Identification of an amino acid-base contact in the GCN4-DNA complex by bromouracil-mediated photocrosslinking.

The bZIP DNA-binding proteins are characterized by a 50-amino-acid DNA binding and dimerization motif, consisting of a highly basic DNA-binding region ('b') followed by a leucine zipper dimerization region ('ZIP'). The best characterized bZIP DNA-binding protein is GCN4, a yeast transcriptional activator. GCN4 binds to a 9-base-pair two-fold-symmetric DNA site, 5'-A-4T-3G-2A-1C0T+1C+2A+3T+4-3' (refs 7-10). A detailed model known as the 'induced helical fork' model has been proposed for the structure of the GCN4-DNA complex. Using a site-specific bromouracil-mediated photocrosslinking method, we show here that the alanine at position 238 of GCN4 contacts, or is close to, the thymine 5-methyl of A.T at position +3 of the DNA site in the GCN4-DNA complex. Our results strongly support the induced helical fork model. Our site-specific bromouracil-mediated photocrosslinking method requires no prior information regarding the structure of the protein or the structure of the protein-DNA complex and should be generalizable to DNA-binding proteins that interact with the DNA major groove.


Release of endogenous acetylcholine in the hypothalamus of conscious rats.

The release of endogenous acetylcholine was investigated by the push-pull technique. The posterior hypothalamus of conscious rats was superfused through a push-pull cannula with artificial cerebrospinal fluid (ACSF) which contained 1 mumol/l neostigmine. Acetylcholine was determined in the superfusate by high pressure liquid chromatography and electrochemical detection. Hypothalamic superfusion with potassium-rich (100 mmol/l) ACSF led to a pronounced increase in the release rate of acetylcholine. Tetrodotoxin (1 mumol/l) almost abolished the basal release of the neurotransmitter. Superfusion of the hypothalamus with atropine (10 or 50 mumol/l) led to a concentration-dependent increase, whereas superfusion with oxotremorine (50 mumol/l) inhibited the release rate of acetylcholine. It is concluded that acetylcholine released into the superfusate of the hypothalamus originates from cholinergic neurons. Furthermore, the release of acetylcholine seems to be modulated by muscarinic acetylcholine receptors, probably located on cholinergic neurons of the hypothalamus.


Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli.

Recombinant tissue-type plasminogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with 125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (alteplase). BM 06.021 demonstrated a longer (p less than 0.05) half-life (5.6 +/- 2.6 vs. 2.1 +/- 0.3 min) and a lower (p less than 0.05) clearance rate (7.5 +/- 0.8 vs. 22.2 +/- 3.1 ml.min-1.kg-1) than alteplase in rabbits upon intravenous infusion. The dose-response curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and alteplase (5.7 +/- 1.8 vs. 6.3 +/- 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (alteplase).(ABSTRACT TRUNCATED AT 250 WORDS)


Dopamine and adrenaline, but not isoprenaline, are substrates for uptake and metabolism in isolated perfused lungs of rats.

The uptake and subsequent metabolism by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) of dopamine, adrenaline, isoprenaline and noradrenaline in isolated perfused lungs of rats has been examined. In lung preparations in which COMT and MAO were inhibited, the uptake of 3H-labelled dopamine, (-)-adrenaline and (-)-noradrenaline, but not (+/-)-isoprenaline, was reduced by cocaine (10 or 100 mumol/l). The rank order of the Km values of the amines that were substrates for uptake in the lungs were: dopamine (0.246 mumol/l) less than noradrenaline (0.967 mumol/l) less than adrenaline (3.32 mumol/l). These results are consistent with transport of catecholamines in rat lungs by Uptake1. In lung preparations with COMT and MAO intact, dopamine and noradrenaline were removed from the circulation (50% and 32%, respectively) and mainly metabolized. There was very little (3.0%) removal of isoprenaline by the lungs and adrenaline was not included in this part of the study. In lung preparations in which only MAO was inhibited, the rank order of COMT activity for O-methylation of the amines was dopamine much much greater than noradrenaline greater than or equal to adrenaline (kCOMT values: 4.98 min-1, 0.357 min-1 and 0.234 min-1, respectively). If dopamine or adrenaline are perfused through the pulmonary circulation in isolated lungs of the rat, they are taken up and then metabolized by COMT and MAO, as also occurs for noradrenaline. Isoprenaline is not a substrate for uptake in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)


Modulation by sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency.

The effects of the high affinity sigma (sigma) ligands 1,3-di(2-tolyl)guanidine (DTG), (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-yl-amine hydrochloride (JO-1784), (+)3-[3-hydroxyphenyl]-N-(1-propyl)piperidine hydrochloride [(+)3-PPP] and haloperidol were studied on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline (NA) from preloaded hippocampal slices made from Sprague-Dawley rats. The [3H]NA release was evoked once by a 4 min exposure to NMDA, 40 min after the beginning of superfusion with a Mg+(+)-free Krebs' solution. In the absence of any drug, NMDA evoked a concentration-dependent [3H]NA release. Mg++ and EGTA abolished the [3H]NA release induced by NMDA. JO-1784 and (+)3-PPP potentiated in a concentration-dependent manner NMDA-induced [3H]NA release, without affecting the basal outflow. DTG concentration-dependently inhibited the overflow of [3H]NA evoked by NMDA, without affecting the basal efflux. Haloperidol, which did not modify NMDA-evoked [3H]NA release by itself, completely prevented the effects of JO-1784, (+)3-PPP and DTG. In contrast, spiperone, also a potent dopamine receptor antagonist but with low affinity for sigma binding sites, failed to prevent the potentiation of NMDA-evoked release of [3H]NA by JO-1784 and (+)3-PPP. The possible involvement of Gi/o proteins in the modulation by sigma ligands of NMDA-evoked [3H]NA release in the rat hippocampus was also investigated. To this end, Gi/o proteins were inactivated with pertussis toxin (PTX), injected locally 3 to 11 days prior to the experiment or with in vitro preincubation with N-ethylmaleimide (NEM) for 30 min prior the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular structural basis of ligand selectivity for 5-HT2 versus 5-HT1C cortical receptors.

A molecular structural criterion of ligand selectivity for the 5-HT2 versus 5-HT1C receptor was hypothesized on the basis of radioligand binding data. Despite the large number of compounds which have been tested at both receptors, analysis of published data led to the identification of only five agents which are greater than 10-fold selective for the 5-HT2 versus the 5-HT1C receptor. Comparison of the two-dimensional structures revealed that, although these five compounds represent three distinct structural classes, they share a common structural feature located in the region hypothesized to be involved in receptor binding: a carbonyl or carboxyl oxygen interposed spatially between an aromatic ring and nitrogen atom. This structural feature was used to predict the relative selectivity of compounds that had not previously been analyzed at both the 5-HT2 and 5-HT1C receptors. All six drugs tested which contain the identified reactive carbonyl or carboxyl group were found to be selective for the 5-HT2 versus the 5-HT1C receptor with selectivity ratios ranging from 26 to 380. By contrast, three agents which are structurally similar but do not contain the reactive carbonyl or carboxyl group displayed equally high affinity for both receptor binding sites. Since the physiological roles of the 5-HT2 and 5-HT1C receptor are markedly different, it would be of potential clinical and scientific value to utilize this molecular structural feature to further identify chemical compounds which would selectively interact with only one of the two receptors.


Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine.

The purpose of this study was to investigate the possible role of the central histaminergic neuron system in electrically-induced seizure in mice. For this purpose, we examined the effects of intraperitoneal (i.p.) injections of histaminergic agents, such as L-histidine, metoprine, and alpha-fluoromethylhistidine (FMH), on electrically-induced seizure. L-Histidine decreased the duration of clonic convulsion in electrically-induced seizure, but not affected that of tonic convulsion. This effect of L-histidine was antagonized by pretreatment with FMH, indicating that it was due to histamine formed by decarboxylation of L-histidine in the central nervous system. The anticonvulsive effect of L-histidine was also reduced by the H1-antagonist pyrilamine, but not by the H2-antagonist zolantidine, indicating that the effect on electrically-induced seizure is mediated through central H1-receptors. Metoprine, which increased the histamine levels in the cerebral cortex, diencephalon and midbrain of mice, decreased the duration of clonic convulsions dose-dependently. Conversely, FMH, which decreased the brain histamine levels, increased the duration of clonic convulsions. Good inverse correlations were found between the duration of clonic convulsions and brain histamine levels, especially in the diencephalon: the histamine levels were inversely proportional to the duration of clonic convulsions. No correlation was found between the duration of tonic convulsions and brain histamine levels. These results suggest that the histaminergic neuron system is important in inhibition of the duration of clonic convulsion on electrically induced seizure in mice.


Calcium mobilization and its desensitization induced by endothelins and sarafotoxin in human astrocytoma cells (1321N1): comparison of histamine-induced calcium mobilization.

Intracellular free Ca2+ concentration ([Ca2+]i) was monitored in monolayer of 1321 N1 astrocytoma cells by using a fluorescent Ca2+ indicator fura-2. Endothelin-1 (ET-1), endothelin-2 (ET-2), and sarafotoxin Sb6 (SRTX) increased [Ca2+]i from 56 +/- 6 nM to 360 +/- 82, 120 +/- 51, 143 +/- 29 nM, respectively, immediately after their addition to the perfusate with maximum response of more than 0.1 microM of peptides. Endothelin-3 (less than 1 microM) did not affect [Ca2+]i. The increase in [Ca2+]i in response to either ET-1, ET-2, or SRTX could be almost completely inhibited by pretreating cells with ET-1 or ET-2. The homologous desensitization of [Ca2+]i induced by ETs and SRTX is in good agreement with their affinity toward an ETA receptors. The responses in [Ca2+]i by ETs and SRTX were not affected in the desensitized state induced by the pretreatment of histamine in the presence of extracellular Ca2+. However, the response in [Ca2+]i by ETs and SRTX were reduced in the desensitized state induced by pretreatment of histamine in the absence of extracellular Ca2+. These results indicate that depletion of the intracellular Ca2+ stores is responsible for the heterologous desensitization between ETs and histamine.


Effects of taurine, homotaurine and GABA on hypothalamic and striatal dopamine metabolism.

To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of gamma-aminobutyric acid (GABA) and homotaurine (a GABAA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 mumol/rat, and rat were sacrificed 15 and 60 min later, respectively. Homotaurine (by 11%) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 mumol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 mumol the amino acids decreased striatal 3-MT by about 40%. At 36 mumol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 mumol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 mumol but not at 36 mumol slightly (20%) increased DA.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification of a novel high affinity adenosine binding protein from bovine striatum.

In solubilized extracts from bovine striatal membranes three different binding sites for 5'-N-ethylcarboxamidoadenosine ([3H]NECA) were observed after separation of the extract by gel filtration on Sepharose CL-6B. The first peak was eluted in the void volume and contained the A2 adenosine receptor. In the second peak, [3H]NECA binding sites were eluted with a pharmacological profile characteristic of adenotin, a low affinity non-receptor adenosine binding protein. The third peak represented approximately 50% of the [3H]NECA binding activity. This site bound [3H]NECA in a reversible and saturable manner with KD of 17 nmol/l and a binding capacity of 11.3 pmol/mg protein. In competition experiments, adenosine, NECA, NAD, inosine, 5'-AMP and S-adenosyl-L-homocysteine were the most potent ligands. In contrast to adenosine receptors, this site did neither bind adenosine receptor antagonists nor the A2 selective agonist CGS 21,680 (2-[p-(2-carboxyethyl)phenethylamino]5'-N-ethylcarboxamidoadeno sin e). These results suggest the existence of a novel high affinity binding site for adenosine of unknown function in bovine striatum.


Veratridine causes the Ca(2+)-dependent increase in diacylglycerol formation and translocation of protein kinase C to membranes in cultured bovine adrenal medullary cells.

Our previous studies suggested that protein kinase C is involved in the veratridine (an activator of voltage-dependent Na+ channels)-induced phosphorylation and activation of tyrosine hydroxylase as well as the synthesis of catecholamines in adrenal medulla (Uezono et al. 1989). In the present study, we investigated whether treatment of cultured bovine adrenal medullary cells with veratridine causes the accumulation of diacylglycerol, a physiological activator of protein kinase C and the translocation of protein kinase C from cytosol to membrane, a process required for protein kinase C activation. Veratridine (100 mumol/l) increased diacylglycerol level about 2.2 fold in a monophasic manner, with peaking at 5 min and declining toward the basal level within 20 min. Veratridine also increased membrane protein kinase C from 15.6% to 26.9% of total protein kinase C in a time-course similar to that of diacylglycerol accumulation. Both stimulatory effects of veratridine were inhibited by tetrodotoxin and not observed in Ca(2+)-free, EGTA-containing medium. Amiloride, an inhibitor of Na+/Ca2+ and Na+/H+ exchange, did not alter veratridine-induced events. These results suggest that veratridine-induced Ca2+ influx contributes to the accumulation of diacylglycerol and the activation of protein kinase C in adrenal medullary cells.


5-HT1D binding sites in various species: similar pharmacological profile in dog, monkey, calf, guinea-pig and human brain membranes.

Radioligand binding studies were performed in membranes of calf caudate, guinea-pig cortex, dog caudate and whole brain, monkey caudate and whole brain, and human caudate using the novel iodinated radioligand, Serotonin-5-O-Carboxymethyl-Glycyl[125I] Tyrosinamide (abbreviated [125I]GTI for the sake of simplicity), a ligand known to label 5-HT1B and 5-HT1D sites. In all membrane preparations tested, [125I]GTI labelled high affinity sites with the following rank order of affinity: 5-carboxamidotryptamine greater than 5-HT = DHE = ergotamine greater than or equal to sumatriptan greater than or equal to metergoline = CGS 12066 greater than or equal to yohimbine = methysergide greater than or equal to methiothepin greater than 8-OH-DPAT greater than or equal to mianserin greater than or equal to CP 93129 greater than or equal to (-)pindolol = ketanserin greater than or equal to isamoltane = mesulergine greater than or equal to corynanthine = spiperone greater than MDL 72222. The affinity profiles were very similar in the membranes of the different species, especially in dog, monkey and human brain. The pharmacological profile of [125I]GTI binding (determined with up to 25 different drugs) was fully comparable to the binding profile reported previously in human substantia nigra (using [125I]GTI) or in a variety of brain preparations known to contain 5-HT1D sites using [3H]5-HT as a radioligand.(ABSTRACT TRUNCATED AT 250 WORDS)


"5-HT1R" or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain.

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT1B and 5-HT1D sites, Serotonin-5-O-Carboxymethyl-Glycyl[125I]Tyrosinamide ([125I]GTI). [125I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, Bmax = 191 +/- 47 fmol/mg protein, pKD (-log mol/l) = 8.50 +/- 0.13, n = 5. The pharmacological profile of [125I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT1D sites (using either [3H]5-HT or [125I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamido-tryptamine greater than 5-HT = dihydroergotamine greater than or equal to ergotamine greater than or equal to sumatriptan greater than or equal to CGS 12066 greater than or equal to metergoline greater than yohimbine greater than or equal to methysergide greater than ICYP greater than 8-OH-DPAT greater than or equal to CP 93129 greater than (-)pindolol greater than ketanserin greater than isamoltane greater than mesulergine greater than corynanthine greater than buspirone greater than MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and mesulergine (in order to mask 5-HT1A and 5-HT1C binding sites) and [125I]CYP (iodocyanopindolol) in the presence of 3 mumol/l isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask beta adrenoceptor and 5-HT1A binding sites). There was no detectable specific binding of [125I]CYP through the brain, thus excluding the presence of 5-HT1B sites in rabbit brain.(ABSTRACT TRUNCATED AT 250 WORDS)


M1 muscarinic receptors mediate intracellular calcium release in NB-OK1 human neuroblastoma cells.

Muscarine acetylcholine receptors were characterized in NB-OK1 cells using radioligand (3H-NMS) binding experiments and second messenger (calcium and phosphatidylinositol (PI) turnover) studies. In radioligand binding experiments the displacement curves of pirenzepine (KI = 1.3 x 10(-8) M), AF-DX 116 (KI = 8.2 x 10(-7) M), methoctramine (KI = 8.4 x 10(-8) M) and parafluorohexahydrosiladifenidol (pF-HHSiD) (KI = 1.8 x 10(-8) M) were monophasic and indicated the presence of M1 muscarinic receptors. Schild analysis with the muscarinic antagonists pirenzepine, AF-DX 116, methoctramine and pF-HHSiD yielded pA2 values of 8.40 +/- 0.13, 6.48 +/- 0.09, 7.61 +/- 0.12 and 7.22 +/- 0.08 in the calcium experiments and pA2 values of 8.13 +/- 0.30 and 6.26 +/- 0.26, 7.65 +/- 0.16 and 7.46 +/- 0.11, respectively, in the PI turnover experiments. These results indicate that both the carbachol-induced increase in intracellular calcium and the increase in PI turnover are mediated by M1 muscarinic receptors. In calcium free buffer, stimulation with carbachol induced similar responses to those seen under control conditions. From functional and radioligand binding experiments we conclude that the muscarinic receptor expressed in NB-OK1 cells is the M1 subtype. In addition, the M1 receptor-induced calcium response is related to PI turnover and is independent on extracellular calcium.


Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone.

Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed reversible, tight-binding type of inhibition of soluble rat liver COMT with a Ki-value of 14 nmol/l and it also caused 50% inhibition of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor, since the formation of homovanillic acid (HVA), the O-methyl metabolite of dopamine in the striatum, was not reduced, even after the highest dose of 30 mg/kg. In rat blood serum, the concentration of 3-O-methyldopa (3OMD), the O-methylated product of L-dopa, was reduced in a dose-dependent manner, and the concentration of L-dopa was increased after the administration of entacapone (3-30 mg/kg p.o.) together with L-dopa + carbidopa. These changes were reflected, in the striatum, by a significant rise in the dopamine concentration and a reduction in the 3OMD concentration. Consequently, when entacapone was added to the treatment with L-dopa + carbidopa, the dose of L-dopa could be lowered from 50 mg/kg to 15 mg/kg in order to produce the same striatal dopamine concentrations as with 50 + 50 mg/kg of L-dopa + carbidopa alone.


Regional differences in evoked dopamine efflux in brain slices of rat anterior and posterior caudate putamen.

Fast cyclic voltammetry using carbon fibre microelectrodes in rat brain slices, was used to investigate regional differences in electrically-evoked dopamine (DA) efflux at 10 different sites in the anterior caudate putamen (aCPu) and 10 sites in the posterior caudate putamen (pCPu). For each site DA overflow was evoked by both single pulse (1P) stimulation and by trains of 25 pulses applied at a frequency of 50 Hz (25P/50 Hz). Peak DA efflux evoked by 1P was about 58% greater in the aCPu (0.19 mumol/l DA) than in the pCPu (0.12 mumol/l DA), but showed no mediolateral variation in either region. Peak DA efflux evoked by 25P/50 Hz relative to 1P efflux also varied between the two regions; the aCPu contained predominantly low ratio (25P/50 Hz: 1P) sites ranging from 1.47 to 3.71, whereas in the pCPu these ratios were higher, ranging from 2.73 to 9.40, and were particularly high in the dorsomedial region of the pCPu. Efflux detected in low ratio sites of the aCPu showed little dependence on the frequency (10 to 500 Hz), or the number of pulses (5 to 20) in a train. By contrast DA efflux evoked in high ratio sites of the pCPu responded in a pulse and frequency dependent manner, the maximum ratio (approximately 8 times 1P) being at 20P/20 Hz. Interestingly the frequency response relationship obtained in the pCPu resembled the profile observed in the nucleus accumbens (NAc). Voltammetric evidence and experiments with selective reuptake blockers indicated that only DA was measured in our studies and 5-HT did not significantly contribute to the frequency dependent pattern of efflux detected in high ratio sites of the pCPu, where striatal 5-HT concentrations are highest. Experiments with the selective D2 receptor antagonists metoclopramide or (-)sulpiride revealed that under our experimental conditions, DA efflux in the aCPu was not modulated by DA autoreceptor activation. By contrast, autoreceptor modulation did occur in high ratio sites of the pCPu at stimulations lasting longer than approximately 1000 ms. These observations support the concept that the caudate putamen is heterogeneously organised with respect to the frequency characteristics of evoked DA release. The factors controlling frequency dependent release under these conditions may be a function of A10 innervation, since high ratio release sites occur in areas where the density of such innervation is greatest, for example, the dorsomedial pCPu. This is supported by the observation that high ratio release sites are also found in the NAc, which receives dopaminergic fibres predominantly from an A10 region.(ABSTRACT TRUNCATED AT 400 WORDS)


Biotransformation of L-dopa in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study.

Microdialysis was used to study the biotransformation of L-DOPA in the striatum and substantia nigra of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. The animals were pretreated with carbidopa (50 mg/kg p.o.) for 5 days. They were anaesthetized, and microdialysis probes were implanted into the intact and denervated striatum and into the intact and lesioned substantia nigra. The biotransformation of L-DOPA (5 mg/kg i.p.) in these regions was investigated. These results were compared with those obtained after administration of a much higher dose of L-DOPA (100 mg/kg i.p.). Changes in extracellular L-DOPA, 3-O-methyldopa (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC with electrochemical detection. Although rats with a unilateral nigrostriatal lesion did not show rotational behaviour after 5 mg/kg L-DOPA, DA levels were increased significantly both in the intact and the denervated striatum and in the intact and the lesioned substantia nigra. This increase was most pronounced in the denervated striatum. At 100 mg/kg L-DOPA, the increases in extracellular dopamine in intact and denervated striatum were about twice as high as the increases observed at the lower dose. A similar increase was observed in the intact substantia nigra. However, in the lesioned substantia nigra there was a fourfold increase. L-DOPA, at both doses, was evenly distributed between the brain areas studied and the lesion had no effect on the uptake of the drug at the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)


Predominance of oxidative deamination in the metabolism of exogenous noradrenaline by the normal and chemically denervated human uterine artery.

Longitudinal strips were prepared from human uterine arteries obtained at hysterectomy. The artery had a low content of noradrenaline and dopamine, contrasting with a high content of the deaminated catechols, dihydroxyphenylglycol (DOPEG) and dihydroxymandelic acid (DOMA), which together represented 98% of endogenous catechols. When incubated with 3H-noradrenaline (0.1 mumol/l), the uterine artery removed, accumulated and metabolized noradrenaline. Deaminated metabolites predominated, DOMA being the most abundant metabolite. Cocaine markedly reduced the accumulation of 3H-noradrenaline and abolished 3H-DOPEG formation, but did not change 3H-DOMA. Selective monoamine oxidase (MAO) inhibitors (clorgyline, selegiline and 2-amino ethyl carboxamide derivatives) caused a marked decrease in the amounts of 3H-DOPEG, 3H-DOMA and 3H-O-methylated and deaminated metabolites (OMDA) formed by the tissue and an increase in 3H-normetanephrine (NMN) formation. Inhibition of catechol-O-methyltransferase suppressed NMN formation and reduced that of OMDA; hydrocortisone slightly depressed the formation of DOMA and OMDA. Homogenates of the uterine artery deaminated 3H-5-HT, 14C-phenylethylamine and 3H-tyramine; inhibition curves of the deamination of 3H-tyramine by clorgyline and selegiline were compatible with the presence of both MOA A and MOA B. Exposure of the strips to 6-hydroxydopamine (1.5 mmol/l for 20 min; 3 exposure periods followed by washout periods of 15,15 and 30 min) resulted in complete and selective chemical denervation of the arterial tissue. This chemical denervation had effects which were similar to those of cocaine. The 2-amino ethyl carboxyamide derivatives markedly reduced the formation of deaminated metabolites by the denervated strips.(ABSTRACT TRUNCATED AT 250 WORDS)


An analysis of the inhibitory effects of prazosin on the phenylephrine response curves of the rat aorta.

On the endothelium-intact rat aorta some studies have shown prazosin to cause nonparallel rightward shifts of alpha 1-adrenoceptor agonist response curves. The aim of the present study was to analyze the inhibitory effect of prazosin on the phenylephrine responses of the endothelium-intact and endothelium-denuded rat aorta. Firstly I used phenoxybenzamine treatment to characterize the phenylephrine responses. The KA values for phenylephrine were 0.13-0.18 microM and 0.07-0.16 microM in the endothelium-intact and endothelium-denuded rat aorta, respectively. In order to produce maximal responses of the endothelium-intact or--denuded preparation, phenylephrine had to occupy 95-99% of the alpha 1-adrenoceptors. Secondly I compared the inhibitory effects of phentolamine and prazosin on the endothelium-intact rat aorta. Phentolamine at 0.1 and 1 microM caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses (phentolamine pA2 = 7.9). The inhibitory effects of phentolamine were readily reversible. Prazosin at 0.1-10 nM caused nonparallel rightward shifts of the phenylephrine response curves with a depression of the maximal response. These inhibitory effects of prazosin were either irreversible or only very slowly reversible in drug-free solution and slowly reversible in the presence of phentolamine. Ninety min was required for the inhibitory effect of prazosin to reach equilibrium whereas phentolamine was at equilibrium after 45 min. Finally I have characterized the inhibitory actions of prazosin on the endothelium-denuded rat aorta. Prazosin caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses. The inhibitory effects of prazosin were at equilibrium after 45 min and were readily reversible.(ABSTRACT TRUNCATED AT 250 WORDS)


Spinal 5-HT pathways and the antinociception induced by intramedullary clonidine in rats.

The possible involvement of spinal 5-hydroxytryptamine (5-HT) pathways in antinociception induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata was investigated in rats. Microinjection of clonidine (10-20 micrograms), but not yohimbine (1 microgram) or 0.9% saline, into the lateral medulla prolonged the hot plate latency in rats. This clonidine-induced antinociception was abolished by intramedullary injection of the alpha 2-adrenoceptor antagonist, yohimbine. Selective destruction of spinal 5-HT neurons produced by intraspinal injection of 5,7-dihydroxytryptamine (5,7-DHT; 10 micrograms) or postsynaptic blockade of spinal 5-HT receptors produced by intrathecal injection of cyproheptadine (1 microgram; a mixed 5-HT1/5-HT2 antagonist) also abolished clonidine-induced antinociception. Rats given 5,7-DHT intraspinally or cyproheptadine intrathecally showed a decrease in hot plate latency as compared with the controls. In anesthetized rats, the 5-HT release from the thoracic spinal cord was enhanced by microinjection of clonidine into the lateral medulla. This enhanced spinal 5-HT release evoked by intramedullary injection of clonidine was abolished by pretreatment of rats with intraspinal injection of 5,7-DHT. These results indicate that 5-HT pathways to the spinal cord mediate the antinociceptive effect induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata in rats.


Effect of calcium antagonists (omega-conotoxin GVIA, verapamil, gallopamil, diltiazem) on bronchial smooth muscle contractions induced by soman.

The effect of the calcium antagonists omega-conotoxin GVIA, verapamil, gallopamil and diltiazem was investigated on in vitro bronchial smooth muscle contraction in the rat induced by the nerve agent soman. Soman inhibits the acetylcholinesterase activity irreversibly. The effect of the calcium channel antagonists on contractions induced by electrical field stimulation and carbachol was also investigated, in order to elucidate the mechanism by which calcium antagonists inhibit the soman induced contraction. omega-Conotoxin GVIA reduced the bronchial smooth muscle contraction induced by electrical field stimulation with an almost complete inhibition at approximately 1.0 x 10(-6) M. The soman induced contraction was only inhibited by 15% at a concentration of 3.0 x 10(-6) M omega-conotoxin GVIA. The organic calcium antagonists verapamil, gallopamil and diltiazem reduced both electrically and soman induced smooth muscle contraction. Complete inhibition of the contractions induced by soman was achieved at 1.4 x 10(-4) M for verapamil and gallopamil, while diltiazem inhibited the contraction to 7% of control at 1.4 x 10(-4) M. Verapamil, gallopamil and diltiazem increased the EC50 for carbachol significantly, while omega-conotoxin GVIA had no effect. None of the calcium antagonists had any effect on the maximal contraction induced by carbachol. Verapamil, gallopamil and diltiazem blocked, however, sub-maximal contractions induced by carbachol (10(-7)-10(-5) M) resulting in a right-shift of the dose response curve. The results show that omega-conotoxin GVIA inhibits the calcium-dependent release of acetylcholine which causes contraction of airway smooth muscle, while it has no effect on smooth muscle contraction induced by soman.(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence for a link between specific proteolysis and inhibition of [3H]-noradrenaline release by the light chain of tetanus toxin.

The light chain of tetanus toxin is known to inhibit the Ca(2+)-evoked release of [3H]-noradrenaline from digitonin-permeabilized bovine adrenomedullary cells in culture but does not change the basal outflow or the total cellular radioactivity. Evidence for the involvement of proteolysis in this effect was obtained by three approaches. First, the permeabilized cells were exposed to a series of enzymes. The endoproteinase Glu-C mimicked the inhibition produced by the light chain. Second, protease inhibitors of different specificities were assessed for blockade of the action of light chain on [3H]-noradrenaline release from permeabilized cells. Blockade was complete with EDTA (2.5 mmol/l) or 1,10-o-phenanthroline (1 mmol/l), and absent with the highest concentrations tested of diisopropylfluorophosphate, phenylmethylsulfonyl fluoride, pepstatin, leupeptin, bestatin, phosphoramidon, thiorphan or trans-epoxysuccinic acid (E64) which is regarded as an inhibitor of thiol proteases. This inhibitor spectrum suggested that light chain might be a metalloprotease. Finally a sequence-His-Glu-Leu-X-His-occurring in the light chains of tetanus toxin and of the botulinum neurotoxins A, C, D, E was also found in many endoproteinases and an aminopeptidase. The motif is known to constitute their active site and to bind Zn2+. In fact Zn2+ (0.6-0.9 mol/mol) was found in thoroughly dialysed two-chain tetanus toxin. The three approaches jointly support the hypothesis that the light chain of tetanus toxin, and probably of all clostridial neurotoxins, inhibits [3H]-noradrenaline release from adrenomedullary cells by degradation of (a) specific, still unknown protein(s) involved in exocytosis.


Evidence for direct vasoconstrictor activity of melatonin in "pressurized" segments of isolated caudal artery from juvenile rats.

Responses of isolated, 60 mmHg 'pressurized' segments of the distal caudal artery of adult and juvenile Wistar rats to melatonin and the selective alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate (UK-14304) were examined using the Halpern pressure myograph. Melatonin showed no direct vasoconstrictor activity in vessels from adult rats, whereas UK-14304 produced moderate vasoconstriction (pD2-7.43 +/- 0.09). In the presence of phenylephrine-induced tone, melatonin produced a variable but small constrictor response (less than 10 microns reduction in diameter) in some vessels; the response to 1 mumol/l UK-14304 was less than in the absence of tone. In vessels isolated from juvenile rats, melatonin caused concentration-dependent vasoconstriction with a maximum response about 70% of the maximum response elicited by UK-14304. Vessels from juvenile rats were more sensitive to melatonin (pD2-9.40 +/- 0.07) than they were to UK-14304 (pD2-8.12 +/- 0.14). In the presence of phenylephrine-induced tone, the vasoconstrictor responses to both melatonin and IK-14304 were markedly less; the sensitivity to melatonin was not different from that seen in the absence of tone. These findings indicate that 'pressurized' segments of the isolated distal caudal artery may provide a simple and convenient, functional model of melatonin receptors. The findings also appear to implicate melatonin in thermoregulatory processes in juvenile rats.


Why does the injured drunk driver escape arrest and conviction? A case presentation and discussion by health care and law enforcement professionals.

Serious injury protects the drunk driver from prosecution and conviction for driving drunk. This escape from liability occurs despite the fact that almost half of all traffic fatalities are attributable to alcohol. Consequently, the drunk driver who is injured may resume driving as soon as he is physically able to do so, thereby becoming a renewed threat to himself and others. On the other hand, a conviction for driving while impaired (DWI) results in loss of the driving privilege, reducing exposure of other drivers to a public health hazard. A DWI conviction may also stimulate the drunk driver to seek treatment for alcoholism. Unless they are prosecuted, even seriously injured drunk drivers are seldom referred for alcoholism counseling or treatment. To explore the reasons for this continuing cycle of impairment and injury, a panel of experts from the fields of health care and law enforcement was convened on October 30, 1991, during the Third Annual North Carolina Conference on Injury Control. The panel considered the hypothetical case of an alcohol-related motor vehicle crash in which a passenger was killed. We present here an edited transcript from that conference.


Continuing education in state hospitals using external consultants.

A continuing education project for registered nurses in a state psychiatric hospital was implemented collaboratively by a nurse administrator and two nurse consultants. This program sought to enhance the nurses' knowledge of psychiatric-mental health nursing practice and prepare them to take the American Nurses Association certification examination for psychiatric-mental health nursing. The project was based on the premise that the nursing departments that offer educational services for their nurses foster professional competency and maintain current standards of nursing care. Twenty-one registered nurses volunteered for and completed the 16-week program. Improvements in their knowledge base were evidenced by mean test scores. A t-test analysis indicated a significant difference. The pretest mean score was 70.2%, the posttest mean score 79.4%. Mean scores varied with the education level of the nurses.


Early precursors of psychiatric nursing, 1838-1907.

Care of the insane during the 17th and 18th centuries was undeniably grim until the advent of moral therapy. Wasserbauer and Brodie explore the humanistic approach that laid the groundwork for early psychiatric nursing.


Upward mobility for LPNs: a vision made reality.

A recurrent theme in the nursing literature is the shortage of realistic, long-term solutions directed toward registered nurse (RN) recruitment and retention. If fragmentation of RN recruitment and retention is to be eliminated, innovative programs involving collaboration and use of existing resources will be required. This article provides an overview of how collaboration among nurses, administrators, educators, and a personnel specialist resulted in an upward mobility program for licensed practical nurses (LPNs) to become RNs. While the program is specific to one setting, there are numerous implications for other hospitals confronted with persistent recruitment and retention problems.


Facilitating research utilization through collaboration.

The rhetorical gap between clinical practice and academia was tested by the development of a special program grant to facilitate use of research by staff nurses. The grant capitalized on an established collaborative relationship between a university school of nursing and a community hospital. The merger of education and practice demonstrated the principles of interinstitutional collaboration in action. Resources of the grant included a doctorally-prepared nurse and a clinical librarian to provide research utilization classes for staff nurses, and an academic credit course to address reality-based practice problems for nurse managers. The model developed for this effort is described and critical behavioral aspects of research utilization for practicing nurses and academic nurses are outlined.


Resolution of ethical value conflicts by nurse educators: a pilot study.

The literature on ethical conflict resolution in nursing is sparse, but studies concentrating on ethical conflicts in nursing education are rarer still. Lyndaker looks at this emerging area of inquiry and adds her contribution.


Successful implementation of case management.

Hospitals must critically evaluate all aspects of operations to identify opportunities to cut operating expenses without sacrificing quality of patient care. Many health care organizations are moving toward nurse case management as a possible solution to these concerns. There is a considerable body of literature on the theory and principles of case management, and it is the basis for this article. The purpose of this manuscript, however, is to describe essential factors in the actual application of this theory in building a viable program in a community hospital.


Nursing care centers: a collaborative effort.

Nursing care centers evolved as a way to deliver health care as well as to bridge the gap between nursing education and nursing practice. This article defines the purposes of a nursing care center, and describes one such center developed by a large Southern university school of nursing, services it renders and the community's need for these services. The importance of collaborative practice in enhancing the success of nursing care centers is discussed.


Nurse education legislation: 1935-1992.

Most of us cannot remember a time when the feds didn't massively support nursing education. Mahrenholz traces the events that led to what has become our expectation and asks some probing questions about our future needs.


[The treatment of leg length discrepancy using Phemister's method of epiphysiodesis].

A retrospective study is reported of the results of epiphysiodesis in 67 children. In 47 patients (70%) the final inequality was less than or equal to 1.0 cm. In 9 patients the final inequality was greater than or equal to 1.6 cm. The average leg length inequality could be reduced from 3.2 cm preoperatively to 1.2 cm at maturity. Technical errors were minimal. Failures (9 patients) resulted mainly from problems in timing epiphysiodesis.


[Biopsy of potentially malignant bone disorders using an electric minidrill; results of 215 diagnostic drillings].

The results were evaluated of cytological and histological examination of 215 bone biopsies taken with an electric minidrill in 211 patients with suspected malignancies in bones. 171 biopsies were taken in 167 patients with a known malignancy. In 78 cases a malignancy was demonstrated including 4 cases of a second primary malignancy. 44 biopsies of patients without a known primary malignancy resulted in 19 cases of malignancy, mainly metastatic disease. There were no primary bone tumours. Follow-up showed a false negative result in 5 patients, all with known primary malignancies. Follow-up of the patients without known malignancies showed no false negatives. The sensitivity of cytology alone was 92% and the sensitivity of histology alone was 76%. The combination of cytology and histology resulted in a sensitivity of 95%. The specificity of the procedure was 100%.


[Distinction between renal and nonrenal hematuria using immunoperoxidase staining of erythrocytes in urine for Tamm-Horsfall protein].

A recently described immunocytochemical staining method to distinguish renal from non-renal haematuria was adapted for use in the standard clinical chemical laboratory. The method is based on the observation that only in case of renal haematuria are erythrocytes in urine coated with so-called Tamm-Horsfall protein, originating from the renal tubuli. Erythrocytes in urine were stained using an indirect immunoperoxidase method, resulting in cells with dark-brown stained surfaces. The staining methods were validated with material from clinically diagnosed cases of haematuria of renal or non-renal origin and compared with scores of the number of dysmorphic erythrocytes, another method to distinguish renal from non-renal haematuria. In specimens of presumed strictly renal haematuria 86% (SD 8.7; n = 26) of the erythrocytes stained immunocytochemically. However, in specimens of haematuria originating from bleeding in the renal pelvis few cells stained (6%; SD 5.8; n = 4). In specimens of purely non-renal haematuria only 13% (SD 13.5; n = 21) stained. Immunocytochemical staining of erythrocytes permitted a much better distinction between renal and non-renal haematuria, with better sensitivity and specificity, than the inspection of erythrocyte morphology. We conclude that immunochemical staining of erythrocytes in urine is a valuable method for distinguishing renal and non-renal haematuria.


[Doctor's delay in HIV infection caused by blood transfusion].

Transfusion-associated symptomatic HIV infection in four patients led to death in two patients and to development of serious neurological sequelae in a third patient who also transmitted HIV infection to his spouse. The tardy diagnosis of HIV-associated disease in all cases can be ascribed to ignoring the earlier blood transfusion as a possible cause of HIV infection. This was due partly to advanced age of the patients and partly to lack of familiarity of the attending physicians with HIV-associated problems. This resulted in a substantial doctor's delay.


[Ibuprofen meningitis].

A case of aseptic meningitis in an otherwise healthy women aged 47 yr after taking one tablet containing 400 mg ibuprofen is reported. The patient recovered in a few days.


[The number of admissions to Dutch hospitals for barbiturate poisoning from 1981-1989 and those for poisoning with sedatives and hypnotics,and benzodiazepines].

Over the period 1981 to 1989, the number of admissions to Dutch general hospitals for barbiturate poisoning has dropped sharply and steadily, due to a more restrictive policy in prescribing regarding these sedatives. This trend is also present concerning poisoning with sedatives and hypnotics in general (ICD-code 967), but not concerning those with benzodiazepines (ICD-code 969.4). The female-male ratio was nearly 2:1. This difference is possibly due to the fact that females take more medication than males.


[Digoxin therapy in 24 automated family physician practices].

Since recent insights indicate that most patients with heart failure and a normal cardiac rhythm (HFNR) should not be treated with digitalis, we investigated the treatment policy of general practitioners in this respect. Our descriptive study consisted of a questionnaire followed by a computer based review of patient records of 14 family practices cooperating in the Registration Network of Family Practice (RNFP) and 10 'external' practices. All GPs (n = 51) received the questionnaire on the prescription policy of the GP and cooperating specialists, and on their experience with adverse effects of digitalis therapy. After 2-4 months the GPs of the RNFP (n = 41) received a floppy disc with an algorithm selecting from their problem lists patients with a registered diagnosis of heart failure. The external GPs (n = 10) received an algorithm selecting patients treated with digitalis, since their problem lists were not completely up to date. In all, data of 63,500 patients were examined. On anonymised standard forms, generated by the practice computer, the GPs provided data on the exact diagnosis, medication and adverse effects. Outcome measures of the study were: prescription attitudes (questionnaire) and actual digitalis use (in the selected cases). 33% of the GPs stated that they used digitalis as the preferred therapy of heart failure with normal cardiac rhythm; 30% of the 82 selected HFNR patients had digitalis, while in 42% of the 149 selected patients treated with digitalis a HFNR was registered. Adverse effects had been observed in 3 cases, but could not be excluded retrospectively in 70 cases (49%). Many GPs have not yet adapted their prescription behaviour to recently published insights. Development of a 'digitalis standard in general practice' is recommended.


[Consensus on diagnosis, screening and treatment of diabetic retinopathy].

The management and timing of the treatment of diabetic retinopathy has changed in recent years. Screening for diabetic retinopathy should preferably be performed by ophthalmologists. However, in concert with the local ophthalmologist general physicians with knowledge and experience of eye investigations can play a certain part in the screening for diabetic retinopathy. Good communication between general physician and ophthalmologist is of special interest in detecting the risk factors; systemic hypertension, poor metabolic control, pregnancy, proteinuria and rapid metabolic control of previously high blood glucose levels. For the time being fundus photography as a screening method can only be used on a limited scale and under scientific conditions. No consensus could be reached concerning the pre-treatment use of fluorescein angiography.


[The treatment of congenital clubfoot in The Netherlands; results of a survey among orthopedic surgeons].

As the result of an inquiry among Dutch orthopaedic surgeons a consensus is formulated on the treatment of congenital talipes equinovarus in the first year of life. From this, the following general directives emerge: Treatment should start early and consist of repeated redressing followed by immobilisation; In more severe cases often surgical release is necessary, this should be performed preferably between the 4th and 9th months of life, in order to make normal motor development possible.


[Diabetic patients: no danger on the road].

The evaluation of the risk of traffic accidents among drivers with IDDM and the grounds for excluding them from a driver's license are topical issues, because the E.C. is issuing strict new guidelines. The risk of diabetic patients being involved in traffic accidents as reported in foreign studies and calculated from Dutch data, does not exceed that which is to be expected on account of the prevalence of DM. This justifies a flexible policy for the licensing of drivers with diabetes mellitus.


[Initial results with breast screening in the Enschede area. I. Effectiveness].

After one year, the effects of breast cancer screening in the region of Enschede were evaluated by means of seven parameters indicating the long-term health benefits. These parameters were: attendance rate, predictive value of a positive screening test, detection rate, incidence rate, tumour stage, surgical possibilities and type of surgical operations. The results were compared with figures from the national cost-effectiveness analysis. The attendance rate (79%), the predictive value (57%) and the detection rate (0.74%) were well over the national figures of 70%, 41% and 0.64%, respectively. The incidence of breast cancer in the age group 50-69 was 2.5 times higher, as expected. The tumour stage differed significantly (p less than 0.001) from the stages of regularly detected tumours; there was a shift to the lower stages (average tumour size was halved). The surgical possibilities increased significantly (p less than 0.01) and surgical operations performed were mostly less mutilating (not significant). We conclude that the screening for breast cancer in the Enschede region fulfills the criteria of efficacy. It is particularly the combination of a high predictive value and a relatively high detection rate compared with the clinical incidence in the previous years that is indicative of the efficacy. This does not mean that the results prove the long term health benefits of screening for breast cancer. They only give an indication of the future efficacy of screening. The impact on the quality of life is still an open question.


[Initial results with breast screening in the Enschede area. II. Efficiency].

The efficiency of breast cancer screening in the Enschede region was evaluated after 18 months on the basis of unfavourable side effects and possible difficulties. These side effects were: 1. for women: psychological burden, period of uncertainty and increasing waiting times; 2. for general practitioners: limited referral; 3. for specialists: increased diagnostics and consultation. The results were compared with the figures derived from the national cost-effectiveness analysis. The psychological burden on women with a positive screening result appeared to be considerable, in conjunction with the length of the period of uncertainty. The final result was only known after approximately five weeks when a biopsy was required. In 83 women (41% of all referred women) the overall result of the procedure was false-positive. Occasionally the woman was not referred to a known specialist centre, in contradiction to the guidelines. The increase in the number of diagnostic and therapeutic operations was larger than expected, and is largely accounted for by the radical increase of clinically non-palpable tumours (factor 17). On average, the waiting time for the (first) biopsy was three weeks. A great deal of multi-disciplinary consultation was necessary because of the large increase of non-palpable tumours and in-situ ductal carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)


[The treatment of children with idiopathic nephrotic syndrome using cyclosporin].

We report our experience with cyclosporine in 14 children with steroid dependent and 7 children with steroid resistant nephrotic syndrome. Cyclosporine was started at a dose of 6 mg/kg/day and was adjusted to maintain a blood level between 60 and 100 ng/ml. 15 patients went into remission with a combined treatment of cyclosporine and prednisone; 9 of these did not have a recurrence following discontinuation of prednisone. In 7 out of these 9 patients cyclosporine was also discontinued, this led in 5 of these 7 patients to a recurrence. Seven out of 14 patients with minimal change nephropathy remained in remission following discontinuation of prednisone and in 4 others the dose of steroid required to maintain remission decreased. In only I out of 4 patients with focal segmental glomerulosclerosis was a remission obtained while in two patients with mesangial proliferation the urine remained protein free during cyclosporine treatment. In 13 patients a repeat biopsy was performed after one year or longer of cyclosporine treatment. Histopathological abnormalities related to cyclosporine were found in 9 patients. In 4 of these severe nephrotoxicity required withdrawal of cyclosporine. Treatment with cyclosporine should be restricted to steroid dependent patients with severe steroid toxicity.


[Theo van Gogh's medical record].

In the final months of his life Theo van Gogh was admitted to the 'Geneeskundig Gesticht voor Krankzinnigen te Utrecht'. In November 1990 from the archives of the Willem Arntsz Huis, psychiatric centre in Utrecht, the medical files from this period were made available and a transcription was made by Han van Crimpen and Sjraar van Heugten, scientific collaborators of the Van Gogh Museum. From these data it is acceptable to conclude that Theo van Gogh had dementia paralytica and suffered a fast deterioration of his situation in these last few months. It is, however, probable that at least as early as 1886 Theo showed the first symptoms of this disease when he was in Paris, and that he was treated for this reason by dr. Rivet and dr. Gruby. There are insufficient indications that in Vincent van Gogh's case the same diagnosis can be put forward. It is most probable that during Vincent's visit to Theo in Paris in July 1890 in Theo's case symptoms of his medical deterioration were to be seen and this may have influenced the considerations finally leading to Vincent van Gogh's suicide.


[Expectant management in extrauterine pregnancy is possible].

Twenty-nine patients with presumed ectopic pregnancies, who visited the Onze Lieve Vrouwe Gasthuis outpatient clinic in Amsterdam between January 1990 and July 1991, received expectant management because of mildness of the symptoms. Five patients were shown to have a non-intact intrauterine pregnancy. Only three of the remaining 24 patients needed surgery because of increasing serum HCG concentrations and (or) complaints. Our results therefore indicate that with declining HCG levels and mild symptoms, regardless of the HCG level at presentation, expectant management is justified.


[Limited value of routine preoperative laboratory studies in children].

In order to determine whether in routine preoperative laboratory testing of children abnormal results were reported which influenced the course of the anesthesia or of the operation, a retrospective survey of charts was carried out at the University Children's Hospital, Groningen. The patients involved were 143 low risk children, admitted for ENT surgery. The main outcome measures were abnormalities and perioperative complications. There were 1.4% laboratory abnormalities (including five children with a haemoglobin concentration less than 7.1 mmol/l, one with a calcium concentration less than 2.2 mmol/l, one with an albumin concentration less than 30 g/l), and seven complications (bradycardia during intubation, bronchial obstruction, bleeding, excessive vomiting (three times), and leakage of perilymphatic fluid). There were no correlations between the abnormal test results and the complications. Routine laboratory testing in children scheduled for surgery might be reduced to measurement of haemoglobin, especially in non-white children.


[Prevalence of HIV in clients of an outpatient clinic for sexually transmissible diseases and in a group of prostitutes and their clients].

In order to gain insight into the heterosexual spread of HIV infections in Amsterdam, a study was carried out in 1991 among persons attending an outpatient clinic for sexually transmitted diseases (STD) and among a group of prostitutes and prostitutes' clients. Out of 2362 persons attending the STD clinic, 2138 (90.5%) could ultimately be examined for presence of HIV antibodies. The HIV seroprevalence was 4.2% (90/2138); among homosexual males it was 22% (70/324), among heterosexual male intravenous drug users 12% (2/17) and among heterosexual males who never had used i.v. drugs 0.5% (5/997). The HIV seroprevalence among female intravenous drug users was 41% (12/29) and that among females who never had used i.v. drugs it was 0.1% (1/771). Among the heterosexually active subjects (active in the preceding six months, including the groups of bisexual males and intravenous drug users), the seroprevalence amounted to 1.5% (28/1884). HIV antibodies could be demonstrated in 1.5% (3/199) of the prostitutes and in 0.5% (1/213) of prostitutes' clients. However, the one positive male had had homosexual contacts in the past. Out of the total of nine heterosexually infected persons, two originated from the Netherlands, two from Ghana, two from Turkey, one from Nigeria, one from Pakistan and one from the Dominican Republic; six of them had commercial contacts. The heterosexual spread of HIV among the heterosexual population of Amsterdam can for the moment be classified as slight. However, further heterosexual transmission of HIV cannot be excluded, considering the frequency of unprotected sex.


[Diagnosis of infection in full-term infants born after prolonged status of ruptured membranes: clinical observation is sufficient].

We retrospectively studied our strategy in 80 full-term newborns, born more than 24 hours after rupture of amniotic membranes. Six patients developed clinical signs of sepsis, in four of them sepsis was proven by a positive blood culture. In all cases, clinical symptoms were the first sign of infection. Routine laboratory tests (CRP, leucocyte counts and differentiation, thrombocyte counts) and microbiological investigations (surface cultures, cord blood cultures) were not helpful for the diagnosis of infection at an early stage. These findings are in accordance with the literature. We conclude that after prolonged rupture of membranes with full-term newborns postnatal paediatric care can be limited to a close observation period of 48 hours. There is no need for any further routine investigation of infants without clinical signs of infection.


[AIDS epidemiology in The Netherlands in persons infected through heterosexual contact].

Ten years after the start of the AIDS epidemic in the Netherlands the proportion of persons infected by heterosexual contacts among the total of AIDS cases diagnosed is small (7.4%). Up to December 1991 the cumulative totals of females and males in the Netherlands reported with the diagnosis and infected by heterosexual contact were 55 and 93, respectively. Of the 55 heterosexual females, 69% had the Dutch nationality, of the 93 heterosexual males, 67%. Considerable proportions of the numbers of AIDS patients in this group (males 47%, females 45%) were diagnosed in the four largest cities (Amsterdam, Rotterdam, The Hague and Utrecht). The remaining cases of AIDS diagnosed in this group were scattered throughout the country. Among heterosexual females a gradual increase of the number of AIDS cases diagnosed was observed since 1985. In the males there was no clear trend in the number of diagnoses since 1984. Of the 55 females, 19 originated from an area endemic for AIDS or had had sexual contacts with a person from such a region (34.6%). Among the 93 males this number was 29 (31.2%). Nineteen of the 55 females (34.6%) were known to have sexual contact with a person from the known risk groups. The same held true of 12 males (12.9%). Of the remaining 17 females (30.9%) and 52 males (55.9%) it was only known that they were heterosexual without further risk factors or risk contacts.(ABSTRACT TRUNCATED AT 250 WORDS)


[Malignant neuroleptic syndrome: complete anticoagulant treatment or not?].

A case is reported, in which fatal pulmonary embolism complicated the course of a neuroleptic malignant syndrome (NMS). This syndrome includes several risk factors for the development of venous thromboembolism, such as: protracted immobility; severe rigidity causing a slowing of blood flow through the deep venous system; hypovolaemia with increased blood viscosity and activation of coagulation by rhabdomyolysis. An analysis of 115 case reports in the literature on NMS showed that 3 out of 13 patients with fatal NMS (23%) died of pulmonary embolism. The reviewed case, the literature findings and the risk factors mentioned cause us to believe that complete anticoagulant therapy may have a place in the therapeutic approach to patients with NMS.


[Abdominal aortic aneurysm as incidental finding in abdominal ultrasonography].

Abdominal aortic aneurysm is a life-threatening condition, which usually remains without symptoms until rupture occurs. The only way to reduce the high mortality rate (estimated at over 80%) is elective surgery on suitable patients. Therefore the presence of such an aneurysm has to be detected. For this ultrasonography is the method of choice. We studied 4399 consecutive patients aged 50 years and older, who underwent abdominal ultrasonography for the first time. According to the recommendation of the Dutch Society for Radiodiagnostics the whole abdomen was screened. In 4026 patients (1717 men and 2309 women) the ultrasound examination was performed for non-vascular reasons. In 199 of these patients (4.9%) an abdominal aortic aneurysm was an adventitious finding (133 men (7.7%) and 66 women (2.9%)). In men aged 60 years and older it was even found in 10.2%. When abdominal ultrasonography is performed for the first time in a patient aged 50 years or older, the aorta has to be screened for presence of an aneurysm.


[Screening for familial occurrence of abdominal aortic aneurysm].

To detect familial occurrence of abdominal aortic aneurysms (AAA), the siblings of patients with an AAA were screened by ultrasonography. 128 siblings of 32 patients operated on for AAA were invited. 56 brothers and 52 sisters accepted the invitation. An AAA was diagnosed in 16 brothers (28.6%) and in 3 sisters (5.8%). Six of these siblings were operated on because of an aneurysmal diameter 20 mm in excess of that of the rest of the abdominal aorta, the others were included in a follow-up programme. We conclude that the prevalence of the AAA among brothers is higher in comparison with previously known risk groups and that the family of patients with an AAA are to be considered for screening first.


[Psychiatric disorders in elderly patients admitted in a general hospital].

To determine the prevalence of psychiatric disorders, especially depressive illness, in elderly medical inpatients. University Hospital Leiden. Two-stage design. In six somatic wards a series of 250 patients were randomly selected and screened with two self-rating scales for depression (Beck Depression Inventory, Geriatric Depression Scale) and one screening scale for cognitive dysfunctions (Mini-Mental State Examination). The 52 drop-outs differed significantly from the other patients only in a greater general illness severity, and a higher prevalence of a psychiatric history. Eighty-two patients were selected for a diagnostic procedure with a standardised, semi-structured psychiatric interview, and were classified according to the DSM III-R. Fifty-nine of them were probable cases according to the screening instruments, 23 were selected at random from the probable non-cases. A psychiatric disorder was detected in 25 patients, all but one patient with schizophrenia were found in the group of probable cases. Only five patients were classified as major depression, which lead to a prevalence rate of 2.9% (95% CI 0.4-5.4%). We found evidence of many psychiatric disorders in the group of 52 drop-outs, but these were mostly organic psychiatric disorders, and just one mood disorder. The prevalence of major depression is lower than found until now among elderly medical inpatients.


[Chorea and primary antiphospholipid syndrome].

Primary antiphospholipid syndrome or PAPS is characterised by antiphospholipid antibodies and arterial and/or venous thromboses. Numerous other clinical features have been shown to be related to this syndrome. Chorea is a well known but rare phenomenon in systemic lupus erythematosus; it has been shown to be strongly related to the presence of antiphospholipid antibodies. We describe two patients with chorea that appeared to be caused by the PAPS.


[Promoting work during the sick leave period through cooperation between health insurance physician and the attending physician].

The task of the Dutch social insurance physician is to evaluate claims for disability compensation and to support clients in the process of vocational rehabilitation. Because rehabilitation outcome is associated with length of time out of work, individual rehabilitation plans should be designed at an early stage. Of vital importance in the design of such plans are the client's remaining working capacities. Earlier assessment of functional capacity could be stimulated by more reciprocal consultation and closer collaboration between social insurance and treating physicians. When complete rehabilitation is not yet possible, working shorter hours, if necessary in a different job, could be an initial solution. As a result the client keeps in touch with the working environment and also a clearer picture is provided of what he or she is still capable of doing. Besides, the influx into the disability law system, which automatically follows if the non-working period exceeds 1 year, with its serious financial, social and emotional effects for the client, may be reduced.


[Surgical rehabilitation in patients with Graves' ophthalmopathy; favorable results of orbital decompression via coronal approach].

Bilateral decompression of the orbit by a coronal approach was performed for cosmetic rehabilitation in 53 female patients with proptosis in the non-inflammatory stage after Graves' ophthalmopathy. Proptosis reduction averaged 5.9 mm Hertel value one year after surgery. All patients were satisfied with the cosmetic result obtained. Advantages of the technique used are: good access to all orbital walls facilitating adequate proptosis reduction; no visible scars after surgery; only very few complications. In our group there was no loss of visual acuity and the incidence of diplopia after surgery of only 4% is the lowest reported in the literature.


[Favorable results of the surgical treatment of intra-articular crush fractures of the distal femur].

Severely comminuted intra-articular femoral fractures are usually associated with major soft-tissue damage as a part of serious multiple injuries. Surgical treatment should aim at exact anatomical restoration of the articular surface. Internal fixation should be stable so that functional after-treatment is possible, a condition of achieving an optimal result. In a period of over 7 years, 24 patients with 26 intra-articular comminuted fractures were operated on. Twenty patients had multiple injuries (ISS > 18), 11 fractures were complicated. Postoperatively, impaired wound healing occurred in three elderly patients; in two of these amputation was necessary. Considering the severity of the injury, the long-term results were good: ten of the 16 patients examined with 18 fractures recovered completely, in the other cases the functional result wa adequate to good. Surgical treatment of comminuted intra-articular fractures of the distal femur is to be adapted to the individual case; depending on the fracture type and the associated damage a selection is to be made from various implants and techniques. With consistent, individually adapted application of the current AO techniques good results can be obtained.


[Quantification of the gnostic sensitivity via measurement of the vibration threshold and of finger tip sensation].

Quantification of vibration perception and fingertip sensation in routine neurological examination. Neurological Clinic, University Hospital, Groningen, the Netherlands. Prospective, controlled investigation. Vibration perception and fingertip sensation were quantified in a large group of normal control persons of various ages and in neurological patients and compared with the usual sensory tests at routine neurological examination. The vibration perception limit was measured with a biothesiometer without accelerometer, the fingertip sensation with a device for two-point discrimination slightly modified according to Renfrew ('Renfrew meter'). Concordance of the tests was studied by calculating kappa values. The normal values of both sensory qualities had a log-normal distribution and increased with age. The values obtained with the Renfrew meter correlated well with those of the two-point discrimination and stereognosis but were systematically higher than those indicated by Renfrew. Both methods appear useful at routine neurological examination if certain measuring precautions are taken.


[The phenomenon of the delayed initial attack of tertian malaria].

From 1986 to 1990 we have treated 215 patients with falciparum malaria. In 8 patients (4%) who had not returned to any malarial area, malaria attacks recurred after 6-20 weeks. Curiously these were now caused by different species: Plasmodium vivax (4 patients) and P. ovale (4 patients). After proper management of malignant tertian malaria caused by P. falciparum, patients are considered cured, provided the treatment has been in accordance with the resistance pattern of the parasite in the country of origin. Yet, in a small number of patients attacks of malaria recur after different time intervals. The explanation of this seemingly paradoxical phenomenon is that these were delayed primary attacks of benign tertian malaria rather than recrudescences of malignant tertian malaria. Consequently the patients must have been infected by two different species of malaria at a time. In P. vivax and P. ovale hypnozoites occur (notably absent in P. falciparum), dormant stages in the liver that are not susceptible to the antimalarials in use for the eradication or prophylaxis of the blood stages which cause the acute attacks of malaria. After a variable amount of time the blood is then (re)invaded and the patient suffers a delayed primary attack or a relapse. Physicians should be aware that definite cure of malignant tertian malaria does not prevent future attacks of benign tertian malaria. They should inform their patients accordingly.


[Cause of death in nursing homes].

Data from the Verpleeghuis Informatie Systeem (Nursing Home Information System, SIVIS) of the Stichting Informatiecentrum Gezondheidszorg (Foundation Information Centre Public Health, SIG) unlike data from the Central Bureau voor de Statistiek (Central Statistics Office, CBS) can afford insight into the primary causes of death of patients in Dutch nursing homes. We studied the question whether the causes of death of patients in somatic and psychogeriatric care differed and whether in these groups there was difference between those decreased within and after six months. Also, using the death certificates issued for the 29 patients deceased in nursing home De Bieslandhof in the first quarter of 1991, a comparison was made of reporting to the SIG and to the CBS. In 1989, data on 82.5% of the nursing home patients were registered in the SIVIS. Irrespective of the interval between admission and death and the nature of the multidisciplinary care (somatic or psychogeriatric), pneumonia was the cause of death most frequently stated (16%). Of the somatic patients decreased within six months the cause of death was mostly a malignancy. The psychogeriatric patients mostly died due to dehydration and cachexia. However, uncertainties in establishing the primary cause of death and registration errors are not made sufficiently clear in the SIVIS registration. The reporting to SIG and CBS does not always tally.


[Prevention and treatment of respiratory distress syndrome in premature infants using intratracheally administered surfactants].

To study the effects of administration of surfactant immediately after birth (prophylactic) or after 6 hr (therapeutic) to 81 Dutch preterm infants from a multicentre trial. University Hospital Leiden and Sint Joseph Hospital, Veldhoven. A randomized controlled trial with stratification for biochemical lung (im)maturity. The aims of the study were (I): to improve the TcPO2/FiO2 ratio by 40% and (2) to prevent the respiratory distress syndrome by 50% at 6 hours after birth. The secondary goal was to compare effects of prophylactic versus therapeutic use of exogenous surfactant (from 6 hours onwards) in surfactant-deficient infants. The entrance criteria of the study were: (I) inborn children with a gestational age between 26 and 30 weeks, (2) elective intubation and (3) sampling of bronchotracheal or gastric aspirate. After randomization the children received surfactant within 10 minutes after birth prophylactically (n = 42) or 6 hours after birth if they needed more than 60% oxygen (13 of 39 control infants). A second dose of surfactant was given if, at 6 hours after the first dose, the FiO2 was still high (> or = 0.6). We used a natural porcine surfactant preparation (Curosurf) in a dose of 200 mg/kg given through the endotracheal tube. The mean gestational age of the 81 infants was 28.2 weeks. The TcPO2/FiO2 ratios increased in the prophylactic group compared with the controls (38 versus 30 kPa; p < 0.05). RDS occurred less often and less severely in the prophylactic group (p < 0.05). Neonatal mortality was lower in the prophylactically treated infants (3/42) than in the control group (10/39; p < 0.05). Compared with the control infants with immature lungs, the immature prophylactically treated infants had six hours after birth higher TcPO2/FiO2 ratios (35 vs 13 kPa; p < 0.001), a 35% reduction of the incidence of RDS with a significant reduction of its severity (p < 0.05), and significantly lower mean airway pressures (0.87 versus 1.24 kPa; p < 0.005). The surfactant given 6 hours after birth to the immature controls resulted in an immediate improvement of the oxygenation. Nevertheless, these infants spent more time on the respirator and needed extra oxygen for longer periods than the immature infants prophylactically treated (p < 0.05). Surfactant, given either prophylactically or therapeutically, results in clinical improvement of children with biochemically immature lungs. A prophylactic treatment, moreover, results in reduced incidence and severity of RDS, in a significant shortening of the time spent on the respirator and in reduced need of extra oxygen compared with therapeutic treatment. We recommend to give surfactant prophylactically or at the first signs of RDS.


[Diagnosis in recurrent bacterial meningitis; a literature study].

Recurrent bacterial meningitis can be caused by different mechanisms. In order to make the diagnostics more efficient, we studied literature to find these underlying mechanisms. Two groups could be identified: group I, patients with a congenital or posttraumatic defect in the bones of the skull and group II, patients with a deficiency of a component of complement. The patients in group I were much younger at the time of their first meningitis and suffered more often from otitis, rhinorrhoea and deafness diagnosed before the first meningitis. Streptococcus pneumoniae was most frequently cultured in the cerebrospinal fluid, the group with complement deficiency showed Neisseria meningitidis almost exclusively. Family history revealed more members with infections caused by neisseriae spp. Although it was difficult to diagnose the bony defects, physical examination, radiography and high resolution CT scanning of the skull were helpful. Age, history, physical examination and cerebrospinal fluid culture were the most helpful in diagnostic factors.


[Pain in the forefoot: a support sole is no panacea].

Three case histories of a painful forefoot due to an uncommon disease are given: Freiberg's disease, Morton's neuroma and metatarsal stress fracture. The differential diagnosis of metatarsalgia should include these diseases, especially if no static deformities are found.


[Are the long-term results of venous aortocoronary bypass procedures really so bad? A prospective 13-year-long study of 428 patients].

To assess the long-term results of coronary surgery using venous bypasses. Prospective study. St. Antonius Hospital, Nieuwegein, the Netherlands. In 446 successive patients subjected to coronary surgery between 1 April 1976 and 1 April 1977, a complete long-term follow-up study was carried out after an average of 11.5 years (1.5 months-14.3 years). The peroperative mortality was 3%, a peroperative myocardial infarction occurred in 6.3% and complete revascularization was achieved in 77.6% of the patients. In 90 of 100 patients selected at random, cardiac catheterization was performed 13.5 months on average after the operation. The patency of the single grafts was 89.8%, that of the side-to-side and end-to-side anastomoses of the sequential grafts was 90.4% and 83%, respectively. Mortality, myocardial infarction, necessity of a second operation and angina pectoris occurred with low frequency during the first five years after the operation. Subsequently, complications increasingly occurred. Ten years after the operation 18.8% of the patients had died, 11.9% had suffered a myocardial infarction, 13.4% had been subjected to a second operation and 6.4% to balloon angioplasty, while 46.4% had once more developed angina pectoris. Thirteen years after the operation 29% of the patients had remained completely free from cardiac problems. Although arterial bypasses have been increasingly used in recent years, an indication for the use of venous transplants will continue to exist in the future, also, for certain groups of patients (those younger than 50 or older than 75 years). Our study clearly shows that with venous bypasses, also, satisfactory long-term results can be obtained.


[Ischemic hepatitis].

Triggered by a case of ischaemic hepatitis (shock liver) in a patient with severe respiratory insufficiency, we tried to gather information about clinical characteristics and incidence. To our surprise, this information could be found neither in major critical care, medical or gastroenterology textbooks nor in textbook indices or works on differential diagnosis. From Sept. 1989 to May 1990 we studied all possible cases of ischaemic hepatitis in a 390 bed general hospital, to establish incidence. Using computerised data from the clinical chemistry laboratory, all patients with grossly abnormal liver function tests were identified. In this nine-month period 27 adult patients had a peak ALAT level of > 500 U/l: 8 of these suffered from ischaemic hepatitis, using the criteria described by Gibson et al. In another 5 this diagnosis was suspected but could not be ascertained before death (30% and 18% of all cases). In all these cases ASAT, ALAT, LDH levels were 8-100 times normal, but bilirubin, alkaline phosphatase, gamma-glutamyl transferase and prothrombin time were only slightly abnormal. With correction of the underlying disorder enzyme levels returned to normal very rapidly, in 5-10 days. Ischaemic hepatitis could easily be distinguished from other causes such as alcoholic, viral or drug-induced hepatitis. Ischaemic hepatitis was the most frequent cause of severely elevated ASAT, ALAT and LDH in hospitalised patients. The diagnosis can easily be made on clinical characteristics and the typical biochemical pattern. An elaborate work-up or invasive procedure is redundant. Prognosis per se is excellent but depends on the underlying disorder.


[Disseminated lupus erythematosus induced by carbamazepine (Tegretol)].

A 20-year-old man is described with drug-induced lupus erythematosus (DILE) induced by carbamazepine prescribed for epilepsy. The symptoms consisted mainly of arthritis and largely disappeared when carbamazepine was replaced by oxcarbazepine. With a simple decision scheme based on serological findings, differentiation between (idiopathic) systemic lupus erythematosus and DILE is possible.


Advances in hospital infection control programs.

The past decade in infection control has seen remarkable growth of both practitioners and the basic infection control program. Technical advances led to more sophisticated data collection, analysis, and strategies. Health care is being streamlined to be highly effective and efficient. It is easy to become enchanted with new, exciting, and high-tech aspects of disease prevention and control, but we must all remember that the basics of a good program from 10 years ago are still applicable today.


Airway obstruction following transhiatal esophagogastrectomy.

A 79 year old man suffered acute respiratory distress secondary to delayed gastric emptying several months following esophagogastrostomy. No drainage procedure was performed at the time of the procedure. The need for a drainage procedure is controversial. Symptoms of gastric stasis have reportedly improved with a drainage procedure and the risk of concomitant pyloromyotomy or pyloroplasty has been shown to be minimal and may prevent a potentially catastrophic complication as described in this report.


Effects of AIDS, cocaine, and family violence on children in out of home care.

The medical practitioner encounters more medical and psychological illness in foster children than in the general population. The number and complexity of problems in foster children and their families has been increased by acquired immunodeficiency syndrome, cocaine, and family violence. Clinicians who are aware of the high rate of chronic medical problems in foster children will be prepared to diagnose, treat, and coordinate care and follow-up. It is helpful to understand the vulnerability of foster children to emotional disturbance both as a result of family dysfunction which necessitated placement and as a morbidity of the psychological stress of the crisis of placement with subsequent risk of deterioration in foster care. Practitioners' formal knowledge of the problems of foster children and of the structure of the child welfare system promotes appropriate patient care and better directed advocacy.


Acute and chronic effects of hypoglycemia on cognitive and psychomotor performance.

The acute and chronic effects of hypoglycemia on cognitive and psychomotor performance are reviewed. Studies involving pediatric and adult subjects, both with and without diabetes were evaluated. The preponderance of studies suggest that hypoglycemia can be an unintended yet frequent result of treatment of patients with IDDM. Significant cognitive and psychomotor deficits were reported even with mild episodes of hypoglycemia. Early age of diabetes onset and frequent episodes of hypoglycemia were found to be highly related to significant deficits in intellectual and academic performance. Patients evidencing performance deficits did not always report symptoms of hypoglycemia. Recovery of cognitive functioning lagged restoration of euglycemia but typically returned to baseline levels of performance. Recommendations for improved patient care are provided.


[Psychotherapy research and therapeutic management].

The history of psychotherapy research has been closely allied with the development of clinical practice, as this review demonstrates. Empirical psychotherapy research aims at the scientific evaluation of existing practice and at the discovery of new fields of application. The early phases of psychotherapy research were concerned with scientific justification and societal legitimation. These questions changed with the extension of possible indications, the growing differentiation of treatment procedures and the progressive implementation of psychotherapy within the health-care system. The early issue "does psychotherapy work at all?" has been replaced by the questions "to whom is psychotherapy helpful?" and "how does psychotherapy work?". As an established part of the health-care system, psychotherapy is now faced with the same urgent problems as other medical specialties: therapeutic goals and economic conditions have to be brought in balance. Thus the perspectives of psychotherapy research have to encompass the individual patient as well as the system of care. These demands create new questions which enlarge the approaches of traditional psychotherapy research; new structural and logistic methodologies are asked for. We conclude by referring to a multicenter study on the psychodynamic treatment of eating disorders that has been initiated by the Center for Psychotherapy Research in Stuttgart as a prototype form of the new look in psychotherapy research.


[Conversion symptoms of patients in psychiatric liaison care].

At the consultation-psychiatric service of a large university hospital conversion disorders present ca. 50% of the "somatoform disorders". The rate of incidence of conversion disorders was 4% of all patients seen in the service, i.e. 20-30 referrals per annum. A report on 103 patients referred during 1987-1990 is given concerning basic sociodemographic data, symptom clusters, course of illness, age at onset of the disorder, psychiatric and family history, psychosocial conditions and intrapsychic conflicts, additional affective disorders and psychophysiological symptoms, illness behaviour, cognitive attitudes towards illness. The rate of 35% patients showing an underlying somatic disorder in addition to their conversion symptoms had to be appreciated. Possible relations of conversion disorders to affective illness, somatization disorder and neurologic disease had to be discussed as to course of illness and theoretical concepts.


[Psychopathologic findings and results of treatment of pension applicants].

As part of a broader follow-up study (n = 1088) in a psychosomatic hospital, 35 patients who had applied for early retirement on health grounds were examined by means of a psychosomatic personality inventory (PSKB-Rudolf). In addition to confirming previous findings in relation to the character-profile and defence-mechanisms of such patients, the present study describes a cluster of characteristics that would lead to unfavourable therapeutic results. The fact that these persons had applied for early retirement had in itself no appreciable therapeutic consequences.


[Recognition of emotions in facial expression of visual half-field images by schizophrenic and depressed patients].

Twenty schizophrenics, 20 depressives, and 20 normal controls were asked to identify positive and negative emotional expressions of faces tachistoscopically presented to the left and/or right visual hemifields. Results replicated the frequently cited recognition advantage for emotional stimuli presented in the left visual hemifield (right hemispheric processing). A significant reduction in decoding advantage was observed in both patient groups, which could be explained in terms of an interhemispheric disconnection syndrome in schizophrenics and depressives. Bilateral findings in particular tend to support this hypothesis, since they revealed that both cerebral hemispheres processed contrary information simultaneously.


[Dementia diseases and minor cognitive impairments in elderly patients in general practice. Results of a cross-sectional study].

General practitioners in 24 Mannheim practices kept a record of all over-65-year-old patients seen during four weeks (n = 3,737), and made ratings of their cognitive functioning with the help of simple guidelines. For a sub-sample of patients (n = 407), these ratings could be compared with assessments made by the research team, on the basis of a standardized interview and test procedure (Hierarchic Dementia Scale). The research data indicate that 8% of the patients manifested clinical dementia, a further 8% so-called 'mild dementia' and 17% milder, non-disabling degrees of cognitive impairment. The proportion of affected persons in each of the groups rises steeply with increasing age above 65 yr. The ability of the practitioners to detect dementia--including the milder degrees--among their elderly patients exceeded expectation (sensitivity 92%; specificity 76%). The test-score profiles of the patients, grouped according to their own doctors' ratings, conformed to clinical concepts of the progressive course ('staging') of dementing illness, while the degree of disability in everyday life, and dependency on others, also increased steeply across the groups. These findings emphasize the importance of general medical practice for the early detection of dementia in the elderly population, and potentially also for case management.


[Symptom severity and symptom progression in Alzheimer's disease-- comparison between two cases with early and late onset].

Since the first description of Alzheimer's disease rapid symptom progression and relatively severe cognitive symptoms have been frequently associated with early onset age, while slow symptom progression and relatively mild cognitive symptoms were often related to late onset age. In a longitudinal study of 90 patients with mild to moderate Alzheimer's disease we investigated these hypotheses. We found that neither severity of cognitive symptoms nor symptom progression in Alzheimer's disease were associated with onset age. In addition, a comparison of extreme groups (group 1: less than 60 years of age; group 2: greater than 75 years of age), taken from the study sample, showed similar results with respect to the independent variables. The results of this study suggest that the interindividual variability of cognitive impairment as well as the large variation of symptom progression in Alzheimer's disease cannot be explained by onset age.


[Organic correlates of depressive symptoms in Alzheimer's dementia. Results of a prospective study, review of the literature].

The diagnosis of Alzheimer's disease (AD) was verified at post-mortem examination in 46 patients (9 male: 37 female; mean age 83.6 +/- 6.5 years) from a prospective clinical study. Compared to 10 age-matched controls, the total AD group showed a significant neuronal loss in the locus coeruleus, dorsal raphe nucleus, substantia nigra and in the basal nucleus of Meynert. Twelve patients (1 male: 11 female) had experienced symptoms of depression. These patients had significantly lower neuronal counts in the locus coeruleus, but less severe cell loss in the basal nucleus of Meynert compared to the AD patients without depression.


Ursodeoxycholic acid treatment in primary biliary cirrhosis with the emphasis on late stage disease.

We studied the effect of ursodeoxycholic acid in 19 patients with primary biliary cirrhosis, mainly stages III and IV. The dose of UDCA employed was 10-15 mg/kg body weight per day. After 1 yr, 17 patients were still using UDCA, and the mean values of serum alkaline phosphatase, gamma-glutamyltranspeptidase and alanine-aminotransferase had fallen significantly. Serum bilirubin, initially elevated in 7 of the 13 late-stage (III and IV) patients, showed a further increase in 3 of the 7 patients. In 2 of these 3 patients, UDCA had to be withdrawn (dose reduction had no effect). One patient developed a decompensated cirrhosis in spite of UDCA withdrawal. Pruritus worsened in 4 patients, all of whom were late stage patients. Ten late-stage (III-IV) patients showed improvement in liver biochemistry and clinical findings as did all early-stage PBC patients. Thus, UDCA treatment is not beneficial for all PBC patients. Special care should be taken in the early phase of UDCA therapy in later-stage (III-IV) patients: frequent biochemical checks should be carried out, for instance every 2 weeks in the first 2 months after starting UDCA, especially the estimation of bilirubin.


Additive value of transoesophageal echocardiography in the visualization of carcinoid heart disease.

A 65-yr-old woman with atypical complaints and a tricuspid insufficiency murmur underwent transthoracic echocardiography, which showed right-sided abnormalities, but did not allow clear visualization of the valves. Subsequent transoesophageal imaging, however, raised the suspicion of carcinoid heart disease, because of the typical lesions. The diagnosis was thereafter confirmed by biochemical investigations, scintigraphy and abdominal ultrasound. This case suggests that transoesophageal echocardiography may have additive value in the detection of carcinoid heart disease.


Pyrexia of unknown origin as the only manifestation of colorectal carcinoma.

Patients with colon cancer rarely present with pyrexia of unknown origin (PUO) without other manifestations or symptoms. The present paper reports a patient who presented with a 6-month history of fever. The patient was found to suffer from well-differentiated adenocarcinoma of the sigmoid colon. A few days after sigmoidectomy the fever subsided and the patient recovered. Investigation of the large bowel should always form part of the evaluation in patients with pyrexia of unknown origin.


Malabsorption due to a ventral hernia.

A case of malabsorption due to a stagnant loop which occurred in a huge ventral hernia is presented. The clinical course was relatively indolent with symptoms of malabsorption and occasional abdominal pain. Although rare, abdominal hernia can lead to malabsorption due to bacterial overgrowth as a result of stagnant loop.