Biomedical subjects

S J Watson

Publications and source records attributed to S J Watson.

At least 19 recordsLinked to original sources

PubMed2006

Crucial role of c-Jun NH2-terminal kinase 1 (JNK1) in cold-restraint stress-induced gastric lesions in mice.

c-Jun NH2-terminal kinase 1 /JNK1, is activated in response to a broad array of cellular stresses. We investigated the role of JNK1 in the pathophysiology of cold-restraint stress-induced gastric lesions in mice. B6/129, wild type (WT) mice, or mutant mice deficient in Jnk1 (Jnk1-/- mice) were exposed to cold-restraint stress for different time periods. Gastric lesions were identified and quantitated by morphometric analysis. JNK1 activity in mucosal homogenates was quantitated by immunoprecipitation and in-vitro kinase assays. JNK1 expression and Akt activation were assessed by Western blots with anti-JNK1 and anti-phospho Akt antibodies, respectively. Gastric mucosal homogenates from Jnk1-/- mice exhibited no significant expression of JNK1 and no detectable level of JNK1 activation. Exposure of WT mice to cold-restraint stress led to the development of significant gastric lesions and to a greater than three-fold induction in JNK1 activity, while no lesions were detected in the gastric mucosa of Jnk1-/- mice. Since cold-restraint stress-induced gastric lesions involve the activation of cholinergic pathways, we tested the effect of atropine on both the development of gastric lesions and JNK1 activation. Pretreatment of WT mice with atropine completely inhibited both cold-restraint stress-induced lesions and JNK1 activation. Cold-restraint stress induced protein kinase B/Akt to a similar level in the gastric mucosa of both WT and Jnk1-/- mice indicating the integrity of other signaling pathways. JNK1 plays a key role in the development of cold-restraint stress-induced gastric lesions in mice through the activation of cholinergic, atropine sensitive pathways.

Animals↗

PubMed2006

Application of a generic biosphere model for dose assessments to five European sites.

The BIOMOSA (BIOsphere MOdels for Safety Assessment of radioactive waste disposal) project was part of the EC fifth framework research programme. The main goal of this project was to improve the scientific basis for the application of biosphere models in the framework of long-term safety studies of radioactive waste disposal facilities and to enhance the confidence in using biosphere models for performance assessments. The study focused on the development and application of a generic biosphere tool BIOGEM (BIOsphere GEneric Model) using the IAEA BIOMASS reference biosphere methodology, and the comparison between BIOGEM and five site-specific biosphere models. The site-specific models and the generic model were applied to five typical locations in Europe, resulting in estimates of the annual effective individual doses to the critical groups and the ranking of the importance of the exposure pathways for each of the sites. Uncertainty in the results was also estimated by means of stochastic calculations based on variation of the site-specific parameter values. This paper describes the generic model and the deterministic and stochastic results obtained when it was applied to the five sites. Details of the site-specific models and the corresponding results are described in two companion papers. This paper also presents a comparison of the results between the generic model and site-specific models. In general, there was an acceptable agreement of the BIOGEM for both the deterministic and stochastic results with the results from the site-specific models.

Body Burden↗

PubMed2006

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders.

Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders.

Antidepressive Agents↗

PubMed2005

Common peroneal nerve injury during varicose vein operation.

Common peroneal nerve (CPN) injury produces considerable and serious disability. The nerve is most frequently damaged as a result of trauma (sharp or blunt, traction, fracture, laceration, and avulsion). Less often iatrogenic injury is the cause of damage (application of tight plaster, retraction injury, division during operation). Even rarer is the complete or partial division of CPN during varicose vein operations. In the UK, on average 34 patients every year begin legal action against their medical attendants in connection with the treatment of varicose veins, on a background of an estimated 100,000 procedures performed. Nerve damage is the most frequent of all major complications that result in legal action; it is cited in 15% of cases. The commonest nerve injury, accounting for about half the cases, is to the common peroneal nerve just before or, as it crosses the neck of the fibula. We present three examples in two cases, which outline the risk of CPN injury, the spectrum of clinical presentation and the problems produced by a failure to recognise the deficit immediately. Regional anatomy, consequences of nerve damage and management options is discussed.

Adult↗

PubMed2005

Review of the radiation exposure of the UK population.

Since 1974 the National Radiological Protection Board (now the Radiation Protection Division of the Health Protection Agency) has produced reviews of the levels of exposure to ionising radiation in the UK, from sources of natural and artificial origin. The latest review (Watson et al 2005 Ionising Radiation Exposure of the UK Population: 2005 Review HPA-RPD-001 (Chilton: HPA-RPD)) in the series gives estimates of annual doses based predominantly on data collected for the years 2001-2003. The overall average annual dose is rounded to 2.7 mSv, and the average annual dose from natural radiation is found to be 2.2 mSv. The overall average annual dose is slightly increased over that found in the previous, 1999, review. This increase is mainly due to a larger contribution from medical irradiation.

Environmental Exposure↗

PubMed2005

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression.

Abnormalities in L-glutamic acid (glutamate) and GABA signal transmission have been postulated to play a role in depression, but little is known about the underlying molecular determinants and neural mechanisms. Microarray analysis of specific areas of cerebral cortex from individuals who had suffered from major depressive disorder demonstrated significant down-regulation of SLC1A2 and SLC1A3, two key members of the glutamate/neutral amino acid transporter protein family, SLC1. Similarly, expression of L-glutamate-ammonia ligase, the enzyme that converts glutamate to nontoxic glutamine was significantly decreased. Together, these changes could elevate levels of extracellular glutamate considerably, which is potentially neurotoxic and can affect the efficiency of glutamate signaling. The astroglial distribution of the two glutamate transporters and L-glutamate-ammonia ligase strongly links glia to the pathophysiology of depression and challenges the conventional notion that depression is solely a neuronal disorder. The same cortical areas displayed concomitant up-regulation of several glutamate and GABA(A) receptor subunits, of which GABA(A)alpha1 and GABA(A)beta3 showed selectivity for individuals who had died by suicide, indicating their potential utility as biomarkers of suicidality. These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression.

Bipolar Disorder↗

PubMed2005

Relation between the hypothalamic-pituitary-thyroid (HPT) axis and the hypothalamic-pituitary-adrenal (HPA) axis during repeated stress.

Previous work has indicated that acute and repeated stress can alter thyroid hormone secretion. Corticosterone, the end product of hypothalamic-pituitary-adrenal (HPA) axis activation and strongly regulated by stress, has been suggested to play a role in hypothalamic-pituitary-thyroid (HPT) axis regulation. In the current study, we sought to further characterize HPT axis activity after repeated exposure to inescapable foot-shock stress (FS), and to examine changes in proposed regulators of the HPT axis, including plasma corticosterone and hypothalamic arcuate nucleus agouti-related protein (AGRP) mRNA levels. Adult male Sprague-Dawley rats were subjected to one daily session of inescapable FS for 14 days. Plasma corticosterone levels were determined during and after the stress on days 1 and 14. Animals were killed on day 15, and trunk blood and brains were collected for measurement of hormone and mRNA levels. Repeated exposure to FS led to a significant decrease in serum levels of 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4). Stress-induced plasma corticosterone levels were not altered by repeated exposure to the stress. Despite the decrease in peripheral hormone levels, thyrotropin-releasing hormone (TRH) mRNA levels within the paraventricular nucleus of the hypothalamus were not altered by the stress paradigm. Arcuate nucleus AGRP mRNA levels were significantly increased in the animals exposed to repeated FS. Additionally, we noted significant correlations between stress-induced plasma corticosterone levels and components of the HPT axis, including TRH mRNA levels and free T4 levels. Additionally, there was a significant correlation between AGRP mRNA levels and total T3 levels. Changes in body weight were also correlated with peripheral corticosterone and TRH mRNA levels. These results suggest that repeated exposure to mild-electric foot-shock causes a decrease in peripheral thyroid hormone levels, and that components of the HPA axis and hypothalamic AGRP may be involved in stress regulation of the HPT.

Adaptation, Physiological↗

PubMed2005

Estrogen receptor alpha and beta mRNA expressions by proliferating and differentiating cells in the adult rat dentate gyrus and subventricular zone.

Numerous factors modulate neurogenesis in the adult dentate gyrus and subventricular zone, but it is often not clear if the modulation is mediated by direct effects on the proliferating and differentiating cells or secondary to effects on other cells. Also, while some factors selectively affect neurogenesis in one of the neurogenetic zones, it is not clear how selectivity is achieved. Estrogen is a hormonal modulator of neurogenesis. To address the issues of direct versus indirect control and regional specificity we investigated the colocalization of immunoreactivity for a proliferating cell marker, Ki-67, and a marker for migrating and differentiating cells with a neuronal phenotype, doublecortin, with the expressions of mRNA for estrogen receptors alpha and beta. We found an extensive colocalization of estrogen receptor alpha with both markers in the dentate gyrus and only with Ki-67 in the subventricular zone. An extensive colocalization of estrogen receptor beta with both markers was found in the dentate gyrus, but only a few Ki-67-immunoreactive and no doublecortin-immunoreactive cells of the subventricular zone expressed estrogen receptor beta mRNA. Estrogen receptor alpha and beta mRNAs were not expressed in other telencephalic Ki-67-immunoreactive cells or in constitutively doublecortin-immunoreactive cells of the piriform cortex. The extensive colocalization of immunoreactive markers for cell proliferation and differentiation with mRNAs for estrogen receptor alpha and estrogen receptor beta points to the direct modulation of dentate cell proliferation, differentiation and survival by estrogen, while direct effects of estrogen in the subventricular zone appear restricted to estrogen receptor alpha-mediated effects operating at the time of cell proliferation.

Animals↗

PubMed2004

Dysregulation of the fibroblast growth factor system in major depression.

In this report we describe findings that imply dysregulation of several fibroblast growth factor (FGF) system transcripts in frontal cortical regions of brains from human subjects with major depressive disorder (MDD). This altered gene expression was discovered by microarray analysis of frontal cortical tissue from MDD, bipolar, and nonpsychiatric control subjects and was verified by quantitative real-time PCR analysis and, importantly, in a separate cohort of MDD subjects. Furthermore, we show, through a separate analysis of specific serotonin reuptake inhibitor (SSRI)-treated and non-SSRI-treated MDD subjects that the observed changes in expression of FGF transcripts are not secondary to drug treatment. Rather, changes in specific FGF transcripts are attenuated by SSRIs and may thus be partially responsible for the mechanism of action of these drugs. We also make available the gene-expression profile of all of the other growth factors and growth factor receptors detected in these postmortem samples.

Adult↗

PubMed2004

Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii.

The establishment of a productive infection by an obligate intracellular pathogen is dependent on subversion of cellular defences. Apoptosis, or programmed cell death, is a property of metazoan cells that plays a critical role in inhibiting the proliferation of invasive organisms and viruses thereby protecting uninfected cells and limiting damage to the host organism. Not surprisingly, manipulation of the machinery of apoptosis plays a critical role in the pathogenesis of several intracellular pathogens. Toxoplasma gondii, arguably one of the most successful protozoan pathogens, has evolved several strategies to inhibit both the initiation and propagation of the apoptotic cascade. Recent work from several groups indicates an exquisite level of sophistication in the mechanisms to inhibit apoptosis along its diverse pathways. Much of this ability appears to centre around the manipulation of host transcription, specifically of genes involved in the pro-survival/anti-apoptotic response effectively manipulating the infected cell into a highly anti-apoptotic state. The implications of these observations extend beyond Toxoplasma biology to the broader area of microbial pathogenesis and cell signalling in mammalian cells.

Animals↗

PubMed2004

The search for the neurobiological basis of vulnerability to drug abuse: using microarrays to investigate the role of stress and individual differences.

Basic neurobiological studies have led to great progress in our understanding of the mechanisms of action of drugs of abuse. Much has been learned about the brain response from the moment a psychoactive drug enters the organism onwards, including the psychological, neurobiological and peripheral effects of repeated drug administration, withdrawal and re-exposure. However, to relate this knowledge to the human experience requires further research on the antecedents of drug-taking behavior and the factors that predispose particular individuals to drug seeking and drug abuse. Thus, it is important to address several issues at the fundamental level: (1) Why are some individuals more vulnerable to drugs of abuse more than others? Is there a broader dimension or dimensions of emotional reactivity that contribute to this difference in vulnerability? (2) What is the effect of psychosocial stress on drug-seeking and drug-taking behavior, and are the effects distinct across individuals? (3) Since both drug-taking behavior and stress have sustained and pervasive effects on the brain, can we use microarrays to discern the "neural signature" or "neural phenotype" associated with these processes, and can we distinguish this signature across individuals with differing propensities to taking drugs? In the present paper, we summarize some of our early attempts at addressing these questions. We rely on animal studies aimed at characterizing the emotional and stress reactivity of rats with different propensities to self-administer drugs (high responders and low responders); we briefly describe the effect of a psychosocial stressor on these animals; we then detail a study using microarray technology aimed at investigating the "neural phenotype" associated with social defeat stress in the high vs. low responder animals. This "discovery" approach is used as a starting place for identifying novel mechanisms that might alter the vulnerability of different individuals to drug-seeking behavior. The power and limits of this approach, and its future directions, are discussed within this general framework.

Animals↗

PubMed2004

Effects of chronic cocaine exposure on corticotropin-releasing hormone binding protein in the central nucleus of the amygdala and bed nucleus of the stria terminalis.

The neuropeptide, corticotropin-releasing hormone (CRH), has been shown to play a role in behavioral and neurobiological effects of drugs of abuse. An important modulator of CRH, the CRH binding protein (CRH-BP), has not, on the other hand, been assessed for its role in drug-associated effects. The primary objective of the present experiment was to assess whether prior, chronic exposure to cocaine modulates expression of CRH-BP, and to compare expression of the BP with that of the peptide itself. We assessed CRH-BP and CRH mRNA expression in two brain regions where CRH is known to affect responses to drugs of abuse; namely, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Male Long-Evans rats were given 14 daily injections of cocaine (30 mg/kg, i.p.) or saline. One, 3, 10, 28, or 42 days post-treatment, animals were killed and adjacent brain sections through the CeA and BNST were processed for CRH-BP and CRH by in situ hybridization. In the CeA, cocaine pre-exposure increased both CRH and CRH-BP mRNA expression 1 day post-treatment. In the dorsal BNST, cocaine pre-exposure elevated levels of CRH-BP, but not CRH, mRNA 3 days post-treatment. Taken together, the results suggest that withdrawal-induced changes in the expression of the CRH-BP, and CRH itself, are relatively short-lived and that a dysregulation in basal expression of either gene is not likely responsible for long-lasting behavioral effects noted with cocaine and other drugs of abuse.

Amygdala↗

PubMed2004

Regulatory mechanisms of corticotropin-releasing hormone and vasopressin gene expression in the hypothalamus.

Tuberoinfundibular corticotropin-releasing hormone (CRH) neurones are the principal regulators of the hypothalamic-pituitary-adrenal (HPA)-axis. Vasopressin is primarily a neurohypophysial hormone, produced in magnocellular neurones of the hypothalamic paraventricular and supraoptic nuclei, but parvocellular CRH neurones also coexpress vasopressin, which acts as a second 'releasing factor' for adrenocorticotropic hormone along with CRH. All stress inputs converge on these hypothalamic neuroendocrine neurones, and the input signals are integrated to determine the output secretion of CRH and vasopressin. Aminergic, cholinergic, GABAergic, glutamatergic and a number of peptidergic inputs have all been implicated in the regulation of CRH/vasopressin neurones. Glucocorticoids inhibit the HPA-axis activity by negative feedback. Interleukin-1 stimulates CRH and vasopressin gene expression, and is implicated in immune-neuroendocrine regulation. cAMP-response element-binding protein phosphorylation may mediate transcriptional activation of both CRH and vasopressin genes, but the roles of AP-1 and other transcription factors remain controversial. Expression profiles of the CRH and vasopressin genes are not uniform after stress exposure, and the vasopressin gene appears to be more sensitive to glucocorticoid suppression.

Animals↗

PubMed2003

Environmental context and drug history modulate amphetamine-induced c-fos mRNA expression in the basal ganglia, central extended amygdala, and associated limbic forebrain.

The context in which amphetamine is administered modulates its ability to induce both behavioral sensitization and immediate early gene expression. When given in a novel test environment amphetamine produces greater levels of c-fos and arc mRNA expression in many brain regions relative to when it is given in the home cage. The purpose of the current study was to determine if environment and drug history interact to influence amphetamine-induced c-fos mRNA expression. Rats with a unilateral 6-hydroxydopamine lesion were treated for 7 days with saline or 0.5 mg/kg of d-amphetamine (i.v.) in a distinct and relatively novel test environment (Novel), or in their home cage (Home). Following a 10-12-day withdrawal period, a challenge injection of either saline or 0.5 mg/kg d-amphetamine was administered. In situ hybridization histochemistry was used to examine c-fos mRNA expression in several regions of the basal ganglia, the central extended amygdala, and limbic forebrain. In most brain regions amphetamine given in the Novel environment produced greater c-fos mRNA expression than when given it was given at Home, and drug history had no effect on amphetamine-induced c-fos mRNA expression. However, within the subthalamic nucleus, substantia nigra reticulata, and central nucleus of the amygdala prior experience with amphetamine in the Novel but not Home environment enhanced the effect of an amphetamine challenge injection on c-fos mRNA expression. In contrast, there was a decrease in c-fos mRNA expression in amphetamine-pretreated animals, regardless of environmental context, in the ventral portion of the far caudal striatum. Reexposure to an environment previously paired with amphetamine produced a conditioned increase in c-fos mRNA expression in portions of the caudate-putamen, the subthalamic nucleus, the nucleus accumbens shell and a conditioned decrease in c-fos mRNA expression in the central nucleus of the amygdala. We conclude that environmental context and drug history interact to alter the basal ganglia and central extended amygdala circuitry engaged by subsequent exposure to amphetamine, or exposure to an environment previously paired with amphetamine.

AIDS-Related Complex↗

PubMed2003

Estrogen receptor beta in the paraventricular nucleus of hypothalamus regulates the neuroendocrine response to stress and is regulated by corticosterone.

The function of the second nuclear estrogen receptor, estrogen receptor beta (ERbeta), in the brain is largely unknown. The present study tested whether 1) ERbeta in the paraventricular nucleus (PVN) of the hypothalamus has a direct role in the hypothalamic-pituitary-adrenal (HPA) axis-mediated stress function, and 2) whether corticosterone (CORT) can regulate ERbeta gene expression in the PVN in the intact, cycling female rat. To test the first hypothesis a pure estrogen receptor antagonist, ICI182, 780, was microinjected into the PVN bilaterally and stress-induced CORT response to an acute stressor (15 min restraint) was measured at 0, 15, 30, 60 and 90 min time points. Estrogen antagonist-injected rats showed inhibited CORT levels at the peak (15 min) of the stress response compared with vehicle-injected animals. To test the second hypothesis, ERbeta mRNA levels were measured in the PVN using in situ hybridization histochemistry following sham surgery, adrenalectomy, and adrenalectomy with low or high CORT replacement. Adrenalectomy reduced ERbeta mRNA expression in the PVN, whereas CORT replacement fully reversed this effect in a dose-dependent fashion. Both antagonist inhibition of CORT response and CORT-mediated regulation of ERbeta mRNA were found to be estrus cycle-dependent in the intact, cycling female. These data suggest that ERbeta in the PVN may critically modulate the HPA axis response to stress and is, in turn, regulated by circulating CORT.

Adrenalectomy↗

PubMed2003

DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles.

Transcriptional profiles within discrete human brain regions are likely to reflect structural and functional specialization. Using DNA microarray technology, this study investigates differences in transcriptional profiles of highly divergent brain regions (the cerebellar cortex and the cerebral cortex) as well as differences between two closely related brain structures (the anterior cingulate cortex and the dorsolateral prefrontal cortex). Replication of this study across three independent laboratories, to address false-positive and false-negative results using microarray technology, is also discussed. We find greater than a thousand transcripts to be differentially expressed between cerebellum and cerebral cortex and very few transcripts to be differentially expressed between the two neocortical regions. We further characterized transcripts that were found to be specifically expressed within brain regions being compared and found that ontological classes representing signal transduction machinery, neurogenesis, synaptic transmission, and transcription factors were most highly represented.

Aged↗

PubMed2002

Interlayer structures of the chiral smectic liquid crystal phases revealed by resonant X-ray scattering.

The structures of the liquid crystalline chiral subphases exhibited by several materials containing either a selenium or sulphur atom have been investigated using a resonant x-ray scattering technique. This technique provides a unique structural probe for the ferroelectric, ferrielectric, antiferroelectric, and SmC(*)(alpha) phases. An analysis of the scattering features allows the structural models of the different subphases to be distinguished, in addition to providing a measurement of the helical pitch. This paper reports resonant scattering features in the antiferroelectric hexatic phase, the three- and four-layer intermediate phases, the antiferroelectric and ferroelectric phases and the SmC(*)(alpha) phase. The helicoidal pitch has been measured from the scattering peaks in the four-layer intermediate phase as well as in the antiferroelectric and ferroelectric phases. In the SmC(*)(alpha) phase, an investigation into the helical structure has revealed a pitch ranging from 5 to 54 layers in different materials. Further, a strong resonant scattering signal has been observed in mixtures of a selenium containing material with as much as 90% nonresonant material.

Journal Article↗

PubMed2002

Influence of electric fields on the smectic layer structure of ferroelectric and antiferroelectric liquid crystal devices.

The electric-field-induced structural rearrangement of smectic layers in the antiferroelectric and ferroelectric phases of three different materials is reported. The materials all have high optical tilt angles (around 30 degrees ), compared with the steric tilt angles deduced from layer spacing measurements (around 18 degrees ). The chevron angles observed in devices agree well with values found for the steric tilt angle across the tilted mesophase range. Electric fields were applied to liquid crystal devices while the smectic layer structures, in both the depth and in the plane of the device, were probed using small angle x-ray scattering. Two separate aspects of the influence of the field on the layer structure were studied. First, the organization of the smectic layers in the antiferroelectric phase is described before, during, and after the application of an electric field of sufficient magnitude to induce a chevron to bookshelf transition. Second, the evolution of the field-induced layer structure change has been investigated as the field was incrementally increased in both the antiferroelectric and ferroelectric phases. It was found that the chevron to bookshelf transition has a distinct threshold in the antiferroelectric phase, but shows low or zero threshold behavior in the ferroelectric phase for all the materials studied.

Journal Article↗