[Optimising antibiotic policies in the Netherlands. IX. SWAB guidelines for antimicrobial therapy in adults with acute infectious diarrhoea]. / Optimaliseren van het antibioticabeleid in Nederland. IX. SWAB-richtlijn voor antimicrobiële therapie bij acute infectieuze diarree.

The 'Stichting Werkgroep Antibioticabeleid' (SWAB; Dutch Working Party on Antibiotic Policy) develops evidence-based guidelines for the use of antibiotics in hospitalised adults. This guideline on acute infectious diarrhoea (AID) concerns the antibiotic treatment of acute infectious inflammation of the gastrointestinal tract, manifesting primarily as diarrhoea. AID can be subdivided into community-acquired diarrhoea, traveller's diarrhoea and hospital-acquired (nosocomial) diarrhoea. In the first 2 categories, the need for antibiotic treatment is generally restricted to individuals with severe illness, dysentery or a predisposition to complications. High rates of primary fluoroquinolone resistance can be found in human Campylobacter isolates from the Netherlands and from other parts of the world. Therefore, if antibiotic treatment is necessary for community-acquired AID or AID in travellers returning to the Netherlands, it is advised to use oral azithromycin for 3 days as empirical treatment. If intravenous treatment is necessary, the combination of ciprofloxacin and erythromycin for 5-7 days may be considered. As soon as the identity of the causative organism is known, antimicrobial treatment should be tailored accordingly.

Emergency resection of an extra-adrenal phaeochromocytoma: wrong or right? A case report and a review of literature.

Phaeochromocytomas are rare neuroendocrine tumours that produce symptoms through excess release of catecholamines. Treatment of choice is elective, complete surgical removal after pretreatment with alpha-adrenergic blocking drugs, to prevent dangerous haemodynamic fluctuations. In rare cases a 'catecholamine crisis' develops presenting with pulmonary oedema and circulatory shock. We report such a case of a patient with familial extra-adrenal phaeochromocytoma who successfully underwent emergency surgery. Pathophysiological mechanisms are discussed. Although pretreatment with alpha-adrenergic blocking drugs seems advisable in terms of morbidity and mortality, the concept is based on theory rather than clinical evidence. Surgical management of a catecholamine crisis is associated with high mortality rates. However, proof of better outcome by avoidance or discontinuation of emergency surgery is not available. Based on literature and on this case, we conclude that emergency surgery in phaeochromocytoma does not have to be structurally avoided and may be considered under life-threatening circumstances.

Hemodialysis-induced degranulation of polymorphonuclear cells: no correlation between membrane markers and degranulation products.

BACKGROUND/AIMS: Degranulation of polymorphonuclear leukocytes (PMN) during hemodialysis (HD) is usually assessed by measuring degranulation products. However, this process might also be estimated by the assessment of cell surface markers. In this study, the relationship between the expression of PMN degranulation markers (CD63 and CD66b) and the release of degranulation products [myeloperoxidase (MPO) and lactoferrin (LF)] was investigated during clinical HD in order to evaluate cell surface markers as a useful index of PMN degranulation. METHODS: The expression of CD63 and CD66b on PMN and the release of MPO and LF were investigated in 10 chronic HD patients, during both heparin (HDhep) and trisodium citrate anticoagulation (HDcit), in a randomized order. Samples were drawn from both the efferent and afferent lines of the dialyzer at 0, 7.5, and 180 min. RESULTS: During HDhep at first passage, a major increase in MPO (from 158 +/- 32 to 448 +/- 177 microg/l, p = 0.001) and LF (from 134 +/- 52 to 260 +/- 120 microg/l, p = 0.01) was found across the dialyzer, whereas marked changes were not observed during HDcit. The expression of CD63 and CD66b increased across the dialyzer during both anticoagulation modalities, but was only significant in the case of HDhep (CD63: mean fluorescence intensity from 247 +/- 61 to 331 +/- 118, p < 0.01; CD66b: mean fluorescence intensity from 340 +/- 76 to 434 +/- 103, p = 0.01). During HDhep a correlation was noted between the degranulation products and markers of both azurophilic and specific granules (MPO and CD63: r = 0.35; p < 0.01; LF and CD66b: r = 0.39, p < 0.01). Significant differences in the expression of CD63 and CD66b between HDhep and HDcit were not observed. When analyzing the combined data for both HDhep and HDcit, no correlation was observed between degranulation products and markers. CONCLUSION: Our data suggest that the measurements of cell surface markers may not be a reliable indicator of the degree of HD-induced PMN degranulation.

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 1: Synthesis and in vitro pharmacological characterization.

Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17alpha-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17alpha-pre gna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16alpha-ethyl-19-norpregn-4-ene-3, 20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17alpha-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5alphaDHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17alpha-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their 123I-labelled analogues to determine their usefulness as PR imaging agents.

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 2: In vivo pharmacological characterization.

On the basis of the observed high selective binding to both the human and rat progesterone receptor (PR) in vitro, three 17alpha-iodovinyl-substituted nortestosterone derivatives, i.e., the Z-isomer of 17alpha-iodovinyl-19-nortestosterone (Z-IVNT; Z-IPG1) and both the stereoisomers of 17alpha-iodovinyl-18-methyl-11-methylene-19-nortestosterone (E- and Z-IPG2), were selected for radio-iodination and subsequently evaluated as potential radioligands for PR imaging in human breast cancer. Their target tissue uptake, retention, and uptake selectivity were studied in female rats. The distribution studies revealed that PR-mediated uptake in the uterus and ovaries could only be demonstrated for Z-[123I]IPG2. The target tissue uptake selectivity was, however, low, with the highest uterus-to-nontarget tissue uptake ratios observed at 2-4 h postinjection (p.i.), being 4.4, 1.8, and 7.4 for the uterus-to-blood, -fat, and -muscle ratio, respectively. For Z-[123I]IPG2, distribution was also studied in dimethylbenzanthracene (DMBA)-induced mammary tumour-bearing rats and in normal rabbits. Mammary tumour uptake of Z-[123I]IPG2 in the mammary tumour-bearing rat was also found to be PR-specific. In rabbits, higher selective target tissue uptake of Z-[123I]IPG2 was observed than in rats, resulting in uterus-to-blood, -fat, and -muscle ratios of 6.6, 2.2, and 21.3 at 2-4 h p.i., respectively. In conclusion, Z-[123I]IPG2, which displayed high binding affinity for both the human and rat PR in vitro, showed specific PR-mediated target tissue uptake in rats and rabbits in vivo, the uptake selectivity being highest in the latter. Because the binding characteristics appeared to vary between species, a pilot study in breast cancer patients may be needed to decide whether Z-[123I]IPG2 can be of potential use as PR imaging agent in breast cancer.

Synthesis, estrogen receptor binding, and tissue distribution of a new iodovinylestradiol derivative (17alpha,20E)-21-[123I]Iodo-11beta-nitrato-19-norp regna-1,3,5 (10),20-tetraene-3,17-diol (E-[123I]NIVE).

We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).

Low polymorphonuclear cell degranulation during citrate anticoagulation: a comparison between citrate and heparin dialysis.

INTRODUCTION: Haemodialysis (HD)-induced bio-incompatibility includes alterations in both cellular elements and humoral factors. As far as polymorphonuclear (PMN) cells are concerned, an increase in both adhesion and degranulation has been reported. However, whereas increased PMN adherence and aggregation is highly linked with early transient complement activation, degranulation seems a continuous process, independent from the formation of complement degradation products. In the process of cell activation, including PMN degranulation, divalent cations (Ca2+) appear to play a pivotal role. As regionally administering citrate creates an almost Ca(2+)-free environment within the dialyser, it is tempting to speculate that Ca2+ dependent phenomena of bio-incompatibility, originating within the dialyser, can be attenuated by substituting conventional heparin for citrate. METHODS: Therefore, both anticoagulation modalities were compared in 10 stable patients, undergoing haemodialysis (HD) treatment with cellulose-triacetate membranes (CTA) only. Apart from the intracellular granule products myeloperoxidase (MPO) and lactoferrin (LF), the classical parameters of bio-incompatibility, peripheral blood neutropenia and complement activation, were measured. RESULTS: Analysis of MPO and LF gradients across the dialyser (concentration in efferent line-concentration in afferent line) suggested that degranulation is an early process, that occurs mainly within the extracorporeal circuit. Citrate abolished the release of MPO almost completely, whereas LF release was partially inhibited. Neither neutropenia, nor complement activation could be correlated with the occurrence of degranulation. CONCLUSIONS: HD-induced PMN degranulation seems largely independent from complement activation, but primarily reliant on Ca2+, at least in the case of CTA membranes.

Mechanisms of intra-dialyser granulocyte activation: a sequential dialyser elution study.

INTRODUCTION: During haemodialysis (HD), an early and transient white blood cell (WBC) reduction is noted in the peripheral blood, which has been attributed mainly to the sequestration of polymorphonuclear cells (PMN) in the pulmonary vasculature. However, WBC also adhere to the dialyser, as demonstrated before in an elution study performed after HD. In the present study, we investigated if intradialyser WBC sequestration contributes to the WBC nadir in the blood shortly after the start of HD and whether or not different mechanisms underlie PMN adherence in dialyser and lung. In addition, PMN degranulation was analysed not only in peripheral blood but also in dialyser eluates (DE). SUBJECTS AND METHODS: Dialysers were eluted after 7 1/2 (DE-7 1/2) and 180 (DE-180) min of HD in eight patients. Blood samples were taken before HD (t0), and at t7 1/2 and t180. Besides WBC count and differentiation, PMN adhesion (CD11b and CD62L) and degranulation markers (CD63 and CD66b) were assessed by flow cytometry. RESULTS: In the blood, a WBC fall was noted at t7 1/2 (from 5.8 to 4.8 x 10(9)/l; absolute about 5 x 10(9) cells). DE contained 3.0 x 10(6) cells at t7 1/2, and 57.2 x 10(6) at t180 (P = 0.015). As for CD11b, at t7 1/2 both in the blood and DE an increased expression was observed, as compared to t0 (P = 0.01); CD11b expression in DE-7 1/2 was higher than in DE-180 (P = 0.025). In contrast, CD62L showed downregulation only in DE both at t7 1/2 (mean fluorescence intensity (MFI) PB 4172 and DE-7 1/2 2353, P = 0.01), and at t180 (MFI 794, P = 0.03 versus DE-7 1/2), when compared to blood at t0. As for degranulation markers, an increase was observed in blood at t7 1/2 (MFI CD63 from 357 to 506, P = 0.02; CD66b from 507 to 794, P = 0.001), in comparison with t0. Eluted PMN at t7 1/2 showed a higher expression of CD63 than PMN in blood at t7 1/2 and DE-180 (MFI in DE-7 1/2 1280 and blood 506, P = 0.003). The expression of CD66b was increased in DE-7 1/2 (MFI 1803 versus blood 794, P = 0.01), and even more in DE-180 (MFI 2763, P = 0.002), when compared to blood. CONCLUSIONS: From these data it is concluded first, that intradialyser PMN sequestration does not contribute markedly to the WBC nadir in the circulation. Second, intradialyser PMN trapping appears to result primarily from non-adhesion-molecule-mediated factors, as indicated by an increased expression of CD11b at t7 1/2 on eluted PMN associated with low cell numbers in DE, and normalized CD11b expression at t180 associated with considerably higher cell numbers in DE. Third, HD-induced degranulation seems to be a complex phenomenon. After a rapid transient onset, characterized by an early upregulation of CD63 and CD66b on PMN leaving the dialyser, degranulation continues within the device as indicated by an additional rise in the expression of CD66b on PMN in DE-180.

Development of radioligands for the imaging of cardiac beta-adrenoceptors using SPECT. Part I: Asymmetric synthesis and structural characterization of five new iodine-containing beta-adrenoceptor antagonist derivatives.

The asymmetric synthesis of a series of iodinated beta-adrenoceptor ligands is described. One ligand, (S)-(-)-[1-(2-iodophenoxy)]-3'-(tert-butylamino)-2'-propanol (CYBL3), is based on the beta-adrenoceptor antagonist penbutolol. The other ligands are N-iodovinyl and N-iodoaryl analogues of the beta-adrenoceptor antagonist CGP12177. These have been synthesized from 2-amino-3-nitrophenol. Furthermore, radioiodinated [123I]CYBL3 and [123I](2'S,2"E)-[4-(3'-(1",1"-dimethyl-3"-iodo-2" propenylamino)-2'-hydroxy propoxy)]-benzimidazol-2-one have been prepared by radiolabelling the corresponding trialkyltin precursors using [123I]-NaI in the presence of hydrogen peroxide.

Development of radioligands for the imaging of cardiac beta-adrenoceptors using SPECT. Part II: Pharmacological characterization in vitro and in vivo of new 123I-labeled beta-adrenoceptor antagonists.

Cardiac beta-adrenoceptors are assumed to play a key role in chronic heart failure. Although several radioligands labeled with 11C or 18F have been synthesized for imaging purposes with positron emission tomography (PET), so far no optimal ligands are available to image cardiac beta-adrenoceptors using single photon emission tomography (SPECT). In the present study, we characterized four new synthesized analogues of the nonselective beta-adrenoceptor antagonist 4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-2-one (CGP12177) and one analogue of the nonselective beta-adrenoceptor antagonist penbutolol. Using classical in vitro displacement studies with left ventricular tissue of New Zealand White rabbits and [125I]iodocyanopindolol as a radioligand, binding affinity to the receptor was determined. From the four analogues, only (2'S,2"E)- [4-(3'-(1",1"-dimethyl-3"-Iodo-2" propenylamino)-2'-hydroxypropoxy)]-benzimidazol-2-one proved to have a high affinity, with Ki = 1.25 +/- 0.09 nM, n = 3. The other analogues showed relatively low affinity, with Ki-values > 1 nM. The analogue of penbutolol ((S)-(-)-[1-(2-Iodophenoxy)]-3'-(tert-butylamino)-2'-propanol) also showed a Ki value of 0.64 +/- 0.26 nM, n = 3. Subsequently, (2'S,2"E)-[4-(3'-(1",1"-dimethyl-3"-Iodo-2" propenylamino)-2'-hydroxypropoxy)]-benzimidazol-2-one and (S)-(-)-[1-(2-Iodophenoxy)]-3'-(tert-butylamino)-2'-propanol were radioactively labeled with 123I to study their biodistribution in New Zealand White rabbits and to determine specific binding. Significant uptake was observed in both lungs and left ventricles. However, both compounds showed high nonspecific binding in vivo because uptake of the radioligand could not be inhibited by preinjection of different (selective- and nonselective-adrenoceptor antagonists and hydrophilic and lipophilic antagonists) antagonists. In conclusion, although two analogues showed reasonable affinity in vitro for the receptor, their binding in vivo proved to be largely nonspecific, suggesting that these two compounds are unsuitable for imaging purposes. However, because marked differences in affinity for the receptor were observed with only little structural changes between compounds, the present results offer future perspectives for the synthesis of a more specific radioligand.

Synthesis and in vitro and in vivo characteristics of an iodinated analogue of the beta-adrenoceptor antagonist carazolol.

A new (radio)iodinated, beta-adrenoceptor ligand, (S)-(-)-4-[3-[(1,1-dimethyl-3-iodo-(2E)-propenyl)-amino]-2- hydroxypropoxy]carbazole (CYBL8E, 1), was prepared. 1 is an iodinated analogue of the high-affinity beta-adrenoceptor antagonist carazolol (2). The asymmetric synthesis was achieved in four steps starting from 4-hydroxycarbazole. The iodine-123-labeled form was obtained by an iododestannylation reaction with [123I]NaI in the presence of H2O2. Using classical in vitro displacement experiments with membrane fractions of cardiac left ventricular muscle, 1 proved to have a high affinity for the receptor (Ki = 0.31 +/- 0.03). Biodistribution studies performed in New Zealand white rabbits demonstrated the specificity of the binding in vivo to the receptor. Uptake of [123I]1 was reduced significantly in both atrial muscle, left ventricular muscle, frontal cortex, cerebellum, and striatum, by the pretreatment of the animals with different beta-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective beta-adrenoceptor antagonist, which binds specifically to the beta-adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of beta-adrenoceptors using single photon emission computerized tomography.

Pharmacologic characterization in vitro and in vivo of iodine 123-labeled derivatives of the beta-adrenoceptor antagonist CGP12177, designed for the imaging of cardiac beta-receptors.

BACKGROUND: Potential new radioligands for the noninvasive imaging of cardiac beta-adrenoceptors with single-photon emission computed tomography were investigated. METHODS AND RESULTS: Two iodinated derivatives of CGP12177 para (S-CYBL2B) and ortho (CYBL2A) substituted CGP12177 and an iodinated form of nadolol (CYBL1) were synthesized. Their affinity was tested in vitro (left ventricular homogenates). The biodistribution of [123I]S-CYBL2B was evaluated in rabbits. Specific binding was assessed by pretreatment of the animals with 0.1 mumol propranolol. The inhibition constant values (in nanomolars, means +/- SEM; n = 3 to 5) were determined at 1.17 +/- 0.42, 28800 +/- 9260, 11.1 +/- 2.1, 53.0 +/- 19.9, and 1790 +/- 700 for CGP12177, CYBL2A, S-CYBL2B, nadolol, and CYBL1. Myocardial uptake of [123I]S-CYBL2B was not inhibited by pretreatment of the animals with propranolol, but uptake by lung tissue could be blocked by propranolol (0.63% +/- 0.09% vs 0.33% +/- 0.02% % injected dose/g x kg; p < 0.05). In isolated right atria, preincubation with S-CYBL2B induced a parallel rightward shift of the concentration-response curve with isoprenaline. CONCLUSIONS: S-CYBL2B shows high affinity for cardiac beta-adrenoceptors, but binding proved nonspecific in vivo, whereas binding in lung tissue was specific. These results suggest that S-CYBL2B is probably not a suitable radioligand for receptor imaging.

The stereoisomers of 17alpha-[123I]iodovinyloestradiol and its 11beta-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus, and their distribution in immature rats.

We studied the potential of both stereoisomers of 17alpha-[123I]iodovinyloestradiol (E- and Z-[123I]IVE) and of 11beta-methoxy-17alpha-[123I]iodovinyloestradiol (E- and Z-[123I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17alpha-[123I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17alpha-tri-n-butylstannylvinyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17alpha-iodovinyloestradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their 123I-labelled analogues were studied in immature female rats. All four 17alpha-iodovinyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE > or =E-IVE. Neither of these 17alpha-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that of E- and Z-[123I]MIVE being higher than that of E- and Z-[123I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24h), were exhibited by both isomers of [123I]MIVE. The uterus-to-blood uptake ratio was higher for E-[123I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for the Z-isomer of [123I]MIVE, especially at 24h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude that E- and Z-[123I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.

Ex vivo elution of hemodialyzers. An additional criterion for the assessment of bioincompatibility.

The analysis of hemodialysis (HD)-related bioincompatibility is focused mainly on phenomena observed in peripheral blood. However, since biocompatibility originates inside the dialyzer, white blood cells (WBC) adhering to the dialyzer are probably most subject to the influence of both dialyzer membrane and dialysate. In order to collect membrane-adherent cells, a reliable and reproducible elution technique was developed. After 3 h of HD, blood was returned to the patient with 0.9% NaCl. Then, dialyzers were eluted by recirculation of phosphate-buffered saline (PBS) or PBS/3 mM EDTA for 20 min, with or without prior flushing with 200 ml PBS. Finally, remaining adherent cells were collected by an afterwash with 10% trypsin. These solutions, as well as blood samples, were analyzed for WBC count, viability and differentiation. Random eluate samples were analyzed by flow cytometry, and the influence of elution on PMN activation was tested in a separate control experiment. WBC numbers decreased by flushing before elution, whereas cell numbers were maximal after elution with PBS/3 mM EDTA (30 x 10(6)). Trypsin afterwash resulted in a further yield of 12 x 10(6) cells. The eluates contained 81% PMN (blood 68%, p < 0.01), with a degranulated appearance, and only 12% lymphocytes (blood 21%, p < 0.05); cell viability in the eluates was > 95%. The eluted cells could be analyzed by flow cytometry, and the procedure itself induced only minimal PMN activation. In conclusion, a maximal number of adherent cells, consisting mainly of PMN, was obtained by direct elution with PBS/3 mM EDTA. The method itself did not induce marked PMN activation, and the cells obtained were suitable for further investigations, including flow cytometry.

["The Soul-Searchers"--discussion of circulars of the Secret Committee. With a letter by Freud and Rank]. / Die "Seelensucher"-Diskussion in den Rundbriefen des Geheimen Komitees. Mit einem Brief von Freud und Rank.

The appearance of Georg Groddeck's novel Der Seelensucher (1921) in the Internationaler Psychoanalytischer Verlag caused a stir among the members of the Secret Committee which, as hitherto unpublished circulars from Committee members testify, then developed into a full-grown controversy. Proceeding from the documents themselves, the author traces the course and the eventual settlement of the difference of opinion over Groddeck's novel. His concern in so doing is not so much to throw light on an episode in the early history of psychoanalysis but rather to take that episode as an instance demonstrating the nature of the discourse mechanisms introduced by Freud to protect the central tenets of his teachings. Bos concludes that these were largely institutional defence mechanisms designed to control the generation of psychoanalytic discourse among the Committee members. In present-day terms, the question arises to what extent psychoanalytic societies and institutions employ such discourse strategies vis-à-vis non-conformists and outsiders.

The surgical anatomy of the superior gluteal nerve and anatomical radiologic bases of the direct lateral approach to the hip.

In view of the increasing popularity of the direct lateral approach to the hip joint for hemi- or total hip arthroplasty, the location of the superior gluteal nerve (SGN) was studied. This nerve is in danger when using a transgluteal incision. In 20 embalmed specimens the relation of the SGN to the tip of the greater trochanter (TT) was studied as well as the relation to the iliac crest. For this purpose macroscopy, microscopy and CT were used. In 13 hips a so-called most inferior branch was found at an average of 1 cm distal to the inferior branch, the main trunk of the nerve. There was substantial variation in the course of both the inferior and the most inferior branch of the SGN. In order to prevent nerve damage, proximal extension of the transgluteal incision should be limited to 3 cm cranial to TT. Furthermore the incision has to be confined to the distal one third of the distance TT-iliac crest. In tall people extra care should be taken.

[Congenital hip dislocation; causes and sequelae of late diagnosis]. / Congenitale heupluxatie; oorzaken en gevolgen van late diagnose.

The causes of late diagnosis of congenital dislocation of the hip were examined retrospectively in a group of 49 children (56 hips affected). It appears that at neonatal examination as well as a further screening during the first year of life, the classical symptoms of this condition are not infrequently missed. The classical tests for the early diagnosis are described and the consequences of late diagnosis are studied. In spite of late detection, the final result of the treatment in most cases is quite favourable. However, this result can only be achieved by prolonged and intensive treatment, including hospitalization and surgery.

[Surgical treatment of persistent congenital clubfoot in the young child]. / Operatieve behandeling van de recalcitrante congenitale klompvoet bij het jonge kind.

From 1979-1985 seventeen children with twenty-six club-feet were treated. Thirty-four operations have been carried out, divided in three surgical procedures. The heel cord was lengthened in eight feet, a posterior release was done in thirteen feet and a posteromedial release according to Turco was done thirteen times as well. Lengthening of the heel cord seemed to be an insufficient procedure, because six out of eight feet showed a recurrent deformity. The posterior release has given in half of the cases a good result. After posteromedial release we saw in 70% a good or excellent result, when this procedure has been performed between the age of six to twelve months.

Subtotal mesh-wrapping in the treatment for abdominal aortic aneurysm.

A new technique for managing abdominal aortic aneurysms is described. This so called "subtotal mesh-wrapping" may be considered for high-risk patients with large or growing aneurysms even those extending proximally to the renal arteries. The results in 19 patients, treated by this method, are discussed. Poor general condition renders peri-operative mortality high. But long-term prognosis is improved and with the abandoning of appendectomy will benefit still more.