The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers.

Latent inhibition (LI) is a measure of reduced learning about a stimulus to which there has been prior exposure without any consequence. It therefore requires a comparison between a pre-exposed (PE) and a non-pre-exposed (NPE) condition. Since, in animals, LI is disrupted by amphetamines and enhanced by antipsychotics, LI disruption has been proposed as a measure of the characteristic attentional deficit in schizophrenia: the inability to ignore irrelevant stimuli. The findings in humans are, however, inconsistent. In particular, a recent investigation suggested that since haloperidol disrupted LI in healthy volunteers, and LI was normal in non-medicated patients with schizophrenia, the previous findings in schizophrenic patients were entirely due to the negative effects of their medication on LI (Williams et al., 1998). We conducted two studies of antipsychotic drug effects on auditory LI using a within-subject, parallel group design in healthy volunteers. In the first of these, single doses of haloperidol (1 mg. i.v.) were compared with paroxetine (20 mg p.o.) and placebo, and in the second, chlorpromazine (100 mg p.o.) was compared with lorazepam (2 mg. p.o.) and placebo. Eye movements, neuropsychological test performance (spatial working memory (SWM), Tower of London and intra/extra dimensional shift, from the CANTAB test battery) and visual analogue rating scales, were also included as other measures of attention and frontal lobe function. Haloperidol was associated with a non-significant reduction in LI scores, and dysphoria/akathisia (Barnes Akathisia Rating Scale) in three-quarters of the subjects. The LI finding may be explained by increased distractibility which was indicated by an increase in antisaccade directional errors in this group. In contrast, LI was significantly increased by chlorpromazine but not by an equally sedative dose of lorazepam (both drugs causing marked decreases in peak saccadic velocity). Paroxetine had no effect on LI, eye movements or CANTAB neuropsychological test performance. Haloperidol was associated with impaired SWM, which correlated with the degree of dysphoria/akathisia, but no other drug effects on CANTAB measures were detected. We conclude that the effect of antipsychotics on LI is both modality and pharmacologically dependent and that further research using a wider range of antipsychotic compounds is necessary to clarify the cognitive effects of these drugs, and to determine whether there are important differences between them.

Differential effects of the CCKA receptor ligands PD-140, 548 and A-71623 on latent inhibition in the rat.

Latent inhibition (LI) is a behavioural paradigm in which repeated exposure to a stimulus without consequence inhibits the formation of any new associations with that stimulus. To the extent that LI reflects a process of learning to ignore irrelevant stimuli, disrupted LI has been suggested as an animal model for the attentional deficits observed in schizophrenia. The antipsychotic potential of cholecystokinin (CCK) stems from its colocalization with dopamine (DA) in the mesolimbic pathway, where it demonstrates both excitatory and inhibitory effects on dopaminergic activity. This may be explained by mediation through different receptor subtypes. A variety of hypotheses has emerged regarding the potential clinical application of subtype-selective CCK-based drugs. The present experiments examined the effects on LI of two selective CCKA ligands: PD-140,548 (a CCKA antagonist, Experiment 1: 0.001, 0.01, and 0.1 mg/kg) and A-71623 (a CCKA agonist, Experiment 2: 0.02, 0.05, and 0.1 mg/kg). In both experiments, the effects of haloperidol (0.1 mg/kg) were also investigated. Animals receiving 0.1 mg/kg of haloperidol or 0.001 or 0.1 mg/kg (but not 0.01 mg/kg) of PD-140,548 treated the preexposed stimulus as irrelevant after a low number of preexposures. In contrast, no facilitatory effect on LI was detectable at any of the A-71623 doses. The finding that A-71623 failed to enhance LI indicates that it is unlikely that this compound would have any antipsychotic effect within the clinical setting. Considering the facilitatory effect exerted by PD-140,548 on LI, it is probable that the inhibition of CCK activity might prove a more promising strategy for the pharmacological treatment of schizophrenia.

Poly(epsilon-caprolactone) and poly(epsilon-caprolactone)-polyvinylpyrrolidone-iodine blends as ureteral biomaterials: characterisation of mechanical and surface properties, degradation and resistance to encrustation in vitro.

This study describes the physicochemical properties and in vitro resistance to encrustation of solvent cast films composed of either poly(epsilon-caprolactone) (PCL), prepared using different ratios of high (50,000) to low (4000) (molecular weight) m.wt., or blends of PCL and the polymeric antimicrobial complex, poly(vinylpyrrolidone)-iodine (PVP-I). The incorporation of PVP-I offered antimicrobial activity to the biomaterials. Films were characterised in terms of mechanical (tensile analysis, dynamic mechanical thermal analysis) and surface properties (dynamic contact angle analysis, scanning electron microscopy), whereas degradation (at 37degreesC in PBS at pH 7.4) was determined gravimetrically. The resistance of the films to encrustation was evaluated using an in vitro encrustation model. Reductions in the ratio of high:low-m.wt. PCL significantly reduced the ultimate tensile strength, % elongation at break and the advancing contact angle of the films. These effects were attributed to alterations in the amorphous content and the more hydrophilic nature of the films. Conversely, there were no alterations in Young's modulus, the viscoelastic properties and glass-transition temperature. Incorporation of PVP-I did not affect the mechanical or rheological properties of the films, indicative of a limited interaction between the two polymers in the solid state. Manipulation of the high:low m.wt. ratio of PCL significantly altered the degradation of the films, most notably following longer immersion periods, and resistance to encrustation. Accordingly, maximum degradation and resistance to encrustation was observed with the biomaterial composed of 40:60 high:low m.wt. ratios of PCL; however, the mechanical properties of this system were considered inappropriate for clinical application. Films composed of either 50:50 or 60:40 ratio of high:low m.wt. PCL offered an appropriate compromise between physicochemical properties and resistance to encrustation. This study has highlighted the important usefulness of degradable polymer systems as ureteral biomaterials

BRCA1 Functions as a Differential Modulator of Chemotherapy-induced Apoptosis

We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10–1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G2/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult.

SOCS2 Can Enhance Interleukin-2 (IL-2) and IL-3 Signalling by Accelerating SOCS3 Degradation

Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.

A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1alpha (HIF-1alpha) does not impair Pro-564 hydroxylation

The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the alpha subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1alpha in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE).

Expression of gentisate 1,2-dioxygenase (gdoA) genes involved in aromatic degradation in two haloarchaeal genera.

Gentisate-1,2-dioxygenase genes (gdoA), with homology to a number of bacterial dioxygenases, and genes encoding a putative coenzyme A (CoA)-synthetase subunit (acdB) and a CoA-thioesterase (tieA) were identified in two haloarchaeal isolates. In Haloarcula sp. D1, gdoA was expressed during growth on 4-hydroxybenzoate but not benzoate, and acdB and tieA were not expressed during growth on any of the aromatic substrates tested. In contrast, gdoA was expressed in Haloferax sp. D1227 during growth on benzoate, 3-hydroxybenzoate, cinnamate and phenylpropionate, and both acdB and tieA were expressed during growth on benzoate, cinnamate and phenylpropionate, but not on 3-hydroxybenzoate. This pattern of induction is consistent with these genes encoding steps in a CoA-mediated benzoate pathway in this strain.