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S Waters

Publications and source records attributed to S Waters.

At least 19 recordsLinked to original sources
PubMed2005

MCP-1 and murine prion disease: separation of early behavioural dysfunction from overt clinical disease.

Prion diseases are chronic, fatal neurodegenerative conditions of the CNS. We have investigated the role of monocyte chemoattractant protein-1 (MCP-1) in the ME7 model of murine prion disease. MCP-1 expression increased in the CNS throughout disease progression and was positively correlated with microglial activation. We subsequently compared the inflammatory response, pathology and behavioural changes in wild-type (wt) mice and MCP-1 knockout mice (MCP-1-/-) inoculated with ME7. Late-stage clinical signs were delayed by 4 weeks in MCP-1-/- mice, and survival time increased by 2-3 weeks. By contrast, early changes in affective behaviours and locomotor activity were not delayed in onset. There was also no difference in microglial activation or neuronal death in the hippocampus and thalamus of wt mice and MCP-1-/- mice. These results highlight an important dissociation between prolonged survival, early behavioural dysfunction and hippocampal/thalamic pathology when considering therapeutic intervention for human prion diseases and other chronic neurodegenerative conditions.

Animals↗
PubMed2003

Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease.

Prion diseases are fatal, chronic neurodegenerative diseases of mammals, characterized by amyloid deposition, astrogliosis, microglial activation, tissue vacuolation and neuronal loss. In the ME7 model of prion disease in the C57BL/6 J mouse, we have shown previously that these animals display behavioural changes that indicate the onset of neuronal dysfunction. The current study examines the neuropathological correlates of these early behavioural changes. After injection of ME7-infected homogenate into the dorsal hippocampus, we found statistically significant impairment of burrowing, nesting and glucose consumption, and increased open field activity at 13 weeks. At this time, microglia activation and PrPSc deposition was visible selectively throughout the limbic system, including the hippocampus, entorhinal cortex, medial and lateral septum, mamillary bodies, dorsal thalamus and, to a lesser degree, in regions of the brainstem. No increase in apoptosis or neuronal cell loss was detectable at this time, while in animals at 19 weeks postinjection there was 40% neuronal loss from CA1. There was a statistically significant reduction in synaptophysin staining in the stratum radiatum of the CA1 at 13 weeks indicating loss of presynaptic terminals. Damage to the dorsal hippocampus is known to disrupt burrowing and nesting behaviour. We have demonstrated a neuropathological correlate of an early behavioural deficit in prion disease and suggest that this should allow insights into the first steps of the neuropathogenesis of prion diseases.

Animals↗
PubMed2001

A behavioural pattern analysis of hypoglutamatergic mice--effects of four different antipsychotic agents.

In a hypoglutamatergic rodent model, we have observed certain behaviours that might have relevance for the cognitive impairments seen in autism and schizophrenia. Thus, hypoglutamatergic mice show defective habituation, impaired attention, a meagre behavioural repertoire and a general behavioural primitivization. The aim of the present study was to characterise and quantify changes in movement pattern in mice rendered hypoglutamatergic by means of MK-801 treatment, using an automated video tracking system. Further, the effects of four different antipsychotic drugs, the classical neuroleptic haloperidol, the atypical antipsychotic clozapine, the DA D2/5-HT2A antagonist risperidone and the selective 5-HT2A-receptor antagonist M100907, were compared with respect to effects on NMDA antagonist-induced movement pattern alterations. We found that each receptor antagonist had a unique effect on the MK-801-induced behavioural primitivization. Haloperidol was unable to affect the monotonous behaviour induced by MK-801, while risperidone, clozapine and M100907 produced movement patterns of high intricacy.

Animals↗
PubMed2001

Production of free radicals measured by spin trapping during operations for stenosis of the carotid artery.

OBJECTIVES: To analyse production of free radicals during operations for stenosis of the internal carotid artery. SETTING: University hospital, Sweden. SUBJECTS: 10 patients operated on for carotid artery stenosis. INTERVENTIONS: Blood samples were repeatedly drawn from the sigmoid sinus through a catheter in the internal jugular vein on the same side, before, during, and after clamping of the internal carotid artery. OXANOH was added to the blood samples in vitro and the radical production calculated from the amount oxidised to OXANO as electron spin resonance. MAIN OUTCOME MEASURES: The relation between radical production and certain clinical variables investigated by partial least squares regression analysis. RESULTS: There were several significant relations. High systolic blood pressure and advanced age were associated with low, and severe degree of stenosis with increased, free radical production. Certain anaesthetic drugs as well as blood variables also influenced the production of radicals. CONCLUSIONS: The technique used seems to offer the possibility to find and study methods to reduce free radical production during this kind of operation.

Age Factors↗
PubMed2000

Translocation (2;8)(p12;q24) associated with a cryptic t(12;21)(p13;q22) TEL/AML1 gene rearrangement in a child with acute lymphoblastic leukemia.

We report a case of childhood acute lymphoblastic leukemia with the simultaneous occurrence of a t(2;8)(p12;q24) typically associated with mature B cell or Burkitt leukemia, and a t(12;21)(p13;q22) exclusively associated with pre-B cell ALL. The lymphoblasts were characterized as L2 morphology by the French-American-British classification. However, there were atypical morphologic findings for L2 ALL, including vacuolization in some cells. The lymphoblasts were periodic acid-Schiff positive and myeloperoxidase negative. Immunophenotypic analysis revealed that the majority of lymphoblasts were TdT+, CD10+, CD19+, CD20-, and cytoplasmic mu+. These features were consistent with an immature pre-B cell leukemia phenotype with some characteristics of a mature B-cell leukemia. A t(2;8)(p12;q24)(p12;q24), characteristic of mature B-cell leukemia or Burkitt type leukemia, was detected by conventional cytogenetics with no other cytogenetic abnormalities. However, diagnostic peripheral blood and bone marrow specimens demonstrated simultaneous occurrence of a cryptic t(12;21)(p13;q22) by both FISH and RT-PCR. The simultaneous occurrence of these translocations in a pediatric patient have implications for the pathogenesis of leukemias with t(2;8)(p12;q24) as well as t(12;21)(p12;q22). Analysis of additional cases of leukemia with translocations involving the MYC locus on 8q24 will be required to determine the frequency of association with the cryptic t(12;21)(p13;22), and the prognostic significance of the simultaneous occurrence of the translocations.

Base Sequence↗
PubMed2000

Network interactions in schizophrenia - therapeutic implications.

Research into the role of neurotransmitters and neural networks in the pathogenesis of schizophrenia has been remarkably successful in recent years. The hypothesis postulating a dopamine dysfunction, which has for a long time been supported only by indirect evidence, has received direct support by means of sophisticated imaging techniques. Interactions between dopamine and several other neurotransmitters in complex neural networks have been revealed, largely thanks to the advent of an array of new pharmacological probes. Two major pharmacological models of schizophrenia, based on hyperdopaminergia and hypoglutamatergia, respectively, are ready for clinical testing. In addition, the hypothesis of network stabilization as a major therapeutic strategy in psychiatry and neurology has now reached the 'proof-of-concept' level. From a therapeutic perspective, several ongoing and forthcoming clinical trials, using drugs acting on dopaminergic, serotonergic and glutamatergic receptors, give rise to optimism.

Animals↗
PubMed1999

The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.

The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.

Amphetamine↗
PubMed1997

MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride.

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (-)-[4aR, 10 aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl- benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.

Animals↗
PubMed1997

11C-diprenorphine binding in Huntington's disease: a comparison of region of interest analysis with statistical parametric mapping.

We compare region of interest (ROI) analytical approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomography findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital reference area. Ratios of striatal-occipital uptake from averaged static images centered at 60 minutes showed a mean 20% reduction in caudate (P = 0.034) and 15% reduction in putamen (P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral analysis to give regional impulse response functions. Regional data at 60 minutes after impulse showed a mean 29% decrease in caudate (P = 0.006) and 23% decrease in putamen (P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral analysis on a voxel basis. The images of the unit impulse response function at 60 minutes showed a mean 31% decrease in caudate (P = 0.005) and a 26% decrease in putamen binding (P = 0.011) in HD. The voxel-based parametric images were transformed into standard stereotactic space, and a between-group comparison (patient versus controls) was performed with SPM. This approach revealed symmetrical decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with additional nonhypothesized changes in cingulate, prefrontal, and thalamic areas. The significance and precision of changes measured with spectral analysis applied to dynamic data sets were superior to ROI-based ratio analysis on static images. The SPM replicated the striatal reductions in opioid binding in HD and detected additional nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI analytical approaches for determining binding changes with positron emission tomography and may have advantages over region-based analyses in exploratory studies.

Adult↗
PubMed1997

Sources and nature of heterogeneity in recombinant phenol hydroxylase derived from the basidiomycetous soil yeast Trichosporon cutaneum.

Preparations of the dimeric flavoenzyme phenol hydroxylase derived from Trichosporon cutaneum were found to contain an active tetrameric form when the enzyme was produced in Escherichia coli. The relative content of the tetramer was estimated from scans of silver-stained native PAGE gels and/or size-exclusion chromatography (SEC). Proportions of up to 22% of the enzyme protein, depending on the growth temperature and the level of added inducer, were observed in independent cultures as well as in purified preparations. No tetramer was ever seen in cell extracts or purified preparations from T. cutaneum. Traces of higher multimers and of possibly deamidated species were also detected in preparations of the recombinant enzyme. The rate of enzyme production seems to be the major factor in promoting formation of the tetramer, whereas the specific growth rate of the fermentor culture appears to be of minor importance. The dimeric and the tetrameric forms were purified using either SEC or ion-exchange chromatography as a final step. The two purified species did not interchange under a variety of conditions, indicating that they are not undergoing rapid equilibria. The FAD of either form, as isolated by SEC, was present to a lower-than-expected extent of 2 equiv/dimer. However, by removing FAD and reconstituting the resulting apoproteins with the cofactor, the FAD content could be increased to 2 equiv. in the dimer and 3 equiv. in the tetramer. Both reconstituted forms exhibited absorption spectra identical with that of phenol hydroxylase from T. cutaneum as well as that of the recombinant enzyme. All spectra were equally perturbed by one equivalent of phenol per enzyme-attached FAD. The ratio of specific activities of the dimeric and the tetrameric forms was, however, lower than expected from the ratio of their FAD contents. The results are compatible with the notion that the tetramer consists of a native phenol hydroxylase dimer associated with a non-native one with a decreased ability to bind FAD, either in one or both of its constituent 'monomers'.

Binding Sites↗
PubMed1995

Viral measurement by polymerase chain reaction-based assays in human immunodeficiency virus-infected infants.

Serial samples from human immunodeficiency virus-infected infants in the first year of life were analyzed by quantitative human immunodeficiency virus polymerase chain reaction assays. Very high, persistent levels of plasma RNA and proviral DNA were detected throughout the study period, suggesting the absence of an effective immune response. Most patients had normal CD4 lymphocyte counts and were symptom free for the first 3 to 6 months despite high levels of viral replication. These findings support the evaluation of early intervention (before symptoms develop) and efforts to establish the predictive value of these assays.

CD4 Lymphocyte Count↗
PubMed1995

Effects of unilateral hearing loss on teacher responses to the SIFTER. Screening Instrument for Targeting Educational Risk.

Eighteen school children with unilateral hearing loss were compared to their peers through administration of the Screening Instrument for Targeting Educational Risk (SIFTER) to their teachers. Results indicate that children with unilateral hearing loss are given SIFTER scores significantly lower than their peers in all five SIFTER areas of academics, attention, communication, participation, and behavior. Such results support previous findings regarding teachers' attitudes toward students with unilateral hearing loss and indicate a need for in-service education for the classroom teacher and special attention to the educational risks of such children.

Achievement↗
PubMed1994

Crystallization and preliminary X-ray analysis of phenol hydroxylase from Trichosporon cutaneum.

Recombinant phenol hydroxylase from the soil yeast Trichosporon cutaneum has been crystallized with PEG 4000 as precipitant. The crystals are monoclinic, space group P2(1) with cell dimensions a = 101.8 A, b = 153.0 A, c = 116.0 A and beta = 114.8 degrees. The crystal asymmetric unit most likely contains two dimers of phenol hydroxylase corresponding to a packing density in the crystals of 2.54 A 3/Da. The self-rotation function is consistent with the packing of two dimers in the asymmetric unit. The observed diffraction pattern extends beyond 2.8 A resolution and the crystals are well suited for structural analysis by X-ray diffraction methods.

Crystallization↗
PubMed1994

A fermentor culture for production of recombinant phenol hydroxylase.

Fermentor cultures using the fed-batch technique produced the FAD-containing enzyme phenol hydroxylase (EC 1.14.13.7) originated in the lower eukaryote Trichosporon cutaneum, but expressed in Escherichia coli under the control of the tac promoter. At 30 degrees C and isopropyl beta-D-thiogalactopyranoside (IPTG) concentrations of 0.5-2 mM, the enzyme protein was expressed to high cellular content, but aggregated into inclusion bodies. At 25 degrees C similar levels of enzyme protein were synthesized after induction with 0.05 mM IPTG, but a soluble, active enzyme was obtained. The active enzyme was produced at up to 45% of total protein and constituted more than 50% of soluble protein. The total yield was 5 g x liter-1. The FAD content of the cells increased after induction at a rate not limiting the formation of active enzyme. The enzyme was purified in two chromatographic steps. The N-terminal amino acid residue and the kinetic properties of the purified recombinant enzyme were similar to those reported for the enzyme from T. cutaneum.

Chromatography, Gel↗
PubMed1992

Polyamines in liver and their influence on chromatin condensation after 17-beta estradiol treatment of Atlantic salmon.

Atlantic salmon (Salmo salar) were treated with 17-beta estradiol to induce vitellogenin synthesis in liver. This led to an increase in liver wet weight and total DNA. After incubation with micrococcal nuclease (EC 3.1.31.1) less soluble chromatin was obtained from nuclei of the estradiol treated than the control fish, but active gene regions were solubilized by the nuclease. Thus, in the estradiol treated fish soluble mononucleosomes contained hybridizable vitellogenin gene sequences. As a result of estradiol treatment the content in total liver of putrescine rose 3-fold, that of spermidine 2-fold, while spermine was unchanged. In muscle no significant changes were observed. The regulatory functions of polyamines during gene expression were investigated by binding (14C)spermine to isolated liver nuclei depleted of endogenous polyamines. The number of binding sites was higher in nuclei of estradiol treated than control fish. (14C)spermine associated preferentially with micrococcal nuclease insensitive chromatin. Thus, the high content of putrescine and spermidine in liver supported the view of polyamine accumulation in proliferating tissues. The preferential binding to condensed chromatin indicated a stabilizing effect of polyamines on the organization of inactive chromatin structures.

Animals↗
PubMed1992

Tissue-specific sensitivity of chromatin and the vitellogenin gene to micrococcal nuclease after continuous exposure of salmon (Salmo salar) to 17 beta-estradiol.

Smoltified Atlantic salmon (Salmo salar), 2 years old and weighing 217 +/- 13 g, were treated for 2 weeks with 17 beta-estradiol containing silastic capsules implanted intraperitoneally. Control fish received empty capsules. Vitellogenin, present in the blood of both groups of fish, was enhanced by estradiol treatment. Nuclei were isolated from liver, blood cells, and brain and incubated with increasing concentrations of micrococcal nuclease (EC 3.1.31.1). In liver there were more mononucleosomes as a percentage of total chromatin in hormone-treated than in control fish. Using vitellogenin cDNA as a probe the highest hybridization signals were seen when 2 to 4% of the chromatin was digested to mononucleosomes. In blood cell and brain nuclei independent of the extent of the chromatin released the hybridization signals remained low. The expression of the vitellogenin gene in immature females was potentiated by exogenous estradiol to give increased micrococcal nuclease sensitivity of the chromatin without enhancement of the hybridization level. Micrococcal nuclease digestion and hybridization of the vitellogenin gene demonstrated that the hepatic specificity of vitellogenin synthesis is manifested as structural modulations of the chromatin containing the vitellogenin gene.

Animals↗