative localizing examination, we conclude that there seems

Intemistendagen to be no place for ultrasound ration of the neck in PHP.

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explo-

46. Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss. J.G. Langendonk, H. Pijl, J. Burggraaf, M. Friilich, R. Schoemaker, A.F. Cohen, A.E. Meinders. Department of General Internal Medicine and Centre for Human Drag Research, Leiden University Medical Centre, L&den, Netherlands. Obesity is characterized by high levels of leptin, which are positively correlated with the size of the body fat mass. In vitro studies have shown that the mRNA expression of the ob gene (leptin) is higher in subcutaneous (s.c.) compared to visceral adipocytes. However, the influence of a predominately S.C. or visceral fat accumulation on leptin levels, is unknown. Therefore, the influence of body fat distribution on plasma leptin levels was studied. The study was performed in 8 normal weight (NW), 8 lower body obese (LBO) and 8 upper body obese women (UBO). UBO had a waist-to-hip ratio (WHR) of 0.96 + 0.05 (mean + SD) and LB0 had a WHR of 0.77+0.03. The obese subjects were similar for body mass index (NW 22+ 2 kg/m*, LB0 33 +4, UBO 34 + 3) and all 3 groups were matched for age (NW 38 + 8 years, LB0 35 f 5, UBO 38 k 8). Visceral and S.C. fat areas were determined using MRI. Blood was sampled every 20 min over 24 h, starting at 09.00 h. Leptin was measured by a highly specific RIA. A circadian rhythm without obvious spiking for leptin was confirmed, and in all three groups, a similar pattern was observed, with maximum concentrations occurring between 0.30 and 3.00 h. The amplitude of a cosine-fit as well as the average 24-h leptin level were increased by 280 and 420%, respectively, in obese compared to normal weight women. All characteristics of leptin profiles were similar in UBO and LB0 women, except for a significantly higher amplitude in the LB0 group. Multiple regression analysis indicated that total S.C. fat was the best predictor of average 24-h leptin levels (r2 = 71%). Addition of visceral fat to the equation, hardly improved the predictive value (r2 = 75%). A loss of 50% of overweight amount was associated with a 55% decrease in the average 24-h leptin level in obese women (95% CI 12.3/26.6), while the characteristics of the circadian rhythm of leptin remained unchanged. This study shows that the diurnal rhythm of leptin is not different in obese and normal weight women. Furthermore, body fat distribution over upper body and lower body fat depots does not affect the average 24-h leptin level or its circadian rhythm to a major extent. In addition, it also proves that S.C. fat predominately determines the correlation, which is in accordance with in vitro results.

47. Diabetes insipidus as the presenting symptom of Wegener’s granulomatosis. W.M.A.J. Miesen, E.N.W. Janssens, E.F.H. van Bommel. Department of Internal Medicine, Drechtsteden Hospital, Dordrecht, Netherlands. Introduction: Wegener’s granulomatosis (WG) is a necrotizing granulomatous vasculitis, classically involving the respiratory tract and kidneys. However, any organ system may be affected, includ-

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ing the central nervous system (i.e. cerebrovascular events, cranial neuropathy, seizures and cerebritis, meningitis, external ophthalmoplegia). Central diabetes insipidus (DI) as the first manifestation of WG, however, is a rare phenomenon. We describe the third patient in literature with central DI as the presenting symptom of WG. Case report: This 45-year-old male patient was admitted to our hospital with a gradual onset of polyuria and polydipsia, with daily urine output of up to 9 1. Central DI was diagnosed by means of a water-deprivation test and a vasopressin test. While CT scanning of the sella showed no abnormalities, magnetic resonance imaging (MRI) scanning showed abnormalities of the pituitary gland and hypothalamus, typical of central DI. Symptomatic treatment was started with intranasal vasopressin. Testing for antineutrophil cytoplasmatic antibodies (ANCA) was not performed. Fifteen months afterwards, the patient was readmitted with a pulmonary-renal syndrome, necessitating acute dialytic support. A diagnosis of WG was inferred from the histological appearance of renal biopsy and the presence of ANCA (titre 1:5 12) with specificity for proteinase-3 and myeloperoxidase. Concomitant with marked clinical response to cyclophosphamide and prednisone therapy, repeat MRI scanning of the brain revealed almost complete resolution of the typical findings of central DI following immunosuppressive therapy, thus establishing WG as the probable cause of the DI. Intranasal vasopressin could be stopped with persistence of normal urine output (2-2.5 l/day). Conclusion: Although not mentioned in major textbooks, WG should be considered in the differential diagnosis of central DI. In addition, the present case demonstrates the utility of MRI scanning and c-ANCA in the evaluation of diseases of the hypothalamic-pituitary axis.

48. No effect of long-term physical exercise on the glycaemic control in type I diabetes patients: a cross-sectional study. PC. Ligtenberg ’ , M.C.A. BIans i, I. van der Tweel *, J.B.L. Hoekstra 3, D.W. Erkelens 2. ’ Department of Internal Medicine, ’ Centre for Biostatistics, Utrecht Universi@ Hospital, Utrecht, University, Utrecht and ‘Department of Internal Medicine, Diakonessen Hospital, Utrecht, Netherlands. Physical activity was shown to be inversely related to mortality risk in type I diabetes patients. It is not clear whether the reduced death rate was due to an ameliorated glycaemic control or occurred from reduction of other risk factors. In the present study, the relationship between levels of physical activity and glycaemic control was evaluated in a cross-sectional observation. Medical and demographic data, besides blood samples for glycated haemoglobin and lipid profile, were collected in consecutive type I diabetes patients between 18 and 45 years of age without late complications. A self-reported questionnaire was used to determine the degree of physical activity. Additional information on insulin therapy, and the self-measurement of blood glucose levels (SMBG) was obtained. Correlation coefficients and analysis of variance were used for statistical analyses. Three hundred and sixty-three type I diabetes patients were screened. Data of 221 patients were analyzed. No correlation was observed between the different levels of physical activity and glycaemic control or lipid

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profile. Females showed a significantly higher total physical acti\,ity index than males (P = 0.0041, mostly due to the leisure-time activity index. More active patients used a lower amount of insulin (r = -0.20, P = 0.002) than less active patients. SMBG at least once a day was associated with a significantly lower glycated Hb. HDL-cholesterol was inversely correlated with the total number units of insulin per day (males, r = -0.27, P = 0.003; females, r = -0.21, P = 0.04). Glycaemic control and lipid profile were not found to be associated with long-term physical exercise in type I diabetes patients. However, a higher physical activity level was related to a lower insulin dosage, which may be of benefit. Exercise apparently did not negatively affect long-term glycaemic control, so it can be safely advised for people with type I diabetes on the condition that metabolic balance is maintained.

49. Cardiomyopathy as presenting symptom of Addison’s disease. J. Mulder, R.A.A. van Zanten, G.C.M. Linssen, A.J.J. Woittiez. Departments of Internal Medicine and Cardiology and Intensive Care Unit, Twenteborg Hospital, Almelo, Netherlands. Sometimes, Addison’s disease may be life-threatening, despite sufficient fluid administration and steroid supplementation. An ll-year old boy, already known to have idiopathic primary adrenal insufficiency, but refusing to take steroids, was admitted to the ICU for treatment of persistent severe shock. Blood pressure and diuresis did not respond to massive fluid challenge and steroid therapy. Haemodynamic measurements showed a low outputfailure (cardiac index 1.1 l/min/m’, pulmonary capillary wedge pressure 21 mmHg1. Echocardiography revealed the typical picture of cardiomyopathy, with an ejection fraction of 26%, global hypokinesia and normal valves. Well-known causes for myocardial failure, such as viral, protozoic or bacterial infections, and thromboembolic and ischaemic diseases were excluded. The patient was treated with dobutamine (up to 20 pg/kg/min), diuretics and digitalis. Mechanical ventilatory support was given for 8 days. No signs of multiple organ failure developed. After 3 weeks, the patient was dismissed with diuretics, digitalis and steroid supplementation. Echocardiographic control after 4 months showed no abnormalities, and diuretics and digitalis could be withheld. To our knowledge, this is the first case in the Dutch literature (and the third case in the international literature), describing severe and reversible cardiomyopathy as a presenting symptom of Addison’s disease.

50. Sympathoadrenal activation and the dumping syndrome. D.J. Schipper I, J.W.M. Lenders ‘, W.P. Hopman ‘, Th. Thien ‘, J.B.M.J. Jansen ‘. I Department of Medicine, Division of General Internal Medicine and ‘Division of Gastroenterology, St. Radboud University Hospital, Nijmegen, Netherlands. Background: In the early phase of the dumping syndrome, the sympathetic nervous system is reflexively activated by an enhanced splanchnic vasodilation and decreased plasma volume, while in the late phase, the adrenomedullary system is activated by the hypoglycaemia.

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Objective: To examine the time relationship between the clinical dumping signs and the responses of plasma catecholamines after oral glucose loading in patients with the dumping syndrome. Subjects and methods: Sixteen patients with the dumping syndrome (D) after gastric surgery (age 49.4 + 9.8 years, mean f SD), fourteen subjects without a dumping syndrome (ND) after gastric surgery (49.2 f 11.3 years) and fourteen healthy volunteers (C) (45.6& 10.5 years) underwent a standardized dumping test. The dumping score according to Sigstad, blood pressure (BP) and heart rate, plasma catecholamines, plasma glucose and the breath hydrogen excretion were measured before and up to 3 h after oral administration of 50 g glucose/m2 body surface area. Results: All D subjects developed dumping symptoms within 15-30 min postcibally and four of them developed late symptoms of reactive hypoglycaemia. In contrast to the C group, both the D and ND groups showed significant increments in heart rate and breath hydrogen excretion after ingestion of glucose, whereas systolic and diastolic BP were not affected. There was no difference between D and ND subjects. Plasma glucose increased in all 3 groups with the highest levels in the D group. Plasma norepinephrine increased significantly within the first hour and this increment was slightly larger in the D (+ 100%) than in the ND (+80%) group, whereas it did not change in the C group. There was no correlation between the increase in plasma norepinephrine and that of heart rate or dumping score. Plasma epinephrine increased 2 h after glucose administration in the D and ND groups, but not in the C group. There was no significant correlation between the plasma epinephtine responses and the plasma glucose responses. Conclusion: The present study indicates that even in the absence of dumping symptoms, oral glucose loading elicits a pronounced sympathoadrenal activation in patients who have undergone gastric surgery, suggesting that dumping symptoms are unrelated to the sympathoadrenal activation.

51. Feasibility of intensive lipid-lowering in patients with diabetes mellitus. S.J.D.M. Kanters ‘, A. Algra 2, T.W.A. de Bruin ‘, D.W. Erkelens ‘, J.D. Banga I. ’ Department of Internal Medicine and ’ Julius Centre for Patient-Oriented Research, University Hospital, Utrecht, Netherlands. Macrovascular disease causes premature morbidity and mortality in diabetic patients. Aggressive lipid-lowering may prevent macroangiopathy. The aim of our study was to investigate the feasibility of intensive lipid-lowering in diabetic patients and to determine the effect of this therapy on the composition of plasma lipoproteins. Thirty-six IDDM and 59 NIDDM patients were included in an open study at the diabetes clinic. Target values for plasma lipids were: LDL-cholesterol < 2.6 mmol/l, triglycerides > 1.7 mmol/l and HDL-cholesterol > 0.9 mmol/l for men and > 1.1 mmol/l for women. After 6-12 weeks of diet, lipid-lowering medication (statin/fibrate/acipimox) was prescribed and extended until all target levels were reached. Mean baseline lipid levels for IDDM and NIDDM were: total cholesterol 5.6 and 5.8 mmol/l, LDL-cholesterol 3.6 and 3.7 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, for women 1.4 and 1.2 mmol/l and

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triglycerides 1.7 and 2.2 mmol/l, respectively. Target values were reached in 66% of patients. The total cholesterol decreased by 1.3 mmol/l (95% CI 1.0-1.5) in IDDM and 1.7 mmol/l (95% CI 1.4-2.0) in NIDDM patients, LDL-cholesterol by 1.2 mmol/l (95% CI 0.8-1.5) and 1.3 mmol/l (95% CI 1.0-1.5) and triglycerides by 0.7 mmol/l(95% CI 0.3-1.0) and 1.1 mrnol/l(95% CI 0.9- 1.41, respectively. HDL-cholesterol increased only in men and women with IDDM: by 0.15 mmol/l (95% CI 0.01-0.28) and 0.34 (95% CI 0.02-0.711, respectively. The cholesterol/triglycerides ratio decreased significantly in VLDL in IDDM and in IDL in NIDDM. The ratio increased significantly in HDL in NIDDM patients. In conclusion, these results show that intensive lipid-lowering in diabetes mellitus is feasible and affects the composition of plasma lipoproteins, in agreement with improved lipoprotein metabolism and a less atherogenic lipid profile.

52. Spontaneous necrosis of phaeochromocytoma presenting with myocardial infarction. S.S. &nit-Sewbaks ‘, E. Maartense ‘, P.T.E. Postema ‘, H.J. Bonjer 2. t Department of Internal Medicine, Reinier de Graaf Hospital, Delft and 2 Department of Surgery, University Hospital Dijkzigt, Rotterdam, Netherlands. A 43-year-old woman, with no medical history, presented with upper abdominal pain radiating to her back. Vomiting, headache. fever and dizziness were accompanying symptoms. On physical examination, slight abdominal tenderness was found and a remarkable hypertension: 170/120 mmHg. Laboratory evaluation only showed a slight leucocytosis (11.4 X 109/1). An ECG showed an atria1 rhythm with negative T-wave in AVL. Ultrasound examination of the abdomen and endoscopic examination of the upper gastrointestinal tract did not reveal abnormalities. The complaints subsided, but the blood pressure remained too high. A repeated ECG 2 days later showed negative T-waves in all leads. Cardiac enzymes were elevated (CK 466 U/l, LDH 581 U/l, ASAT 49 U/l), raising the suspicion of acute myocardial infarction. Further treatment was established at the department of cardiology. After an uneventful recovery, she was discharged from hospital, 8 days after admission. Her blood pressure had normalized under treatment with metoprolol. The diagnostic procedure to establish the cause of me hypertension had included a 24-h urine collection to determine the excretion of catecholamines. The results showed highly elevated values: 5596 mnol noradrenaline/ h and 1746 nmol adrenaline/24 h (normal values: O-4.50 nmol noradrenaline/24 h and O-100 nmol adrenaline/24 h). A second sample, 2 days later, showed much lower values (3077 nmol noradrenaline/ h and 872 nmol adrenaline/24 h. At further evaluation, another 24-h urine sample, 20 days later, showed normal values of catecholamines. MRI scanning revealed a tumour of the sympathetic cord, para-aortal at the level of the right adrenal gland, but the characteristic hyperintensive T2-weighted signal was not present, possibly due to tumour necrosis. Somatostatin receptor and MIBG scintigraphy did not show hot spots. Meanwhile coronary angiography was completely normal. With the presumptive diagnosis of necrosis in phaeochromocytoma and after treatment with phenoxybenzamine and propranolol the patient was operated upon and a tumour of the sympathetic cord was

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removed. Histological examination confirmed the diagnosis of paraganglioma with necrosis. Conclusion: This unique case illustrates that necrosis of a phaeochromocytoma can cause acute severe hypertension followed by myocardial infarction, despite normal coronary arteries. Necrosis makes it difficult to recognize a phaeochromocytoma on MRI, MIBG and somatostatin receptor scintigraphy.

53. Metabolism of iron in the early inflammatory phase. Th.B. Twickler ‘, J.J.H. Hens 2, F.A.L. v.d. Horst 2, A.F.W. Barnaart 3, A.K.M. Bartelink ‘, A. v.d. Wiel I. Departments of t Internal Medicine, 2 Clinical Chemishy and 3 Orthopaedics, Eemland Hospital, Amersfoort, Netherlands. Introduction: The influence of inflammation on iron metabolism is a well-known interaction in many clinical conditions and activation of the cytokine network is considered to play an intermediating role. Because of the temporary absence of blood, the total knee replacement has been introduced as an excellent model to study the acute local and systemic effects of inflammation. After removal of the tourniquet, high levels of cytokines are found. We used this model to study the interaction of cytokines and iron metabolism in healthy subjects. Methods: Healthy subjects, admitted for a knee replacement, not taking medication preoperatively were entered in the study. At day 1 before surgery (Tl), 4 h (T2) and 8 h (T3) after the start of surgery and at day 1 (T4) and day 2 (T5) after surgery, venous blood was sampled. Tests included Hb, MCV, Fe, ferritin, transferrin, transferrin receptor, IL-6, IL-8 and C-reactive protein. All patients had an autologous blood transfusion (between T2 and T3). Data are presented as mean values f SD. Results: In this study, 13 patients (10 female, 3 male) were included. IL-6 increased IO-fold at T2, with a maximum of 118 + 5 1 pg/ml at T3. CRP reached the maximum level after the rise of IL-6. IL-8 did not change. Haemoglobin levels remained stable (6.5 mmol/l). Serum iron decreased significantly at T3 (at Tl from 14.5 +5.1 pmol/l to 3.5 + 1.6 pmol/l at T4). Transfertin slightly lowered, but not significantly. Transfetrin receptor levels decreased significantly at T2 and remained low until T5. Conclusion: At the onset of inflammation, an increase of IL-6 seems to precede a significant decrease in serum iron. No change in ferritin levels are found during the first 24 h. IL-8 does not seem to play any role in this kind of inflammatory response.

54. Licorice tea as a cause of hypopotassaemia and hyporeninaemic hypoaldosteronism. J.N.H. Timmer-Bonte, M.B. Graal. Department of Internal Medicine, University Hospital, Maastricht, Netherlands. Case history: A 20-year-old female attended the out-patient department of our hospital for a second opinion. She complained of fatigue, muscular weakness, nausea on exercise and headaches. These complaints had existed for almost 2 years. Physical examination revealed no abnormalities, including a normal blood pressure. Because routine laboratory investigations showed persistent mild hypopotassaemia and metabolic alkalosis, further analysis

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was carried out: urine potassium excretion was 40-50 mmol/day and a hyporeninaemic hypoaldosteronism (aldosterone < 0.07 nmol/l (0.11-0.86); aPRC < 6 (7-10.5)) was found. Our patient denied the use of licorice. For further evaluation, she was admitted to hospital. During admission, it was noticed that she drank large amounts (2 l/day) of licorice tea (‘zoethoutthee’ in Dutch). After discontinuation of this habit, the potassium level, pH as well as the aldosterone and renin levels returned to normal (0.51 and 10.7, respectively). Discussion: Licorice is known to be a cause of the syndrome of apparent mineralocorticoid excess. A steroid in licorice, glycyrrhizic acid, is capable of developing a reversible syndrome indistinguishable from primary hyperaldosteronism. This steroid has mineralocorticoid activity, but, more importantly, it impairs the action of 11 P-hydroxysteroid dehydrogenase (that converts cortisol to the inactive metabolite cortisone) in aldosterone target tissues, thereby allowing cortisol to activate the mineralocorticoid receptors. Endogenous aldosterone secretion is suppressed. Chromatography showed that 1 g of licorice tea contained 15 pg of glycyrrhizic acid! Conclusion: Although our patient did not have hypertension. we believe her laboratory abnormalities can be explained by the ingestion of large amounts of licorice tea. (Her presenting complaints, however, cannot be attributed to this habit since she started drinking licorice tea only 6 months previously, whereas her complaints had existed for 2 years). In a patient denying the use of licorice, one should consider licorice tea as cause of hypopotassaemia and hyporeninaemic hypoaldosteronism as it is now widely available and it contains a high concentration of glycyrrhizic acid.

55. The AMICE model (angina and myocardial infarction cytokines experiment) in a study of iron metabolism. Th.B. Twickler I, M.J.M. Cramer ‘, F.A.L. v.d. Horst 3, W.L. Mosterd ‘, A. v.d. Wiel ‘. Departments of ’ Internal Medicine, 2 Cardiology and 3 Clinical Chemistry, Eemland Hospital, Amersfoort, Netherlands. Introduction: An acute decrease in serum iron and a gradual increase in serum ferritin can be observed in acute stressful conditions, such as after surgical procedures. Although cytokines are considered to play a pivotal role, the exact pathogenetic mechanism has not yet been elucidated. Triggering factors may be tissue damage and inflammation, but physical and psychological stress have also been suggested to provoke a cytokine response. Unstable angina pectoris (AP) is a stressful condition that may be followed by myocardial infarction (MI) with tissue damage and inflammation. By comparing AP and MI patients, the contribution of stress to changes in cytokines and iron metabolism can be studied. Methods; In this preliminary study, 58 patients with unstable AP and 13 patients with an acute MI all being admitted to the coronary care unit, were analyzed. Blood was taken on admittance and at 8 and 24 h thereafter. Tests included serum iron, ferritin. creatinine kinase (CK), CK-MB, C reactive protein (CRP) and the interleukins 6 and 8. Data are shown as median levels, Results: In the MI patients, significant increases were observed in IL-6 (2-72 pg/ml), IL-8 (32-150 pg/ml) and CRP

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(I-47 pg/ml), while no significant rises occurred in the AP patients (IL-6, 3.3-7.9 pg/ml; IL-S, 23-30 pg/ml; CRP, 5- 16 mg/l). Serum iron dropped from 16 to 8 ymol/l in the MI group, remaining stable in the AP group. Serum ferritin levels did not change significantly within the first 24 h of admission. Conclusions: The AMICE model may be helpful in analyzing the contribution of various factors, including stress, with regard to changes in iron metabolism in acute-phase situations. Tissue damage (and inflammation) and not stress is necessary to provoke a response in IL-6 and IL-8 followed by changes in iron metabolism. The diagnostic value of cytokines in patients with acute chest pain deserves further attention.

56. The clinical value of PTH-related peptide assay in the differential diagnosis of hypercalcaemia. I. van der Lee ‘, B.C. Kuenen ’ , E.L. van Scheyen ‘. P.H.Th.J. Slee ‘_ Departments of ’ Internal Medicine and ’ Clinical Chemistry, St. Antonius Hospital, Nieuwegein, Netherlands. Background: Hypercalcaemia is a frequent, clinical diagnostic problem, especially in patients with a malignancy. PTH-related peptide (PTHrP) is a frequent cause of hypercalcaemia of malignancy independent of the presence of bone metastases. Aim: Several laboratory tests are available to determine the cause of hypercalcaemia. A new test to determine PTHrP has become available. We studied the question, as to whether this assay changed the diagnosis and/or treatment of hypercalcaemia. Methods: Consecutive patients with a calcium (corrected for albumin) of more than 2.7 mmol/l were included in the study. Besides routine biochemical tests, plasma samples were taken for PTHrP. After the assays were carried out, it was studied whether the results of the PTHrP assay changed the diagnosis and/or the treatment. The determination of PTHrP was performed on heparinized plasma which had been treated with a protease inhibitor cocktail. In a two-site immunoradiometric assay (IRMA) PTHrP was assayed: one antibody binds only to amino sequence 60-72, the other antibody recognizes the N-terminal l-40 and is radiolabelled for detection (Nichols Institute). Results: From January 1993 to February 1997, 92 patients were included in the study. In 19 patients, primary hyperparathyroidism (PHPT) was diagnosed from biochemical data and frequently proven by surgery (11,’ 19). PTH varied from 5.4 to 33 pmol/l, with a mean of 14 +7.4. In all patients, PTHrP was less than 2.1 pmol/l, except for one patient who had an elevated level, which, even at autopsy 3 years later, could not be ascribed to a malignancy. Two other patients had a malignancy and PHPT. When the malignancy was treated curatively, the PHPT still existed. In 65 patients, a malignancy was diagnosed as the cause of the hypercalcaemia. In all patients, PTH was less than 2 pmol/l. The PTHrP was elevated ( > 2 pmol/l) in 29/65 (45%): the values ranged from 2.6 to 29.3 pmol/l with a mean of 8.88t7.23. In one patient, a normalization of the PTHrP was observed after removal of the (lung) malignancy. In 8 patients. other explanations, such as immobilization and vitamin D intoxication, could be given. PTH was less than 2.0 pmol/l and PTHrP was not detected in the plasma of these patients. Other biochemi-

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cal tests, such as vitamin D metabolites etc., were only of minor help to establish a diagnosis. Conclusions: (1) An elevated PTH (interpreted in relation to an increased serum Ca) always, in this study, meant PHPT; a PTH less than 2 pmol/l excluded a PHPT as a cause of the hypercalcaemia. (2) In malignancy-associated hypercalcaemia, frequently an elevated PTHrP, but mostly a non-detectable PTHrP level was found. Only in one patient was an elevated PTHrP found that was not caused by a malignancy. (3) The PTHrP assay does not contribute, in our study, to diagnosis or treatment in clinical medicine.

57. Hypoglycaemia and hypoglycaemic symptoms in healthy individuals: Montignac’s theories refuted. K.A.M.I. van der Pant, F. Holleman, J.B.L. Hoekstra. Department of Internal Medicine, Diakonessenhuis, Utrecht, Netherlands. Introduction: In his dietary theories, Montignac states that hypoglycaemia is a common disease in healthy individuals. Symptomatic episodes of hypoglycaemia would result in snacking behaviour and consequent obesity. Methods: A total of 133 healthy persons (96 female, 37 male) answered a questionnaire about breakfast food intake, the occurrence of hypoglycaemic symptoms in the morning, and possible relief of these symptoms by food intake. In addition, blood glucose levels were determined at 08.00 h (early postprandial) and 11 .OO h (late postprandial) using an Accutrend Sensor home blood glucose monitoring device. Participants were not allowed to eat any food between breakfast and 11.00 h. Results: Average glucose fell from 5.9& 1.0 mmol/l (range 2.9-9.7 mmol/l) to 5.3kO.6 mmol/l (range 3.8-6.7 mmol/l). Participants who ate carbohydrates at breakfast (n = 109) had higher early postprandial glucose values than those who did not (5.9 vs. 5.5 mmol/l, P = 0.02). Fifty percent of participants occasionally experienced symptoms of hypoglycaemia in the morning. Their morning glucose values did not differ from participants who never experienced symptoms. Seventy-four percent of participants normally snacked around 11 .OO h. Of the participants who experienced symptoms (n = 65), 33 felt that their symptoms were relieved by having a morning snack. Their glucose values were not different from the glucose values of those who did not experience relief. Those who experienced relief tended to have more symptoms than those who did not (2.7 vs. 1.8, P = 0.06). Conclusions; Contrary to Montignac’s statements, morning hypoglycaemia does not occur in healthy individuals. Hypoglycaemic symptoms do not correlate with objective hypoglycaemia. The intake of a morning snack is a cultural, rather than a physiological necessity.

58. Evaluation of practiced strategies for the assessment of the vascular status prior to a lower extremity amputation in patients with diabetes mellitus. W.H. van Houtum ‘, K. Bakker 3, J.A. Ranwerda 2, R.J. Heine ‘. Departments of’ Internal Medicine and 2 Vascular Surgery, Free University Hospital, Amsterdam and ’ Department of Internal Medicine, Spaame Hospital, Heemstede, Netherlands.

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The aim of this study was to evaluate the current strategies used to estimate the presence and severity of peripheral arterial occlusive disease in diabetic patients that eventually required an amputation. Surgeons working in 18 hospitals in the province of North-Holland in the Netherlands (total number of hospitals in the Netherlands 1321, serving about 2 million patients, were asked to participate in the survey. The medical records of diabetic patients were carefully reviewed concerning palpation of the arterial pulses, ankle brachial index (ABI), duplex scanning, hallux pressure, TcpO,, and angiography. Optimal vascular assessment was defined by the medical record showing the results of ABI measurements of the amputated leg, and, in case the ABI was lower than 0.9 or higher than 1.15, the results of an angiography. In 1994, a total of 283 diabetic patients (149 males, 134 females, median age 73 years) suffered one or more lower extremity amputations. Overall, the following distribution of vascular parameters could be identified: palpation of pedal pulses, 79.9%; ankle brachial index, 62.9%; duplex scanning, 10.6%; hallux pressure, 11.7%; TcpO,, 3.5% and angiography, 59.7%. Optimal vascular assessment was only performed in 76 patients (52.1%) undergoing a major amputation and in 62 patients (45.3%) with minor amputations. Therefore, the total number of patients with an optimal assessment was 138 (48.8%). Both university hospital (P < 0.01) and a history of a ipsilateral revascularization (P < 0.01) were found to correlate significantly with an optimal vascular assessment. Age group, gender, level of amputation and amputation history did not show a significant association. In conclusion, diabetic amputees were shown to have had an inadequate vascular assessment in about half the cases. In order to live up to the expectations created by the Saint Vincent Declaration to lower the incidence of lower extremity amputations among diabetic patients by 50%. the diagnostic strategies currently applied by physicians need to be altered. Limbs can only be saved when perfusion is optimal and therefore, all diabetic patients with a lower limb problem will have to be evaluated using objective and reproducible measurements.

59. The role of adenosine in the vasodilator response to insulin. G. Vervoort ‘, E.J. Zandbergen ‘, C.J.J. Tack ‘, J.A. Lutterman ‘, N.C. Schaper 2, P. Smits ‘. ’ Department ofMedicine, University Hospital, Nijmegen and 2 Department of Medicine, University Hospital, Maastricht, Netherlands. Hyperinsulinaemia induces vasodilation in human skeletal muscle. This vasodilation is impaired in insulin-resistant conditions. The mechanism mediating the vasodilation has not yet been completely clarified, but may be of importance in treatment strategies of insulin resistance. Based on animal data, we hypothesized that stimulation of the adenosine receptor in vascular smooth muscle cells is involved in insulin-induced vasodilation. A hyperinsulinaemic euglycaemic clamp was performed in 24 healthy volunteers to investigate the vasodilator response to insulin in the forearm vascular bed. These volunteers were randomly assigned to three groups, matched for age, BMI and blood pressure. In group 1, placebo was infused into the left brachial artery (experimental arm). Draflazine (an adenosine uptake blocker, 250 ng/min/dl) and theophylline (an adenosine receptor antagonist, 50

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mg/min/dl) were infused in groups 2 and 3. Forearm blood flow (FBF) was measured by plethysmography. The FBF ratio (FBF experimental arm/FBF control arm) was used to test our hypothesis. Data are expressed as means& SE. Statistical analysis was performed by ANOVA. Hyperinsulinaemia induced vasodilation; FBF in the control arm increased from 1.8 +0.2 to 2.3 +0.3 ml/min/dl (P < 0.001). In the placebo group, FBF ratio decreased significantly by 18.2 f 9.4% (P < 0.01). The change in FBF ratio in the draflazine group was significantly less prominent thanintheplacebogroup(-1.6k13.1 vs.18.2+9.4%, P=O.Ol). The decrease in FBF ratio was more pronounced in the theophylline group (30.9k5.2 vs. 18.2+9.40/o, P < 0.01). Conclusion: These results demonstrate that the insulin-induced increase in blood flow is augmented during adenosine uptake blockade by infusion of draflazine, whereas this was diminished during adenosine receptor antagonism by theophylline. These results are in agreement with our hypothesis that insulin-induced vasodilation is, at least partly, mediated by the release of adenosine

VII. Cardiac diseases and circulatory disorders 60. Non-invasive assessment of pulse pressure at different peripheral arteries in man. J.N.J.M. de Hoon ‘, A.P.G. Hoeks *, J.M. Willigers 2, L.M.A.B. van Bortel ‘. Depamnents of ’ Pharmacology and ’ Biophysics, University of Maastricht, Maastricht, Netherlands. Introduction; In general, pulse pressure ( Ap) measured at the level of the brachial artery (BA) is used to calculate distensibility (DC) and compliance (CC) of different large arteries in man. However, as Ap increases centrifugally, this might result in an overestimation of Ap for more central arteries and an underestimation for more peripheral arteries. Objective: To present an alternative method for the assessment of local Ap, its reproducibility and its effect on DC and CC. Methods: The radial artery (RA), femoral artery (FA), common carotid artery (CCA) and BA were measured in 10 healthy, young subjects each. Using applanation tonometry, pressure waveforms (PWF) were recorded and calibrated with Dinamap BA diastolic (DBP) and mean arterial pressure (MAP). For each PWF, the nadir and mean were equalled to DBP and MAP, respectively. After calibration, local Ap (Ap,) was calculated and compared with Dinamap BA Ap (Ap,,,). Vessel wall movement was measured using ultrasound. Repeatability coefficients (Bland-Altman analysis) were calculated to assess intra- CRC,,,,,) and intersession (RC& reproducibility. Ap,,,, and Ap,, as well as the corresponding DC and CC, were compared using Wilcoxon’s signed-rank test. P I 0.05 is considered statistically significant. Results: RC,,,, and RCinter (mmHg) of the CCA, FA, BA and RA equalled 4.7/8.4, 3.3/l 1.9, 5.3/15.7 and 4.9/16.7, respectively. Ap, (mean + SEM, mmHg) of the CCA (39.4 + 3.0) and FA (42.5 + 2.0) were smaller (P < 0.05) than Apdina (48.6+ 1.7

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and 50.6+ 1.9, respectively). In contrast, Ap, of the RA (54.6_+ 2.9) was larger (P < 0.05) than Apdi,, (47.2 rt 1.8). For the CCA and FA, DC and CC calculated with Ap, were larger (P < 0.01) than those calculated with Ap,,,,. For the RA, DC using Ap, was smaller (P < 0.05) than DC using Ap,,,,. Conclusions: The presented non-invasive method to assess Ap of peripheral arteries in man: (1) is reproducible; (2) results in pulse pressures which are in agreement with the known centrifugal increase in Ap; and (3) might offer a more accurate calculation of vessel wall properties.

61. Gastric perforation after electric cardioversion for atria1 fibrillation. F.E. de Jongh ‘, P.T.H. Langendijk 2, L.G.P.M. van Zeijl ‘. Departments of ’ Internal Medicine, ’ Surgery and -’ Cardiology:y, Haven Hospital, Rotter&m, Netherlands. Introduction: Synchronic direct current (DC) cardioversion is frequently used in the treatment of both supraventricular and ventricular arrhythmias. Complications are rare and generally minor. Case hisfop: A 77.year-old woman electively underwent DC cardioversion because of lone atria1 fibrillation. Just before this procedure, our patient had no physical complaints and appeared healthy and relaxed. She had been fasting for at least 6 h. During general anaesthesia with propofol, DC shocks of 50 and 200 J were applied. The second countershock resulted in an 8-s asystolic period followed by a short period of sinus bradycardia and recurrent atria1 fibrillation. No external cardiac massage was performed and breathing remained spontaneous. Immediately after the procedure, the patient had severe abdominal pain with rapid development of pneumoperitoneum. At emergency laparotomy, the stomach showed signs of overstretching with small areas of haemorrhage. On the lesser curvature, two small perforations were present which were closed by sutures. There were no signs of pre-existing gastroduodenal disease. The postoperative course was uncomplicated. Discussion: To our knowledge, gastric perforation has never been mentioned as a complication of DC cardioversion. Rupture of the stomach, however, is a known complication of cardiopulmonary resuscitation procedures. In these circumstances, perforation is usually caused by excessive insufflation of air into the stomach during artificial ventilation. External forces, such as the Heimlich manoeuvre or cardiac massage, may also contribute in some cases, Our patient, however, did not receive artificial ventilation or external forces other than the DC cardioversion in itself. A possible explanation is that the DC countershock resulted in a sudden activation and relaxation of the diaphragm and abdominal wall musculature leading to rapid changes in intragastric pressure and gastric wall tension causing small haemorrhages and perforations. In accordance with the literature on gastric perforation after cardiopulmonary resuscitation, most damage is seen on the lesser curvature. This area has relatively few mucosal folds, low elasticity and high wall stress, Conclusion; Gastric perforation is a very rare, but serious. complication of DC cardioversion.

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62. High prevalence of left ventricular hypertrophy in patients with abdominal aortic aneurysm. M. den Heijer 1,3, M. Wullink ‘, Th. Thien 3, S.E. Kranendonk ‘, S.J. Graafsma i. Departments of ’ Internal Medicine and ’ Surgery, Tweesteden Hospital, Tilburg and 3 Department of Internal Medicine, University Hospital, Nijmegen, Netherlands. The aim of our investigation was to study the presence of left ventricular hypertrophy (LVH) in patients with abdominal aortic aneurysm @AA) since both types of organ damage are increased in patients with hypertension. As the association between hypertension and left ventricular mass (LVM) is stronger when ambulatory blood pressure monitoring (ABPM) is used, instead of office blood pressure (OBP) measurement, ABPM was employed. All sequential patients visiting the out-patient clinic with an AAA (infrarenal aortic diameter > 30 mm) were invited to participate. Each patient was asked to bring his own control subject. In the control subjects, AAA was ruled out by ultrasonography. OBP was measured after 5 min supine rest and 2-3 readings were averaged. For the ABPM, a Spacelabs 92907 was used. LVM was assessed with echocardiography according to standard techniques. Thirty-eight out of 88 patients and 13 out of 65 control subjects used antihypertensives. OBP in the AAA patients was lSS/SS k 21/11 (mean+SD) and 153/87*25/12 mmHg in the controls (not significant, n.s.). Daytime (07.00-24.00 h) ABPM values amounted to 140/81 f 15/9 and 138/83+ 17/11 mmHg, respcctively (n.s.). In addition, night-time ABPM values were similar in the two groups. Mean LVM was 272 g in patients compared with 226 in control subjects (P = 0.01). The prevalence of LVH (LVM > 355 g, 95th percentile of the control group) was 19% (1 l/57) in patients compared with 3.9% (2/51) in control subjects (odds ratio 5.9. 95% CI 1.2-28). Our results show no apparent differences in OBP and ABPM parameters between patients with AAA and control subjects. Echocardiographic assessment of LVM shows an unexpected high prevalence of LVH (19%) in patients with AAA. This difference could not be explained by a difference in blood pressure.

63. Feasibility of 24-h cerebral blood flow velocity monitoring and continuous finger arterial blood pressure in healthy subjects. M. Diamant, M.P.M. Harms, R.V. Immink, J.J. van Lieshout. G.A. van Montfrans. Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands. In acute stroke, blood pressure autoregulation is defective and the height of blood pressure therefore seems vital for adequate brain perfusion. To frame a reference, we assessed the feasibility of simultaneous prolonged monitoring of blood pressure, cerebral blood flow velocity (CBFV) and end-tidal CO, during a 24-h period in healthy subjects. Blood pressure (Portapres). bilateral middle cerebral artery (MCA) flow velocity (transcranial Doppler, TCD) and end-tidal CO, were measured in 7 healthy subjects (mean age 58 years, range 50-66 years). Finger blood pressure was recorded continuously over a 24-h period, CBFV and CO, during the first 15 min of every hour. The subjects remained supine during recording of CBFV and during the night (22.0006.00 h), otherwise they were seated upright in bed. The protocol was well tolerated and > 90% of the recordings, both of CBFV

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and blood pressure data, could be analyzed. Throughout the 24-h period, CBFV in the right vs. left MCA was comparable (62.6 f 1 and 59.7 + 0.9 cm/s, respectively). Intrasubject comparison of the twenty-four 15-min CBFV recordings showed marked variations, but no difference between the day (60.3 f 1.2 cm/s) and night (63.0+ 1.5 cm/s). Under resting conditions throughout the 24 h, no relationship was found between blood pressure and CBFV. A reduced circadian rhythm of blood pressure was found when daytime blood pressure was evaluated from data recorded in the upright position, whereas circadian rhythmicity was absent when data were obtained from supine recordings. Simultaneous monitoring of blood pressure by Portapres, CBFV by TCD and end-tidal CO, during a 24-h period in healthy subjects is technically attainable. In contrast to blood pressure, CBFV does not follow a circadian rhythm. However, from these preliminary dam, we cannot definitely exclude the existence of a 24-h rhythm of CBFV, as the diurnal variation in blood pressure was reduced, by physical immobility and possibly non-optimal sleep.

64. Homocystehte, serum folate, mutated methylenetetrahydrofolate reductase and factor V Leiden and the risk of venous thrombosis. M. den Heijer i, H.P.J. Willems ’ F.R. Rosendaal ‘s3 G.M.J. Bos ‘, N. van der Put ‘, W.B.J. Gerrits *, H.J. Blom 5. ’ Department of Internal Medicine, Tweesteden Hospital, Tilburg, Departments of2 Haematology and ’ Clinical Epidemiology, University Hospital, L.&den. Daniel den Hoed Clinic, 4Laboratory of Paediatrics and Neurology, University Hospital, Nijmegen and 5 Leyenburg Hospital, The Hague, Netherlands. Hyperhomocysteinaemia is associated with venous thrombosis. Whether determinants of homocysteine, such as low serum folate and mutated methylenetetrahydrofolate reductase @ITHFR), are also risk factors for venous thrombosis is unknown. We evaluated the possible risk of these factors and the interaction with factor V Leiden in 185 patients with a history of venous thrombosis and 500 healthy volunteers. Hyperhomocysteinaemia was defined at the 90th percentile and low serum folate at the 10th percentile of the control group. In this study, the risk for venous thrombosis was 3.7 (2.4-5.7) for fasting homocysteine, 0.8 (0.4-1.5) for low serum folate, 0.9 (0.5-1.8) for mutated MTHFR and 5.8 (3.2-10.4) for factor V Leiden. The combined risk for hyperhomocysteinaemia and factor V Leiden was 6.9 (2.4-20) and for mutated MTHFR and factor V Leiden 13.9 (1.6-116). Hyperhomocysteinaemia and factor V Leiden are risk factors for venous thrombosis. Low folate concentration and mutated MTHFR are important determinants of homocysteine levels, but do not seem to be risk factors for venous thrombosis. There might be some positive interaction between hyperhomocysteinaemia, mutated MTHFR and factor V Leiden, although confidence limits are rather wide to allow definite conclusions.

65. Dependency of cardiac output and mixed venous oxygen saturation on preload of the heart. M.P.M. Harms, J.J. van Lieshout, M. Jenstrup, F. Pott, K.H. Wesseling, J.M. Karemaker, N.H. Secher. Department of Internal Medicine and Physiology and TN0 Biomedical Instrumentation, Academic Medical Centre,

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Amsterdam, Netherlands and Department of Anaesthesia, Copenhagen Muscle Research Centre, Rigshospitalet, Denmark. Introduction: Mixed venous oxygen saturation (SvOa) is an indicator of systemic oxygen delivery vs. the demand of the perfused tissue. According to the Fick principle, a change in cardiac output (CO) is expected to be paralleled in S,O? as long as the oxygen consumption and the arterial oxygen content are invariant. We hypothesized that both CO and S,O, should reach a minimum and maximum by lowering and raising the preload of the heart, This hypothesis was tested in nine healthy subjects by varying the central blood volume through gravitational depletion (70” head-up tilt (HUT)) and repletion (-20’ head-down tilt

(HDT)). oxygen saturation (SsOz), and Methods: S,O, 1 arterial haemoglobin (Hb) were sampled and CO was calculated as the average of four thermodilution estimates at the different body positions. Oxygen consumption (V02) was calculated from CO and the arterial and central venous oxygen content difference. Results; CO ranged from 3.8 to 8.7 I/min and S,,O, from 58 to 79%. From HDT to supine, CO and S,O, did not change. From supine to prolonged, HUT 70” (60 min maximally) S,O, decreased from 74 f 3 to 64 f4% (P < 0.05) concordant to a decrease in CO from 6.0 (5.3-8.7) to 4.7 (3.9-5.6) I/min (P < 0.05). From the non-linear relationship between CO and S,Oz. CO was predicted from S,O, with an error of 0.62 (-0.04-I 89) l/mm (ns.) for HDT, and 0.12 (-0.98-0.74) l/min (ns.) for sustained HUT 70”. Supine S,O, was 98+ 1% and was not influenced by body position. Increments in Hb 8.6kO.3 to 9.1 + 0.6 mmol/l (P < 0.05 vs. supine) and VO, 280 + 30 to 331+ 65 ml/min (P < 0.05 vs. supine) were only observed during prolonged HUT 70”. Conclusion: By changing the preload of the heart, a change in CO is paralleled by a concordant change in S,,O, with a minimum and maximum for both. Accounting for the variance in VO,, Hb and CO, a change in S,O, of more than 10% reflects a true change in CO.

66. Continuous cardiac output monitoring in patients with septic shock by simulating a model of the arterial system: comparison with bolus thermodilution. W.T. Jellema ‘, K.H. Wesseling ‘, C.P. Stoutenbeek 3, A.B.J. Groeneveld 4, J.J. van Lieshout ‘. Deparmzents of I Internal Medicine, 2 TNO-BioMedical Znsrrumentation and 3 Intensive Care, Academic Medical Centre, Amsterdam and 4 Department of Internal Medicine, Free University Hospital, Amsterdam, Netherlands. Objective: To evaluate the accuracy of continuous cardiac output monitoring based on model simulation of the arterial system in 21 mechanically ventilated patients with severe sepsis or septic shock. Setting: Two university hospital medical/surgical intensive care units. Znteruentions: Cardiac output was altered by varying the dosages of vasoactive drugs. Measurements: Cardiac output was computed beat-by-beat from intra-arterial pressure by simulating a three-element model of the arterial system (Modelflow). Thermodilution cardiac output

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was estimated using automated phase-controlled injections of ice-cooled 5% glucose, equally spread over the ventilatory cycle. The first paired cardiac output measurement in each patient was used to calibrate model cardiac output. In 5 patients, measurements were repeated the next day. Results: A total of 94 pairs of thermodilution and model cardiac output measurements were obtained from 21 patients. Cardiac output ranged from 4.3 to 18.0 I/min. The mean difference between thermodilution and model simulation cardiac output before calibration was 1.25 +2 l/min (n = 21). In the five patients studied on the next day, this difference did not change (0.14 I/mm, P > 0.05). After calibration the difference reduced to 0.1 + 1 l/min (n = 73), with 95% limits of agreement of - 1.8 to 2.0 l/mitt. Conclusions; Continuous cardiac output monitoring by simulating a model of the arterial system is accurate and precise in mechanically ventilated patients with severe sepsis or septic shock when compared with a boius thermodilution technique over a wide range of cardiac output estimates. In addition, one calibration appears sufficient to measure cardiac output reliably over a 2-day period.

67. Nocturnal blood pressure decline as a predictor of cardiac and renal damage in hypertension. A.A. Kroon ‘, S.A. Rodriguez ’ , S. Lyons 2, P. Owens 2, P.W. de Leeuw ‘, E.T. O’Brien 2. ’ Department of Internal Medicine, University Hospital, Maastricht, Netherlands and 2 Blood Pressure Unit, Beaumont Hospital, Dublin, Ireland. Patients with an absence of nocturnal fall of blood pressure. could be at a higher risk for cardiovascular complications. Left ventricular hypertrophy, has been reported as more frequent in non-dippers. We evaluated the relationship between nocturnal decline in blood pressure (BP) (mean arterial pressure: MAP) as determined by ambulatory blood pressure monitoring and echographic variable as left ventricular mass (LVM) in 479 unselected adequately treated hypertensive patients. In addition. we assessed renal damage by measuring serum creatinine, creatinine and microalbuminuria. For analysis, patients were divided into groups on the basis of degree of nocturnal BP fall. Dipping defined as the percentage fall in BP during the night, averaged 23% in group I, 14% in group II and 3% in group III. Although patients in group 111 were significantly older than the rest, the groups did not differ in other demographic aspects. Patients in group III had significantly higher left ventricular mass index. In addition, serum creatinine was significantly higher and creatinine clearance lower in group III. This group also excreted significantly more albumin in their urine. The difference between groups III and I/II could not be explained on the basis of age. We concluded that even in adequately treated hypertensives. target organ damage is related to a reduction in nocturnal BP dipping. This suggests that antihypertensive treatment may not necessarily reduce cardiovascular risk.

68. Dissociation between the renal effects of angiotensin I and II in sodium-restricted normal subjects. M.M.E. Krekels ‘, W. Spiering 2, N.C. Schaper 2, A.J.H.M. Houben 2, P.W. de Leeuw ‘.

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’ Department of Internal Medicine, Maasland Hospital, Sittard and 2 Department of Internal Medicine, University Hospital, Maastricht, Netherlands. In the present study, we compared the systemic and renal effects of equimolar doses of Ang I and Ang II, in order to determine whether the effects of Ang I can be fully explained by conversion of Ang I to Ang II in the plasma compartment. Ten healthy male volunteers whom were in balance on a sodium-restricted diet were studied on two separate occasions during which, in random order, infusions of human Ang I or Ang II were given in stepwise increasing doses of 0.3, 1 or 3 pmol/kg * min. Mean arterial pressure (MAP), heart rate, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), renin (APRC), Ang I, Ang II, aldosterone (Aldo) and catecholamines were assessed at baseline, after each dose of Ang I or Ang II and 30 and 60 min after discontinuation of the Ang I/Ang II infusion. The rise in Ang II was significantly lower during the Ang I infusion than during the Ang II infusion (P < 0.05). The increments in MAP and Aldo and the decrease in GFR, however, were comparable during both the infusion regimens. In the kidney, on the other hand, the fall in APRC and ERPF during the Ang II infusion exceeded those during Ang I (P < 0.05). After cessation of the Ang l/Ang II infusion, the Ang II concentrations resumed to baseline as did MAP, ERPF and Aldo. Only renin remained significantly inhibited (P < 0.05). Catecholamines did not change during any of the experiments. Our data suggest that the effects of Ang I on blood pressure and aldosterone release may be brought about by Ang II, formed, at least partly, from the Ang I at tissue sites. However, due to a low capacity of the kidney to convert Ang I, the renal effects of Ang I are less prominent than those 01 Ang II. The longer lasting inhibition of renin after cessation of the Ang I/Ang II infusion points towards accumulation of Ang II in the kidney.

69. Family history of hypertension is not associated with increased blood pressure variability. A.A. Kroon ‘, S.A. Rodriguez ‘, S. Lyons 2, P. Owens ‘, P.W. de Leeuw ‘, E.T. O’Brien 2. ’ Department of Internal Medicine, Unioersity Hospital, Maastricht, Netherlands and 2 Blood Pressure Unit, Beaumont Hospital, Dublin, Ireland. It is assumed that normotensives with a positive family history of hypertension will develop hypertension more often than those without it. We therefore examined normotensive subjects with and without a positive family history with regard to their 24-h blood pressure profiles. In all, 237 normotensives (WHO/ISH classification) were enrolled and had a 24-h ambulatory blood pressure monitoring (ABPM; Space Labs 90207) and an M-mode echocardiography (performed by the same investigator). Subjects with a white-coat phenomenon (initial BP > 140/90 mmHg, normalizing I 1 h) were excluded. The population was divided into two groups, those with a positive (POS) and those with a negative family history (NEG). A positive family history was defined as a first-degree family member with hypertension. Blood pressure variability was expressed relatively as the coefficient of variation (SD/mean X 100%). Dipping was calculated as follows: {(daytime mean MAPnight-time mean MAP)/daytime mean MAP) X

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100%. Forty-four subjects with white-coat hypertension were excluded. The remaining study population of 193 subjects was divided into the two groups: NEG (n = 95) and POS (n = 98) with a male/female ratio of 35:60 and 33:65, respectively, age 43 + 14 and 41+ 12 years, respectively, and a LV mass index of 97.6 + 27.3 and 96.4 + 27.4 g/m”, respectively. No differences were found between the two groups with respect to the initial mean systolic blood pressure (SBP), the diastolic blood pressure (DBP), the mean arterial pressure (MAP), and the heart rate (HR). During the daytime, the mean SBP was 128 +6 and 130+7 mmHg, for the NEG and POS groups, respectively, and the mean DBP was 80 + 6 and 80 + 6 mmHg, respectively, mean MAP was 96 + 6 and 97 + 6 mmHg, respectively, and mean HR was 82 + 11 and 80t9 per min, respectively. The percentage of dipping was 13 + 9 and 14k7, respectively. The variability of the initial, daytime, and night-time SBP, DBP, MAP, and HR showed no significant differences (t-test). These data did not show a relationship between blood pressure variability and family history in normotensives. This may be due to the exclusion of subjects with a white-coat phenomenon.

70. The effect of weight loss upon the visceral and subcutaneous fat depots and cardiovascular risk profile in upper and lower body obese women. J.G. Langendonk I, H. Pijl I, J. Doombos ‘, A.E. Meinders I. Depar?ments of ’ General Internal Medicine and 2 Radiology, L.&den University Medical Centre, Leiden, Netherlands. An accumulation of visceral fat is a generally accepted risk factor for diabetes, cardiovascular disease and related mortality. The waist-to-hip ratio (WHR) is used to identify obese subjects with relatively high or low amounts of visceral fat, respectively, upper body obese (UBO, high WHR) and lower body obese people (LBO, low WHR). The study objective was to determine the decrease in visceral fat mass and cardiovascular risk profile after substantial weight loss in UBO and LB0 women. The amount of visceral and subcutaneous (s.c.) fat was assessed with MRI, in 8 normal weight women (NW; mean f SD, BMI 22.4 + 2.1 S.C. fat 11.9k3.1 dm2 and visceral fat 1.4+0.5 dm2), 8 kg/m2, LB0 (33.8k4.4, 28.7k6.6, 3.0+1.0, respectively), 8 UBO (33.9 +3.1, 26.2k4.1, 5.8k2.2, respectively). UBO and LB0 were studied again after a very low calorie diet, resulting in a mean weight loss of 14 kg in each group (7 LBO-p 27.9 + 3.1 kg/m2, S.C. 20.0+5.1 dm2 visceral 1.6+0.7dm2 and7UBO-p28.7+2.2, 19.7+3.3 and 3.6f 1.3, respectively). Serum cholesterol and LDL-cholesterol levels were increased in obese compared to NW, but always within the normal range. Weight loss resulted in both UBO and LB0 in a relatively greater loss of visceral fat than S.C. fat. The amount of visceral fat normalized in LB0 after weight loss (1.6 dm’), although their BMI was still 5 points higher than NW. The absolute decrease of visceral fat was higher in UBO compared to LB0 (2.OkO.7 and 1.2 +0.2 dm2, respectively, P = 0.007). In all UBO women, serum glucose (5.4kO.7 to 4.8 +0.6 mmol/l, 95% CI 0.3/0.9), total cholesterol (5.4 f 0.9 to 4.5 +0.6 mmol/l, 95% CI 0.5/1.4) and LDL-cholesterol levels (3.8f0.9 to 3.lkO.6 mmol/l, 95% CI 0.5,‘l.l) decreased significantly. Weight loss had a variable effect on individual serum levels in LB0 women. Considerable weight loss is accompanied

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by a large decrease in visceral fat in UBO women, resulting in an improvement of their cardiovascular risk profile. This suggests that UBO will obtain the greatest health benefit from energy intake restriction.

71. Lipoprotein(a) concentrations in patients with familial combined hyperlipidaemia and hypertension. R.T. Netea, M.G. Netea, S.J.H. Bredie, P.N.M. Demacker, Th. Thien, A.F.H. Stalenhoef. Department of Medicine, University Hospital, Nijmegen, Netherlands. Lipoprotein(a) (Lp(a)) is an independent risk factor for coronary heart disease (CHD), and its association with hyperlipidaemia and/or hypertension greatly increases the risk of premature CHD. Aim: To assess plasma concentrations of Lp(a) in patients with familial combined hyperlipidaemia (FCH), with essential hypertension (EH) and normo- or hyperlipidaemia, and with secondary hypertension due to renal artery stenosis (RAS), and to compare it with Lp(a) plasma levels in healthy volunteers. Patients and methods: Groups of 262 hyperlipidaemic subjects from families with well-defined FCH (123 men, age 48.6+ 14.6 years), 81 normolipidaemic EH (48 men, age 61 .O + 10.2 years), 61 hyperlipidaemic patients with EH (32 men, age 60.9 & 11.7 years), 26 patients with RAS (7 men, age 63.8k9.6 years) patients, and 371 healthy controls (202 men, age 36.5 + 15.9 years) were studied. Lp(a) levels were measured by a specific radioimmunoassay. Results: There was a tendency of increased plasma concentrations of Lp(a) in FCH patients (median 204 mg/l, range 16-2163 mg/l) when compared with the control group (155, 16-1846 mg/l). but the differences were not statistically significant (P > 0.05). The Lp(a) levels in patients with EH (164, 10-l 170 mg/l) was similar to that of controls, and did not differ from that of EH patients with concomitant hyperlipidaemia (118, lo-1985 mg/l). A tendency towards higher levels of Lp(a) was observed in RAS patients (232, 16-l 110 mg/l). but this was not statistically significant. Conclusion: Plasma concentrations of Lp(a) are similar in patients with FCH, with EH, either normo- or hyperlipidaemic, and with RAS, when compared with healthy controls. A tendency towards higher Lp(a) levels was apparent in patients with FCH and the group with secondary hypertension due to RAS.

72. F’rointlammatory cytoldnes in patients with essential hypertension. A.C.T.M. Peeters, M.G. Netea, M. Janssen, P.N.M. Demacker, B.J. Kullberg, Th. Thien, J.W.M. van der Meer. Department of Medicine, Uniuersi@ Hospital, Nijmegen, Netherlands. Abnormalities in the immune response have been recently suggested to play a role in the pathogenesis of essential hypertension (EH). The circulating concentrations and the lipopolysaccharide (LPS)-stimulated production of the proinflammatory cytokines TNF-(Y (TNF) and interleukin-10 (IL-l), and of the anti-inflammatory cytokines IL- 1 receptor antagonist (IL- I ra) and

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IL-6, were investigated in 23 patients with EH and compared with 144 healthy volunteers. The EH patients were untreated for at least 2 weeks before the study, and they had no infections, autoimmune diseases or neoplasms. EH was deemed as blood pressure above 140/90 mmHg on different occasions, with exclusion of secondary hypertension. TNF, IL-1 and IL-lra concentrations were determined by specific radioimmunoassays, and IL-6 levels by ELISA. Circulating concentrations of TNF, IL-I and IL-6 did not differ between EH patients and controls, In contrast, IL-lra circulating levels were higher in EH patients when compared with healthy controls (244 + 106 vs. 156 & 78 pg/ml, P < 0.001). Hypertensive patients had a 2-fold increased IL-1 production capacity and a 50% higher IL-6 production when whole blood was stimulated ex vivo with LPS (P < 0.001 for both cytokines). LPS-stimulated TNF was 40% lower in the hypertensive patients (P < 0.01). IL-lra production capacity did not differ between patients and controls. In conclusion, patients with EH have a disturbed profile of pro- and anti-inflammatory cytokines, probably due to monocyte activation in the circulation. The importance of these immune changes for the pathogenesis of EH and/or its secondary complications remains to be elucidated.

73. Angiotensin AT, receptor blockade abolishes the reflex sympathoexcitatory response to adenosine in humans. G.A. Rongen I,‘, S. Brooks ‘, S.-I. Ando a, B.L. Abramson *, J.S. Floras ‘. ’ Department of Medicine, Rijnstate Hospital, Arnhem, Netherlands, 2 Department of Medicine, Division of Cardiology. Mount Sinai Hospital and 3 Toronto General Hospital, Toronto, Ont., Canada. We hypothesized that endogenous angiotensin 11 participates in the direct (prejunctional) and indirect (reflex) actions of adenosine on the sympathetic nervous system of normal humans. A double-blind, placebo-controlled, randomized, crossover trial was performed in 9 young healthy men aged 32.6 + 9.4 years (mean + SD) given losartan (LOS) 100 mg p.o. for 1 week to determine the effect of AT, receptor antagonism on bilateral forearm blood flow and forearm and total body norepinephrine (NE) release (tracer technique), in response to graded brachial i.a. infusion of adenosine (0.5, 1.5, 5 and 15 pg/lOO ml forearm tissue/mm), and nitroprusside (NTP; vasodilator control). NE appearance rate was a more accurate representation of local NE release than NE spillover during NTPinduced changes in blood flow. Adenosine increased total body NE spillover by 34+ 12% (SE; P < 0.05). whereas NTP did not. Losartan lowered blood pressure (P < 0.051, had no effect on total body NE spillover at rest, or forearm vasodilation during either infusion, but reduced the systemic noradrenergic response to adenosine from + 1.0+0.4 nmol/min on the placebo day to +0.2,0.3 nmol/min (34112 vs. 0+7%: P < 0.01). During losartan, adenosine reduced forearm NE appearance rate in the infused arm (P < 0.05 vs. baseline and vs. contralateral arm). The sympathoexcitatory reflex elicited by adenosine is mediated through pathways involving the angiotensin II AT, receptor. Interactions between adenosine and angiotensin II may assume importance during conditions that are associated with increased levels of adenosine and activation of the sympathetic

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such as ischaemia or congestive heart failure and to the benefit of converting enzyme inhibition in

74. Altered phenotype of the renin-angiotensin aldosterone system in normoand hypertensive patients genotyped for the angiotensin 11 type 1 (AT,) receptor polymorphiim. W. Spiering ‘, A.A. Kroon I, M.J.M.J. Fuss-Lejeune ‘, M.J.A.P. Daemen ‘, P.W. de Leeuw I. Departments of’ Internal Medicine and * Puthology, Uniuersity Hospital, Maastricht, Netherlands. Most studies concerning the genetic polymorphisms of the renin-angiotensin aldosterone system (RAAS) explored the relationships between these polymorphisms and various end points of cardiovascular diseases. For future therapeutic implications, it is important to determine whether or not, and if so how, these different genotypes lead to different phenotypes. We investigated in hypertensive and normotensive men, genotyped for the angiotensin II type 1 (AT,)-receptor polymorphism (mismatchPCR/RFLP strategy), whether phenotypic differences in functional characteristics of the RAAS could be observed. After a 4-day low-sodium diet (55 mmol/day), we continuously infused angiotensin II (Ang II) in increasing doses (0.3, 1.0 and 3.0 ng/kg/min) in 18 subjects with the AA genotype and 16 subjects with one or more C-alleles (AC or CC). With equal basal plasma Ang II @IA) levels, the effective renal plasma flow (ERPF; PAH clearance) was lower in AC/CC (424&36 ml/min * 1.73 m*) than in AA subjects (382+ 34 mI/min * 1.73 m2) (P-0.07), although the endogenous creatinine clearance (AA 95 + 3 ml/min * 1.73 m* vs. AC/CC 86&S ml/min * 1.73 m2) and glomerular filtration rate (GFR; inulin clearance) (AA 121+ 7 ml/min * 1.7.3 m* vs. AC/CC 122k9 ml/min * 1.73 m*) were comparable in both groups. With increasing doses of Ang II, the GFR showed a slight increase in AC/CC subjects (+ 4%) compared with a slight decrease in AA subjects (- 3%) (highest Ang II dose: P = 0.09). This was accompanied by a more pronounced increase in filtration fraction. The maximal increase in mean arterial pressure and renal vascular resistance was higher in AC/CC subjects during the experiment (5.9 and 22.6%, respectively). The most important neurohumoral difference was a more pronounced decrease in active plasma renin concentration (IRMA) in AC/CC subjects (highest Ang II dose: P = 0.09). There were no overall differences between normo- and hypertensive subjects. From these data, we conclude that one or more C-alleles of the AT,-receptor alter phenotype: these subjects tend to be more sensitive to Ang II.

75. AntiphosphoIipid antibodies as a corollary of severe atherosclerosis in hyperhomocysteinaemia? P.E. Spronki ‘, E.O. Overbosch 2, N.H. Schut ‘. Departments of I Internal Medicine and *Radiology, Kennemer Hospital, Location EG, Haarlem, Netherlands. We demonstrate the case histories of two patients with severe premature systemic atherosclerosis. One patient presented with accelerated hypertension, which proved to be due to aortic occlusion and renal artery stenosis. Huge intercostal arteries were

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feeding collaterals over the abdominal wall to the pelvic and leg arteries, resulting in a surprisingly mild clinical picture. The other patient presented with hypertension and dysbasia complaints due to generalized atherosclerosis. In both patients, homocysteine levels were very high, partly due to mild folate deficiency. Surprisingly, anticardiolipin antibodies were present (repeated testing). Treatment with coumarins and aspirin was started. The patient with the occluded aorta declined the offer of major surgical revision of his vascular system due to the absence of complaints. So far (2 years later), he is doing well. The other patient underwent several vascular by-passes with good clinical results. In our patients, anticardiolipin antibodies were present in high titres. Antiphospholipid antibodies (APLA) can be found in patients with systemic lupus erythematosus (SLE) and in patients without signs of lupus, the so-called ‘primary phospholipid antibody syndrome’. This syndrome is characterized by the presence of anticardiolipin antibodies, lupus anticoagulant, and/or a positive VDRL, as well as thrombocytopenia and thrombotic events. No signs of SLE or thrombotic events were present in our patients. The finding of anticardiolipin antibodies in high titres might be a phenomenon secondary to severe atherosclerosis. This observation is of interest in view of the possible pathogenesis of these autoantibodies.

76. A randomized placebo-controlled study of loop-diuretics in patients with essential hypertension, the BUFUL clinical study report. S.M. ten Have ‘, T.J. Cleophas ‘, C.W. Ho1 2, J. van der Meulen I, M.G. Niemeyer 2, B.A. de Planque ‘, on behalf of the BUFUL (BUmetanide and FUrosemide on Lipid profile) Study Group. ’ Menvede Hospital, Dordrecht and ’ Martini Hospital, Groningen, Netherlands. Background: Diuretics are effective for the treatment of essential hypertension and they reduce mortality in these patients, but their effect on serum lipids may minimize their long-term benefit: thiazide diuretics/chlorthalidone increased total cholesterol (TC) and LDL-cholesterol (LDL-C) lo-15 and 15-20%. The effect of loop diuretics on serum lipids was markedly less in normotensive subjects, but so was their capacity to reduce blood pressure in one study of hypertensive subjects. Bumetanide is more potent and provides better bioavailability than furosemide, but it is not known whether this translates in better clinical effectiveness in patients with hypertension. Objectiue: To determine whether loop diuretics are more effective than placebo in reducing blood pressure without raising serum lipids in these patients. Secondly, to assess whether bumetanide is more effective than furosemide in this respect. Methods: In a double-blind 24-week placebo-controlled crossover study, 27 patients with essential hypertension were treated in 4 periods of 6 weeks with placebo twice, furosemide 40 mg/day, and bumetanide 5 mg/day. Patients were assessed for several metabolic parameters including serum lipids, and for blood pressures. Results: The supposed better effect of bumetanide compared to furosemide on serum lipids and blood pressures could not be confirmed. The overall levels of TC, triglycerides (TG), and LDL-C were, however, 5, 12.4, and 4.8% (P < 0.002, P < 0.01,

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P < 0.01) higher during loop diuretic than during placebo treatment. The overall systolic and diastolic blood pressures were 8.2 and 4.5% (12 and 4 mmHg, P < 0.0002 and P < 0.002) lower during loop diuretic than during placebo treatment. Conclusions: Our results indicate that: (1) the loop diuretics, bumetanide and furosemide, influence blood pressure and serum lipids similarly; and (2) as a group, they are effective for reducing blood pressure and influence serum lipids markedly less than thiazide diuretics/chlorthalidone usually do.

77. Restoration of colloid osmotic pressure in hypoalbuminaemic patients. B. Timmer, Y. Hondebrink, J. Oude Nijhuis, A.J.J. Woittiez. Intensive Care Unit, Twenteborg Hospital, Almelo, Netherlands. Objective: The majority of postoperative patients develop hypoalbuminaemia and low colloid osmotic pressure (COP), giving rise to oedema. In this placebo-controlled, randomized trial, we compared the effects of albumin and hydroxy-ethylstarch (HES) on COP and clinical parameters. Methods: Fifty-seven patients who developed hypoalbuminaemia ( < 20 g/l) after major surgery were randomized to infusions of saline (500 ml/24 h), albumin 20% (300 ml/24 h) or HES 10% (500 ml/24 h) for 3 days. Changes in fluid balances, serum albumin, COP and clinical signs of oedema were followed daily. Results: HES and albumin were equally effective in raising COP after 48 h. Serum albumin only increased after albumin infusion. Fluid balances after 48 and 72 h did not differ between saline, HES or albumin. COP and serum albumin were correlated (r = 0.78, P < 0.001). Peripheral oedema and pulmonary oedema did not correlate with low COP. Clinical outcome was not different between the groups. Conclusions: HES and albumin are both effective in raising low COP in hypoalbuminaemic patients. These COP-raising effects are not associated with an improvement in fluid balance, clinical outcome or prevention of oedema. Correction of hypoalbuminaemia and low COP in postoperative patients is seldom necessary and not useful in preventing oedema.

78. Night-time hypotension in hypertensive patients prevented by /I-blockers but not by ACE-inhibitors or calcium channel blockers. H.J. van de Luit ‘, T.J. Cleophas t, J. van der Meulen ‘, A.H. Zwinderman *. t Department of Medicine, Merwede Hospital, Dordrecht and ’ Department of Statistics, Academic Hospital, L&den, Netherlands. Circadian rhythms of heart rate and blood pressure are well established in normal subjects, and may follow amplified amplitudes in patients with hypertension due to increased daytime and largely normal night-time values. We examined in a double-blind fashion and placebo-controlled study the effects of a single dose of different classes of antihypertensive drugs on circadian rhythms of heart rates and blood pressures in 10 patients with mild to moderate hypertension. Data were assessed by polynomial analysis (Harvard Graphics 3). The P-blockers celiprolol(200 mg) and

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carvedilol (25 mg) caused a significant fall in daytime blood pressures (P < 0.01). whereas night-time blood pressures did not differ from placebo values. The ACE-inhibitor enalaptil (10 mg) and the calcium channel blocker amlodipine (5 mg) reduced both daytime (P < 0.01, and P < 0.05) and night-time (P < 0.001 and P < 0.01) blood pressures, leading to periods of obvious hypotension during the night-time. Thus, unlike ACE inhibitors and calcium channel antagonists, P-blockers did not cause night-time hypotension in patients with mild to moderate hypertension. These data were confirmed by an g-week crossover trial comparing enalapril 10 mg daily, and celiprolol 200 mg daily in 8 of these patients. This property of P-blockers reflects the circadian rhythm of sympathetic activity and may have clinical implications since night-time hypotension has been associated with the precipitation of cardiac failure and a fall in cerebral blood flow in susceptible individuals,

79. Lipid-lowering treatment in patients with non-insulin-dependent diabetes mellitus and coronary artery disease: have clinical trials changed prescription practice yet? M.A. van de Ree I,*, M.V. Huisman ‘, J.C.M. van der Vijver ‘. ’ Department of Internal Medicine, Leyenburg Hospital, The Hague and * Department of General Internal Medicine, Leiden University Medical Centre, L&den, Netherlands. Objective: Evaluating the impact of large intervention trials with HMG-coA reductase inhibitors on prescription practice in patients with non-insulin-dependent diabetes mellitus. Design: Cross-sectional study with random cohort follow-up. Setting: The out-patient clinic of internal medicine at a large non-academic teaching hospital. Subjects; During 1995 and 1996, the medical data of 1198 consecutive patients with non-insulin-dependent diabetes mellitus were studied. A random sample of 175 diabetic patients with coronary artery disease was selected to compare the change in prescription rate of lipid-lowering drugs. Main outcome measures: The prescription rate of lipid-lowering drugs in patients with non-insulin-dependent diabetes mellitus. The change in prescription rate in the diabetic patients with coronary artery disease between the first 3 months of 1995 and the first 3 months of 1997. Results: In the 1198 patients with non-insulin-dependent diabetes mellitus, the prescription rate of lipid-lowering drugs was 6.6% and the prevalence of coronary artery disease was 31%. In the diabetic patients with coronary artery disease. the prescription rate of lipid-lowering drugs was 5.7% in 1995 and 12.6% in 1997. Conclusions: The results of two large clinical trials showing beneficial effects of HMG-coA reductase inhibitors have not yet led to clinically relevant increases of the prescription of lipidlowering drugs in these patients.

80. Replacement of ACE inhibitors by All-receptor antagonists in hypertensive patients with type II diabetes mellitus: metabolic and haemodynamk consequences. J.P. van der Sluijs ‘, J. van der Meulen t, T.J. Cleophas ‘, A.H. Zwinderman ‘.

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‘Department of Medicine, Metwede Hospital, Dordrecht and 2 Department of Statistics, University Hospital, Leiden, Netherlands. Background: The main pharmacodynamic difference between ACE inhibitors (ACE-i) and AH-receptor antagonists (AH-r) is that ACE-i increase levels of bradykinin, which, in addition to vasodilation, may cause a decrease in insulin resistance. Hypertensive patients with diabetes type II suffering from the side effects of ACE-i are frequently changed over to AH-r. Objectiue: (1) To study whether this procedure reduces metabolic control. (2) To study effects on blood pressure and forearm blood flow (FLOW). (3) To study possible associations between the variables HbAlc and FLOW. Methods: A self-controlled sequential comparison is required to address such questions. Sixteen patients were treated with 10 mg of enalapril or equipotent doses of other ACE-i for 6 months, and, subsequently, with the AII-r losartan 40 mg daily for 6 more months. Patients were examined at the out-patient clinic every 4-8 weeks during the trial. FLOW was measured by iridium strain gauge venous occlusion plethysmography. Results: Mean arterial pressure (MAP) increased by 2.9k5.5 mmHg (P < 0.05) after 6 months of losartan treatment compared to the point of withdrawal of ACE-i. FLOW decreased by 5.5 + 5.0 ml/100 ml tissue * min (P < O.OOl), and HbAlc rose by 0.6 f 0.8 mmol/l (P < 0.05). Other metabolic variables including cholesterol, HDL cholesterol, triglycerides, were not significantly influenced by the change in therapy. Multiple regression analysis revealed that after adjustment for difference in HbAlc, the difference in FLOW was still significant (P < 0.003), and that after adjustment for FLOW, the difference in HbAlc was no longer significant. Conclusions: Replacement of ACE-i by AH-r in hypertensive patients with type II diabetes mellitus induced a significant rise in HbAlc and MAP, and a fall in FLOW. The associations of HbAlc and FLOW with MAP were at least partly independent of each other, suggesting that mechanisms other than the bradykinin system, e.g. the AT, receptor system, are involved. Our study design did not control for placebo and time effects, and so the data are of a preliminary nature.

81. Blood pressure and heart rate response of active old and young persons to physical strain. M.S. van de Steen i, G. de Wild *, J. den Arend ‘, J.W.M. Lenders I, W. Hoefnagels 2, Th. Thien ‘. Departments of’ Medicine, Diuision of General Internal Medicine and 2 Geriatric Medicine, University Hospital, Nijmegen, Netherlands. Aim: The aim of this study was to look at BP (blood pressure) and heart rate (HR) response of active normotensive young and old subjects to endurance compared to a non-active day. We also looked at the differences between the measurements with an ambulant monitor (ABPM) and a mercury sphygmomanometer. Subjects and methods: BP and HR of 12 old (7 male; aged 75 + 3 years (mean + SD)) and 12 young (3 male; 40+ 10 years) subjects were analyzed during long-distance walking (‘De vierdaagse’ a 4-day walk of 30-50 km) and on a non-active day (08.00-16.00 h). The auscultatory Oxford Medilog system

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(ABPM) was used. Measurements were made every 10 min. Calibration was done 3 times with a mercury sphygmomanometer after 10 min rest in the sitting position. This was also performed during a day of long-distance walking. Statistical methods used were the Wilcoxon signed-rank test and Mama-Whitney U-test (BP and HR of the old and young subjects on both days). Results: The calibration showed a non-significant difference of about -5 mmHg for systolic BP on both days for the two groups. For diastolic BP, this difference was significant for young c-4+7) and old c-3+6) subjects on the rest day. Paired measurements after 10 min rest on the walking day showed higher correlation for both DBP and SBP in the older group. (SBP r = 0.93 vs. 0.74, DBP r = 0.84 vs. 0.6). While walking DBP and HR increased more in older subjects (14 and 38%, respectively, young subjects 7 and 23%). At rest, young subjects had a smaller pulse pressure (BP&SD 109/74+ 1 l/7) than older persons (123/78+13/g). Conclusion: Young subjects had a smaller pulse pressure at rest; with intensive walking, HR and DBP rose more in older subjects. As expected, the cardiovascular capacity is lower and the peripheral resistance is higher in older subjects. The correlations between ABPM and sphygmomanometer BP measurements were higher in older subjects than in younger subjects, both for systolic and diastolic BP.

82. Blood pressure response to active standing improves after furosemide withdrawal in elderly patients with diastolic heart failure. D. van Kraaij, R. Jansen, I. Go, L. Bouwels, W. Hoefnagels. Department of Geriatric Medicine, Universiry Hospital, Nijrnegen, Netherlands. Elderly patients with diastolic heart failure are particularly dependent on adequate preload to maintain cardiac output. Furosemide lowers left ventricular (LV) filling pressure and this might deteriorate blood pressure (BP) response on active rising in older patients with diastolic heart failure. We determined IO-mm beat-by-beat non-invasive BP responses (Finapres) to active standing before and 3 months after double-blind furosemide withdrawal in 20 elderly diastolic heart failure patients (ejection fraction 61+ 13% on echocardiography) without current congestion. Results: Thirteen patients were withdrawn from furosemide (WG, age 76& 3 years) and 7 patients continued furosemide therapy (FG, age 75 +3 years). Baseline systolic @BP) and diastolic (DBP) blood pressures did not differ between WG and FG patients. SBP response to standing significantly increased in WG patients compared to FG patients (P < 0.05, ANOVA for repeated measurements). In the WG, maximal decrease in SBP after rising changed from - 8 f 17 to + 5 +9 mmHg (P < 0.05). DBP decrease also changed from -2*9 to +5*8 mmHg (P < 0.05). In the FG, maximal BP decrease remained unchanged mmHg; DBP -2+5 vs. -2+7 (SBP -7+10 vs. -8+12 mHg). Conclusion: Furosemide withdrawal improves SBP and DBP response to active standing in elderly patients with diastolic heart failure. Careful evaluation of the indication for continued diuretic therapy is needed in these patients, since successful withdrawal

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or ameliorate

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1998/Netherlands and its adverse

83. Non-invasive continuous cardiac stroke volume monitoring: evaluation of a novel technique. E.J. van Lieshout ‘, K. Toska 3, M. Eriksen 3, L. Walloe 3, K.H. Wesseling *, J.J. van Lieshout ‘. Departments of ’ Internal Medicine and 2 TN0 Biomedical Instrumentation, Academic Medical Centre, Amsterdam, Netherlands and -’ Institute of Basic Medical Sciences, Unit~ersity of Oslo, Oslo, Norway. Introduction: A proper understanding of the cardiovascular mechanisms involved in complaints of short-lasting dizziness requires continuous monitoring of cardiac stroke volume (SV) apart from blood pressure and heart rate. We evaluated a novel method of non-invasive continuous SV monitoring, Modelflow with Doppler ultrasound as the single other continuous technique available. Methods: Beat-to-beat stroke volume was calculated by two methods: Doppler ultrasound (US) (Vingmed Sound A/S, Horten. Norway) and a non-linear, time-varying three-element model of aortic impedance (Modelflow; MF) applied to the continuous finger arterial pressure wave (Finapres). Changes in SV during supine rest and passive 30” head-up tilt were measured in 6 healthy subjects (mean age 27 (2 I-56) years). Changes in SV are expressed in percentages of the mean values at rest. Results: SV variations were adequately tracked by both methods during rest with a small MF-US difference (range - 10.8 to +9.5%). Tilting induced an MF-US difference of 10.8%, maximal at 12 s (range -4.2 to + 21.3%). The MF-US difference was reproducible during 3 consecutive tilts (ANOVA; P = 0.77). Atria1 premature contractions recorded in one subject induced a large drop in SV ( + 50%) lasting two heart beats and was assessed by both methods. Conclusion: Beat-to-beat changes in SV in supine rest are equally well assessed by both MF and US. The MF-US difference during a change in body position may be attributed to both methods. MF seems a promising tool in evaluating symptoms in cardiac arrhythmia.

84. Postprandial hypotension is related to left ventricular filling and improves after furosemide withdrawal in elderly patients with diastolic heart failure. D. van Kraaij, R. Jansen, I. Go, L. Bouwels, W. Hoefnagels. Department of Geriatric Medicine, University Hospital, Nijmegen, Netherlands. The pathophysiology of postprandial (PP) hypotension is not fully understood. We hypothesized that PP hypotension might be related to diastolic left ventricular (LV) filling. Particularly in elderly patients with diastolic heart failure, diuretics may further impair LV tilling and thus aggravate PP hypotension. We examined non-invasive beat-by-beat systolic blood pressure at (SBP, Finapres) response to a standardized meal and its relationship to Doppler echocardiographic parameters of LV diastolic filling (peak E and A, E/A ratio, and deceleration time) before and 3 months after double-blind withdrawal of furosemide in 20 elderly heart failure patients with a preserved LV ejection fraction (61 f 13%) and without current congestion.

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Results; Thirteen patients were successfully withdrawn from furosemide (WC, age 76k3 years) and 7 control patients (CC, age 75 + 3 years) continued on furosemide. In the WG, maximum PP SBP changes improved from - 25 f 13 to - ilk 6 mmHg (P < 0.01). SBP response remained unchanged (- 19+ 11 vs. - 16 + 6 mmHg) in the CG. Before withdrawal, E/A ratios were correlated to changes in PP SPB (rs = 0.58, P = 0.007) for all 20 patients. In the WG, E/A ratios increased from 0.65 + 0.10 to 0.75+0.14 (P < 0.05). E/A ratios did not change in the CG (0.72 + 0. I2 vs. 0.67 + 0.05). Improvement of PP SBP response after withdrawal was correlated to increases in peak E (rS = 0.80, P = 0.002) and E/A ratio (rs = 0.66, P = 0.02) (n = 13). Conclusions: PP reductions in SBP are related to LV diastolic filling and improve following furosemide withdrawal in elderly heart failure patients with preserved LV systolic function.

VIII. Gastrointestinal and liver diseases 85. Octreotide in a patient with treatment-resistant collagenous colitis. S. Boorsma, G. van Olffen, J.J. Kolkman. Department of Internal Medicine, Medical Spectrum Twente, Enschede. Netherlands. A 54-year-old man was admitted because of therapy-resistant diarrhoea. Eight years earlier, his complaints began with watery diarrhoea, 10 bowel movements per day. Extensive examination including faecal cultures, parasite examinations, sigmoidoscopy, small bowel series and gastroscopy with duodenal biopsies had revealed no cause. Symptomatic therapy with cholestyramine had been unsuccessful. A few months later, repeated sigmoidoscopy showed normal macroscopy; however, biopsies showed inflammation of the lamina propria with a thickened eosinophilic basal membrane, characteristic of collagenous colitis. The patient was treated with salazopyrine, loperamide, metronidazole and prednisolone, all without result. Over the years that followed, the diarrhoea waxed and waned. Several colonoscopies were normal, without any signs of collagenous colitis in the biopsies. His current admission was due to relapse of severe watery diarrhoea. complicated by dehydration. Endoscopy of the colon was normal. but biopsies again showed collagenous colitis. Treatment with polymeric diet, prednisolone and metronidazole was without any effect. Finally, treatment with octreotide 1004 fig S.C. b.i.d. was started. The diarrhoea gradually disappeared over the following 2 weeks. One year later, octreotide was stopped, resulting in a relapse of the diarrhoea, again disappearing with octreotide. Conclusion: Collagenous colitis is an uncommon cause of chronic watery diarrhoea. In the literature, several therapies have been described, all with mixed results. This case illustrates that octreotide should be considered in severe cases of treatment-resistant collagenous colitis.

86. A population-based sant use in 24 general Hurenkamp ’ , H.G.L.M.

inventory practices Grundmeyer

of long-term acid in the Netherlands. ‘, P.J.E. Bindela

suppresG.J.B. ‘, G.N.J.

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Tytgat ‘, R.W.M. van der Hulst ‘. Departments of ' General Practice and ’ Gastroenterology, Academic Medical Centre, Amsterdam, Netherlands. A considerable portion of the medication budget of the Dutch General Practitioners (GP) is spent on acid suppressant drugs. These high expenses relate to the high cost of the drugs, the high frequency of prescription and, in particular, the long duration of medication. The aim of this study was to investigate the magnitude of long-term medication with acid suppressant therapy in general practice, the clinical grounds for the fiit prescription and the frequency and objective means of the primary working diagnosis. Patients on long-term acid suppressant therapy were identified in a population of 46,813 patients in 24 general practices in the Amsterdam region by extraction from pharmacologists’ computerized medication databases. The indications for the prescription and the investigations performed to confirm the working diagnosis were obtained from the patients’ files in the general practices. Long-term acid suppressant therapy was defined as a prescription for at least 12 weeks in 1 year. Nine hundred and twenty-two patients (2% of the population) were on long-term acid suppressant therapy (0.9-4.2% per practice). Mean duration of therapy was 33 weeks (range 12 (in 8%) to > 52 (in 23%) weeks). In more than 50% of the patients, acid suppressant therapy was prescribed in a continuous fashion. In 25% of the patients, no objective investigations were performed. In 75% of the patients, endoscopy or radiology was done; the predominant diagnoses were ulcerative disease (39.2%), GORD (38.3%) and other (gashtis, H.D., normal aspect) (29.5%). The Helicobacter pylon’ status had been established in 29% of the patients with ulcerative disease. Eradication therapy was reported in 40% of these patients. Long-term acid suppressant therapy is often administered without a firm clinical indication and without a confmed working diagnosis.

87. Plugged-percutaneous liver biopsy, a safe and simple method in high-risk patients. F.S. Koops ‘, Tj.G. Wiersma ‘, R.A. de Vries ‘. Departments of I Internal Medicine and 2 Radiology, Rijnstate Hospital, Arnhem, Netherlands. Liver biopsy is an important diagnostic tool in daily practice of internal medicine. As it is an invasive procedure, it has the risk of complications. Amongst these, the most common are haemorrhage and biliary leakage leading to biliary peritonitis. For this reason, routine percutaneous liver biopsy is contraindicated in certain circumstances. Although transjugular biopsy can safely be performed in this situation, it has important disadvantages as it is a complex procedure. In high-risk patients with severe impaired haemostasis, suspicion of haemangioma, ascites or dilated intrahepatic bile ducts, plugged percutaneous liver biopsy can be a suitable alternative. In a pilot study, we investigated the safety and efficacy of the technique of plugged percutaneous liver biopsy in a group of 26 patients with impaired haemostasis (n = 12), ascites (n = 8), impaired haemostasis and ascites (n = 2), haemangioma (n = 2) and dilated intrahepatic bile ducts (n = 2). Criteria for impaired haemostasis: prothrombin time prolonged by 3 s or more over control, a platelet count between 20 and 70 X 109/1 and/or prolonged bleeding time, more than 360 s. In this procedure, the

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plugged liver biopsy is performed under ultrasound guidance with a True-cut needle in a biopsy firing system. After taking the biopsy, the needle is withdrawn. A fluid with local haemostatic properties (Ivalon) is then injected through the sheath while this is gradually withdrawn. In all 26 patients fulfilling the criteria, the plugged liver biopsy procedure was uncomplicated and diagnostically successful. Plugged percutaneous liver biopsy in high-risk patients suspected of having liver disease, is a safe and relatively simple diagnostic procedure.

88. Serum eosinophil cationic protein in active and quiescent ulcerative colitis. R.K. Linskens, C.J. Pronk-Admiraal, A.A. van Bodegraven, P.C.M. Bartels, H.A.R.E. Tuynman. Departments oj Gastroenterology and Clinical Chemistry, Medical Centre, Alkmaar, Netherlands. Background: In the patbogenesis of ulcerative colitis (UC), many proinflammatory cytokines activate eosinophils, thereby releasing eosinophil cationic protein (ECP). ECP is a pivotal cytotoxic mediator, causing mucosal damage. Data of serum ECP (sECP) concentration in the course of UC are sparse. Moreover, standardization of sECP determination is complex. Aim: To measure sECP concentration in the course of UC using a previously described standardized analytic method. Methods: In 6 patients with active UC, 5 patients with quiescent UC (established by clinical and endoscopic findings) and 8 IBS controls (Manning criteria positive, lactose tolerant), sECP was measured at baseline and at 12 weeks. In patients with active UC, samples were also drawn at 2, 4 and 8 weeks. The preanalytic phase of ECP determination was standardized by spontaneous clotting of blood for 2 h at 37°C. After incubation, samples were centrifuged for 10 min at 1350 g, Mann-Whitney and Spearman rank tests were used. Results: At baseline, mean sECP was significantly higher in active UC (100.3 wg/l) compared with both quiescent UC (33.7 kg/l, P < 0.02) and IBS controls (23.9 pg/l, P < 0.005). During reconvalescence of UC, sECP decreased to 22.8 pg/l at t = 2 weeks (P < 0.01). In both active and quiescent UC, eosinophil count was raised compared with controls (P < 0.005). We found a positive correlation between eosinophil count and sECP concentration (r = 0.58, P = 0.02). Conclusions; With this standardized method of sECP determination, we found elevated levels in all patients with UC as compared with controls. sECP and total eosinophil count were correlated with disease activity. ECP may play a significant role in the pathophysiology of UC.

89. Gastric tonometry exercise testing: towards an easier test? J.A. Otte I, E. Oostveen ‘, J.J. Kolkman I. Departments of’ Internal Medicine and Gastroenterology and ’ Pulmonology, Medical Spectrum Twente, Enschede, Netherlands. Gastric tonometry is regularly used as a monitoring technique in intensive care units. It measures gastric mucosal blood flow and can be used as an early parameter for haemodynamic changes. When measured during submaximal exercise, it can be used to

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detect chronic gastric ischaemia. The gradient between arterial ( paC02) and in&alumina1 ( piCO,) emerged as the most accurate parameter for gastric ischaemia. Thus, the procedure involves arterial blood sampling for determination of p,CO, and, to determine the intensity of the exercise, lactate. In order to make the test easier and less invasive, we examined whether we could do without arterial blood sampling by substituting p,CO, with end tidal pC0, (petCOz) and lactate (LAC) with decrease of base excess (BE) or bicarbonate (BIC), which could both be measured in a capillary blood sample. Methods; Thirty-three gastric tonometry exercise tests. both in healthy volunteers and in patients suspected of having chronic gastric ischaemia, were evaluated. Nine healthy volunteers (5 female, 4 male, mean age 25 years, range 23-28 years) were studied twice: before and during submaximal and maximal exercise. Fifteen patients (11 female. 4 male. mean age 51 years, range 23-71 years) were tested, of whom 9 had stenosis of one or more of the splanchnic arteries. Prior to all tests, 100 mg ranitidine was administered i.v., a nasogastric tonometer placed and connected to an automated air tonometry device (Tonocap, Datex, Finland), and a radial artery catheter inserted. paCOZ, pe,COZ intragastric pCOl (p,CO,), gradients between p,CO, and p,CO, and piCO, and P,~CO, (A, pCO,, respectively, A,,pCO,), BE, BIC and LAC were measured before and after a IO-min episode of bicycle ergometry exercise testing. All values are given as mean f SD. Results: Before exercise, paCOz was 5.1+ 0.5, p,,CO, 4.6 i 0.6 (correlation coefficient 0.88). A, pC0, -0.1 +0.8 and A,, pC0, 0.5 + 0.6 kPa (correlation coefficient 0.80). After exercise, p,CO, was 4.7kO.6, petCOz 4.8kO.7 (correlation coefficient 0.78), A, pC0, 0.9 + 0.8 and A,, pC0, 0.7 + 1.O kPa (correlation coefficient 0.75). Using a normal threshold for A, pC0, of 0.9 kPa, 17 subjects showed an abnormal test result, indicating gastric ischaemia. A,, pC0, in this group ranged from - 0.4 to 2.8 kPa. In the group with normal tonometry, A,, pC0, ranged from - 1 .O to 1.2 kPa. Therefore, the use of A,, pC0, cannot discriminate between normal and abnormal results. During exercise, LAC increased to 8.3 + 3.9 mmol/l which correlated excellently with the decrease in BE (7.5 + 3.9 mmol/l, Y = 0.98) and BIC (6.4 + 3.1 mmol/l, I = 0.96). Conclusion: In gastric tonometry exercise testing. when determining the intensity of exercise, instead of lactate, decrease of base excess (or bicarbonate) can be used. perCOZ cannot substitute paC02 when calculating ApCOz.

90. Mean hydrogen ion concentration: a valuable parameter in 24-h oesophageal monitoring? E.C. Niemantsverdriet ‘, R. Timmer ‘, R. Breumelhof ‘, A.J.P.M. Smout ‘. ’ Department of Gastroenterology, St. Anton& Hospital, Nienwegein and ’ Depnrtment of Gastroenterology, University Hospital, Utrecht, Netherlands Introduction; The traditional parameters used in the analysis of ambulatory 24-h pH monitoring utilize the arbitrary threshold of pH < 4. They suffer from the shortcoming that they do not take into account the differential effect of refluxates with different acidities. The aim of this study was to assess the additional value

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52 (1998)

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of parameters based on the calculated mean hydrogen ion concentrations [H+ 1. Patients and methods: One hundred and fourteen ambulatory pH recordings, obtained from four patient groups with different stages of mucosal damage, were analyzed. In all subjects, 5-channel pH monitoring was carried out, using ISFET (ion-sensitive field effect transistor) technology. Thirty-eight patients with gastro-oesophageal reflux disease (GORD) without oesophagitis or Barrett’s metaplasia, 45 patients with oesophagitis (grade I-IV) and 28 with Barrett’s oesophagus (BO) were included. The results of 21 healthy volunteers were used to define normal values. The traditional parameters of percentage time with pH < 4 were analyzed and compared with mean [H+ ] parameters. Results: Percentages of time with pH < 4 and mean [H+ ] showed similar global patterns consisting of an increase with increasing severity of reflux disease and a decrease with increasing distance from the lower oesophageal sphincter. Both with the traditional and the [H+ ] parameters significant differences were found between controls and endoscopy-negative patients. between the latter and patients with oesophagitis, and between patients with oesophagitis and patients with BO. However, the traditional parameter of time with pH < 4 distinguished slightly better between subjects with and without oesophagitis, and between oesophagitis and BO. Conclusion: Parameters based on the mean [H’ ] appear not to be better determinators of oesophageal mucosal damage, than the time with pH < 4.

91. Heavy exercise of short duration can provoke gastric ischaemia in healthy subjects. J.A. Otte ‘, E. Oostveen ‘, R.H. Geelkerken ‘, J.J. Kolkman ‘. Departments qf ’ Internal Medicine and Gastroenterology, ’ Pulmonology and .’ Surgery. Medical Spectrum Twente, Enschede, Netherlands. Gastric tonometry exercise testing can be used to detect chronic gastric ischaemia. We have previously shown that an increase in intragastric pC0, (p,CO,) and gastric blood pC0, gradient ( ApCO,) during submaximal exercise occurs only in patients with splanchnic artery stenosis. It is unknown whether heavy exercise of short duration can provoke gastric ischaemia in healthy subject as well. Therefore, we performed a gastric tonometry study in healthy volunteers at submaximal and maximal exercise. Methods: Ten healthy, untrained subjects (5 female, 5 male, mean age 25 years, range 23-28 years), non-smoking and without any other risk factors for arteriosclerosis underwent Duplex sonography of the coeliac (CA) and superior mesenteric artery (SMA). Prior to the gastric tonometry exercise testing, 100 mg ranitidine was administered i.v., a gastric air tonometer was inserted nasogastrically and connected to a Tonocap (Datex, Finland). A radial artery catheter was inserted. Heart rate (HR). arterial pCOz ( p,CO,), lactate, p,CO, and ApCO, (presented as mean + SD) were measured during 5 episodes: baseline, 10 min submaximal exercise, 60 min recovery, repeated baseline, and 10 min maximal, exhaustional exercise. Exercise was performed on a bicycle ergometer. Results: With Duplex sonography, all subjects had normal

Intemistendagen

1998/Netherlands

flow velocities in SMA, in two subjects, CA was not visualized sufficiently to make reliable measurements, the rest had normal CA flow velocity. No differences in any parameter between the two baseline episodes was seen. After submaximal exercise, HR and lactate differed from baseline as expected: HR increased from 78 f 14 to 162 +5 beats/min, lactate rose from 0.5 +O.l to 6.5 +2.4 mmol/l; piCO, rose from 4.9kO.6 to 5.2+0.6 kPa. paC02 and A&O, remained unchanged (5.1 +0.7 vs. 5.0*0.5 kPa, and -0.3 +0.4 vs. 0.2kO.5 kPa, respectively). On exhaustional exercise, ApCO, increased over baseline (P < O.OOl), as did all other parameters: HR 189 + 7 beats/mm, lactate 12.8 + 3.2 mmol/l, piCO, 5.5 *0.6, paC02 4.4+0.7 and ApCO, 1.1 + 1.0 kPa. With increasing exercise level, gastric hypoperfusion increased as indicated by the correlation between lactate and ApCO, (r = 0.74, P < 0.001). In 5 subjects, A&O, exceeded 0.9 kPa. indicating gastric ischaemia; their lactate levels ranged from 8.4 to 16.6 mmol/l. Conclusion: Heavy exercise of short duration, with lactate levels > 8 mmol/l, can provoke gastric ischaemia in healthy volunteers with normal splanchnic vasculature. Thus, when using gastric exercise tonometry for detection of gastric ischaemia, the exercise level should not exceed this threshold to prevent falsepositive results.

92. Symptom-reflux association in patients with gastrooesophageal reflux disease. EC. Niemantsverdriet ‘, R. Breumelhof ‘, R. Timmer ‘, A.J.P.M. Smout *. ‘Department of Gastroenterology, St. Antonius Hospital, Nieuwegein and ’ De partment of Gastroenterology, University Hospital, Utrecht. Netherlands. Introduction: The relationship between symptoms of gastro-oesophageal reflux and the degree of distal oesophageal acid exposure is rather poor. The aim of this study was to investigate the role of more proximal oesophageal sites in symptom generation in gastro-oesophageal reflux disease (GGRD). Patients and methods: Five-channel 24-h oesophageal pH recordings obtained from 27 patients with endoscopy-negative GORD, 26 patients with erosive oesophagitis, 14 patients with healed oesophagitis and 22 patients with Barrett’s oesophagus (BO) were analyzed. All patients had one or more symptoms during the 24-h monitoring period. Symptom-reflux associations were assessed by the symptom index ‘$11, the symptom sensitivity index (SSI) and the symptom association probability (SAP) at all 5 oesophageal levels. Results: Patients with endoscopy-negative GORD had the lowest number of reflux episodes during the 24-h study, but showed the highest symptom indices for the distal oesophageal sites. The highest numbers of reflux episodes were recorded in BO, these patients had the lowest SSI and SAP in the distal segment. In BO, the reflux-related symptoms originated from a significantly higher oesophageal level than in the other patient groups (P < 0.003, P < 0.0001, P < 0.0001, BO vs. healed oesophagitis, erosive oesophagitis and endoscopy-negative, respectively). Patients with healed oesophagitis had symptom scores indicating a relatively insensitive proximal oesophagus. Conclusions: In BO, the columnar-lined segment appears to be

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less acid-sensitive than the proximal squamous cell segment, while in other patients with GORD, most reflux-related symptoms originate from the distal oesophagus. Distal acid sensitivity is increased in endoscopy-negative GGRD, proximal sensitivity is decreased in patients with healed oesophagitis.

93. Chronic gastric ischaemia: a 2-year experience in 21 patients. J.A. Otte ’ , R.H. Geelkerken *, E. Oostveen 3, A.B. Huisman 4, J.A. Rauwerda 5, S.G.M. Meuwissen ‘, J.J. Kolkman ‘. Departments of ’ Internal Medicine and Gastroenterology, 2 Surgery, ’ Pulnwnology and 4 Radiology, Medical Spectrum Twente, Enschede and Departments of 5 Vascular Surgery and 6 Gastroenterology, Free Uniuersity Hospital, Amsterdam, Netherlands. Chronic gastric ischaemia is considered a rare condition. In our hospitals, it used to be diagnosed l-3 times per year. The diagnosis, based on angiography as the golden standard, is notoriously difficult and often postponed, lacking a simple, minimally invasive test. Gastric tonometry during exercise has been advocated as such an alternative diagnostic test. We evaluated our 2-year experience with combined gastric exercise tonometry and angiography in patients suspected of having gastric ischaemia. Patients and methods: Between 1995 and 1997, we evaluated 36 patients (25 female, 10 male, mean age 52 years, range 23-75 years) with unexplained abdominal pain, weight loss, diarrhoea or gastric ulcer. All subjects underwent gastroscopy and selective arteriography of coeliac (CA), superior (SMA) and inferior mesenteric artery (IMA). Gastric tonometty was performed, measuring the gastric blood pC0, gradient ( ApCO,) before and after a IO-min period of submaximal exercise. Results: In 22 patients, stenosis > 50% of vessel diameter was found. Twelve patients had single-vessel stenosis (10 CA, 2 SMA). Six had two-vessel stenosis (2 CA and SMA, 3 CA and IMA and 1 SMA an IMA). Stenosis of all three vessels was seen in 4 patients. The maximal ApCO, (mean + SD) was higher in patients with stenosis (2.3 + 2.6 vs. 0.4 +0.7 kPa, P = 0.01) with similar exercise levels (bicarbonate decrease 4.5 + 2.9 vs. 3.6 f 2.3, n.s.1. Using a normal threshold of 0.9 kPa, 18/22 patients with stenosis showed an abnormal tonometty. In 4, the test was normal: 2 had minimal complaints and probably have stenosis without ischaemia; 1 could not be tested adequately due to pulmonary emphysema; and 1 had a non-healing B-II ulcer. The sensitivity for clinically important ischaemia is therefore 90-95%. Among 14 patients with normal vessels, 4 had an abnormal tonometry test: 1 had spasms of CA and SMA during angiography and probably also during the exercise testing, 2 had an increased ApCO, which decreased during exercise, indicating insufficient acid suppression despite ranitidine treatment. In 1 patient, a marginally elevated ApCO, could not be explained, indicating a false-positive test. The presenting complaints of 21 patients with chronic gastric ischaemia were: pain in 18, weight loss in 11, gastric ulcers (Hpand NSAID-negative) in 6, and diarrhoea in 3. Of these 21 patients with stenosis or spasm, 6 were operated; 1 of these died postoperatively, the others are free of symptoms. Five patients were treated with dietary measures including small, frequent meals and MCT fats, with good result, in 4.

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Conclusion; Chronic gastric ischaemia is more common than often assumed. It should be considered in patients with unexplained abdominal pain, weight loss and gastric ulcers. Most patients have moderate complaints and can be treated conservatively. Gastric exercise tonometry may be used to screen for gastric ischaemia, although some methodological problems, including optimal acid suppression and monitoring need further study.

94. Collagenous colitis: an epiphenomenon of autoimmune disorders? K. Rostami i, J.W.R. Meijer *, C.J.J. Mulder ‘. Departments of I Hepatogastroenterology and 2 Pathology, R&state Hospital, Arnhem, Netherlands. Collagenous colitis (CC) is a rare and underdiagnosed disease causing watery diarrhoea in middle-aged women. Seventeen patients diagnosed with CC were investigated. Methods: Clinical, treatment and pathological data were retrospectively analyzed. Cases were identified at the Rijnstate Hospital, Arnhem, using gastroenterology records between 1990 and 1996. Results: Our collagenous colitis patients developed diarrhoea. abdominal pain and fever. Diarrhoea was present in all 17 patients (100%). No consistent laboratory abnormalities have been recognized. In this study group, 14 of 17 ( > 82%) had an association with the diseases such as ulcerative colitis, coeliac and thyroid diseases. The presence of lymphocytic colitis was noted in 8 of 17 patients (44%) as a histological variety. Immunomodulation therapy (azathioprine and prednisone) was the most effective choice with a response rate of 100% for azathioprine and 81% for prednisone in 11 patients. Clinical and histological improvement were obtained in all of them (1 l/l 1). Complete remission has been recognized in one coeliac patient on a gluten-free diet. Conclusion: There are reported associations between CC and a number of diseases of unknown aetiology in which immunological mechanisms are thought to be involved (autoimmune diseases). It seems unlikely that they are all fortuitous, and a common underlying immunological defect has to be considered. On the basis of these associations in our study and information reported in the literature, we suggest that collagenous colitis is not an apart entity. CC might be an associated epiphenomenon, which is often related to other diseases mainly with an autoimmune aetiology. The treatment and prognosis of CC might depend on the underlying associated diseases.

95. Screening of first-degree relatives of coeliacs: looking for a logarithmic approach. K. Rostami ‘, J. Kerckhaert ‘, J.W.R. Meijer ‘, M.B.V. von Blomberg ‘, F.M. van Overbeek ‘, .I. Verhage ‘, C.J.J. Mulder i, H.S.A. Heymans 3. ’ Department of Hepatogastroenterology, Rijnstate Hospital, Arnhem, * Department of Immunology, Free University, Amsterdam and 3 Department qf Paediatric Gastroenteroloy, Academic Medical Centre, Amsterdam, Netherlands. The diagnosis of coeliac disease (CD) may be facilitated using a standardized logarithmic approach. In order to identify new

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coeliacs, family screening has been performed in the period of 1994-1997. The aim of this study was to evaluate the predictive value of screening parameters for the detection of CD. Methods: Questionnaire and physical examination were used followed by haematological analyses, and serology for anti-endomysium (EMA) and antigliadin (AGA) antibodies. The screening was performed in 346 first-degree relatives. In relatives with abnormal laboratory tests (haematology, serology) or clinical complaints, a small intestinal biopsy (SIB) was performed. SIB was indicated in 146, but only performed in 123 (35%) of the study group. Results: CD has been diagnosed in 16 cases by our screening. However, another 16 have been recognized by earlier screening (total diagnosed coeliacs 32/362, > 9%). We present our results of screenings performed in 346 first-degree relatives. Sixteen of 123 showed villous atrophy (VA) in their biopsy specimens. Milder histological abnormalities (Marsh I-II) were found in 33/123 (27%) and 74/123 (60%) showed no abnormalities in their SIB. AGA was measured in 335 relatives. Twenty of the 335 had a positive AGA (4%). Eight patients with raised AGA had CD (sensitivity 50%). AGA was positive in 12 relatives without CD (specificity 94%). EMA was measured in 294/346. Thirteen of 294 had a positive EMA. A (subkotal VA has been recognized in nine of them. Biopsy specimens of another four EMA-positive relatives showed no abnormalities (Marsh 0) (specificity 98%). EMA was performed in 14 of 16 coeliacs and was positive in 9/14 (sensitivity 64%). Four of 16 diagnosed coeliacs with partial VA had negative EMA, AGA and (25%). They underwent an SIB because of their clinical complaints. Conclusion; A significant proportion of coeliac patients may be missed, because the small intestine in untreated CD is not always flat and serology may not be capable of detecting the patients with partial VA. We argue that using EMA and AGA is not enough for investigation of the true prevalence of CD. It is important to consider the diagnosis of CD, not only in those with non-specific complaints and abnormal serology, but also in those with clinical complaints and negative serology. A combination between clinical and laboratory tests (AGA and EMA) is an important and practical contribution to the diagnosis which will improve the detection rate of CD.

96. Sensitivity and specificity of tissue transglutaminase test, antigliadin and antiendomysiwn compared to the histopathological features of coeliac disease. K. Rostami ‘. S. Stapel ‘, J.W.R. Meijer i, C.J.J. Mulder ‘. ’ Rijnstate Hospital, Arnhem and 2 Central Blood Transfusion Laboratov (CLB), Amsterdam, Netherlands. The sensitivity and specificity of the IgA antiendomysium (EMA), IgA antigliadin (AGA) and the recently described IgA tissue transglutaminase (tTG) have been compared with the histopathological features of coeliac disease (CD). Methods: Fifty-five cases, including 28 untreated coeliacs, 22 first-degree relatives and 5 coeliacs on a gluten-free diet (GFD), were investigated. Two coeliacs with IgA deficiency were excluded from this study group. IgA antibodies to tTG were deter-

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mined by ELISA, as described by Dietrich et al. (1997). Results were correlated with the degree of abnormality of the intestinal mucosa in patients with CD according to the Marsh 1992 criteria revised in 1997 (Marsh IIIa; partial villous atrophy, Marsh W; subtotal villous atrophy and Marsh IIIc; total villous atrophy). Results: EMA, AGA and tTG were found in all patients with untreated CD and total villous atrophy (5/5; 100%). However, patients with partial villous atrophy (Marsh III) gave disappointing values of sensitivity for EMA, AGA, and tTG, respectively, 40, 40 and 20%. Two of 5 (40%) patients on a non-strict GFD were positive for EMA, 2/5 for AGA (40%) and l/5 for tTG (20%) while 21/22 first-degree relatives were negative for all parameters (EMA, AGA, tTG). EMA was positive in one fust-degree relative whose biopsy showed no abnormality. In patients with subtotal villous atrophy (Marsh IIIb), EMA, AGA and tTG sensitivity was 81, 72 and 54%, respectively. Conclusion: The positive predictive value of tTG for all histopathological features of CD was excellent. However, the negative predictive value of tTG was extremely low and unreliable in patients with partial/subtotal villous atrophy. EMA and AGA are more reliable for detection of patients with milder histopathological abnormalities; however, we have to realize that > 40% of coeliac population presents with milder villous atrophy (Marsh IIIa) and a substantial part of them is negative in even AGA and EMA.

97. The value of duodenal biopsies in patients with lactose malabsorption: a retrospective study. C.M.J. Spiertz, E.J. Schoon, R.W. Stockbtigger, W. Hameeteman. Department oj Internal Medicine, Division of Gastroenterology, University Hospital, Maastricht, Netherlands. Introduction: Lactose malabsorption can be primary or secondary. Secondary lactose malabsorption can be caused by, for example, villous atrophy, lambliasis or Whipple’s disease. Diagnosis of secondary lactose malabsorption is important as this may have therapeutic consequences apart from lactose restriction. Aim: The aim of our study was to evaluate the diagnostic impact of duodenal biopsies in patients with an abnormal outcome of lactose-HZ-breath-test (H,-BT). Patients and methods: Patients’ records were evaluated following H,-BT with regard to subsequent, gastroduodenoscopy (GD) and duodenal biopsies (DB). Ha-BTs were considered abnormal if H, rise was over 10 ppm above baseline and/or serum glucose was less than 1.2 mmol/l following a lactose load of 50 g. From January 1995 to December 1995, 256 Hz-BTs were performed for clinical symptoms of lactose malabsorption, e.g. diarrhoea (lS%o), meteorism (14%), epigasttic pain (9%) or abdominal cramps (8%). One hundred and fifty-four women and 102 men over 18 years were investigated (mean age 45 years; 107 patients < 40 years). In this group, a total of 93 GDs were performed with biopsies of the duodenum taken in 85 patients. Results: One hundred and fori+seven HZ-tests (57%) were considered abnormal. In 70 cases, GDs were performed and 66 biopsies were taken. Abnormal biopsies were present in 8 patients. In 2 cases, lambliasis was found. In both patients, stool cultures.

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for lambliasis were negative. Patients with lambliasis were treated with antibiotics. In 3 patients, villous atrophy was found. One patient had villous atrophy, but IgA antibodies against gliadine and endomysin were negative due to IgA deficiency. Patients with coeliac disease were treated by a gluten-free diet. Three patients had varying degrees of chronic (focal) inflammation in their biopsies. The significance of the focal inflammation in this aspect is not clear. In the group with a normal outcome of H,-BT (n = 109), 23 GDs were performed to exclude upper intestinal pathology. In 19 patients, biopsies of the duodenum were taken. One biopsy showed hyperplastic features close to the papilla of Vater, the others were normal. Summary and conclusion: Even from this small population of patients undergoing endoscopy we may conclude that duodenal biopsies are helpful in diagnosing secondary lactose malabsorption. On duodenal biopsy, 5 of 66 patients (7%) with lactose malabsorption had well-defined small-intestinal disease. After treatment, they are not obliged to follow a life-long lactose-free diet. Therefore, in patients with lactose malabsorption, duodenal biopsies are advised to discover primary causes of clinical significance.

98. Hormone treatment for gastrointestinal bleeding: a case report. S.J. van den Hazel, G. den Hartog. Department of Znternal Medicine and Hepatogastroenterology, Rijnstate Hospital, Arnhem, Netherlands. An 88-year-old woman was admitted for recurrent iron-deficiency anaemia. Blood loss in the intestinal tract was suspected, although melaena was never seen. Gastroscopy and colonoscopy performed previously had not revealed a bleeding focus. In order to maintain her haemoglobin > 6 mmol/l, she needed a transfusion every 5-6 days. Over a 6-month period, she received 38 units of blood. Repeat endoscopies of the stomach, duodenum and colon were unremarkable, except once when blood was seen in the distal duodenum, coming from the jejunnm. An erythrocyte scan made during a period of active bleeding showed at accumulation of blood in the left abdomen, possibly an arteriovenous malformation of the jejunum. Because this patient was deemed inoperable on the basis of age and co-existing coronary artery disease, hormone treatment was given: ethinyloestradiol 0.05 mg and noretbisterone 1 mg, both once daily. One month after commencement of treatment, the last transfusion was given after which her haemoglobin level remained stable. In the following 7 months, she only needed a single transfusion of 2 units of blood. Treatment was complicated when, after 25 days, the patient developed a thrombosis of the right iliac vein. Low molecular weight heparin was given subcutaneously (Fraxiparine 20,000 U b.i.d.). Her symptoms ameliorated promptly. After 14 days of treatment, the dose was reduced to 7500 U once daily for 3 months. Despite this anticoagulant, no recurrent bleeding was observed. Conclusion: We report the successful treatment of a patient with slow, but persistent, gastrointestinal bleeding with oestrogen and progesterone which was complicated by venous thrombosis that required anticoagulant therapy.

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99. The serological detection of Helkobacter pyhi in mechanically ventilated intensive care patients. P.H.J. van der Voort ‘. R.W.M. van der Hulst 3, D.F. Zandstra ‘, A.A.M. Geraedts ‘. G.N.J. Tytgat 3, Departments of’ Intensive Care and ’ Gastroenterology, Onze Lierle Vrouwe Hospital, Amsterdam and 3 Department of Gastroenterology, Academic Medical Centre, Amsterdam, Netherlands. Helicobacter

pylori is known for its causative role in gastric and duodenal ulcer disease and the associated complication of bleeding. Stress ulceration is the leading cause of upper gastrointestinal bleeding in intensive care patients (ICP). It is unclear whether H. pylon’ plays a role in the pathogenesis of stress ulceration. Only one study has addressed this question (Ellison RT et al. Crit Care Med 1996;24: 1974- 1981) and found a higher IgA antibody titre of H. pylon’ in ICP with stress ulcer-related bleeding (SURB) compared to ICP without SURB. It is unknown whether serology is useful and reliable for the detection of H. pylori in ICP. Therefore, we studied the effect of blood loss and haemodilution due to cardiac surgery on serological detection of H. pylori in ICP. Thirty-three consecutive patients admitted for elective cardiac surgery were included having given informed consent. Patients currently taking antibiotics were excluded. From each patient, a blood sample for H. pylon’ IgG antibodies was withdrawn before the operation and afterwards in the intensive care unit. IgG antibodies were detected using an ELISA with a cut-off value of 0.67 U/l. Preoperatively, 10 patients (30%) had a positive test, indicating H. pylori infection. Postoperatively, only 5 patients (15%) had an antibody titre above the cut-off value. The mean preoperative titre was 0.52 U/l (0.08-I .41 U/l) compared to a postoperative titre of 0.37 U/l (0.06-1.10 U/l). This mean reduction of 0.15 U/l (95% CI 0.099-0.206) was highly significant (P < 0.0001 by Student’s t-test). Blood loss, haemodilution and transfusion are the most likely causes of this decline in antibody titre. Conclusion: In patients undergoing cardiac surgery, a significant decline in antibody titre occurs resulting in false-negative tests due to blood loss and haemodilution. Serological detection of H. pylori appears to be unreliable in the postoperative intensive care condition and interpretation of test results should be made with caution in patients with blood loss or haemodilution.

100. One-week triple therapy with ranitidine bismuth citrate (RBC), clarithromycin (CLA) and metronidazole versus 2week dual therapy with RBC and CLA for Helicobacterpylori infection: results of a randomized, controlled, clinical trial. E.J. van der Wouden i, J.C. Thijs ‘, A.A. van Zwet *, A. Kooy ‘, J.H. Kleibeuker 3. ’ Bethesda Hospital, Hoogereen, 2 Regional Public Health Netherlands.

Laboratory

and 3 University

Hospital,

Groningen,

Purpose: To compare the efficacy and side effects of 1 triple therapy with RBC 400 mg b.i.d., CLA 500 mg b.i.d. metronidazole (MET) 500 mg b.i.d. (T) with those of 2-week therapy with RBC 400 mg b.i.d. and CLA 500 mg b.i.d. (D) randomized, controlled, clinical trial. Methods: Patients (18-80 years) with culture-proven cobacter pylori (HP) infection were randomized to receive

week and dual in a Heli-

T or

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D. Side effects were scored on a semi-quantitative scale (Eur J Gastroenterol Hep 1996;8:641). Endoscopy was performed 24 weeks after treatment. Antral biopsy samples were taken for culture, haematoxylin-eosin stain (HE), and rapid urease test and corpus samples for culture and HE. A 13C-urea breath test was performed 2 weeks after endoscopy. Treatment failure was defined as detection of Hp by culture or by 2 2 other tests. Results: One hundred and four patients, 54 males, aged 54 & 14 years (36 duodenal ulcer, 16 gastric ulcer and 52 functional dyspepsia) were included. Sex ratio, age and diagnosis were comparable in D and T. Twenty-one and 23% of the strains treated with T and D, respectively, were MET-resistant. Fourteen of 52 patients receiving T and 14/52 receiving D had significant side effects, but all completed the course. Six patients treated with T used extra antibiotics for other indications (Hp eradicated in 5; not known in I). One patient treated with D used extra antibiotics (Hp eradicated). In 1 patient treated with D, lung cancer was diagnosed (no follow-up) and another treated with D took CLA 250 mg b.i.d. (Hp eradicated). ITT eradication results were 49/52 (94%. 84-99%) and 50/52 (96%, 87-100%) for T and D, respectively. In the PP analysis, these data were 44/46 (96%, 85-998) for T and 48/49 (98%, 899100%) for D. Data are given as patients successfully treated/all patients treated (percentage, 95% confidence interval).Conclusion: Both RBC, CLA and MET for 1 week and RBC and CLA for 2 weeks are very effective in eradicating Hp. and both regimens are well tolerated. MET resistance does not seem to influence the efficacy of the triple therapy.

101. Detection of Helicobacter pylori in mechanically ventilated intensive care patients using the LARA-I3 C-urea breath test. P.H.J. van der Voort ‘, R.W.M. van der Hulst 3, D.F. oj Zandstra ‘. A.A.M. Geraedts *, G.N.J. Tytgat 3. Departments I Intensive Care and ’ Gastroenterology, Onze Lieue Hospital, Amsterdam and 3 Department of Gastroenterology, demic Medical Helicobacter

Centre, pylori

Amsterdam,

Vrouwe Aca-

Netherlands.

is known for its causative role in gastric and duodenal ulcer disease and the associated complication of bleeding. Stress ulceration is the leading cause of upper gastrointestinal bleeding in intensive care patients (ICP). It is unclear whether H. pylori plays a role in the pathogenesis of stress ulceration. Whether the 13C-urea breath test (UBT) is useful in detecting H. pylon’ in ICP, also during mechanical ventilation, is not known. Therefore we studied the value of the UBT in ICP using the laser-assisted ratio analyzer CLARA) system (van der Hulst RWM et al. Gastroenterology 1997;112:A320). Consecutive patients admitted for elective cardiac surgery were included in the study having given informed consent. Patients currently taking antibiotics were excluded. In each patient, a LARA-13C-UBT was collected before the operation in the ambulant state (amb-UBT) and compared with a LARA-13C-UBT collected during postoperative mechanical ventilation (MV-UBT) in the intensive care unit. The amb-UBT was considered to be the gold standard. One hundred patients were included. Eighteen patients were excluded from analysis for reasons of technical problems (n = 2), low CO2 in the amb-UBT tn = 1). low CO, in the MV-UBT (n = 14) or in

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both UBT (n = 1). This occurred early in the study during the learning curve for sampling alveolar air during artificial ventilation. In the 82 eligible patients, amb-UBT detected H. pylori in 32,031 (40%) patients and the MV-UBT in 34/81 (42%) mechanically ventilated patients. The MV-UBT had a sensitivity of 94% and a specificity of 92%. The MV-UBT revealed 4 false-positive and 2 false-negative tests compared to the amb-UBT results. Conclusion: The accuracy of the LARA-13C-UBT for detection of H. pylori is equally high both in the ambulant condition and during mechanical ventilation under intensive care conditions. The LARA-i3C-UBT can be easily carried out in mechanically ventilated patients.

102. Gastro-oesophageal reflux in patients suspected of sleep apnoea syndrome. K.G. van Houwelingen, R. van Uffelen, A.C.M. van Vliet. Departments of Pulmonology and Internal Medicine, Drechtsteden Hospital, Dordrecht, Netherlands. Gastro-oesophageal reflux (GOR) has been associated with pulmonary disease. In sleep apnoea syndrome @AS), GOR has frequently been described. Possible explanations for GOR in SAS are the intrathoracic pressure swings in SAS and the high frequency of morbid obesity. In this study, we evaluated patients suspected of having SAS for the occurrence of GOR. Methods: In the period between April 1995 and November 1997 we screened 119 consecutive patients for SAS. To study the relationship between SAS and GOR, we performed polysomnography (PSG) in combination with 24-h pH-metry in the oesophagus. SAS is defined by an apnoea/hypopnoea index (AHI) of over 15 apnoeas and/or hypopnoeas per hour, an AHI of 5-15 may also be diagnostic of SAS. Pathological GOR is defined by a Demeester score of over 14.73. Other factors scored were sex and the occurrence of morbid obesity as defined by a body mass index (BMI) of over 30 kg/m*. Results: The study group consisted of 119 patients, 103 (87%) were male, 16 (13%) female. Morbid obesity was present in 66 (55%) patients. Twenty-seven (23%) patients refused 24-hr pHmetry or had a technically unsatisfactory recording. Of the 92 patients in which analysis of GOR was possible, 37 (40%) had pathological GOR. When regarding SAS, 56 (47%) patients had an AH1 of > 15, 34 (28%) had an AH1 of 5-15 and 29 (24%) had an AHI of < 5. Of the 56 patients with an AHI of > 15, 52 (93%) were male, 38 (68%) had morbid obesity and 20 (54% of the 46 analyzable pH registrations in this subgroup) had pathological GOR. Of the 29 patients with an AI-II of < 5, 23 (79%) were male, 11 (38%) had morbid obesity and 6 (27% of 22 analyzable pH registrations in this subgroup) had pathological GOR. Of the 37 patients with pathological GOR, 34 (92%) were male, 23 (62%) had morbid obesity and 20 (54%) had an AHI of > 15, 11 (30%) had an AHI of 5-15 and 6 (16%) had an AH1 of < 5. Of the 55 patients without pathological GOR, 47 (85%) were male, 33 (60%) had morbid obesity and 26 (47%) had an AHI of > 15. 13 (24%) had an AHI of 5-15 and 16 (29%) had an AI-II of < 5. Conclusions: There is a strong relationship between SAS and the presence of pathological GOR. SAS is also related to male sex and morbid obesity. In this study, the relationship between SAS

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cannot be explained a causal relationship

by the presence of morbid between SAS and GOR.

A51 obesity,

103. Heterotopic gastric mucosa In the rectum. F.H.J. Wolfhagen ‘, H.F.G.M. van Ingh 2, R.J.Th. Ouwendijk ‘. Departments of ’ Internal Medicine and 2 Pathology, Ikazia Hospital, Rotterdam, Netherlands. Heterotopic gastric mucosa (HGM) can occur anywhere throughout the alimentary and biliary tract, although it is most commonly found in a Meckel’s diverticulum. HGM can lead to bleeding, ulceration, intussusception and malignant transformation. HGM in the rectum is very rare, and only about 30 cases have been reported in the international literature. We here present an asymptomatic case of rectal HGM. A healthy, 28-year-old woman underwent a colonoscopy in the context of screening for hereditary non-polyposis colorectal carcinoma syndrome, which runs in her family. The only observed abnormality was a rather inconspicuous, slightly elevated (l-2 mm), erythematous lesion with some polypoid forms measuring about 2.5 X 1 cm, located on the ventral rectal wall at about 7 cm from the anal verge. Multiple biopsies were taken. An anxious pathologist called to notify us that we must have put tissue from two different patients into the same tube, because both colonic and gastric mucosa samples were found. Biopsies taken at a second endoscopy, however, again showed gastric mucosa, mainly of the corpus type, next to colonic tissue. No Helicobacter pylori organisms were detected. Extensive 99m Technetium pertechnetate scanning during pentagastrin stimulation (6 pg/kg s.c.) did not reveal any focal accumulations either in the rectum or in other localizations besides the stomach. In conclusion, rectal HGM can be a rare and surprising finding during endoscopic examination. It can be very subtle and may, therefore, easily be missed. Moreover, it may not be detected by 99mTc pertechnetate scanning. Future follow-up of this patient will clarify the clinical relevance of this finding.

IX. Infectious diseases 104. Respiratory tract colonization with Pseudomonas aeruginosa in intensive care: of endogenous or exogenous origin? M. Bonten, D. Bergmans, H. Speijer, S. van der Geest, J. Tjhie, E. Stobberingh. Department of Internal Medicine and Medical Microbiology, University Hospital, Maastricht, Netherlands. Pseudomonas aeruginosa (PA) is the most important pathogen causing pneumonia in intensive care (10, usually after preceding respiratory tract colonization (RTC; trachea and/or oropharynx). PA may be derived from exogenous (other persons or contaminated devices) or from endogenous sources (intestine or stomach). However, the relative importance of both routes of colonization on the acquisition of PA in non-epidemic settings is unknown. In addition, to what extent colonization with PA is restricted to RTC and the time sequences of colonization of different body sites are unknown. We studied colonization with PA by systematic serial

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surveillance of trachea, oropharynx, stomach and intestine (faeces) on admission and twice weekly in 297 consecutively admitted patients to IC (219 adults, aged 58+ 18 years, APACHE score 19 +8 and 78 children, aged 3 +4 years) over a period of 10 months. In addition, all clinical cultures were analyzed. Acquired RTC was defined as colonization not present on admission. In all, > 2000 surveillance cultures and > 1500 clinical cultures were analyzed. One hundred and fifty-four patients (116 adults) were intubated and ventilated for a median of 4 days (range l-95 days). Twenty-five (8%) patients were colonized with PA on admission to IC: 20 in the intestine, and 9 had RTC. Acquired colonization was demonstrated for another 24 (8%) patients: 23 in the orophar ynx, 20 in the intestine, 19 in the trachea, and 16 in the stomach. Most patients were colonized with PA at multiple body sites; 13 at 4 sites, 11 at 3 sites, and 8 at 2 sites. Sixteen patients were colonized at 1 site, 13 of them in the intestine. About 350 isolates from 44 patients were genotyped using polymorphic DNA analysis. Identity of isolates was based on published criteria (JCM 1996;34:3190). Forty-three genotypes were identified. Acquired RTC with PA occurred in 24 patients (5 had intestinal colonization on admission), and genotyping could be performed for 21 patients. Routes from intestinal colonization to RTC were demonstrated in 6/21 patients (29%), and from gastric colonization to RTC in no patients. Acquired gastric colonization with PA was in 1 l/16 patients (69%) preceded by RTC with identical genotypes. Based on chronological patterns, RTC could be of exogenous origin in 8 patients (38%). Intestinal and RTC were demonstrated simultaneously in 7 patients. Conclusion: These data suggest that in non-endemic settings: (1) intestinal colonization with PA occurs more frequently than RTC with PA; (2) patient colonization with PA is not restricted to RTC; (3) gastric colonization with PA results from RTC; and (4) RTC with PA is in 29% of patients of endogenous origin. The exact percentage of exogenous colonization is under study.

105. Risk factors for infection by Serrutia mureescens in a surgleal ICU. S.M. Arend, S. van der Brugge, A.T. Bemards, J.D.M. Feuth, R.G.J. Westendorp, P.J. van den Broek. Department of Infectious Diseases, L.&den University Medical Centre, L&den, Netherlands. A four-fold increased incidence of infections by Serratia marcescens was observed on the surgical ICU between January 1996 and May 1997. Several genotypically distinctive strains of Serrutia were involved. Improvement of hygienic measures interrupted the outbreak. To investigate individual risk factors for colonization and infection with Serratia, we performed a casecontrol study. We hypothesized that invasive ICU procedures and use of antibiotics would increase the risk of Serratia infection. In cases, Serratia was isolated during their ICU stay. For each case, two controls were selected that were admitted to the ICU as close as possible in time, with a minimum ICU stay of 48 h. In cases, data were collected from ICU admission to the isolation of Serratia. In controls, data collection ended with transfer or with a maximum of 7 ICU days, the latter being the median interval between ICU admission and Serratia isolation, Nineteen cases and 38 controls were included. The mean + SD interval between

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ICU admission and isolation of Serratia was 7.3i5.1 days. In controls, the period of data collection was 4.0 + 1.9 days (P = 0.03). The total duration of both ICU and hospital stay was significantly longer in cases than in controls (P < O.Ol), but this may, in part, have been secondary to infection by Serrutia. By univariate analysis, significant differences were found in body weight (80.7+ 14.0 kg in cases vs. 69.7& 13.3 kg in controls, P = 0.041, the need for mechanical ventilatory support (cases 7.2k7.0 days vs. controls 2.8 +2.4 days, P < O.Ol), cumulative use of antibiotics, expressed as the sum of the number of days per antibiotic (cases 8.3 + 7.0 days vs. controls 4.4 f 4.5 days, P = 0.01). parenteral nutrition (68% of cases vs. 21% of controls, OR 8.1, 95% CI 2.3-28.1) and tube feeding (OR 3.4, 95% CI 1.1-I 1.2). The sum of the number of days per invasive device (deep intravenous and intraarterial cannulas, wound drains and urinary catheters) was 33.8rfI30.5 for cases and 19.97t 8.7 for controls, P = 0.08. Categorically, a cumulative number of device days > 25 was significantly associated with Serratia infection (58% of cases vs. 18% of controls, OR 3.7, 95% CI 1.6-8.7). In multivariate analysis weight, mechanical ventilation and number of invasive devices were independent predictors of Serratia infection In conclusion, risk factors for Serratia infection on the surgical ICU were mechanical ventilation, invasive devices and higher body weight. Since Serrafia is mainly transmitted by the hands of personnel, the identified risk factors may act by necessitating an increased frequency and intensity of direct contact.

106. Topical antimicrobial prophylaxis of the oropharynx to prevent ventilator-associated pneumonia: prospective randomized double-blind controlled study. D.C.J.J. Bergmans i, M.J.M. Bonten ‘, CA. Gaillard 3, S. van der Geest ‘. P.W. de Leeuw ‘, I. Paling ‘, F.H. van Tie1 *, E.E. Stobberingh ‘. Departments of ’ Internal Medicine and ’ Medical Microbiology, University Hospital, Maastricht, 3 Department of Internal Medicine, Eemland Hospital, Amersfoort and ’ Department of Surgery, University Hospital, Groningen, Netherlands. Introduction: Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection among ventilated patients, associated with increased mortality. Prevention of VAP is a major aim of intensive care medicine. Previous attempts to prevent VAP have focused on modulation of gastric and/or intestinal colonization. However, recent studies suggested that oropharyngeal colonization, instead of gastric and intestinal colonization, is pivotal in the pathogenesis of VAP. Methods: The effects of topical antimicrobial prophylaxis (TAP) of the oropharynx on colonization of the respiratory tract and stomach and on the incidence of VAP were studied in ventilated patients with an expected duration of ventilation of 2 2 days. TAP consisted of orabase containing 2% vancomycin/gentamicin/colistin, q6h. No systemic antibiotic prophylaxis was used. Colonization of trachea, oropharynx, stomach and rectum was monitored on admission and twice weekly, for eradication of colonization (EC) present on admission and acquired colonization (AC) during the study. Colonization was analyzed for Enterobacteriaceae, Pseudomonadaceae and Staph?-

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lococcus aureus. VAP was diagnosed based on quantitative cultures of bronchoalveolar lavage and protected specimen brush. Results: Eighty-seven patients received TAP and 139 placebo. Baseline characteristics were comparable for both groups. For the oropharynx, EC was higher in TAP patients than in placebo patients (52.6 vs. 1.7%, P < O.OOOl), and AC was lower in TAP patients (10.3 vs. 60.9%. P < 0.00001). In the trachea, EC was higher in TAP patients (34.7 vs. 10.4%, P = 0.003), and AC was lower (35.6 vs. 47.5%, P = 0.08). In both study groups, similar rates of EC (11.5 vs. 12.4%, P-value n.s.) and AC (44.9 vs. 44.4%, P-value n.s.) were found for gastric colonization. Rectal colonization data were also similar in TAP and placebo patients; EC (4.1 vs. 0.8%, P-value n.s.) and AC (51.2 vs. 57.9%. P value n.s.). VAP was diagnosed in 9/87 (10.3%) TAP patients and in 38/139 (27.3%) placebo patients (P = 0.002). Mortality was 25/87 (28.7%) for TAP patients and 53/139 (38.1%) for controls (P = 0.15). Conclusions: TAP of the oropharynx, without influencing gastric and intestinal colonization and without systemic prophylaxis, eradicated respiratory tract colonization present on admission and prevented acquisition of colonization at these sites, which resulted in a 62% reduction of the incidence of VAP.

107. Actinomyces and the IUD: a potentially pathogenic combination. S.M. Arend, H. Oosterhof, A.A.W. Peters, J.T. van Dissel. Department of Infectious Diseases, L.&den UniversiQ Medical Centre, Leiden, Netherlands. We report two women, aged 39 and 44 years, with invasive pelvic actinomycosis in association with an intrauterine device (IUD). The IUD had been in situ for 8 and 15 years, respectively. Both patients presented with a tubo-ovarian abscess and a periuterine infiltrate. Actinomyces viscosus and A. israelii were isolated, respectively, as part of a mixed anaerobic flora. Both patients completely recovered after a prolonged course of peni-cillin. In retrospect, Actinomyces-like micro-organisms had been seen in Papanicolaou-stained cervical smears taken, respectively, 3 and 7 years before invasive actinomycosis was diagnosed. The IUDs had not been removed. Asymptomatic colonization of the cervix by Actinomyces occurs commonly in women with an IUD. On the other hand, invasive pelvic actinomycosis is practically always associated with IUD use. The relationship between these observations thus far remained elusive. Our patients showed that colonization by Actinomyces can indeed be followed by invasive actinomycosis and that the interval between both can be many years. This long interval is compatible with the view that Actinomyces is, on its own, not a primary invasive micro-organisms, but needs a facilitating event to gain access to tissue, such as pelvic inflammatory disease or trauma. The observation of colonization by Acrinomyces, later followed by invasive infection, in these two patients brings us one step closer to a cause-and-effect relationship between Actinomyces colonization and invasive actinomycosis. Since the 197Os, it has been advised to remove an IUD if colonization with Actinomyces is found coincidentally in a cervical smear. The observation in our patients strengthens the basis of that advice.

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108. Intracranial tuberculoma: recognition and treatment. E.J. Buurke, M.E. Bartelink, G. Innemee, J.A.L. Wurzer. Department of Internal Medicine, Westeinde Hospital, The Hague, Netherlands. The incidence of tuberculosis in the developed countries is rising again, mainly due to the spread of the human immunodeticiency ViNS and the increasing immigration from developing countries. Consequently, Western doctors should be aware of the different and sometimes erratic and mimicking symptoms of tuberculosis. We present three patients with an uncommon manifestation of extrapulmonary tuberculosis. The fust case, a 25-yearold Hindu female from Surinam, presented with right arm seizure and intermittent headaches. On MRI scan of the brain, two space-occupying lesions were seen. The preoperative diagnose was glioblastoma. However, biopsy during craniotomy showed necrotizing granuloma, auramine positive. The histological diagnosis was intracranial tuberculoma. There was no evidence of current extracranial tuberculosis, or other infectious disease. The skin test was positive. Ultimately, the tissue culture for Mycobacterium tuberculosis was positive. During treatment with antituberculous chemotherapy, the patient became free of symptoms and control MRl scanning after a year demonstrated resolution of the lesions in the brain. The second case, a 62-year-old Hindu man, was admitted to our hospital with pulmonary tuberculosis (proven by the presence of acid-fast bacilli and a positive DNA probe for tuberculosis in the bronchoalveolar lavage) and retroperitoneal lymphadenopathy. He developed emotional incontinence on admission. Cranial CT scanning demonstrated three space-occupying lesions. These were thought to be intracranial tuberculomas, since there was no evidence of malignancy or other infectious disease. He was treated with antituberculous chemotherapy, the symptoms improved and the intracranial lesions resolved almost completely. The third case, a 30-year-old Chinese man, with miliary tuberculosis (positive M. tuberculosis culture) and a normal brain CT scan, treated with antituberculous chemotherapy for over a month, was admitted to hospital. He suffered from severe headache and diplopia. The cerebrospinal fluid examination showed signs of meningitis. Brain CT scan demonstrated the development of two space-occupying lesions, which where thought to be tuberculomas, and an obstructive hydrocephalus. To regulate the intracranial pressure a Torkildson drainage was performed. The antituberculous therapy was not changed. The symptoms improved, and after another paradoxical expansion of a lesion in the mesencephalon, there was a reduction of the intracranial lesions after a few months. The cases presented here demonstrate that although intracranial tuberculoma is a relatively rare tumour in developed countries, it should still be considered in the differential diagnosis of a space-occupying lesion in the brain, even without any active extracranial tuberculosis and also during treatment of an already recognized extracranial tuberculosis.

109. Guillain-Barr6 syndrome associated with Mediterranean spotted fever. B.E. de Galan ‘, B.J. van Kasteren *, A.W.L. van den Wall Bake ‘, G. Vreugdenhil ‘. Departments of ‘Internal Medicine and 2 Neurology, Sint Joseph Hospital, Veldhouen, Netherlands.

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Mediterranean spotted fever is a tick-borne infection caused by Rickettsia conorii. Neurological manifestations are present in 10% of patients, but long-term neurological sequelae. as presented here, are extremely rare. A 58-year-old woman was admitted to our hospital because of a 5-day history of fever, chills, myalgias. and a rash, shortly after a 2-week visit to Portugal. She did not recall tick bites. Examination disclosed fever (temperature 41°C) and a generalized macular exanthema, including both palms and soles, later to be followed by petechiae and ecchymotic blemishes on the extremities. No tache noire was found. Laboratory studies revealed elevated C-reactive protein, thrombocytopenia, and hyponatraemia. Renal function was initially good, but profound proteinuria and azotaemia developed. Renal biopsy showed interstitial nephritis, but no micro-organisms were demonstrated. On the suspicion of sepsis, treatment with cefuroxime and crythromycin was started, after which, the fever declined. However, recovery was markedly delayed by severe paresis and areflexia in all extremities. Cerebrospinal fluid now demonstrated elevated protein, and electromyographic studies were compatible with Guillain-Barre syndrome. Indirect immunofluorescent antibody testing on the 17th day after disease onset revealed elevated IgM titres to R. conorii (1:1024). Renal function and skin abnormalities completely normalized and neurological symptoms largely recovered without further treatment. Mediterranean spotted fever is endemic in southern Europe, Africa and the Middle East, although sporadic cases have been reported around the world. In Portugal, the estimated number of infections is close to 20,000 each year, although only 5% are reported. Clinical illness is characterized by sudden onset of fever, myalgia, and headache, followed by the appearance of a maculopapular rash within 5 days. Neurological symptoms are rare, but may be severe. Treatment with tetracyclines or chloramphenicol usually cures the disease. In the present case, severe renal involvement and suboptimal antibiotic therapy resulting in inadequate clearance of rickettsial organisms may have contributed to the development of Guillain-Barre syndrome. A diagnosis of Guillain-Barre syndrome has been documented earlier in a patient with R. rickettsii infection, but the association between Mediterranean spotted fever and the syndrome has not been previously reported. In conclusion, Mediterranean spotted fever is worth considering in the differential diagnosis of Guillain-Bar& syndrome when a patient has visited countries where rickettsial infections are endemic.

110. An HIV-infected patient with a Rhodococcus equi pneumonia. H.P.M.G. Evers ‘, J.D.J. Janssen ‘, M.M.E. Schneider ‘, A. Janz ‘, B. Bravenboer ‘. ’ Department of Internal Medicine. Catharina Hospital, Eindhoven and 2 University Hospital, Utrecht, Netherlands. A 35-year-old man was admitted in December 1996 because of a fever, coughing, night sweats, weight loss and diarrhoea. His previous medical history was unremarkable. His physical examination revealed no distinct abnormalities. Laboratory tests: ESR 91 mm/h, Hb 7.8 mmol/l and leucocytes 5.7 X 109/1 with normal differentiation. Other biochemical tests were normal. A chest X-ray showed consolidation of the left upper lobe with

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cavitation. Further analysis revealed an infection with Rhodococcus equi. Subsequently, his HIV serology turned out to be positive with a viral load 630,000 copies/ml and a CD4 count of 0.01 /nl. He was treated with imipenem/cilastatin plus vancomycin iv. for 3 months. After this period, he underwent a left upper lobe resection because of persistent radiological signs of infection. Subsequently, he was treated with the same combination for another 2 weeks because of fear of insufficient removal of all infected tissue. Throughout the entire period, he was treated with triple therapy consisting of zidovudine, lamivudine and saquinavir. His viral load dropped to levels below the detection limit. Presently, 12 months later, he is well and shows no signs of recurrence of the infection.

111. The effect of glucose and pH on bacterial growth rate in human urine: studies using uropathogenic and non-uropathogenie Escherichia coli. S.E. Geerlings i, E.C. Brouwer ‘, W. Gaastra 3, A.I.M. Hoepelman I.*. ’ Department of Infectious Diseases and AIDS, Uniuersity Hospital, Utrecht, 2 Eijkman-Winkle? Laboratory of Medical Microbiology, University Hospital, Utrecht and ’ Department of Bacteriology, Institute of Infectious Diseases and Immunology, Veterinary Faculty, Utrecht Unillersity. Utrecht, Netherlands. Introduction: It is generally assumed that one of the reasons that diabetics are more susceptible to urinary tract infections than non-diabetics is their ‘sweet urine’. Methods; We studied the growth rates of different Escherichia cold strains in human urine with and without the addition of glucose and with and without a constant pH, and compared them with the growth rates in Mueller Hinton broth (MHB). Eight clinical isolates (three from blood cultures of urosepsis patients, two urinary isolates, two faecal isolates and one laboratory strain K12) were used. The glucose concentrations were the same concentrations as used in the clinic to differentiate between minimal 50 mg/dl (+ J, moderate 100 mg/dl (+ +), severe 300 mg/dl ( + + + >, 1000 mg/dl ( + + + + ) and extremely severe 10,000 mg/dl glucosuria (Combu-Test Boehringer Mannheim, Almere, Netherlands). Results: All clinical strains had the same growth rate in urine. Only the laboratory strain E. coli K12 grew worse in human urine. The addition of glucose (up to a concentration of 1000 mg/dl ( + + + 1) to urine and MHB enhanced the growth rate of all isolates (P < 0.01). Increasing the glucose concentration further (to 10,000 mg/dl) in urine and MHB caused a decrease in bacterial growth rate. The stationary phase was reached later and the final bacterial amount was larger when the urinary pH was kept constant than when it was made less acidic. Conclusion: No differences in bacterial growth rate between uropathogenic and non-uropathogenic strains could be documented and therefore better growth in urine is not one of the virulence factors for uropathogenic E. coli. In conclusion, glucose in urine enhances bacterial growth. Extremely high amounts of glucose (10,000 mg/dlJ can inhibit bacterial growth, partially due to a pH effect. Therefore, in diabetics, glucosuria is indeed a risk factor for bacteriuria.

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112. An outbreak of Clostridium difficile-associated diarrboea on a general internal medicine ward. M. Hadithi, J.G.M Koeleman, A.M. Simoons-Smit, P.H.M. Savelkoul, F.A.P. Claessen, R.M. Perenboom. Departments of Internal Medicine, Clinical Microbiology and infection Control, Free University Hospital, Amsterdam, Netherlands. Clostridium dt@icile is the most frequently identified cause of nosocomial diarrhoea. C. dificile infections appear to be increasing, mainly because risk factors for developing disease (e.g. antimicrobial exposure, older age, length of hospitalization, severity of underlying illness) are more frequently encountered in present-day hospitalized patients. In September 1997, an outbreak of C. d&%&e-associated diarrhoea (CDAD) occurred in our hospital. Within a period of 2 weeks, five patients developed diarrhoea due to C. dificile. The outbreak was controlled after implementation of various infection-control measures; however, the index patient suffered 5 recurrences. Genotyping of a number of representative isolates of C. dificile was performed by amplified fragment length polymorphism (AFLP) analysis. Patient characteristics, microbiological data, epidemiological aspects and infection control measures will be presented. Difficulties encountered in the diagnosis and treatment of (recurrent) CDAD will be discussed.

113. Serum concentrations of TNF and IL-1 inhibitors in patients with active tuberculosis and after treatment. N. Juffer mans, A. Verbon, S.J.H. van Deventer, P. Speelman, T. van de1 Poll, Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS and Laboratory of Experimental Internal Medicine, Academic Medical Centre, Universi!, of Amsterdam, Amsterdam, Netherlands. Background: TNF-(Y and IL-lp contribute to granuloma formation and host defence during tuberculosis (TB). The activity of these cytokines is regulated by circulating inhibitors, i.e. soluble TNF receptors (sTNFR) I and II, IL-l receptor antagonist (IL-lRa), and sIL- 1 RII. Aim and methods: To determine activity of TNF-(Y, IL-lp and their inhibitors, sera were obtained from patients with a bacteriologically confirmed infection with M. tuberculosis before (n = 83) during (n = 15) and after completion of therapy (n = 27) and healthy controls. Of patients with active TB, 45 had pulmonary and 38 extrapulmonary disease. Cytokines and inhibitors were measured by ELISA. Statistics by Wilcoxon test. * P < 0.05 vs. other groups. All values are median and range, in rig/ml. Charts of patients with active TB were reviewed. Fever (rectal temperature > 38°C) and anorexia were scored. Results: Cytokines in pulmonary and extrapulmonary TB were similar; therefore, these groups were combined. sTNFRl and sTNFRII were higher in active TB (2.8 (0.9-15.2) * and (6.6 than during (1.6 (0.6-4.3) and 4.3 (1.8-26.7) *, respectively) (2.1-9.3) respectively) and after therapy (2.0 (0.9-2.4) and 4.8 (2.5- 11.2) respectively). In addition, IL-1Ra was higher in active TB (1.4 (O-26.3)) * than during (0.79 ( < 0.26-2.82)) and after therapy (0.80 ( < 0.26-10.06)) while sIL-1RII was similar in all groups, Levels of sTNFR1 and IL-1Ra were higher in patients with fever and anorexia compared to those without these symp-

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toms. Serum TNF-(Y levels and IL-lp were undetectable in all patients. Conclusion: sTNFR1 and -II and IL-1Ra are elevated in active TB and decrease during treatment. sTNFRl and IL-1Ra correlate with clinical symptoms. Therefore, these endogenous regulators of TNF and IL-l activity may be useful as markers of disease activity in tuberculosis.

114. Changing natural history of hepatitis B during antiretroviral therapy for HIV infection. S. Kadir, C. Rovers, R. van Leusen, R.A. de Vries, C. Richter. Department of Internal Medicine, Rijtzstate Hospital, Arnhem, Netherlands. Due to the highly effective therapy for HIV infection, the natural history of associated hepatitis B virus (HBV) infection may change. There are at least two explanations for this phenomenon: first, improvement of the host’s immune response may lead to reactivation of chronic hepatitis B; and second, the drug lamivudine (3TC) which is often part of the antiretroviral regimen, may influence the outcome of hepatitis B infection due to its direct antiviral effect. We describe 2 patients with combined HIV/HBV infection who developed features of hepatitis within 8 weeks of starting antiretroviral triple therapy, including a protease inhibitor and lamivudine. In both patients, we continued therapy and they recovered fast. In patient A, it was striking that the hepatitis developed at a moment when his CD4 and CD8 lymphocyte count had risen significantly. This patient cleared his HBe antigen within 4 months during follow-up. In patient B, a rise of CD4 lymphocytes preceded a sharp elevation of transaminases. Our patients illustrate that effective therapy of HIV infection can lead to clinical manifestations of ‘reactivated’ hepatitis B.

115. Mycobacterium xenopi in HIV-infected patients: an emerging pathogen. N. Juffermans, A. Verbon, E.J. Kuijper, P. Speelman. Departments of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS and Medical Microbiology, Academic Medical Centre, University of Amsterdam, Netherlands. Introduction: Mycobacterium xenopi may cause pulmonary disease in patients with loss of local or general host defence. Isolation of M. xenopi may be indicative of clinical infection; however, colonization without disease occurs. In HIV-infected patients, the clinical significance of M. xenopi isolates is unclear. Aim and methods: To determine the occurrence of M. xenopi, all patients from whom a mycobacteria was isolated in the period from January 1987 to December 1996 were summarized. HIV-infected patients were classified as having definite, probable or unlikely non-tuberculous mycobacterial (NTM) disease, based on recently formulated definitions. Results: M. xenopi was the second most common NTM. In the 1993-1996 period, there was a significant increase of M. xenopi isolates when compared to the 1987-1992 period (14/399 and 25/293, respectively, P < 0.05). Over 4 years, M. xenopi was isolated from 25 patients, 22 of whom were HIV-positive (88%). The HIV-infected patients had definite (n = 5) probable (n = 10)

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or unlikely (n = 7) disease due to M. xenopi. Seven patients presented with extrapulmonary infection. Clinical symptoms (fever, cough, night sweats, dyspnoea and anorexia) did not differ between patients with definite, probable and unlikely disease. The X-ray was abnormal in 8 of the 22 patients, but no cavitation was seen. CD4 count was low, with a median of 20/~1 (range lo-330/ ~1). Therapy was given to patients from all 3 groups. Conclusion: A strong association between M. xenopi and HIV infection exists. M. xenopi may be considered as an emerging opportunistic pathogen. Since symptoms, treatment and outcome were comparable in patients classified as having definite, probable and unlikely disease, new criteria seem necessary for HIV-infected patients. We propose two positive cultures and no other cause of disease as criteria for disease due to M. xenopi in HIV-infected patients.

116. Three cases of septic arthritis caused by Fusobacteria. J.J. Koomstra i, D. Veenendaal *, G.A.W. Bruyn 3, J.F.A.M. Ypma ‘, M. Kloppetburg 5, H. de Graaf ‘. Departments of ’ Internal Clinical Microbiology, Medicine, paedics, Medical Centre Leeuwarden 5 Department of Internal Medicine, Drachten, Netherlands. Introduction: Septic

’ Rheumatology,

4 Ortho-

(&id) Leeuwarden and Ny Smellinghe Hospital,

arthritis caused by Fusobacteria is very uncommon. Fusobacterium sp. are anaerobic Gram-negative rods that belong to the family Bacteroidaceae. F. necrophorum is the major pathogen. Postanginal septicaemia or necrobacillosis (Lemierre’s syndrome) is caused by an infection with F. necrophorum, characterized by an acute systemic illness that typically affects children and young adults. The classical presentation is severe sore throat, painful cervical lymphadenopathy followed by a septicaemic illness involving metastatic infection. most often in the lungs and joints. The infection might lead to acute endocarditis with rapid valve destruction. Even with antimicrobial therapy, mortality rates are reported to be as high as 30%. Treatment should consist of penicillins for 4-6 weeks, sometimes in combination with metronidazole. We present two cases of postangina septic arthritis caused by Fusobacterium necrophorum and a third case of septic arthritis caused by Fusobacterium nucleatum. F. nucleatum is much less known in serious infections Our case is, to our knowledge, the first report in which F. nucleatum is implicated in septic arthritis. Case 1: A previously healthy 1%year-old man presented with high fever (40.4”C) and swelling of the left knee. Two weeks earlier he had complained of a sore throat and low-grade fever. Physical examination revealed tenderness, redness and swelling of the joint. Laboratory tests showed a C-reactive protein (CRP) level of 270 mg/l and a normal leucocyte count. The left knee was aspirated, producing purulent material without detectable bacteria. After 2 days, cultures from both aspirate and blood grew Gram-negative anaerobic bacilli, subsequently identified as Fusobacterium necrophorum. Treatment consisted of metronidazole (3 X 500 mg/day) and penicillin (6 X2 million U/day). The patient made a full recovery after 6 weeks of treatment. Case 2: A 22.year-old male was admitted to hospital because of pain and swelling of the right stemoclavicular area. One week

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before admission he had complained of a sore throat and fever. On admission, the temperature was 39.3”C and the area overlying the stemoclavicular joint was tender and swollen. The leucocyte count was increased (20X 109/1) as was the erythrocyte sedimentation rate (68 mm/h). Fusobacterium necrophorum was isolated from both blood and joint aspirate. The antibiotic regimen was penicillin (6 X 2 million U/day) and metronidazole (3 X 500 mg). Poor clinical response due to the presence of an abscess adjacent to the stemoclavicular joint required surgical drainage and debridement. The patient then improved quickly and was discharged after 4 weeks of treatment. Case 3: A lo-year-old child was admitted to hospital because of progressive pain and swelling of the left knee. The patient had no other musculoskeletal symptoms and no portals of entry for infections. He did not suffer from a sore throat. Examination revealed a healthy looking, afebrile boy, with a tender, erythematous and swollen left knee. The leucocyte count was normal: CRP level 155 mg/l. Cultures from three separate aspirates from the left knee showed Fusobacterium nucleatum. No blood cultures were taken. Treatment with penicillin (6 X 1 million U/day) and metronidazole (3 X250 mg/day) for 4 weeks was given with good result. Conclusion; Although very uncommon, septicaemia with Fusobucteria is a serious condition with high mortality requiring early recognition and long-term treatment with antibiotics. A heightened awareness of Fusobacterium joint infections is warranted. In patients presenting with fever and arthritis following oropharyngeal infection, one should consider Lemierre’s syndrome.

117. Systemic effects of interleukin-12 Lauw. P.E.P. Dekkers, A.A. te Velde, Deventer, T. van der Poll. Laboratory

in chimpanzees. F.N. P. Speelman, S.J.H. van

of Experimental Internal Medicine and Diuision of Infectious Diseases, Tropical Medicine und AIDS, Academic Medical Centre, Unioersi~ of Amsterdam, Netherlands. Background: Interleukin (IL)- 12 has been implicated in the pathogenesis of many different infectious diseases because of its essential role in the direction of naive T-cells towards a Thl response. IL-12 is produced during sepsis and endotoxaemia. Importantly, neutralization of endogenously produced IL-12 has been found to protect mice from the lethal effects of endotoxaemia. Knowledge of the effects of IL-12 in primates is limited. Aim and methods: To determine the systemic effects of IL-12, 4 healthy chimpanzees were intravenously injected with recombinant human IL-12 (1 pg/kg). Blood samples were drawn before and at 1, 2, 3, 4, 8, 24 and 48 h thereafter. Cytokines, chemokines. coagulation and fibrinolytic activation were measured by ELISA. All data are mean + SE. Statistics by ANOVA. Results: IL-12 injection was not associated with a febrile response or haemodynamic changes. IL-12 induced a marked increase in the plasma levels of interferon-y (peak at 24 h, 1261+ 2 16 pg/mll, and a strong anti-inflammatory response (all peaking after 48 h: IL-1 p, 1569+652 pg/ml; soluble TNF receptor type I. 2.7 f 0.2 rig/ml; sTNFRI1, 8.7 f 1.2 rig/ml; IL-1 receptor antagonist, 15 + 2 ng/mll (all P < 0.05). By contrast,

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TNF and IL-l p remained undetectable throughout. IL-12 also induced the production of (Y (IL-8, 11.2& 1.6 pg/ml; IFN-y-inducible protein, 3.5 f 8 rig/ml) and p chemokines (MCP-1, 1.8 + 0.5 rig/ml; macrophage inflammatory protein lp. 726 + 279 pg/ml), all peaking after 48 h. IL-12 administration resulted in a marked leucocytosis (8 h, 23.4 + 3.7 X 109/1; P < 0.051, mainly caused by neutrophilia. Monocyte counts modestly increased while lymphocytes decreased. Activation of coagulation reached a plateau between 8 and 48 h, as measured by TAT complexes and protbrombin fragment F1+2 levels. Plasma levels of tibrinolytic activation products were also measured after IL-12 injection (tPA, 16 f 2 rig/ml; PAP complexes, 1.5 +0.3 mg/l). Conclusion: Intravenous IL-12 elicits the delayed and sustained activation of multiple host mediator systems that are also activated during sepsis and endotoxaemia. Therefore, IL-12 may be involved in sustaining the systemic inflammatory response during sepsis.

118. Haemolytic uraemic syndrome after Capnocytophuga canimorsus (DF-2) septicaemia. A.H. Mulder, P.G.G. Gerlag, L.H.M Verhoef, A.W.L. van den Wall Bake. Department of Internal Medicine, Sint Joseph Hospital, Veldhouen, Netherlands. A 66.year-old man presented with fever (39.7”(Z), diarrhoea, vomiting and signs of a haemolytic uraemic syndrome (acute renal. failure, thrombocytopenia, purpura, haemorrhages, elevated serum LDH and a blood film showing fragmented red cells). He had no history of alcoholism, splenectomy or immunosuppression, but he was on medication to treat his diabetes mellitus and hypertension. There was no evidence of disseminated intravascular coagulation. Capnocytophaga canimorsus was isolated from a blood culture. Retrospectively, the patient was bitten by his dog a few days. before he became ill. The patient was treated with antibiotics, (cefuroxime and metronidazole; replaced by co-amoxiclav when the results of the blood culture were reported), plasmapheresis and haemodialysis. Thrombocytes, LDH and fragmented red cells normalized after the initiation of therapy, but renal function did not improve. In the literature, several cases of renal failure have been described after Capnocytophaga canimorsus infection. The patients described presented with syndromes resembling thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome.

119. Effect of epinephrine on tumour necrosis factor-a and interleukin-10 production induced by staphylococcal enterotoxin B or heat-killed Staphylococcus aureus in whole blood. F.N. Lauw, S.J.H. van Deventer, P. Speelman, T. van der Poll. Laboratory of Experimental Internal Medicine and Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Unioersity of Amsterdam, Amsterdam, Netherlands. Background: Epinephrine can inhibit tumour necrosis factor-o (TNF; a proinflammatory cytokine) and potentiate interleukin-10 (IL-lo; an anti-inflammatory cytokine) release induced by endotoxin, thereby exerting potent antagonistic effects on the cytokine network.

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Aim and methods: To determine the effect of epinephrine on cytokine production induced by staphylococcal enterotoxin B (SEB; a superantigen produced by Staphylococcus aureus) or heat-killed S. aureus (HKSa), human whole blood diluted 1:l in RPM1 was incubated with SEB (1 pg/ml) or HKSa (lo7 CFLJ/ml) for 24 h at 37°C with or without epinephrine (IO-’ 10m5 M, with or without p-blocker propranolol or a-blocker phentolamine (10-s M) or phenylephrine (a-agonist, lo-’ -1O-5 M) or isoprenaline ( P-agonist, lo-* -lo-’ M). TNF and IL-10 were measured by ELISA. Levels (mean + SE) are expressed as% change relative to incubation with SEB or HKSa only. Statistics by Wilcoxon. Results: Epinephrine caused a dose-dependent inhibition of TNF release induced by SEB (10m5 M, - 79+2%; P < 0.05). This effect was mediated predominantly by b-adrenergic stimulation, since it was prevented by propranolol, but not influenced by phentolamine. Remarkably, not only selective pstimulation reduced SEB-induced TNF (lo-’ M, - 75 + 4%; P < 0.05), but also o-stimulation (10m5 M, - 70 + 5%; P < 0.05). Epinephrine did not influence SEB-induced IL-IO. By contrast, after incubation with HKSa, epinephrine not only attenuated TNF (-30+4%; P < 0.05), but also enhanced IL-10 (+ 178*64%; P < 0.05). Conclusion: Epinephrine consistently inhibits TNF production elicited by different bacterial challenges in whole blood. Epinephrine does not influence IL-10 production induced by SEB (which causes T-cell activation), while it enhances IL-10 release by HKSa (which, like endotoxin, causes mononuclear cell activation.

120. Potentiation of Candida albicuns growth by lipoproteins. Curfs *, P.N.M. Demacker i, J.F.G.M. M.G. Netea ‘, J.H.A.J. Meis *, J.W.M. van der Meer i, B.J. Kullberg ‘. Departments of ‘Medicine and 2 Medical Microbiology, University Hospital, Nijmegen, Netherlands. Overproduction of proinflammatory cytokines by lipopolysaccharide (LPS) is considered to be a key event in the pathogenesis of Gram-negative sepsis. Lipoproteins bind LPS and inhibit LPSinduced cytokine production, and infusion of reconstituted highdensity lipoproteins (rHDL) has been suggested as an adjunctive therapy in severe Gram-negative infections. However, sepsis can be caused by various micro-organisms, including fungi and Gram-positive bacteria, and more should be known about the possible effects of the lipoprotein infusion in these infections. The influence of lipoproteins on the growth of Candida albicans has been studied. Candida albicans growth curve in vitro was significantly potentiated in plasma containing freshly isolated human HDL, low-density lipoproteins (LDL) or very-low-density lipoproteins (VLDL), when compared with lipoprotein-deticient plasma (lo- to 50-fold increase at 24 and 48 h, P < 0.05). When rHDL 60 mg/kg was infused in healthy volunteers, the growth of Candida albicans did not differ in plasma collected before and after lipoprotein administration. However, when 100 or 120 mg/kg rHDL was infused, the Candida growth was lo- to lOO-fold higher in the plasma collected 4, 8, 12 and 24 h after the infusion, when compared with the growth in control plasma collected

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before the administration. These data suggest that rHDL may have dangerous adverse effects if erroneously infused in patients with Candida albicans infection. The diagnosis of systemic candidiasis should be carefully excluded when rHDL infusion is considered in Gram-negative sepsis.

121. Localized and systemic anti-inflammatory cytokine responses in patients with urosepsis. D.P. Olszyna, J.M. Prim, B. Buis, S.J.H. van Deventer, P. Speelman. T. van der Poll. Labnratory of Experimental Internal Medicine and Department of Internal Medicine, Divt’sion of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, lJnir~ersi@ of Amsterdam. Amsterdam, Netherlands. Background: Interleukin (IL)-1 and tumour necrosis factor-o (TNF) play a key role in infection. Their effects are regulated by soluble inhibitors, i.e. IL-1 receptor antagonist (II-lRa), soluble IL-1 receptor type 11 (sIL-1RII). and sTNFR type I and II and by an anti-inflammatory cytokine, IL-lo, which all circulate in increased concentrations during sepsis. Aim and methods: To determine the systemic and local pro duction of IL-l, TNF and their inhibitors during acute pyelonephritis, serum and urine levels of II-1 p, IL-lRa, sIL-1RII. TNF. sTNFR type I and II and IL-10 were measured by ELISA in serum and urine of 30 patients with culture-proven urosepsis before and 4. 24, 48 and 72 h after initiation of antibiotic therapy. and in 20 healthy individuals. All values are median and range. Statistics by Mann-Whitney V-test. Resu1t.y: IL-lb was not detectable in urine. Urine levels of IL-1Ra and sIL-IRE were similar in patients and controls. In serum, IL-lp was not detectable in the majority of subjects. Serum levels of IL-1Ra were higher in patients (7.40 (0.77-20.00) vs. 0.41 (0.19-0.94) rig/ml; P < 0.001) and decreased during treatment (P < 0.05). Serum sIL-lRI1 was not different between the two groups. Urine and serum TNF were similar in patients and controls. Urine levels of sTNFR were increased in patients; type I 17.55 ( < 0.40-25.00) vs. 1.78 (0.40 3.32) rig/ml (P < 0.001) and type II 14.96 (< 0.20-50.00) vs. 2.34 (0.50-5.34) rig/ml (P < 0.001). Their serum levels were also elevated in patients; sTNFR type 15.79 (1.93-25.00) vs. 1.10 (0.63-1.43) rig/ml (P = 0.005) and sTNFR type II 5.27 (1.60-50.00) vs. 1.77 (0.892.831 rig/ml (P < 0.01). Serum and urine sTNFR type I decreased with therapy (P < 0.05). IL-10 was undetectable in urine from both groups. Its serum levels were elevated in patients (0.12 ( < 0.03-27.32) rig/ml vs. < 0.03 ( < 0.03-0.11) rig/ml (P = 0.001)). Conclusion: During urosepsis, the anti-inflammatory cytokine response is generated predominantly at the systemic level.

122. Intravenous/oral mentation in a large R.P. Koopmans, P.N.J. P. Speelman. Department cal Centre, Amsterdam,

antibiotic switch: guidelines and impleteaching hospital. F. Sevinc, J.M. Prim, Langendijk, P.M.M. Bossuyt, J. Dankert, of Infectious Diseases, Academic MediNetherlands.

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Background: In recent years, a regimen of relatively short intravenous therapy (no more than 2 or 3 days), followed by oral treatment for the remainder of the therapy, known as ‘switch therapy’ has been advocated. Based on the literature. guidelines for i.v./oral switch were established, and subsequently implemented in our hospital. Methods: All antibiotics prescribed on wards for internal medicine, surgery, pulmonology and neurology were registered during a 2.month period (‘in~entoty phase’). An antibiotic course was defined as a course of antibiotics given for an episode of clinical or suspected infection. A prescription was defined as a written order to start or change antibiotics. Consensus was reached between infectious diseases specialists and medical microbiologists on the following guidelines: (11 the patient should be haemodynamically stable and his/her condition should be improving, including the body temperature and the peripheral leucocyte count: (2) with the oral regime, adequate drug levels can be attained at the site of infection. (A number of specific conditions were named m which oral therapy is usually not possible.) Oral therapy is not advisable for infections during severe neutropenia; (3) he/she must be able to take oral medication, and must have a functioning gastrointestinal tract; and (4) if these conditions are met, an i.v./oral switch is justified after 48-72 h of iv. therapy. After introduction of these guidelines, all antibiotics prescribed (with the exception of the neurology ward) were registered during a 2-month period (implementation phase). Results; During the imentor?, phase. 302 patients received 401 antibiotic courses, resulting in 843 prescriptions. The median duration of treatment was 7 days. Prescriptions for empiric therapy (n = 465) were given predominantly intravenously (74.6%), prescriptions for documented therapy (known pathogen; n = 3 1’2) were given predominantly orally (52.6%). In 38% of cases, antibiotics were given orally during the entire course. With the exception of the neurology patients, it turned out that an i.v./oral switch would have been justified in 97/230 (42%) of courses where antibiotics were started intravenously. The criteria were met on day 3 (median). Fifty-two of 97 (54%) of the patients who met the criteria indeed switched to oral therapy. This was done on day 6 (median, range 2-28 days). During the implementation phase. 234 patients received 281 antibiotic courses, resulting in 581 prescriptions. In 35% of courses, antibiotics were given orally during the entire course. For the patients started on iv. antibiotics, X0/182 (44%) met the criteria for i.v./oral switch. In 66/80 (83%) of courses meeting these criteria, antibiotics were indeed switched from i.v. to oral administration. Whereas the criteria were met on day 3 (median), the switch was actually done on day 4 (median) (range 2-16 days). During the 6 weeks after completion of the oral course, there were no indications that an earlier switch to oral treatment resulted in recurrence of the same microorganism, or in readmissions due to reinfections. The estimated potential annual savings were Dfl. 60,000 (less administration costs) and Dfl. 50,000 (lower purchase costs). Conclusion: We believe the available evidence supports the use of ‘early switch therapy’. A substantial number of patients on i.v. antibiotics are candidates for an early i.v./oral switch. This can result in substantial savings in costs and nursing time.

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123. ADAM study: induction-maintenance therapy in HIV-I infection; early results. M. Reijers 1*4, G. Weverling i, S. Jurraans *, F. Wit I, R. van Leeuwen I, S. Bruisten, R. ten Kate 3, F. de Wolf r, H. Schuitemaker 3, J. Lange ‘, J. Frissen 4, H. Weigel 4. t National AIDS Therapy Evaluation Centre, ’ Department of Human Retrovirology, Amsterdam, ’ Kennemer Hospital, Haarlem and 4 Onze Lieve Vrouwe Hospital, Amsterdam, Netherlands. Introduction: The feasibility of induction-maintenance therapy in HIV-l infection has to be studied as toxicities and adherence issues hamper long-term HAART in suppressing viral replication. Design: In a multicentre, randomized, open-label study, the efficacy of 26 weeks’ induction therapy (stavudine (d4T, 40 mg b.i.d.)+ lamivudine (3TC, 150 mg b.i.d.)+ saquinavir (SQV, 600 mg t.i.d.)+nelfinavir (NFV, 750 mg t.i.d.) followed by maintenance therapy (either d4T + NFV or SQV +NFV) or prolonged induction, is evaluated. HIV-1 RNA in plasma is the primary end point ( < 400 copies/ml). HIV-l-infected subjects with 2 200 CD4+ cells/mm3, > 1000 HIV-l RNA copies/ml and no previ-ous exposure to antiretrovirals are enrolled. After 26 weeks of treatment, subjects are only randomized if the viral load is < 50 copies/ml at weeks 24 and 25. Results: Fifty-six subjects have been enrolled since March 1997. At baseline, the median CD4+ cell count was 420 cells/mm3 (IQR 320-510). median CD8+ cell count was 1100 cells/mm3 (IQR 850-15101, and median HIV-l RNA was 4.6 log ,a copies/ml (IQR 4.2-5.1). Except for 2 cases of elevated liver enzymes, no adverse events led to study discontinuation. At week 8, median CD4+ cell count was 570 cells/mm3 (IQR 460-660), no change was observed with respect to the CD4+ cell count, median HIV-l RNA decreased to 50 copies/ml (IQR 50-375). Twenty-six of 27 subjects (96%, 95% CI 81-100%) could be randomized since HIV-l RNA concentration in the plasma was < 50 copies/ml at weeks 24 and 25. At a follow-up of 10 weeks after randomization (n = lo), no virological failure was observed in either arm. Conclusion: The quadruple induction regimen was well tolerated and led to rapid suppression of viral replication to below 50 copies/ml. The absence of viral breakthrough is encouraging for the feasibility of induction-maintenance therapy.

124. Exotoxin A modulates the synthesis of cytokines in human whole blood stimulated with heat-killed Pseudomonas aeruginasa. M.J. Schultz ‘.‘, P. Speelman ‘, S.A.J. Zaat 3, S.J.H. van Deventer *, T. van der Poll I.*. ’ Department of Infectious Diseases, Tropical Medicine and AIDS, ’ Laboratory of Experimental Internal Medicine and ’ Department of Medical Microbiology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. Introduction: Exotoxin A (ETA) is a product released by Pseudomonas aeruginosa that contributes significantly to the severity of Pseudomonas infections in animal models. Proinflammatory cytokines play an important role in host defence against Pseudomonas pneumonia. We hypothesized that ETA influences

Journal

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the course of Pseudomonas infections in part by an effect on cytokine production. Aim: To determine the effect of ETA on cytokine production in whole blood stimulated with heat-killed P. aeruginosa (HKPa). Methods: Heparinized whole blood obtained from 6 healthy donors and diluted 1: 1 in sterile RPM1 was incubated with HKPa (IO6 CFU/ml), with or without purified ETA (Sigma, St. Louis, MO) (0.01-l pg/ml) for 16 h at 37°C. Cytokines were measured in supematant plasma by ELISA. Statistics by Wilcoxon test. Results: HKPa induced production of tumour necrosis factor-a (TNF), interleukin (IL)-6, IL-IO, IL-12 p40, IL-12 p70 and interferon-y @N--r). ETA did not influence the production of IFN-1, IL-12 p40 and IL-12 ~70, but dose-dependently inhibited the production of TNF, IL-10 and IL-6. Maximal inhibition was found after incubation with 1 pg/ml, which reduced cytokine levels to 4.0+2.2% (TNF), 2.0+1.6% (IL-101 and 6.3+1.3% (IL-6) of concentrations detected after incubation with HKPa only (P < 0.05). ETA did not affect cell viability as determined by incorporation of MIT. Furthermore, ETA did not inhibit cytokine production primarily via reduction of TNF synthesis, since ETA still inhibited II-10 and IL-6 production in the presence of saturating concentrations of a neutralizing anti-T?@ monoclonal antibody (P < 0.05). Conclusion: ETA inhibits TNF, IL-10 and IL-6 production induced by HKPA, which may influence the host defence mechanisms during infection with P. aeruginosa.

125. Streptococcus pneumoniue: an unusual cause of a mycotic aneurysm. W.W.H. Roeloffzen, R.A.A. van Zanten, A.J.J. Woittiez. Department of Internal Medicine, Twenteborg Hospital, Almelo, Netherlands. A 53-year-old man was admitted with a 3-month history of progressive and severe low back pain, accompanied by an elevated erythrocyte sedimentation rate (ESR) and leucocytosis. The extremely severe pain was only bearable with high doses of analgesics. The pain did not radiate to the lower extremities and there were no complaints of other joints. On physical and neurological examination, there were no abnormal findings; in particular, there was no fever, there were no heart murmurs and no pulsatile abdominal mass was palpable. Laboratory tests revealed an elevated ESR of 56 mm/h, a normocytic anaemia (Hb 7.6 mmol/l) and a leucocytosis (16X 109/1). Spondylodiscitis and a metastatic bone disease were excluded by isotope scanning and magnetic resonance imaging of the pelvis, hips and lumbar spine. Finally, CT scanning of the abdomen showed an aneurysm of the abdominal aorta with a diameter of 4.5 cm. Blood cultures, taken because of the possibility of a mycotic aneurysm, did not show growth of micro-organisms. Echocardiography showed no signs of endocarditis. Subsequently, the patient underwent surgery. The aneurysm, which appeared to be inflamed, was resected and replaced by an aortic--bifemoral bypass graft which was impregnated with rifampicin. Microbiological cultures of the inflamed aneurysm recovered Streptococcus pneumoniae! Treatment with rifampicin 600 mg b.i.d. was started and continued for 3 months. A mycotic aneurysm is a localized arterial dilatation, caused by

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embolization of infarcted vegetations. The triad of back or groin pain, a pulsatile mass and fever suggest the presence of an infected arterial aneurysm. A history of bacterial endocarditis, other sources of septicaemia, or recent penetrating trauma is important, although no source of infection can be identified in approximately one-quarter of patients. Infections due to Streptococcus species are rare and account for 10% of vascular infections.

126. Erythromycin augments human neutrophil elastase synthesis in whole blood stimulated with heat-killed Streptococcus pneumoniue. M.J. Schultz I,*, P. Speelman ‘, S.J.H. van Deventer 2, T. van der Poll 1,2. ’ Department of Infectious Diseases, Tropical Medicine and AIDS and 2 Laboratory of Experimental Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. Introduction: Erythromycin (EM) can exert actions other than simple antimicrobial activity. This macrolide inhibits tumour necrosis factor-n (TNFJ production in whole blood stimulated with heat-killed Streptococcus pneumoniae (HKSP). Neutrophils contribute to host defence against bacterial infections. Aim: To determine the influence of EM on neutrophil degran ulation. Methods: Blood obtained from 6 healthy volunteers was diluted 1:5 in endogen-free RPM1 and incubated for 2 h at 37°C in 5% CO, with HKSP (lo6 and 10’ CFU/ml), with or without EM (0.01-1.0 mM). In a second series of experiments, 6 healthy volunteers received an intravenous bolus of EM (500 mg in 250 ml 5% glucose); blood was obtained shortly before, directly after and 1, 2 and 4 h after the end of infusion, and stimulated as described above. Human neutrophil elastase (HNE) and TNF levels were measured in supematant plasma by ELISA. Results: Stimulation with lo6 and lo7 CFU/ml HKSP induced significantly more production of HNE, compared with stimulation in the absence of HKSP or EM alone. In the presence of EM, HNE levels were equal or even higher, compared with stimulation in the absence of EM, maximum levels of HNE being measured at 0.1 and 1 mM EM respectively, in blood stimulated with lo7 and lo6 CFU/ml. Directly after and 1 h after the end of an intravenous bolus of EM, HNE levels rose to 139+ 18% and 154 + 19% relative to levels before infusion. This effect seemed to be independent of TNF production, as TNF levels decreased to 64 + 13% and 51 f 14% relative to the production before an intravenous bolus of EM. Conclusion: EM stimulates neutrophil degranulation in whole blood stimulated with HKSP. This effect of EM may have relevance for its antimicrobial activity.

127. An unusual case of rat-bite fever. B. Schuurman ’ A.J. van Griethuysen ‘, J.H. Marcelis 2, A.M. Nijs ‘. Departments of’ Zntemal Medicine and ’ Medical Microbiology, Tweesteden Hospital, Tilburg, Netherlands. Presentation; We present a case history of a 43.year-old woman with a generalized febrile illness, an exanthema with

Journal

of Medicine

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mixed maculopapulous and pustulous eruptions on the lower halves of the extremities, elbows, knees, palms and soles. There was also severe arthralgia and asymmetric arthritis. The disease manifested 8 days after she was bitten by a pet rat. Diagnosis and methods: Routine laboratory investigation did not contribute to the diagnosis. Cultures for Trichomonas uaginalis, Candida, Gardnerella oaginalis and molecular diagnostics on Chlamydia trachomatis were negative. In the Gram-stains of pustules on knees, no micro-organisms were seen. Echocardiography did not reveal signs of endocarditis. Two days after blood cultures, we found Gram-negative rods. In view of the anamnesis of a rat bite, clinical signs and morphology of the micro-organism, we suspected rat bite fever, which is caused by Streptobacillus moniliformis. Furthermore, Streptobacillus moniliformis was isolated from the PIP joint of the right second digit of the hand and from a pustule on the right knee, after 3 days of antibiotic treatment, i.e. 4X augmentin 1200 mg iv./24 h for 2 days combined with a single delivery of tobramycin (240 mg i.v.1 followed by 1 day of penicillin G 6X lo6 U/24 h. Antibacterial resistance patterns were determined using E-tests (AB Biodisk, Solna, Sweden) and disk diffusion (NE0 Sensitabs, Rosco Diagnostica, Taastmp, Denmark) on enriched heart infusion agar plates under microaerophilic conditions. The micro-organism was sensitive to penicillin, amoxycillin, augmentin, doxycycline and ceftriaxone, whereas resistance was found for tobramycin. After 1 week of penicillin G i.v., our patient was treated with doxycycline (once daily 200 mg p.o.1 for 1 week. At discharge, the exanthema had disappeared and the arthritis was almost completely reduced. Conclusions: The diagnosis was rat-bite fever. This diagnosis can be easily missed, even after adequate anamnesis and physical examination, whereas the differential diagnostic considerations are numerous including: rues, viruses, leptospirosis, disseminated gonococcal infection, meningococcaemia, Lyme disease and Rocky Mountains spotted fever. Our patient was completely cured, after intravenous administration of penicillin G. Antimicrobial therapy was completed by an oral course of doxycycline.

128. A rise in% CDS + CD30 + T-cells after ‘triple-therapy’: marker for treatment efficacy in HIV? P.E. Spronk ‘, F.J.M. Bergkamp 23 R.W. ten Kate ‘. Kennemer Hospital, Location EC, Departments of ’ Internal Medicine and 2 Clinical Chemistry, Haarlem, Netherlands. The recent addition of protease inhibitors to the ‘treatment arsenal’ of HIV-infected individuals has resulted in marked reduction of the viral load, clinical improvement, and often persistent increases in CD4 counts. Expression of CD30 on T-lymphocytes may be related to infection with HIV. We evaluated possible changes in CD30 expression on lymphocyte subsets in HIV+ patients treated with retroviral therapy, including a protease inhibitor. We measured CD4’/CD8+ T-cell subsets by flow cytometry (whole blood method) and determined viral load 1 month prior to, and 1, 6 and 12 weeks after starting a retroviral regimen including two nucleoside analogues and one protease inhibitor (‘triple-therapy’). Sixteen patients were evaluated. All had used at least one or more nucleoside analogues for more than 1 year

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before the start of this study. CD4 counts were invariably low (range < 0.01-0.47 X 109/1). A decrease of viral load after starting ‘triple therapy’ for 6 weeks was observed in 14 out of the 16 cases (median - 1.6 log; P = 0.001). In two cases, no change was observed. A slight increase in CD4 counts was observed (median 0.09 X 109/1; P < 0.05). No change in% CD4+ CD30+ T-cells or CD8 counts was found. However,% CD8+ CD30+ T-cells rose markedly (median 29%; P < 0.001). This increase was inversely related to the change in viral load. The% CD8+CD30+ T-cells decreased markedly in the period between 6 and 12 weeks after start of triple therapy in all cases. No relationship was found between the change in viral load and changes in CD4 counts. In conclusion, after starting ‘triple-therapy’ in HIV+ patients, a transient rise in% CD8+ CD30+ T-cells was observed in this study. This rise was related to a decrease in viral load. This suggests a possible role of this subset in the immunopathogenesis of HIV clearance and the possible role as a predictor of responsiveness to ‘triple therapy’.

129. The significance of the detection of cytomegalovirus in the hronchoakolar lavage fluid of renal transplant recipients. C.G. ter Meulen ‘, L.B. Hilbrands ‘, J. Galama ‘. Depaments of Nephrology and Medical Microbiology, University Hospital, Nijmegen, Netherlands. Background: The significance of the detection of cytomegalovirus (CMV) in the bronchoalveolar lavage (BALI fluid of renal transplant recipients is unclear. It can be a sign of CMV pneumonitis (high mortality due to pulmonary superinfections) but also of harmless pulmonary shedding of CMV (favourable outcome). We tried to identify clinical characteristics of patients with a favourable outcome in order to define harmless pulmonary shedding of CMV. Design: Retrospective chart study in all 43 adult renal transplant recipients in whom CMV was detected (by demonstration of early antigen) in the BAL fluid in the period of 1992-1996. Indication for BAL: simultaneous presence of fever, pulmonary infiltrate, and hypoxaemia. The presence of CMV disease, treatment with ganciclovir, CMV-related death, and Pneumocystis carinii pneumonia (PCP) were assessed. CMV disease was defined as CMV infection accompanied by one or more of the following symptoms: leucocytes < 3 X 109/1, thrombocytes <: 100x 109/1, ALAT > 50 U/l or tissue invasive disease. CMV related cause of death was defined as death within 3 months of BAL due to a pulmonary infection (e.g. bronchopneumonia). Results: A subgroup of 15 patients (35% of total population) could be characterized by the lack of signs of CMV disease and absence of PCP. Although none of these patients were treated with ganciclovir, CMV-related death did not occur in this group. One of these patients had a primary CMV infection while the other 14 patients already had CMV IgG antibodies before renal transplantation. Two patients of this subgroup died due to a saddle-type pulmonary embolus and an infected prothesis of the hip, respectively. In the remaining 28 patients, 9 died due to CMV-related causes. Quantitative data on CMV in the BAL fluid were not helpful in identifying a subgroup with a beneficial outcome. Conclusion: Renal transplant recipients with CMV in the BAL

Journal

of Medicine fluid who outcome harmless relatively

52 (1998)

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lack signs of CMV disease and PCP, have a favourable without antiviral treatment. These patients seem to have pulmonary shedding of CMV, which appears to be a frequent finding in renal transplant recipients.

130. Epidemiology of cryptococcosis in the Netherlands between 1986 and 1995: a retrospective study. L.J.R. van Elden ‘, J. Danker? 2, P. Reiss, S. de Marie, I.M. Hoepelman ’ et al. ’ Department of Infectious disease and AIDS, University Hospital, Utrecht and ‘Department of Medical Microbiology, Academic Medical Centre, Amsterdam, Netherlands. Cryptococcosis is a systemic mycotic infection caused by the organism Ctyptococcus neoformans. An increase in incidence of this life-threatening fungal infection has been observed as a result of an increase in the identification of immunosuppressed patients. We retrospectively analyzed data of 236 patients with cryptococcosis over 10 years from 1986 to the end of 1995. Patients were identified through the Netherlands Reference Laboratory for Meningitis in Amsterdam. Extrameningeal foci were found in 49 patients (21%), whereas 187 patients (79%) had meningitis. Predisposing factors were identified in 194 patients (82%) with cryptococcosis. The majority (n = 177) was diagnosed with AIDS, paralleling the AIDS epidemic over the years. Other predisposing factors were haematological malignancies (n = 71, immunosuppressive therapy (n = 61, liver cirrhosis (n = 1) and organ transplantation (n = 2) and cellular immunity disorder (n = 1). Extrameningeal foci were found in 49 patients. We focused on cryptococcal meningitis, being the most common presentation. Cryptococcal meningitis was diagnosed in 187 patients by positive culture in cerebrospinal fluid (CSF, n = 149) and/or positive antigen titres in CSF. Of these patients, 145 (77.5%) were HIVpositive, 15 patients (8%) had other predisposing factors, in 6 patients (3%) no underlying cause was found and of 21 patients (11.5%) the medical history was unknown. The male-to-female ratio was 23: 1 in the HIV-infected patients and 3: 1 in the remaining group. The age ranged from 15 to 77 years with a median of 38 years. Medical records have currently been reviewed of 111 patients with cryptococcal meningitis. Of this group, 98 patients were HIV-positive. The average duration of symptoms before diagnosis was 24.5 days. The most frequent symptoms at presentation were headache (85%) and fever (85%). but other neurological signs, such as meningism (26%) and decreased consciousness (30%) were apparent as well. Median CD4 count on presentation of the HIV-positive group was 30/~1 (range < lo-190/&. In 28 out of 86 CT scans, abnormalities suspect of cryptococcal meningitis were seen. Analysis of the CSF specimens revealed the following: opening pressure average 34, cell count median 12,’ ~1 (range O-490/&, glucose level median 2.6 mmol/l (range 0.1-4.8 mmol/l), protein level median 0.66 9/l (range 0.155.7/1). Twenty-four patients used prophylactic oral antifungal drugs. Patients were treated with various antifungal therapies. Of the 111 patients, 23 (21%) died and 9 (8%) relapsed. Cryptococcal infection without underlying cause is rare. However, cryptococcal meningitis is a common opportunistic fungal infection in severely immunocompromised patients. Clinical awareness and laboratory detection are important features for early diagnosis and treatment.

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131. Coagulation disorders and activation of cytokines in children with severe viral haemorrhagic fever. E.C.M. van Gorp ‘, C. Suharti 4, H. ten Cate i, M. Keuter ‘, W. Dolmans 2, A. van der Ende 3, D.P.M. Brandjes i, R. Djokomoeljanto 4, J.W.M. van der Meer 3. ’ Department of Internal Medicine, Sloteroaart Medicine,

Hospital, Amsterdam, 2 Department Catholic Unicersity, Nijmegen, .’ Centre

sis, Thrombosis, Medical Centre, Internal sia.

Medicine,

for

of Internal Haemosta-

Atherosclerosis and Inflammation, Academic Amsterdam, Netherlands and 4 Department of Uniuersiq

of Diponegoro,

Semarang,

Indone-

Objectives: In viral haemorrhagic fever, e.g. Dengue haemorrhagic fever (DHF), production of cytokines and activation of the coagulation and fibrinolysis cascade are thought to play a crucial role in the development of severe disease, complicated by bleeding and/or shock. DHF is associated with high mortality. Interaction between cytokine production and activation of the coagulation cascade is studied in a group of children with severe haemorrhagic fever. Methods: Twenty-eight children admitted to the intensive care unit in Semarang, Indonesia, with the clinical diagnosis of Dengue haemorrhagic fever were enrolled in the study. Patients were clinically classified as DHF III and IV, according to WHO criteria. Proinflammatory cytokines and inhibitors (TNF-(Y, IL-l p, IL-IRA), ex vivo LPS induced cytokine production capacity of whole blood and markers of coagulation and fibrinolysis were sampled on three successive days, starting at the day of admittance and one sample on the day of discharge. Results: Eight patients died. Mean age of all patients 6.5 years. All values at day of admittance, survivors vs. non-survvors. Early in the disease, mean circulating concentrations ot TNF-o (140 f43 vs. 497 f 885 pg/ml; ns.), IL-1 /3 (76 + 22 vs. 109* 87 pg/ml; n.s.> and the inhibitor IL-IRA (949+668 vs. 1537 + 676 pg/ml; P < 0.05) were elevated in both groups. In the non-survivor group, ex vivo cytokine production capacity in whole blood was lower for IL-l p (2121+4438 vs. 498k296 pg/ml; P < 0.051, higher for IL-IRA (7248+4008 vs. 12,181+5517 pg/ml; n.s.1 and not different for TNF-(Y. Early in the disease, there was an evident increase in markers of thrombin generation. Fl +2 fragments (median 2.4 vs. 5.9; P < 0.05; normal < 1.1 nmol/l), TAT complexes (median 22 vs. 81 mg/l; P < 0.05; normal < 4.1 mg/l), fibrinogen was decreased (mean+SD, 1.6 +0.8 vs. 1.4+0.3 g/l; n.s.; normal 1.7-4.0 g/l). Fibrinolysis increased during hospital stay, most obvious in the non-survivors, measured as t+dimers (third day after admittance, median 457 vs. 649 rig/ml; P < 0.05; normal < 39 rig/ml). Conclusions: Haemorrhagic fever in children is characterized by disseminated intravascular coagulation. Circulating concentrations of proinflammatory cytokines and ex vivo production capacity correlate with the severity of the disease.

132. Two immunocompetent patients with coagulase-negative staphylococcal spondylodiscitis, not associated with a central venous line or other prosthetic medical devices. A.W.R. van Kuijk, R.M. Perenboom, A.M. Simoons, P.H.M. Savelkoul, F.A.P. Claessen. Departments of Internal Medicine and Clinical Micro-

Journal

of Medicine biology dam,

52 (1998)

and Infection

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Control,

Free

University

Hospital,

Amster-

Netherlands.

Coagulase-negative staphylococci are well-known, usually avirulent, commensal organisms of the human skin. Lately, however, they have emerged as pathogens associated with medical progress: coagulase-negative staphylococci are the most frequently isolated organisms in nosocomial bacteraemia and infected prosthetic devices. Especially immunocompromised or critically ill patients in general or neonatal wards or in intensive care units are at risk for bacteraemia with coagulase-negative staphylococci. Often a central venous catheter is the (suspected) source of bacteraemia. Serious complications from bacteraemia with coagulase-negative staphylococci from a simple peripheral venous catheter are not often encountered in a non-immunocompromised host. We describe 2 patients with spondylodiscitis due to coagulase-negative staphylococci. In one patient, the spondylodiscitis occurred several weeks after a suppurative phlebitis by a petiphera1 intravenous catheters. Blood cultures at that time yielded Staphylococcus epidermidis. The association was proven by subtyping the strains by genomic fingerprinting using the amplified fragment length polymorphism (AFLP) method. In the other patient, the most likely source of coagulase-negative staphylococci was a slowly healing wound several months prior to presentation. As coagulase-negative staphylococci are a frequent cause of culture contamination, the clinician faces the problem of how to differentiate a harmless contaminant from a potential lethal pathogen. This dilemma will be discussed.

133. Serum concentrations of Thl/Th2 cytokines with active tuberculosis and after treatment. A. Juffermans, S.J.H. van Deventer, P. Speelman, H. van T. van der Poll. Academic Medical Centre, Uniniuersity dam and Municipal

Health

Centre,

Amsterdam,

in patients Verbon, N. Deutekom,

of AmsterNetherlands.

During tuberculosis, Thl cytokines are thought while Th2 cytokines may impair host defence. Methods: Serum levels of IL-12, IFN-y, IL-4. IL-6 and IL-IO were measured in 122 patients with tuberculosis during various stages of disease, in 16 persons who had been in close contact with contagious tuberculosis and in 17 healthy controls. Results: Of Thl cytokines, IFN-y was elevated during active tuberculosis, declining during and after treatment, when compared with healthy controls. IL-12 $40) serum levels were not significantly higher in patients with active tuberculosis when compared with any of the other groups. Of the Th2 cytokines, IL-4 levels were low in all groups. IL-6 and IL-10 serum levels were elevated in patients with active tuberculosis and during treatment, In patients with active tuberculosis, setum levels of IFN-y and IL-6 were higher in patients with fever, anorexia and malaise. IL-12 levels were higher in patients with a positive smear. Cytokine levels did not correlate with localization of tuberculosis (pulmonary vs. extrapulmonary), or skin test positivity. Conclusions: Cytokines directing a Thl response (IL-12) or a Th2 response (IL-41 were not elevated in sera of this large group of patients with pulmonary and extrapulmonary tuberculosis. Cytokines that were elevated in serum were both of the Thl type (IFN-y) and Th2 type (R-6, IL-IO), suggesting that at least at the Background:

to be protective,

Intemistendagen systemic culosis.

level no clear Thl/Th2

polarization

1998/Netherlands exists

during

tuber-

134. Apoptosis of peripheral blood lymphocytes measured by a sensitive, quantitative method is correlated to lymphocyte count and CD4 depletion in HIV-infected patients. 0. Visser ‘, L. te Velde ‘, I. Vermes 2, R. Overbeeke 2, C. Haanen 2, C. Reutelingsperger 3, C. ten Nape1 2. ’ Department of Internal Medicine, AIDS Unit and 2 Department of Clinical Chemistry, Medical Spectrum, Twente, Enschede and 3 Department of Bio chemistry, University of Limburg, Maastricht, Netherlands. HIV infection leads to proliferation of CD8+, and progressive depletion of CD4+ T-lymphocytes. The latter is still ill understood and cannot be explained by a direct cytopathic effect of HIV. Mounting evidence suggests that apoptotic cell death plays an important role in HIV infection. There arc several methods to detect apoptosis, most of them are qualitative. In our hospital, a quantitative method has been developed. Apoptosis of peripheral blood lymphocytes (ex viva) is measured using the APOPTESTFITC protocol, which numerates early apoptotic cells by probing for cell surface exposed phosphatidylserine (PSI with FITClabelled annexine V and for plasma membrane integrity by propidium iodide (PI) exclusion. It is possible to discriminate between intact cells (FITC-/PI), apoptotic (FITC+/PI) and necrotic cells @ITC+/PI+) The test was recently shown as the most reliable and most sensitive one in vitro as opposed to other tests. In this study, peripheral blood samples of 19 consecutive patients were measured for the absolute number of apoptosis, percentage of apoptosis related to lymphocyte count, lymphocyte count, CD4 and CD8 count and HIV-RNA (viral load), at the same time. None of the patients were treated with a protease inhibitor. Apoptosis was significantly enhanced in HIV patients (P < 0.001) expressed in absolute number/mm3 (48-552, median 158) or as lymphocyte count% (3-39%, median 16%) as opposed to healthy controls (
135. The effect of thalidomide and pentoxifylline on LPSstimulated cytokine production in vitro. A.G. Vonk, M.G. Netea, B.J. Kullberg, J.W.M. van der Meer. Department of Medicine, University Hospital, Nijmegen, Netherlands. The proinflammatory cytokines interleukin-l/3 (IL-11 and tumour necrosis factor (TNF) are main mediators in the pathogenesis of severe infections and autoimmune diseases, and their modulation has been suggested as a possible target therapy. Thalidomide and pentoxifylline have been recently described to posses

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potent inhibitory effects on TNF production. Because the mechanism of action differs for thalidomide (decreases TNF mRNA stability) and pentoxifylline (inhibits TNF gene transcription), the possible synergistic action of a combination of these two drugs on cytokine production has been investigated. Human blood mononuclear cells were stimulated with LPS (1 rig/ml), with or without adding thalidomide and/or pentoxifylline in various concentrations (1, 10 and 100 pg/ml). After a 24-h incubation, the supematants were collected and TNF, IL-l and IL-1 receptor antagonist (IL-ra) concentrations were measured by specific radioimmunoassays. Thalidomide alone decreased TNF synthesis by 30%. and pentoxifylline by 55% at their maximal concentrations (P < 0.05). When a combination of the two drugs was added to cells, the LPS-induced TNF production was decreased by 90% (P < 0.001). While both drugs at the lower concentrations were ineffective in inhibiting TNF, their combination significantly decreased LPS-stimulated TNF (P < 0.05). This effect was specific for TNF, since no modulation of IL-l or IL-lra has been apparent. In conclusion, thalidomide and pentoxifylline are potent inhibitors of TNF production, and they have synergistic effects. Therefore, the thalidomide/pentoxifylline combination may prove beneficial in anti-TNF therapeutic strategies.

136. Acute acalculous candidal cholecystitis: a rare and fatal complication in a critically ill patient. J.P.J. Wester I,*, J.J. Langerveld 3, D.H. Biesma 2, J.A. Leusink ‘,4, B.M.P. de Jongh 5, B. van Ramshorst ‘, P.J. Knaepen 7, J.M.P.G. Ernst 3. Departments of ’ Intensive Care, 2 Internal Medicine, ’ Cardiology, 4 Anaesthesiology, 5 Microbiology, 6 Surgery and ’ Cardiopulmonary Surgery, St. Anton& Hospital, Nieuwegein, Netherlands. Acute acalculous cholecystitis is a well-known complication in seriously ill patients in the intensive care unit. Isolation of Candidu spp., however, is extremely rare and associated with a fatal outcome. A 70-year-old Caucasian woman was admitted elsewhere because of loss of body weight, obstipation, and a microcytic iron deficiency anaemia. Physical examination revealed a systolic murmur. She developed fever, haemodynamic instability, thrombopenia, and renal insufficiency. Gastrointestinal analysis and bone marrow aspiration showed no abnormalities. Echocardiography revealed mitral and aortic valve insufficiency with vegetations, and tricuspid valve insufficiency. Blood cultures yielded Strepfococcus sanguis, thus confirming the diagnosis of subacute bacterial endocarditis. Treatment was started with gentamicin and penicillin intravenously. She was transferred to our hospital for aortic and mitral valve replacement. Postoperatively, continuous arteriovenous haemodiafiltration was started and anticoagulation with warfarin and heparin was instituted. After a few days, her condition deteriorated with evidence of pericardial fluid. Pericar diocentesis was performed without beneficial clinical result. She then developed a leucopenia less than 1.0 X 109/1, possibly due to penicillin. Bone marrow aspiration now revealed agranulocytosis. G-CSF was started and penicillin was changed to vancomycin. Then abdominal pain developed in the right upper quadrant. Ultrasonography showed signs consistent with acute acalculous cholecystitis and cholecystostomy was performed. Bile cultures yielded Cundida guilliermondii. Cultures of blood, urine, sputum,

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and faeces did not yield this micro-organism. Despite systemic treatment with fluconazole, her clinical state deteriorated and she became comatose. CT scanning of the brain revealed multiple cerebral haemorrhages. She died 28 days after admittance. In asymptomatic non-neutropenic patients who have undergone uncomplicated cholecystectomy, Can&da spp. is detected by chance in less than 2% and is associated with bile duct obstruction, cholelithiasis, gangrenous cholecystitis, and diabetes mellitus. In neutropenic patients, acalculous candidal cholecystitis is a rarely recognized complication of disseminated candidiasis in lo-28% of cases. In critically ill patients in the intensive care unit, thus far 5 patients have been described with acute acalculous cholecystitis. Mortality was 100%. To the best of our knowledge, we have described the first patient with acute acalculous Candida guilliermondii cholecystitis. In our opinion, this can be considered as a manifestation of serious immune suppression in critical illness. The outcome is fatal.

137. Diagnosis of Whipple’s Claessen, P.H.M. Savelkoul, R. Perenboom. Department Microbiology,

Free

disease: three T.A.M. Hekker,

of Infectious

University

Hospital,

cases. P.F. Ypma, F. A.M. Simoons-Smit,

Diseases Amsterdam,

and Clinical Netherlands.

Patient 1 is a 65-year-old man presenting with fever of unknown origin (FUO), wasting, arthralgia, myalgia and diarrhoea. A 67gallium citrate scan showed a diffuse increased accumulation of the tracer. Biopsy of skin, fascia and muscle showed polymyositis with periodic acid-Schiff (PAS)-positive, diastase-resistant material in histiocytes. Jejunal biopsies confirmed Whipple’s disease. By polymerase chain reaction (PCR) 16SrRNA of Tropheryma whippelii was demonstrated. Patient 2 is a 47-year-old male with a culture-negative endocarditis of the aortic valve. Histology of the cusps showed a PAS-positive histiocytic infiltrate. By PCR 16S-rRNA of T. whippelii was shown. Duodenal biopsies were negative. A 67gallium citrate scan revealed a hot spot at the anteromedial side of both thighs. Arteriography showed complete obstruction of the superficial femoral arteries with an aneurysm on one side. Patient 3 is a 43-year-old woman with FUO, arthralgia and hepatosplenomegaly. In biopsies of the stomach, 16SrRNA of T. whippelii was demonstrated, but histology was negative. She will be further investigated. The presented case histories illustrate the systemic nature of Whipple’s disease. PCR appears to be a valuable diagnostic tool. It is probably more sensitive than histology and seems to have a good negative predictive value in monitoring therapeutic response. False-positive results are not very likely. The gallium scan may localize manifestations of the infection. The recently reported successful culture of T. whippelii and the antibiotic treatment will be discussed.

138. Combined somatic and psychiatric pants of UN peace-keeping operations. Unck. Psychotrauma Centre, Utrecht Military

Hospital,

52 (1998)

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morbidity in particiW.S. de Loos, F.A.W.

University Netherlands.

Hospital

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Since 1993, Utrecht University Hospital and the Central Military Hospital of the Dutch Armed Forces, as one of their joint efforts in health care, have developed an integrated out-patient service for psychotraumatology combining psychiatric and medical expertise. This implies direct psychiatric expertise and abilities of the physician on the team and regular clinical meetings on diagnosis and management. Over these four years, 19 participants of UN peace-keeping missions aged 19-56 years (median 33 years) were referred to this physician for evaluation of their somatic complaints. Eight patients were referred by social workers of veterans’ services, six by military general practitioners and three by the military psychiatric service after a diagnosis of post-traumatic stress disorder (PTSD) had been established. In two cases, a psychiatric diagnosis of PTSD was suspected by the referring specialists of the military medical service. Only one patient had not been examined by other doctors for the complaints he was referred for. The physical complaint mentioned most frequently was fatigue (n = 10) followed by gastrointestinal disturbances (n = 6) and sweating (n = 4). Neuropsychological problems reported most frequently were sleep disorders (n = 7) and disturbances of concentration and memory (n = 4). Three patients attributed their complaints to mefloquine and vaccinations. In addition to the three referrals with established PTSD, this diagnosis was made or confirmed in ten more patients, while another four had other psychiatric disorders. Only two had uncomplicated pathophysiological diagnoses explaining their symptoms. In 11 of the 13 patients with PTSD, and in three with other psychiatric disorders, physical pathology was present. Numbers for diagnosis categories were: vascular, 6 (of which hypertension 5); gastrointestinal, 5; respiratory and allergic, 4; metabolic, 4; sarcoidosis, 1; IgA nephropathy, 1; a minor surgical problem; and a complicated rehabilitation problem. This made up for 23 diagnoses, 14 of which were new, in 17 patients with psychiatric morbidity. Referral to a physician trained in basic psychiatric skills within an integrated setting proves to be effective in the health care of patients with complicated symptoms of potentially pathophysiological, psychophysiological or of a mixed origin. It was already known that UN peace-keeping operations are far from harmless psychologically. Survivors of trauma tend to dissimulate PTSD, preferably presenting physical symptoms. A combination of physical pathology and psychiatric morbidity, irrespective of age, seems to be the rule rather than an exception in veterans of such operations.

139. Methaemoglobinaemia as an uncommon and clinically important cause of cyanosis. H. Demirel ‘, V.S. Koster *, M.J. Koot 2, H.H. Ponssen ‘, A.C.M. van Vliet ‘_ Departments of I Internal Medicine drecht, Netherlands.

X. Miscellaneous

Central

of Medicine

and 2 Pharmacy,

Drechtsteden

Hospital,

Dor-

Cyanosis usually is caused by decreased arterial oxygen saturation due to pulmoniuy or cardiac disease. Methaemoglobinaemia is a rare cause. sometimes with lethal outcome. Two patients are described, with an unremarkable medical history, who presented with severe cyanosis due to aniline-induced methaemoglobinaemia developed at work. The first patient, a 54-year-old man, presented with progressive dyspnoea, dizziness, headache, ret-

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rosternal pain and nausea of 1 day’s duration. Physical examination revealed central and peripheral cyanosis with blood pressure ISO/SO mmHg, heart rate lOO/min and a normal temperature. Examination of the heart, lungs, abdomen and extremities was normal. No digital clubbing was present. An ECG and chest X-ray were without abnormalities. Routine laboratory investigation was unremarkable except for creatinine 131 pmol/l and urea 11.8 mmol/l. Arterial blood gas analysis, while the patient breathed room air, revealed: pH 7.46, ~$0~ 41.5 mmHg, BE 5.0 mmol/l, actual bicarbonate 29.0 mmol/l, p,O, 53 mmHg, 0, saturation 91%. Methaemoglobin level was 50%. The second patient, a 37-year-old man, was referred to the ER because of dizziness and feeling unwell. During transport he deteriorated and arrived with severe peripheral and central cyanosis, superficial respiration and decreased consciousness. On physical examination, blood pressure was 110/65 mmHg, heart rate lOO/min and temperature 37°C. Examination of the heart, lungs, abdomen and extremities revealed no abnormalities. An ECG and chest X-ray were normal. Laboratory investigations were unremarkable except for arterial blood gas analysis, while breathing room air, with pH 7.42, p&CO, 33.2 mmHg, BE -2.0, actual bicarbonate 21.2 mmol/l, p,O, 48 mmHg, 0, saturation 93%. Methaemoglobin level was measured to be 65%! Both patients were successfully treated with methylene blue i.v., the agent of choice for drug-induced methaemoglobinaemia. Cyanosis, in the absence of cardiopulmonary disease, should arouse, in the mind of the physician, the suspicion of an intra-erythrocytic haemoglobin abnormality, especially methaemoglobin.

140. Training in internal medicine: a description of the fellowship in consultative medicine at a large teaching hospital. G.A. Rongen, L. Verschoor. Department of Medicine, Rijnstate Hospi,tal, Arnhem, Netherlands. Background: In the Netherlands, consultative work is an obligatory part of training in internal medicine. However, neither the minimal requirements, nor the fellowship in itself, are well defined. Aim: As a first step to defining the learning goals for the fellowship in consultative medicine, we evaluated the existing practice in a large affiliated teaching hospital in the Netherlands. Methods: From 1 January to 1 July 1997, the fellowship was evaluated for type of consultations, questions posed, new diagnoses and referrals made. Consultations were carried out on the following surgical wards: urology, orthopaedics, general surgery, ophthalmology, dermatology, anaesthesiology, plastic surgery, TNE surgery and jaw surgery. New diagnoses during consultation were classified according to the ICD-9-CM classification. Results: A total of 3916 admissions were registered for the surgical wards. In 222 patients (age 69.7 + 15.6 years (mean + SD)), 225 consultations were carried out (3 patients were admitted twice). Consultations were asked for on diabetes mellitus (n = 791, cardiovascular (n = 27). lung diseases (n = 31, a variety of reasons (n = 73), without a specific question (n = 43) and in 70 of these consultations, a preoperative assessment was involved. Nine consultations carried 2-3 specific questions. In 119 consultations,

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148 new medical problems were recognized: 16 infections or parasitic diseases, 5 malignancies, 21 endocrine, metabolic and/or dietary disorders, 8 diseases of blood or blood-forming organs, 9 neurological disorders, 34 cardiovascular diseases (including thrombotic disorders), 10 respiratory disorders, 18 problems of the gastrointestinal tract, 8 diseases of the urogenital tract (including renal insufficiencies), 4 diseases of the skin and subcutis (including venous insufficiency), 10 intoxications (mainly drug side effects), and 5 new problems/symptoms without definite diagnosis. Referral to another (sub)specialist was advised 47 times: pulmonologist (n = 13). cardiologist (n = 14). neurologist (n = 31, internal subspecialists (n = 10). anaesthesiologist (n = 11, ophthalmologist (n = 2) or other surgical (sub)specialties (n = 4). A total of 21 patients were transferred to another department; ten of these were advised by the internist. Conclusions: The fellowship in consultative medicine on surgical wards deals with a broad spectrum of internal disease, renders awareness of co-existing diagnoses and sharpens the skills of interdisciplinary work. The majority of problems encountered can be handled by the fellow and the supervisor. On the basis of this inventory, it is possible to define learning goals for this fellowship.

141. Cobalamin supplementation improves cognitive performance and cerebral function in healthy older subjects with low plasma cobalamin. D.Z.B. van Asselt, J.W. Pasman, H.J.J. van Lier, D.M. Vingerhoets, P.J.E. Poels, Y. Kuin, H.J. Blom, W.H.L. Hoefnagels. Depariment of Geriatric Medicine, Uniuersity Hospital, Nijmegen, Netherlands. Mild cobalamin (Cbl, vitamin B ,s ) deficiency is very common in older subjects. The clinical benefits of Cbl supplementation in these subjects has not been adequately studied. In a single-blind intervention study, we investigated the effect of Cbl supplementation on plasma total homocysteine (tHcy), methylmalonic acid performance and quantitative electroen(MMA), cognitive cephalography (qEEG) in 16 community-dwelling older subjects, aged 64-89 years, with low plasma cobalamin concentrations (I 150 pmol/l) and free of significant cognitive impairment. Subjects were examined at baseline, after 1 month of placebo and after 5 months of intramuscular hydroxocobalamin injections. After Cbl supplementation, plasma Cbl concentrations increased and plasma MMA and tHcy concentrations decreased. The performance on three cognitive tests, i.e. verbal word learning test, verbal fluency and similarities, improved. QEEG showed more fast activity and less slow activity. Lower plasma tHcy concentrations were related to increased fast activity on qEEG on the one hand and improved performance on the verbal word learning test on the other. Improved performance on the verbal word learning test was related to increased fast activity on qEEG. In conclusion, electrographical signs of improved cerebral function and improved cognitive cerebral function were found after Cbl supplementation in healthy older subjects with low plasma Cbl concentrations who were free of significant cognitive impairment. These improvements were related to a reduction of plasma tHcy concentration.

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142. A patient with sarcoidosis associated with anti-W-A antibody. A.A. van de Loosdrecht ‘, H. Bootsma’, J.M.L. Henselmany 3, J. Kraan 4. Departments of ’ Internal Medicine, ’ Rheumatology, ’ Neurology and 4 Pulmonology, Unioersity Hospital, Groningen, Netherlands. A 32.year-old woman presented with a 6-month history of pain and swelling of several joints. On physical examination, only slight oedema of the ankles was found. The ESR was 21 mm/h, CRP 59 mg/l and an elevated rheumatoid factor of 105 kIU/l. X-rays of hands and feet showed bilateral cystic lesions and a little erosion of the left basis phalanx of the third radiation. A month later she complained of dry mouth and eyes and pretibial painful red nodules. Erythema nodosum was diagnosed. The parotids were not swollen or painful ACE was elevated (133 U/l). ANA, ENA and anti-dsDNA were negative, whereas antibodies against SS-A (Ro) could be detected. A polyclonal hyperimmunoglobulinaemia was present. A radiograph of the thorax revealed extensive media&al lymphadenopathy. Lung function was normal. The Schirmer’s tear test was slightly impaired. There were no signs of iridocyclitis. Sialometric and sialochemical analysis showed a pattern compatible with inflammation of the parotids. Cervical mediastinoscopy of the lymph nodes revealed an epithelioid cell granuloma with negative auramine stain. Sarcoidosis with a sicca syndrome was diagnosed with co-existing anti-SS-A antibody suggesting association with Sjogren’s syndrome. To date, only a few case reports have described an overlap of sarcoidosis with autoimmune diseases indicating shared immunopathogenic mechanisms.

143. A woman with diabetes insipidus and periorbital swellings: a rarity. I. van der Lee ‘, P.H.Th.J. Slee i, J.R.J. Elbers 2. Departments of’ Internal Medicine and 2 Pathology, St. Antonius Hospital, Nieuwegein, Netherlands. A 55year-old woman, born in Morocco, now living in the Netherlands, was admitted to our hospital in August 1997. Her medical history started in 1987 with central diabetes insipidus, treated with vasopressin 10 pg twice daily. Regular CT and MRI scanning never showed abnormalities of the pituitary region. In 1996, she lost small stones from the right renal pelvis. At that time, she was also diagnosed as having diabetes mellitus type Il. She was admitted because of abdominal pain, fatigue, weight loss (10 kg) and a subfebrile to febrile temperature over the last 2 months. Physical examination showed an obese woman (weight 83.4 kg, length 1.55 m) with bilateral xanthelasmata and a bilateral swelling on the lower orbitarim. Large swellings were present in the axillae and groins (ca. 10 cm diameter). Laboratory examinations showed ESR 48 mm, haematocrit 0.40 l/l, leucocytes 10.3 g/l, thrombocytes 400 g/l, CRP 84 mg/l, y-Gt was slightly increased with 45 U/l, other liver enzymes, electrolytes, creatinine, lipid values and protein electrophoresis were normal. Urine sediment contained up to 5 leucocytes per field. Cultures of blood and urine remained negative. Chest X-ray was unremarkable and colonoscopy was normal. CT scanning of the chest and abdomen showed multiple densities in the mediastinum and retroperitoneum, especially round the kidneys and ureters, causing a slight bilateral dilatation of the renal pelves. MRI scanning showed a

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contrast enhanced process at the base of the pituitary gland. A 99m Tc diphosphonate bone scan showed hyperactivity in the max illa, the mandibula and the metaphysis of the wrists, knees and ankles. Skull X-ray showed sclerotic lesions at the OS occipitale and mandibula, X-rays of the extremities were normal. Pathology of the swellings in the axilla and the orbitarim showed fatty tissue with an infiltration of mononucleated cells with an increase of fibroblasts and some polynucleated giant cells (SIOO staining negative). On electron microscopy non-Langerhans histiocytes, characterized by the absence of Birbeck granules, were noticed. Although there were only sclerotic bone lesions in the skull, the findings are compatible with Erdheim-Chester disease, which is a rare form of non-Langerhans cell histiocytosis. This disease is characterized by symmetrical long bone osteosclerosis (metaphyseal and diaphyseal regions) accompanied by general symptoms, and sometimes exophthalmus and diabetes insipidus, which makes differentiation with Langerhans cell histiocytosis (histiocytosis X) difficult. The diagnosis is made by the above-mentioned histological criteria. Treatment with prednisone improved the well-being of the patient, the temperature normalized within 1 day, CRP normalized in 1 week and the multiple swellings reduced in size. A survey of the scarce reports on this condition will be given.

144. A man with a mysterious hypogammaglobulinaemia and skin rash. E.E.M. van Ginneken ‘, J.W.M. van der Meer ‘, P.M. Netten ‘. ’ Department of Internal Medicine, lJnic;ersity Hospital, Nijmegen and 2 Department of Internal Medicine, Bosch Medical Centre, Netherlands. A 26.year-old man, known to have insulin-dependent diabetes mellitus, was admitted to the intensive care unit because of generalized seizures. Treatment with carbamazepine (continuous release) 400 mg once a day was started. Two months later, he developed erythematous desquamative rash, generalized oedema, stomatitis and fever. Physical examination revealed no other abnormalities. The patient had no known allergy. Laboratory tests showed slightly elevated transaminases and lowered immunoglobulins: IgG 500 (800-1500) mg/dl, IgA 38 (1 lo-3701 mg/dl, IgM 30 (50-300) mg/dl. The cerebrospinal fluid examination 2 months earlier had shown slightly elevated immunoglobulins, which is unlikely to be compatible with hypogammaglobulinaemia. Clinically, drug allergy was suspected and administration of carbamazepine was stopped. The skin lesions progressed and peeled off all over his body. Skin cultures were positive for Staphylococcus aureus, as was one blood culture. Several courses of antibiotic were prescribed. Within a few weeks, the fever subsided and the skin recovered slightly. One week after discharge from hospital, the patient had to be re-admitted because of a relapse of fever with erythema, squamae, pustulae and conjunctivitis. Physical examination: hepatomegaly. Laboratory tests: persisting hypogammaglobulinaemia and marked eosinophilia. Immunofluorescence of peripheral blood: normal B-lymphocyte counts with polyclonal distribution, with slightly elevated CD-8 cells (0.85 X 109/1 (normal 0.1-0.6 X lO’/l)). On the 25th day of admission, we found out that the patient had secretly continued the carbamazepine. The drug was stopped, and the skin abnormalities improved dramatically. The immunoglobulin levels restored

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within 2 weeks and remained nominal. Clinical diagnosis: exfolia.. tive dermatitis and hypogammaglobulinaemia provoked by carbamazepine, with secondary infection of the skin. Hypogammaglobulinaemia in a transient form has been reported to be induced by carbamazepine, as well as by phenytoin. The mechanism behind the phenytoin-induced hypogammaglobulinaemia has been attributed to an increase in T-suppressor cells. The marginally elevated number of CD8 cells in our patient could be in accordance with that. Both drugs are anti-epileptic drugs by virtue of their action on sodium channels. It is tempting to speculate that this mode of action is also operational in the observed side effect; however, there are no studies in vitro that provide support for this.

145. Lead intoxication: an unusual cause of severe abdominal pain. M.G.A. van Vonderen, E. Klinkenberg-Knol, M. Craanen, R. Jonkhoff, D.J. Touw. Departments of Infernal Medicine, Gastroenterology, Haematology and Pharmacy, Free University Hospital, Amsterdam, Netherlands. Lead intoxication is an uncommon cause of abdominal pain. Therefore, it is not easily recognized. We present a woman, aged 35 years, who visited the emergency department frequently with symptoms of severe colicky abdominal pain, vomiting and shooting pains in the extremities. Retrospectively, she also complained

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of loss of concentration and short-term memory. She had used various Ayurvedic herbal preparations for years. Although the patient clearly experienced severe pain, physical examination was unremarkable. Laboratory results showed a hypochromic, normocythaemic anaemia (haemoglobin 5.2 mmol/l) without signs of iron deficiency or haemolysis. Extensive endoscopic and radiological investigation provided no explanation for the abdominal complaints. Suspicion of lead intoxication was based on basophilic stippling in the red blood smear and raised excretion of porphobilinogen and S-aminolevulinic acid in the urine sample. The blood lead level was 1.4 mg/l, which is extremely high. Symptoms, expected at this level, are colicky abdominal pain, vomiting, anaemia due to inhibition of haem synthesis, peripheral neuropathy with limb pains, encephalopathy, and nephropathy with hypertension. All but these last two were experienced by our patient. In this patient, the cause of the lead intoxication is probably the use of Ayurvedic herbal preparations. A few cases of lead intoxication due to the high lead content of these folk remedies have been described. This patient was treated intravenously with calcium-sodium-EDTA, a lead-chelating agent. All symptoms disappeared and the blood lead level decreased to 0.6 mg/l after 5 days of therapy. Oral treatment with dimercaptosuccinic acid will be started when the blood lead level is below 0.3 w/l.