bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute hepatitis C virus seroconversion in a Scottish blood donor: HCV antigen is not comparable with HCV nucleic acid amplification technology screening
Authors: Dow B. C. , Munro H. , Buchanan I. , Ferguson K. , Davidson F. , Lycett C. , Jarvis M. , Cleland A. , Petrik J. , Lumley S. , MacLean A.
Published: January 2004

Background and Objectives  This study was conducted to analyse the usefulness of hepatitis C virus (HCV) core antigen tests for the confirmation of HCV infection in a donor presenting as nucleic acid amplification technology (NAT) positive but negative for antibodies to HCV (anti‐HCV).

Materials and Methods  Blood donations were screened, in parallel, for anti‐HCV using the Abbott PRISM HCV Chemiluminescent immunoassay (ChLIA) and an ‘in‐house’ HCV NAT (pools of up to 95 donations). An HCV NAT‐positive antibody‐negative donor was identified. Twelve follow‐up samples were obtained and tested with various HCV antigen (including the recently marketed Trak‐C second‐generation assay) and HCV antibody assays.

Results  The single HCV NAT‐positive, antibody‐negative donation was identified from 1 117 681 donations screened in the 4‐year period, July 1999 to June 2003. The index donation was positive by Ortho HCV core antigen enzyme immunoassay (EIA) and Ortho Trak‐C (second‐generation HCV core antigen EIA). An archive sample, taken 127 days prior to the index donation, was negative for all HCV markers. Subsequent samples demonstrated a loss of reactivity in the Ortho HCV core antigen EIA and reduced activity in the Ortho Trak‐C until day 69. Immunoblot (Ortho RIBA‐3) and HCV PRISM became positive on day 62, whilst Ortho HCV ELISA was not positive until day 132 or Biorad HCV ELISA until day 160. An alternative immunoblot (Innogenetics Innolia III) was positive from day 55. RNA levels fluctuated considerably during the follow‐up period, being completely undetectable by routine screening methods at the time‐point around seroconversion; subsequently, antibody was detected using all assays investigated.

Conclusions  This HCV‐converting blood donor provided a unique panel of samples for using to assess current (and future) HCV assay systems. The overall test results led to the conclusion that individual HCV antigen testing should not be considered as equivalent to HCV NAT minipool screening. Trak‐C antigen testing may be considered as a suitable confirmatory assay for isolated HCV NAT reactivity.
Massive haemolysis after intramuscular diclofenac in a patient who apparently tolerated oral medication
Authors: Ahrens N. , Schewior L. , Garbe E. , Kiesewetter H. , Salama A.
Published: January 2004

Background and Objectives  Administration of diclofenac may lead to immune haemolytic anaemia (IHA) owing to the presence of drug‐dependent antibodies and/or autoantibodies. A relationship with oral or intramuscular drug administration is unknown. Here, we describe a patient who apparently tolerated oral diclofenac but developed severe IHA following intramuscular injection of the drug.

Patients and Methods  A 66‐year‐old‐female was admitted to hospital because of jaundice and nausea, which were initially presumed to be manifestations of a postcholecystectomy syndrome. The patient soon developed haemolysis and renal failure. Although the symptoms and signs were suggestive of autoimmune haemolytic anaemia (AIHA), the patient had diclofenac‐induced IHA.

Results  Serological testing, including detection of drug‐dependent antibodies, was performed using standard techniques. The patient's serum was found to contain a highly reactive diclofenac‐dependent red cell antibody of the immune complex type (titre 256 000). She recovered after 7 weeks of treatment with prednisolone, blood transfusions, haemodialysis and plasma exchange.

Conclusions  Diclofenac‐induced IHA should always be considered when a patient on diclofenac develops haemolysis.
Intravenous immunoglobulin and autoimmune thrombocytopenic purpura: 22 years on
Authors: Bierling P. , Godeau B.
Published: January 2004

Autoimmune thrombocytopenic purpura is now commonly treated with high doses of intravenous immunoglobulins. Twenty‐two years after this treatment was first shown to be effective, several questions remain. We review here current knowledge concerning the frequency and type of side‐effects and the probable mechanism of action of intravenous immunoglobulins. We suggest that the currently recommended dose of intravenous immunoglobulins (2 g/kg body weight) could be halved, that the total dose of intravenous immunoglobulins should be administered as a single infusion, that non‐responders could be given another equal dose on day 3, and that intravenous immunoglobulins plus prednisolone should be considered as the gold standard for treatment of the most severe forms of the disease. Finally, as intravenous immunoglobulins have only a transient effect, they cannot be considered as a curative treatment for patients with chronic autoimmune thrombocytopenic purpura.
Systematic review: the role of different types of fibre in the treatment of irritable bowel syndrome
Authors: Bijkerk C. J. , Muris J. W. M. , Knottnerus J. A. , Hoes A. W. , De Wit N. J.
Published: January 2004

Background : Both high‐fibre dietary advice and the prescription of fibre as a bulking agent are very common in primary and secondary care management of irritable bowel syndrome. Irritable bowel syndrome patients with constipation may have delayed intestinal transit. Therefore, fibres that accelerate intestinal transit may be beneficial in these patients. The uncertain benefits reported in several clinical studies, however, have led us to reappraise the value of fibre in irritable bowel syndrome management.

Aim : To quantify the effect of different types of fibre on global and symptom relief from irritable bowel syndrome.

Methods : Using a structured literature search in MEDLINE (1966–2002), we selected randomized controlled trials involving irritable bowel syndrome patients treated with fibre. Analyses were performed for the total group and for trials using soluble and insoluble fibre separately.

Results : Seventeen studies were included in the analysis. None investigated primary care irritable bowel syndrome patients. Fibre, in general, was effective in the relief of global irritable bowel syndrome symptoms [relative risk, 1.33; 95% confidence interval (CI), 1.19–1.50]. Irritable bowel syndrome patients with constipation may receive benefit from fibre treatment (relative risk, 1.56; 95% CI, 1.21–2.02), but there was no evidence that fibre was effective in the relief of abdominal pain in irritable bowel syndrome. Soluble and insoluble fibre, separately, had different effects on global irritable bowel syndrome symptoms. Soluble fibre (psyllium, ispaghula, calcium polycarbophil) showed significant improvement (relative risk, 1.55; 95% CI, 1.35–1.78), whereas insoluble fibre (corn, wheat bran), in some cases, worsened the clinical outcome, but there was no significant difference compared with placebo (relative risk, 0.89; 95% CI, 0.72–1.11).

Conclusions : The benefits of fibre in the treatment of irritable bowel syndrome are marginal for global irritable bowel syndrome symptom improvement and irritable bowel syndrome‐related constipation. Soluble and insoluble fibres have different effects on global irritable bowel syndrome symptoms. Indeed, in some cases, insoluble fibres may worsen the clinical outcome. Future clinical studies evaluating the effect and tolerability of fibre therapy are needed in primary care.
GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat
Authors: Somogyi Jozsef , Baude Agnès , Omori Yuko , Shimizu Hidemi , Mestikawy Salah El , Fukaya Masahiro , Shigemoto Ryuichi , Watanabe Masahiko , Somogyi Peter
Published: January 2004

Vesicular glutamate transporter type 3 (VGLUT3) containing neuronal elements were characterized using antibodies to VGLUT3 and molecular cell markers. All VGLUT3‐positive somata were immunoreactive for CCK, and very rarely, also for calbindin; none was positive for parvalbumin, calretinin, VIP or somatostatin. In the CA1 area, 26.8 ± 0.7% of CCK‐positive interneuron somata were VGLUT3‐positive, a nonoverlapping 22.8 ± 1.9% were calbindin‐positive, 10.7 ± 2.5% VIP‐positive and the rest were only CCK‐positive. The patterns of coexpression were similar in the CA3 area, the dentate gyrus and the isocortex. Immunoreactivity for VGLUT3 was undetectable in pyramidal and dentate granule cells. Boutons colabelled for VGLUT3, CCK and GAD were most abundant in the cellular layers of the hippocampus and in layers II–III of the isocortex. Large VGLUT3‐labelled boutons at the border of strata radiatum and lacunosum‐moleculare in the CA1 area were negative for GAD, but were labelled for vesicular monoamine transporter type 2, plasmalemmal serotonin transporter or serotonin. No colocalization was found in terminals between VGLUT3 and parvalbumin, vesicular acetylcholine transporter and group III (mGluR7a,b; mGluR8a,b) metabotropic glutamate receptors. In stratum radiatum and the isocortex, VGLUT3‐positive but GAD‐negative boutons heavily innervated the soma and proximal dendrites of some VGLUT3‐ or calbindin‐positive interneurons. The results suggest that boutons coexpressing VGLUT3, CCK and GAD originate from CCK‐positive basket cells, which are VIP‐immunonegative. Other VGLUT3‐positive boutons immunopositive for serotonergic markers but negative for GAD probably originate from the median raphe nucleus and innervate select interneurons. The presumed amino acid substrate of VGLUT3 may act on presynaptic kainate or group II metabotropic glutamate receptors.
The activation of G‐protein gated inwardly rectifying K+ channels by a cloned Drosophila melanogaster neuropeptide F‐like receptor
Authors: Reale Vincenzina , Chatwin Heather M. , Evans Peter D.
Published: January 2004

A Drosophila melanogaster G‐protein‐coupled receptor (NPFR76F) that is activated by neuropeptide F‐like peptides has been expressed in Xenopus oocytes to determine its ability to regulate heterologously expressed G‐protein‐coupled inwardly rectifying potassium channels. The activated receptor produced inwardly rectifying potassium currents by a pertussis toxin‐sensitive G‐protein‐mediated pathway and the effects were reduced in the presence of proteins, such as the βARK 1 carboxy‐tail fragment and α‐transducin, which bind G‐protein βγ‐subunits. Short Drosophila NPF‐like peptides were more potent than long NPF‐like peptides at coupling the receptor to the activation of inwardly rectifying potassium channels. The putative endogenous short Drosophila NPF‐like peptides showed agonist‐specific coupling depending on whether their actions were assessed as the activation of the inwardly rectifying potassium channels or as the activation of endogenous inward chloride channels through a co‐expressed promiscuous G‐protein, Gα16. As inwardly rectifying potassium channels are known to be encoded in the Drosophila genome and the NPFR76F receptor is widely expressed in the Drosophila nervous system, the receptor could function to control neuronal excitability or slow wave potential generation in the Drosophila nervous system.
Contributions of NMDA receptors to network recruitment and rhythm generation in spinal cord cultures
Authors: Legrand Jean‐Christophe , Darbon Pascal , Streit Jürg
Published: January 2004

N‐methyl‐d‐aspartic acid (NMDA) receptors are implicated in fictive locomotion; however, their precise role there is not clear. In cultures of dissociated cells from foetal rat spinal cord, synchronous bursting (but not fictive locomotion) can be induced by disinhibition, which is produced by blocking glycinergic and γ‐aminobutyric acid (GABA)A‐dependent synaptic conductances. In this study, we investigate the role of NMDA‐R in rhythm generation during disinhibition with multielectrode arrays and patch‐clamp. We previously determined that bursting activity is generated by repetitive recruitment of a network through recurrent excitation. Blocking NMDA‐R with d(−)‐2‐amino‐5‐phosphonopentanoic acid (APV) decreased the burst duration, suggesting a role of such receptors in the maintenance of high network activity during the bursts. In addition, APV reduced burst rate in about a third of the experiments, suggesting a contribution of NMDA‐R in network recruitment. When (±)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid hydrate (AMPA)/kainate receptors were blocked with 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) in the presence of disinhibition, the burst rate was reduced and burst onset was slowed in two‐thirds of the experiments. In the remaining experiments, bursting ceased completely with CNQX. Neither APV nor CNQX changed the spatial patterns of activity in the network, suggesting a co‐operation of both receptors in rhythm generation. While NMDA alone was not able to create a rhythm, it accelerated bursting in the presence of disinhibition, made it more regular and slowed down network recruitment. These effects were most likely due to the depolarization of the interneurons in the network. We conclude that NMDA‐R contribute to rhythm generation in spinal cultures by supporting recurrent excitation and network recruitment and by depolarizing the network.
Lesion‐dependent regulation of transgene expression in the rat brain using a human glial fibrillary acidic protein‐lentiviral vector
Authors: Jakobsson Johan , Georgievska Biljana , Ericson Cecilia , Lundberg Cecilia
Published: January 2004

The ability to regulate transgene expression will be crucial for development of gene therapy to the brain. The most commonly used systems are based on a transactivator in combination with a drug, e.g. the tetracycline‐regulated system. Here we describe a different method of transgene regulation by the use of the human glial fibrillary acidic protein (GFAP) promoter. We constructed a lentiviral vector that directs transgene expression to astrocytes. Using toxin‐induced lesions we investigated to what extent transgene expression could be regulated in accordance with the activation of the endogenous GFAP gene. In animals receiving excitotoxic lesions of the striatum we detected an eightfold increase of green fluorescent protein (GFP)‐expressing cells. The vast majority of these cells did not divide, suggesting that the transgene was indeed regulated in a similar fashion as the endogenous GFAP gene. This finding will lead to the development of lentiviral vectors with autoregulatory capacities that may be very useful for gene therapy to the brain.
Modulation of rhythmic patterns and cumulative depolarization by group I metabotropic glutamate receptors in the neonatal rat spinal cord in vitro
Authors: Taccola Giuliano , Marchetti Cristina , Nistri Andrea
Published: January 2004

The role of group I metabotropic glutamate receptors (mGluRs), and their subtypes 1 or 5, in rhythmic patterns generated by the neonatal rat spinal cord was investigated. Fictive locomotor patterns induced by N‐methyl‐d‐aspartate + serotonin were slowed down by the subtype 1 antagonists (RS)‐1‐aminoindan‐1,5‐dicarboxylic acid (AIDA) or 7‐(hydroxyimino)cyclopropa[b]chromen‐1a‐carboxylate ethyl ester (CPCCOEt) and unaffected by the subtype 5 antagonist 2‐methyl‐6‐(phenylethynyl)pyridine hydrochloride (MPEP). The group I agonist (RS)‐3,5‐dihydroxyphenylglycine (DHPG) depolarized ventral roots and disrupted fictive locomotion, an effect blocked by AIDA (or CPCCOEt) and reversed by increasing the N‐methyl‐d‐aspartate concentration. Cumulative depolarization induced by low frequency trains of dorsal root stimuli was attenuated by DHPG and unchanged by AIDA or MPEP while rhythmic patterns or motoneuron spike wind‐up persisted. Disinhibited bursting induced by strychnine + bicuculline was accelerated by DHPG, slowed down by AIDA (which prevented the action of DHPG), unaffected by MPEP and counteracted by the selective group II agonist (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine. The DHPG transformed regular bursting into arrhythmic bursting, a phenomenon also produced by the group II mGluR antagonist (2S)‐α‐ethylglutamic acid. These results indicate that, during fictive locomotion or disinhibited bursting, endogenous glutamate could activate discrete clusters of subtype 1 mGluRs to facilitate discharges. Diffuse activation by the exogenous agonist DHPG of group I mGluRs throughout spinal networks had an excitatory effect overshadowed by its much stronger depressant action due to concomitant facilitation of glycinergic transmission. Irregular disinhibited bursting caused by activation of subtype 1 receptors or block of group II receptors suggests that mGluRs could control not only the frequency but also the periodicity of bursting patterns, outlining novel mechanisms contributing to burst duration.
Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus
Authors: Khazipov Roustem , Khalilov Ilgam , Tyzio Roman , Morozova Elena , Ben‐Ari Yezekiel , Holmes Gregory L.
Published: January 2004

The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased seizure susceptibility during early development is due to the excitatory action of GABA. Using noninvasive extracellular field potential and cell‐attached recordings in CA3 of Sprague‐Dawley rat hippocampal slices, we compared the developmental alterations in three parameters: excitatory actions of GABA, presence of the immature pattern of giant depolarizing potentials (GDPs) and severity of epileptiform activity generated by high potassium. The GABA(A) receptor agonist isoguvacine increased firing of CA3 pyramidal cells in neonatal slices while inhibiting activity in adults. A switch in the GABA(A) signalling from excitation to inhibition occurred at postnatal day (P) 13.5 ± 0.4. Field GDPs were present in the form of spontaneous population bursts until P12.7 ± 0.3. High potassium (8.5 mm) induced seizure‐like events (SLEs) in 35% of slices at P7–16 (peak at P11.3 ± 0.4), but only interictal activity before and after that age. The GABA(A) receptor antagonist bicuculline reduced the frequency or completely blocked SLEs and induced interictal clonic‐like activity accompanied by a reduction in the frequency but an increase in the amplitude of the population spikes. In slices with interictal activity, bicuculline typically caused a large amplitude interictal clonic‐like activity at all ages; in slices from P5–16 rats it was often preceded by one SLE at the beginning of bicuculline application. These results suggest that, in the immature hippocampus, GABA exerts dual (both excitatory and inhibitory) actions and that the excitatory component in the action of GABA may contribute to increased excitability during early development.
Localization of endoplasmic reticulum and plasma membrane Ca2+‐ATPases in subcellular fractions and sections of pig cerebellum
Authors: Sepúlveda M. Rosario , Hidalgo‐Sánchez Matías , Mata Ana M.
Published: January 2004

Subcellular fractions and sections of the cerebellum were analysed to evaluate the relative activity and distribution of organellar and plasma membrane Ca2+‐ATPases (SERCA and PMCA). Western blot analysis of the fractions with IID8 or Y/1F4 SERCA‐specific antibodies or else with 5F10 or pbPMCA antibodies, specific to PMCA pump, revealed a major content of SERCA protein in microsomes and of PMCA protein in plasma membrane vesicles. The Ca2+‐ATPase activity of microsomes was more sensitive to thapsigargin, a SERCA‐specific inhibitor, whereas the activity of the plasma membrane vesicle fraction was inhibited more by vanadate, a blocker of PMCA activity. The SERCA and PMCA distribution analysed in cerebellar sections revealed IID8 antibody reactions in Purkinje cell cytoplasm, granule cells and cerebellar glomeruli. Y/1F4 gave immunostaining in Purkinje cells, molecular layer interneurons (basket and stellate cells) and glomeruli, but granule cells were not labelled. The 5F10 antibody reacted with Purkinje cells, including their dendritic spines, as well as cerebellar glomeruli, whereas the pbPMCA antibody labelled several processes in all three layers and some synaptic interaction sites. The differential content and localization of the two types of Ca2+ pumps in specific neuronal areas of pig cerebellum indicate precise Ca2+ requirements of specific cellular regions.
Opposing roles of the nucleus accumbens and anterior lateral hypothalamic area in the control of sexual behaviour in the male rat
Authors: Kippin Tod E. , Sotiropoulos Veneta , Badih Julia , Pfaus James G.
Published: January 2004

Opposing roles have been implicated for the nucleus accumbens (NAc) and anterior portion of the lateral hypothalamic area (aLHA) in the regulation of sexual behaviour in male rats based on in vivo neurochemical correlates. The present study provides functional evidence supporting this hypothesis by examining the effects of lesions to these structures on copulation, noncontact erection and receptive female preference. Sexually naïve male Long‐Evans rats received either bilateral 1.0‐µL injections of NMDA (10 µg/µL/side) or vehicle (shams) into either the aLHA or the NAc. During repeated tests of copulation most of the sham‐lesioned males, but few of the aLHA‐lesioned and NAc‐lesioned males, copulated to ejaculation. Most of the NAc‐lesioned males also failed to intromit, whereas the majority of the aLHA‐lesioned males intromitted repeatedly. During exposure to an inaccessible receptive female behind a wire‐mesh screen, aLHA‐lesioned males displayed facilitation of noncontact erections, whereas NAc‐lesioned males displayed impaired noncontact erections. Conversely, during simultaneous exposure to inaccessible receptive and nonreceptive females in different compartments, all males spent more time in the proximity of the receptive female. These findings indicate that the aLHA plays an inhibitory role in the regulation of sexual arousal and an excitatory role in the regulation of ejaculation. Conversely, the NAc plays an excitatory role in the regulation in sexual arousal.
Synaptology of the proximal segment of pyramidal cell basal dendrites
Authors: Alonso‐Nanclares L. , White E. L. , Elston G. N. , DeFelipe J.
Published: January 2004

Pyramidal neurons are covered with dendritic spines, the main postsynaptic targets of excitatory (asymmetrical) synapses. However, the proximal portion of both the apical and basal dendrites is devoid of spines, suggesting a lack of excitatory inputs to this region. In the present study we used electron microscopy to analyse the proximal region of the basal dendrites of supra‐ and infragranular pyramidal cells to determine if this is the case. The proximal region of 80 basal dendrites sampled from the rat hindlimb representation in the primary somatosensory cortex was studied by electron microscopy. A total of 317 synapses were found within this region of the dendrites, all of which were of the symmetrical type. These results suggest that glutamate receptors, although present in the cytoplasm, are not involved in synaptic junctions in the proximal portion of the dendrites. These data further support the idea that inhibitory terminals exclusively innervate the proximal region of basal dendrites.
ZD7288 inhibits postsynaptic glutamate receptor‐mediated responses at hippocampal perforant path–granule cell synapses
Authors: Chen Chu
Published: January 2004

Hyperpolarization‐activated channels (Ih) are widely expressed in the nervous system and believed to play an important role in the regulation of membrane excitability and rhythmic activity. Recent evidence suggests that Ih may be involved in long‐term potentiation (LTP) in the hippocampus; however, the results are controversial. To explore the possible causes of these differing results, the effects of Ih blockers on synaptic activity were evaluated in mouse hippocampal slices. ZD7288 (20 µm), a selective Ih blocker, apparently prevented the induction of LTP, while Cs+ (1 mm), a commonly used Ih blocker, had no effect on LTP at hippocampal perforant path–dentate granule cell synapses. In addition, ZD7288 but not Cs+ abolished basal synaptic transmission. Results from voltage‐clamp experiments showed that ZD7288 produced a very little inhibition on hyperpolarization‐activated currents, indicating a weak expression of the Ih in granule neurons. Outside‐out patch recordings revealed that ZD7288 inhibited glutamate receptor‐mediated responses, while Cs+ had no effect on them. Meanwhile, ZD7288 reduced both α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate and N‐methyl‐d‐aspartate receptor‐mediated excitatory postsynaptic currents. The results suggest that ZD7288‐induced reduction of synaptic transmission may result from its inhibition of the postsynaptic glutamate receptors on dentate granule neurons.
Comparison of learning‐related neuronal activity in the dorsal premotor cortex and striatum
Authors: Brasted Peter J. , Wise Steven P.
Published: January 2004

Previous studies have reported learning‐related changes in neuronal activity during conditional visuomotor learning, also known as arbitrary sensorimotor mapping, conditional visual discrimination, and symbolic or endogenous mapping. Qualitatively similar observations have been reported for the dorsal premotor cortex, the supplementary eye field, the prefrontal cortex, the hippocampus, the striatum and the globus pallidus. The fact that cells in both the dorsal premotor cortex (PMd) and the basal ganglia show changes in activity during associative learning enables a test of the hypothesis that cortex and basal ganglia function in distributed architectures known as cortical–basal ganglionic modules or ‘loops’. We reasoned that if these loops represent functional entities, as proposed, then learning‐related changes in activity should occur simultaneously in both the cortical and striatal nodes of a loop. The present results confirmed this prediction; as monkeys learned conditional visuomotor associations, neurons in the premotor cortex and associated parts of the putamen changed their rates at approximately the same time. For the largest number of neurons, the evolution in neural activity occurred in close correspondence to the monkeys' learning curves. As a population, however, learning‐related changes in activity continued after the monkeys reached an asymptote in performance.
Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within‐subject, within‐task comparison of reference and working spatial memory
Authors: Pothuizen Helen H. J. , Zhang Wei‐Ning , Jongen‐Rêlo Ana L. , Feldon Joram , Yee Benjamin K.
Published: January 2004

Lesions restricted to the dorsal, but not the ventral, hippocampus severely impair the formation of spatial memory. This dissociation was first demonstrated using the water maze task. The present study investigated whether the dorsal and the ventral hippocampus are involved differentially in spatial reference and spatial working memory using a four‐baited/four‐unbaited version of the eight‐arm radial maze task. This test allows the concurrent evaluation of reference and working memory with respect to the same set of spatial cues, and thereby enables a within‐subjects within‐task comparison between the two forms of memory functions. Rats with N‐methyl‐d‐aspartic acid‐induced excitotoxic lesions of the dorsal hippocampus, ventral hippocampus or both were compared with sham and unoperated controls. We showed that dorsal lesions were as effective as complete lesions in severely disrupting both reference and working spatial memory, whereas rats with ventral lesions performed at a level comparable with controls. These results lend further support to the existence of a functional dissociation between the dorsal and the ventral hippocampus, with the former being preferentially involved in spatial learning.
Hippocampal gene expression is modulated by hypergravity
Authors: Del Signore A. , Mandillo S. , Rizzo A. , Di Mauro E. , Mele A. , Negri R. , Oliverio A. , Paggi P.
Published: January 2004

We used the cDNA microarray technique to monitor simultaneously possible changes induced by hypergravity in the expression level of thousands of hippocampal genes. We tested the mRNA level of about 5000 genes in the hippocampus of mice subjected to 1.09 g (1g) or to 1.85 g (2g) for five repeated 1‐h daily rotations in a centrifuge (g = 9.81 m/s2). Data were compared with those obtained for mice kept stationary (C). The ratios 1g/C and 2g/C identified genes affected by rotation and rotation + hypergravity, respectively, whereas 2g/1g ratio identified those affected by hypergravity. We found that about 200 genes were affected by rotation and/or rotation + hypergravity. Almost all the genes affected by rotation + hypergravity were up‐regulated, only five being down‐regulated. The modulated genes code for proteins involved in a wide range of cellular functions (DNA/RNA metabolism, protein processing, intermediate metabolism, cytoskeleton and motility, cell cycle and apoptosis, signal transduction, neuronal structure/function), suggesting that rotation + hypergravity may affect several aspects of the hippocampal function in order to compensate for environmental changes. Six genes directly or indirectly involved in synaptic transmission and plasticity (proSAAS, neuroblastoma ras oncogene, ESTs moderately similar to thymosin beta‐10, syndet, inhibin beta E and Ngfi‐A binding protein 2) were found to be significantly modulated by hypergravity and unaffected or only slightly affected by rotation. The modulation by hypergravity of these genes suggests that this stimulus might induce plastic remodelling of the hippocampal circuits, possibly both at structural and functional level.
Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain
Authors: Finn D. P. , Beckett S. R. G. , Roe C. H. , Madjd A. , Fone K. C. F. , Kendall D. A. , Marsden C. A. , Chapman V.
Published: January 2004

The antinociceptive effects of Δ9‐tetrahydrocannabinol (Δ9‐THC) have been widely described; however, its therapeutic potential may be limited by secondary effects. We investigated whether coadministration of low doses of cannabinoids or cannabinoids and morphine produced antinociception in the absence of side‐effects. Effects of preadministration (i.p.) of Δ9‐THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), Δ9‐THC + morphine, Δ9‐THC + cannabidiol or vehicle on formalin‐evoked nociceptive behaviour were studied over 60 min. Trunk blood and brains were collected 60 min after formalin injection and assayed for corticosterone and tissue levels of monoamines and metabolites, respectively. Drug effects on locomotor activity, core body temperature and grooming were assessed. Δ9‐THC reduced both phases of formalin‐evoked nociceptive behaviour, enhanced the formalin‐evoked corticosterone response and increased the 4‐hydroxy‐3‐methoxyphenylglycol : noradrenaline ratio in the hypothalamus. Cannabidiol alone had no effect on these indices and did not modulate the effects of Δ9‐THC. Morphine reduced both phases of formalin‐evoked nociceptive behaviour. Coadministration of Δ9‐THC and morphine reduced the second phase of formalin‐evoked nociceptive behaviour to a greater extent than either drug alone, and increased levels of thalamic 5‐hydroxytryptamine. While the antinociceptive effects of Δ9‐THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of Δ9‐THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with Δ9‐THC, increased antinociception and 5‐hydroxytryptamine levels in the thalamus in a model of persistent nociception. Nevertheless, these enhanced antinociceptive effects were associated with increased secondary effects on locomotor activity.
Histological findings after angioplasty using conventional balloon, radiofrequency thermal balloon, and stent for experimental aortic coarctation
Authors: Ohkubo Mataichi , Takahashi Ken , Kishiro Masahiko , Akimoto Katsumi , Yamashiro Yuichiro
Published: January 2004

Abstract
Background
: Use of balloon angioplasty or stent implantation has been reported to be effective in relieving coarctation of the aorta. However, restenosis frequently occurs after balloon angioplasty for native aortic coarctation in small infants, and sometimes develops after stent implantation because of vessel growth. The causes of restenosis remain uncertain. The purpose of this study was to assess the histologic differences in vascular responses to angioplasty using conventional balloon, radiofrequency thermal balloon (RFTB), or stent for experimental aortic coarctation.

Methods
: The authors surgically created an aortic coarctation model using 14 puppies. Angioplasty using conventional balloon, RFTB, or stent was performed 1 month after the initial operation. At the acute or chronic phase after angioplasty, the animals were killed and histologic studies were performed.

Results
: More vascular injuries were noted in the specimens from animals undergoing conventional angioplasty than in those with RFTB or stent. However, neointimal hyperplasia was seen more often after RFTB or stent because of the proliferation of smooth muscle cells from the tunica media, caused by secretion of growth factors. Apoptosis reached a peak 1−2 weeks after angioplasty, regardless of the type of intervention.

Conclusions
: The authors conclude that angioplasty with RFTB or stent can provide relatively small injuries in the vessel wall for aortic coarctation, but care must be taken to prevent restenosis caused by intimal hyperplasia, because neointima hyperplasia is more frequent after RFTB or stent.
Effects of buffered and plain acetylsalicylic acid formulations with and without ascorbic acid on gastric mucosa in healthy subjects
Authors: Dammann H.‐G. , M. Saleki  , Torz M. , Schulz H.‐U. , Krupp S. , Schürer M. , Timm J. , Gessner U.
Published: January 2004

Background : The most frequently reported adverse events associated with acetylsalicylic acid intake are minor gastrointestinal complaints. Galenic modifications, such as buffered formulations with or without ascorbic acid, may improve the benefit–risk ratio by decreasing the local mucosal side‐effects of acetylsalicylic acid.

Aim : To assess endoscopically‐proven gastrointestinal lesions and the amount of gastric microbleeding of four different buffered and plain acetylsalicylic acid formulations, one containing paracetamol.

Methods : A randomized, four‐fold cross‐over study was performed in 17 healthy subjects who underwent serial oesophago‐gastro‐duodenoscopy before and after each course of 4‐day dosing. Gastric aspirates were collected for the determination of haemoglobin concentrations to detect microbleeding.

Results : Buffered acetylsalicylic acid plus ascorbic acid yielded the lowest Lanza score, the lowest increase in the number of mucosal petechiae and the lowest increase in the amount of gastric microbleeding. Subjects receiving acetylsalicylic acid plus paracetamol plus caffeine showed the highest Lanza score of all treatments, and a considerably greater sum of petechiae in the oesophagus, stomach and duodenum compared with those receiving buffered acetylsalicylic acid plus ascorbic acid.

Conclusions : The trial confirms that buffering of acetylsalicylic acid improves local gastric tolerability. Acetylsalicylic acid in combination with ascorbic acid shows significantly fewer gastric lesions and the lowest increase in gastric microbleeding compared with the other tested formulations.
Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine‐resistant mutants
Authors: Wong V. W.‐S. , Chan H. L.‐Y. , Wong M. L. , Tam J. S.‐L. , Leung N. W.‐Y.
Published: January 2004

Background : The efficacy of lamivudine therapy in chronic hepatitis B is well established. However, drug‐resistant YMDD mutants emerge with extended therapy. This may result in the resurgence of viral replication, the return of hepatitis and histological deterioration.

Aim : To study the safety of stopping lamivudine when the drug is no longer effective.

Methods : In the 5‐year Asian Lamivudine Study, 34 patients from a single centre were included in this study. They had harboured YMDD mutants for at least 2 years. Lamivudine was discontinued and they were followed up at regular intervals. Clinical symptoms, liver biochemistry and viral serology were monitored.

Results : In a median follow‐up of 20 months after stopping lamivudine (range, 7–39 months), 20 of the 34 patients (58.8%) had elevated alanine aminotransferase (ALT), 13 patients (38.2%) had elevated ALT one to five times the upper limit of normal and seven patients (20.6%) had an ALT flare (ALT more than five times the upper limit of normal with detectable hepatitis B virus DNA). There was no liver decompensation. ALT flare could be predicted by ALT over twice the upper limit of normal at the time of stopping lamivudine (P = 0.037).

Conclusions : It is relatively safe to stop lamivudine after YMDD mutants have emerged. ALT levels greater than or equal to twice the upper limit of normal at the time of stopping lamivudine have a higher risk for ALT flare.
Personal view: to treat or not to treat? Helicobacter pylori and gastro‐oesophageal reflux disease — an alternative hypothesis
Authors: Axon A. T. R.
Published: January 2004

Helicobacter pylori causes acute on chronic gastritis and is responsible for most peptic ulcers and gastric cancer. However, recent papers have suggested that it may protect against gastro‐oesophageal reflux, Barrett's oesophagus and oesophageal cancer. Furthermore, the rapid increase in gastro‐oesophageal reflux disease, Barrett's oesophagus and adenocarcinoma of the oesophagus in the developed world has been attributed by some to the falling prevalence of H. pylori. These considerations have led to the suggestion that H. pylori infection should not necessarily be treated, especially in patients with gastro‐oesophageal reflux disease.

Conversely, data from prospective randomized studies have shown that H. pylori eradication does not cause gastro‐oesophageal reflux disease in patients with duodenal ulcer or in the normal population, nor does it worsen the outcome of pre‐existing gastro‐oesophageal reflux disease. Therefore, although H. pylori is negatively associated with gastro‐oesophageal reflux disease, its eradication does not induce the disease.

A hypothesis is presented suggesting that the increased prevalence of gastro‐oesophageal reflux disease is a result of rising acid secretion in the general population, which, in turn, is a consequence of the increased linear height (a predictor of acid secretion). The greater acid secretion could also explain the decline in the prevalence of H. pylori and perhaps account for the inverse relationship between H. pylori and gastro‐oesophageal reflux disease. These considerations are explored in discussing whether H. pylori infection should be treated in infected patients presenting with gastro‐oesophageal reflux disease.
The pathophysiology of faecal spotting in obese subjects during treatment with orlistat
Authors: Fox M. , Thumshirn M. , Menne D. , Stutz B. , Fried M. , Schwizer W.
Published: January 2004

Background : The intermittent loss of oil or liquid faeces (‘spotting’) is an adverse effect that occurs in obese patients during treatment with the lipase inhibitor orlistat; the pathophysiology is unknown.

Aim : To investigate the effects of orlistat on anorectal sensorimotor function and continence.

Methods : Obese subjects susceptible to spotting were identified by an unblind trial of orlistat. Obese spotters (n = 15) and non‐spotters (n = 16) completed a randomized, double‐blind, cross‐over trial of orlistat and placebo. Anorectal function was assessed by rectal barostat and anal manometry, together with a novel stool substitute retention test, a quantitative measurement of faecal continence.

Results : Orlistat increased stool volume and raised faecal fat and water. Treatment had no effect on anorectal motor function, but rectal sensation was reduced; on retention testing, the volume retained was increased. Subjects susceptible to spotting had lower rectal compliance, heightened rectal sensitivity and weaker resting sphincter pressure than non‐spotters. On retention testing, gross continence was maintained; however, spotters lost small volumes of rectal contents during rectal filling.

Conclusion : Treatment with orlistat has no direct adverse effects on anorectal function or continence. Spotting occurs during treatment with orlistat when patients with sub‐clinical anorectal dysfunction are exposed to increased stool volume and altered stool composition.
Implementation of a computer‐assisted monitoring system for the detection of adverse drug reactions in gastroenterology
Authors: Dormann H. , Criegee‐Rieck M. , Neubert A. , Egger T. , Levy M. , Hahn E. G. , Brune K.
Published: January 2004

Aim : To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology.

Methods : A prospective, 6‐month, pharmacoepidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen‐Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events.

Results : One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR‐positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato‐gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR‐positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm.

Conclusion : This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients.
Intestinal and extra‐intestinal cancer in Crohn's disease: follow‐up of a population‐based cohort in Copenhagen County, Denmark
Authors: Jess T. , Winther K. V. , Munkholm P. , Langholz E. , Binder V.
Published: January 2004

Aim : To determine the long‐term risk of intestinal and extra‐intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark.

Methods : In Copenhagen County, a strictly population‐based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long‐term risk of intestinal and extra‐intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person‐years at risk and 1995 cancer incidence rates for the background population.

Results : The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1–170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20–5.92). Extra‐intestinal cancer did not occur more frequently than expected.

Conclusions : This population‐based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5‐aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60‐fold, but the numbers were small. The risk of extra‐intestinal cancer was not increased and no lymphomas were observed.
Treatment of irritable bowel syndrome with herbal preparations: results of a double‐blind, randomized, placebo‐controlled, multi‐centre trial
Authors: Madisch A. , Holtmann G. , Plein K. , Hotz J.
Published: January 2004

Background : Herbal medications have been used in many countries for the treatment of patients with irritable bowel syndrome. Controlled data supporting the efficacy of these treatments in patients with irritable bowel syndrome are lacking.

Aim : To assess the efficacy and safety of a commercially available herbal preparation (STW 5) (nine plant extracts), the research herbal preparation STW 5‐II (six plant extracts) and the bitter candytuft mono‐extract in patients with irritable bowel syndrome.

Methods : Two hundred and eight patients with irritable bowel syndrome were recruited after standardized diagnostic work‐up into a double‐blind, placebo‐controlled, multi‐centre trial and were randomly assigned to receive one of four treatments: commercially available herbal preparation STW 5 (n = 51), research herbal preparation STW 5‐II (n = 52), bitter candytuft mono‐extract (n = 53) or placebo (n = 52). The main outcome variables were the changes in total abdominal pain and irritable bowel syndrome symptom scores.

Results : Two hundred and three patients completed the trial. STW 5 and STW 5‐II were significantly better than placebo in reducing the total abdominal pain score (intention‐to‐treat: STW 5, P = 0.0009; STW 5‐II, P = 0.0005) and the irritable bowel syndrome symptom score (intention‐to‐treat: STW 5, P = 0.001; STW 5‐II, P = 0.0003) at 4 weeks. There were no statistically significant differences between the bitter candytuft mono‐extract group and the placebo group (P = 0.1473, P = 0.1207).

Conclusions : The commercially available herbal preparation STW 5 and its research preparation STW 5‐II are both effective in alleviating irritable bowel syndrome symptoms.