Guidance for the identification of bony lesions related to smallpox.

OBJECTIVE: This research aimed to address the underrepresentation of smallpox (osteomyelitis variolosa) in palaeopathology, providing a synthesis of published literature and presenting guidance for the identification of osteomyelitis variolosa in non-adult and adult skeletal remains. MATERIALS AND METHODS: Literature regarding smallpox and published reports of individuals with osteomyelitis variolosa were synthesised and critiqued to produce clear diagnostic criteria for the identification of smallpox osteologically. RESULTS: Associated osteological changes begin in non-adults, where skeletal morphology is rapidly changing. Characteristic lesions associated with non-adult osteomyelitis variolosa include inflammation and destructive remodelling of long-bone joints and metaphyses. Where childhood infection was survived, residual osteomyelitis variolosa lesions should also be visible in adults in the osteoarchaeological record. CONCLUSIONS: Despite long-term clinical recognition, only limited osteological and archaeological evidence of osteomyelitis variolosa has yet emerged. With improved diagnostic criteria, osteomyelitis variolosa may be more frequently identified. SIGNIFICANCE: This is the first synthesis of osteomyelitis variolosa encompassing both clinical and palaeopathological literature, providing detailed guidance for the identification of osteomyelitis variolosa in skeletal remains. It will lead to the increased identification of smallpox osteologically. LIMITATIONS: Differential diagnoses should always be considered. The archaeological longevity of smallpox, and the potential for archaeological VARV to cause clinically recognised smallpox, is currently unknown. Characteristic bone changes in the archaeological record may be other, extinct human-infecting-orthopoxviruses. SUGGESTIONS FOR FURTHER RESEARCH: Further consideration of the implications of age of smallpox contraction on bony pathology: whether epiphyses are affected differently due to state of fusion. Reassessment of individuals previously identified with smallpox-consistent lesions, but otherwise diagnosed.

Neolithic culinary traditions revealed by cereal, milk and meat lipids in pottery from Scottish crannogs.

Cereal cultivation in Britain dates back to ca. 4000 BCE, probably introduced by migrant farmers from continental Europe. Widespread evidence for livestock appears in the archaeozoological record, also reflected by ubiquitous dairy lipids in pottery organic residues. However, despite archaeobotanical evidence for domesticated plants (such as cereals), organic residue evidence has been near-absent. Our approach, targeting low-abundance cereal-specific markers, has now revealed evidence for cereals (indicating wheat) in Neolithic pottery from Scottish 'crannogs', dating to ca. 3600 - 3300 BCE. Their association with dairy products suggests cereals may have been regularly prepared together as a milk-based gruel. We also observed a strong association between the occurrence of dairy products and smaller-mouthed vessels. Here, we demonstrate that cereal-specific markers can survive in cooking pots for millennia, revealing the consumption of specific cereals (wheat) that are virtually absent from the archaeobotanical record for this region and illuminating culinary traditions among early farming communities.

Mapping past human land use using archaeological data: A new classification for global land use synthesis and data harmonization.

In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives.

Frames Learned by Prime Convolution Layers in a Deep Learning Framework.

This brief addresses understandability of modern machine learning networks with respect to the statistical properties of their convolution layers. It proposes a set of tools for categorizing a convolution layer in terms of kernel property (meanlet, differencelet, or distrotlet) or kernel sequence property (frame spectra and intralayer correlation matrix). These tools are expected to be relevant for determining the generalization capabilities of a convolutional neural network. In particular, this brief highlights that the less frequency penalizing network among AlexNet, GoogleNet, RESNET101, and VGG19 is the more relevant one in terms of solutions for low-level ice-sheet feature enhancement.

Obesity is associated with shorter telomeres in 8 year-old children.

Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m² increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI.

Prenatal and Childhood Traffic-Related Air Pollution Exposure and Telomere Length in European Children: The HELIX Project.

BACKGROUND: Telomere length is a molecular marker of biological aging. OBJECTIVE: Here we investigated whether early-life exposure to residential air pollution was associated with leukocyte telomere length (LTL) at 8 y of age. METHODS: In a multicenter European birth cohort study, HELIX (Human Early Life Exposome) ([Formula: see text]), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide ([Formula: see text]), particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), and proximity to major roads. Average relative LTL was measured using quantitative real-time polymerase chain reaction (qPCR). Effect estimates of the association between LTL and prenatal, 1-y childhood air pollution, and proximity to major roads were calculated using multiple linear mixed models with a random cohort effect and adjusted for relevant covariates. RESULTS: LTL was inversely associated with prenatal and 1-y childhood [Formula: see text] and [Formula: see text] exposures levels. Each standard deviation (SD) increase in prenatal [Formula: see text] was associated with a [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) change in LTL. Prenatal [Formula: see text] was nonsignificantly associated with LTL ([Formula: see text] per SD increase; 95% CI: [Formula: see text], 0.6). For each SD increment in 1-y childhood [Formula: see text] and [Formula: see text] exposure, LTL shortened by [Formula: see text] (95% CI: [Formula: see text], [Formula: see text]) and [Formula: see text] (95% CI: [Formula: see text], 0.1), respectively. Each doubling in residential distance to nearest major road during childhood was associated with a 1.6% (95% CI: 0.02, 3.1) lengthening in LTL. CONCLUSION: Lower exposures to air pollution during pregnancy and childhood were associated with longer telomeres in European children at 8 y of age. These results suggest that reductions in traffic-related air pollution may promote molecular longevity, as exemplified by telomere length, from early life onward. https://doi.org/10.1289/EHP4148.

The patient reporting and action for a safe environment (PRASE) intervention: a feasibility study.

BACKGROUND: There is growing interest in the role of patients in improving patient safety. One such role is providing feedback on the safety of their care. Here we describe the development and feasibility testing of an intervention that collects patient feedback on patient safety, brings together staff to consider this feedback and to plan improvement strategies. We address two research questions: i) to explore the feasibility of the process of systematically collecting feedback from patients about the safety of care as part of the PRASE intervention; and, ii) to explore the feasibility and acceptability of the PRASE intervention for staff, and to understand more about how staff use the patient feedback for service improvement. METHOD: We conducted a feasibility study using a wait-list controlled design across six wards within an acute teaching hospital. Intervention wards were asked to participate in two cycles of the PRASE (Patient Reporting & Action for a Safe Environment) intervention across a six-month period. Participants were patients on participating wards. To explore the acceptability of the intervention for staff, observations of action planning meetings, interviews with a lead person for the intervention on each ward and recorded researcher reflections were analysed thematically and synthesised. RESULTS: Recruitment of patients using computer tablets at their bedside was straightforward, with the majority of patients willing and able to provide feedback. Randomisation of the intervention was acceptable to staff, with no evidence of differential response rates between intervention and control groups. In general, ward staff were positive about the use of patient feedback for service improvement and were able to use the feedback as a basis for action planning, although engagement with the process was variable. Gathering a multidisciplinary team together for action planning was found to be challenging, and implementing action plans was sometimes hindered by the need to co-ordinate action across multiple services. DISCUSSION: The PRASE intervention was found to be acceptable to staff and patients. However, before proceeding to a full cluster randomised controlled trial, the intervention requires adaptation to account for the difficulties in implementing action plans within three months, the need for a facilitator to support the action planning meetings, and the provision of training and senior management support for participating ward teams. CONCLUSIONS: The PRASE intervention represents a promising method for the systematic collection of patient feedback about the safety of hospital care.

Maternal psychological distress in primary care and association with child behavioural outcomes at age three.

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers' mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women.

Identifying the latent failures underpinning medication administration errors: an exploratory study.

OBJECTIVES: The primary aim of this article was to identify the latent failures that are perceived to underpin medication errors. STUDY SETTING: The study was conducted within three medical wards in a hospital in the United Kingdom. STUDY DESIGN: The study employed a cross-sectional qualitative design. DATA COLLECTION METHODS: Interviews were conducted with 12 nurses and eight managers. Interviews were transcribed and subject to thematic content analysis. A two-step inter-rater comparison tested the reliability of the themes. PRINCIPAL FINDINGS: Ten latent failures were identified based on the analysis of the interviews. These were ward climate, local working environment, workload, human resources, team communication, routine procedures, bed management, written policies and procedures, supervision and leadership, and training. The discussion focuses on ward climate, the most prevalent theme, which is conceptualized here as interacting with failures in the nine other organizational structures and processes. CONCLUSIONS: This study is the first of its kind to identify the latent failures perceived to underpin medication errors in a systematic way. The findings can be used as a platform for researchers to test the impact of organization-level patient safety interventions and to design proactive error management tools and incident reporting systems in hospitals.

Raloxifene blocks estradiol induction of the serotonin transporter and 5-hydroxytryptamine2A receptor in female rat brain.

Sex steroids have potent effects on mood, mental state and cognition. Our previous findings and those of others suggest that these effects may be due at least in part to estradiol actions on central serotonergic mechanisms. Specifically, estradiol-17beta in its acute positive feedback mode for gonadotropin release in the female rat induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN). This is accompanied by an increase in the densities of 5-HT(2A)R and the SERT in forebrain regions which in the human are concerned with the control of mood, mental state, cognition and emotion. Here we report that raloxifene, a benzothiophene and selective estrogen receptor modulator (SERM), completely blocked estradiol stimulation of brain 5-HT(2A)R and SERT expression in acutely ovariectomized rats. Raloxifene also blocked the estrogen-induced surge of luteinizing hormone. Treatment of acutely ovariectomized rats with raloxifene alone increased the density of SERT sites in the mid-frontal cortex and decreased the density of 5-HT(2A)R in the posterior olfactory tubercle. The inhibitory effects of raloxifene on acute estrogen-induction of central serotonergic mechanisms were similar to those of tamoxifen even though there are major differences between the two SERMs in their affinity for the two estrogen receptor subtypes and their actions on the uterus. These findings provide robust evidence that estradiol induction of the 5-HT(2A)R and the SERT in brain is mediated by nuclear estrogen receptors. Our data may provide the basis for obtaining a better understanding of the effects of sex steroids on mood and mental state in the human and the possible rational development of congeners of sex steroids for the treatment of mental disorders.

Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia.

Activation of intracellular signaling pathways involving p38 and p42/44 MAP kinases may contribute importantly to synaptic plasticity underlying spinal neuronal sensitization. Inhibitors of p38 or p42/44 pathways moderately attenuated responses of dorsal horn neurons evoked by mustard oil but not brush and alleviated the behavioral reflex sensitization seen following nerve injury. Activation of p38 and p42/44 MAP kinases in spinal cord ipsilateral to constriction injury was reduced by antagonists of NMDA, VPAC2 and NK2 (but not related) receptors, the glial inhibitor propentofylline and inhibitors of TNF-alpha. A VPAC2 receptor agonist enhanced p38 phosphorylation and caused behavioral reflex sensitization in naïve animals that could be blocked by co-administration of p38 inhibitor. Conversely, an NK2 receptor agonist activated p42/44 and caused behavioral sensitization that could be prevented by co-administration of p42/44 inhibitor. Thus, spinal p38 and p42/44 MAP kinases are activated in neuropathic pain states by mechanisms involving VPAC2, NK2, NMDA receptors and glial cytokine production.

Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory.

Sex steroids exert potent effects on mood and mental state in the human. Our previous experimental findings in female rats suggest that these effects may be mediated, in part, by the action of estrogen on the 5-hydroxytryptamine2A receptor (5-HT(2A)R) and serotonin transporter (SERT) in brain. Here we review our recent findings on the effect of acute (approximately 32 h) testosterone manipulation on central 5-HT(2A)R and SERT in male rats. Castration decreased while testosterone or estrogen, but not 5alpha-dihydrotestosterone (5alpha-DHT), increased significantly the content of 5-HT(2A)R mRNA and SERT mRNA in the dorsal raphe nucleus (DR) and the density of 5-HT(2A)R and SERT binding sites in higher centers of the brain. The lack of effect of 5alpha-DHT, a potent androgen which cannot be converted to estrogen, suggests that the action of testosterone depends upon its conversion to estrogen by aromatase. This may also explain why estrogen, but not testosterone or 5alpha-DHT, increased the density of 5-HT(2A)R binding sites in the caudate-putamen, a brain region where aromatase is scarce. The estrogen induction of SERT mRNA is most prominent in the rostral DR and this together with the correlation between sensitivity of DR serotonin neurons to estrogen and neurotoxic amphetamine derivatives provides a potential topochemical handle with which to investigate testosterone/estrogen regulation of SERT gene expression. These findings are discussed in relation to the possible role of interactions between sex steroids and serotonin mechanisms in mood disorders, schizophrenia and Alzheimer's disease.

Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A) receptor binding sites and mRNA levels in the brain of ovariectomized rats with or without acute estradiol replacement.

Estradiol-17beta (E(2)), in its positive feedback mode for gonadotropin release in the female rat, induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN) with a concomitant increase in the densities of 5-HT(2A)R and the SERT in rat forebrain. The forebrain regions affected are those which, in humans, are concerned with the control of mood, mental state, cognition and emotion. Here we have used the mixed estradiol agonist/antagonist, tamoxifen, to determine whether this action of estradiol is mediated by cytoplasmic estradiol receptors. Acute treatment ( approximately 32 h) of ovariectomized rats with estradiol benzoate (EB) increased significantly the amount of 5-HT(2A)R mRNA and SERT mRNA in the DRN and the densities of 5-HT(2A)R and SERT binding sites in the forebrain. These effects of EB were completely blocked by tamoxifen. Treatment with tamoxifen alone had no effect on either gene expression or the density of binding sites. Together, these data show that tamoxifen acts as a pure estradiol antagonist with respect to serotonergic mechanisms in brain. Detailed analysis of the effects of estradiol and tamoxifen on the DRN showed that SERT gene expression is constitutive only in the posterior DRN; in the anterior DRN, SERT gene expression appears to depend upon estrogen induction which is blocked by tamoxifen. Our findings strongly suggest that estradiol receptors are involved in mediating estradiol action on central serotonergic mechanisms and are relevant for our understanding of the effects of antiestrogens as well as estradiol on mood, mental state and cognition.

Ca2+/calcineurin-inhibited adenylyl cyclase, highly abundant in forebrain regions, is important for learning and memory.

Activation of cAMP synthesis by intracellular Ca2+ is thought to be the main mode of cAMP generation in the brain. Accordingly, the Ca2+-activated adenylyl cyclases I and VIII are expressed prominently in forebrain neurons. The present study shows that the novel adenylyl cyclase type IX is inhibited by Ca2+ and that this effect is blocked selectively by inhibitors of calcineurin such as FK506 and cyclosporin A. Moreover, adenylyl cyclase IX is inhibited by the same range of intracellular free Ca2+ concentrations that stimulate adenylyl cyclase I. Adenylyl cyclase IX is expressed prominently in the forebrain. Substantial arrays of neurons positive for AC9 mRNA were found in the olfactory lobe, in limbic and neocortical areas, in the striatum, and in the cerebellar system. These data show that the initiation of the cAMP signal by adenylyl cyclase may be controlled by Ca2+/calcineurin and thus provide evidence for a novel mode of tuning the cAMP signal by protein phosphorylation/dephosphorylation cascades.

Sex steroid control of mood, mental state and memory.

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.

Estrogen control of central neurotransmission: effect on mood, mental state, and memory.

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome. and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains "social" or "olfactory" memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as "Nature's" psychoprotectant.

An alpha 1 adrenergic mechanism mediates estradiol stimulation of LHRH mRNA synthesis and estradiol inhibition of POMC mRNA synthesis in the hypothalamus of the prepubertal female rat.

We showed previously that the surge of luteinizing hormone-releasing hormone (LHRH) induced by estradiol-17 beta (E2) in the female rat can be blocked by an alpha 1 adrenergic antagonist. The aim of the present study was to determine whether this was due to a direct action of E2 on noradrenergic projections to LHRH neurons or whether it also involved other systems such as the arcuate pro-opiomelanocortin (POMC) neurons which are thought to inhibit LHRH biosynthesis and release. The experimental preparation was the prepubertal female rat in which an LHRH surge is induced by pregnant mare serum gonadotropin. Prazosin was used as a specific alpha 1 adrenergic antagonist and LHRH and POMC mRNA concentrations and cell numbers, in the medial preoptic area and rostral arcuate nucleus, respectively, were determined by in situ hybridization. Prazosin significantly reduced the total number of LHRH mRNA expressing cells, and increased the total number of POMC mRNA expressing cells and the concentration of POMC mRNA per cell. These results suggest that the inhibition of E2-stimulated LHRH biosynthesis and release by alpha 1 adrenergic blockade may be mediated by two mechanisms; (i) increased POMC synthesis leading to inhibition of LHRH neurons and (ii) direct inhibition of a stimulatory alpha 1 adrenergic/LHRH mechanism.

Inhibition by NK2 but not NK1 antagonists of carrageenan-induced preprodynorphin mRNA expression in rat dorsal horn lamina I neurons.

Previous evidence indicated that NK2 rather than NK1 receptors play a central role in mediating the electrophysiological responses of dorsal horn neurons to brief cutaneous stimuli such as noxious heat (but not noxious pinch) and moderately sustained stimuli such as mustard oil, topically applied over 10-20 min. The present experiments were designed to investigate, by in situ hybridisation histochemistry, a delayed genomic response in dorsal horn neurons (the expression of preprodynorphin mRNA induced by intraplantar carrageenan injection) and explore the role of NK1 and NK2 receptors in mediating this response. In anaesthetised rats with bilateral intraplantar injections of carrageenan, neurokinin receptor antagonists were administered unilaterally by prolonged ionophoresis into the superficial dorsal horn. The marked increase in preprodynorphin mRNA expression elicited by carrageenan was inhibited (both in terms of number of expressing cells and their level of expression) by NK2 but not NK1 antagonists.

Testosterone Induces an All-or-None, Exponential Increase in Arginine Vasopressin mRNA in the Bed Nucleus of Stria Terminalis of the Hypogonadal Mouse.

The bed nucleus of the stria terminalis (BNST) in rodents contains arginine vasopressin (AVP) neurons which project to the lateral septum (LS) and habenula (LH) and are thought to be important for social recognition or memory. In previous studies we demonstrated that AVP immunoreactivity in the LS and LH is absent in the hypogonadal (hpg) mouse and that AVP immunoreactivity in the LH and LS of this mutant can be induced by testosterone. The aim of the present study was to determine whether this action of testosterone was due to the induction of AVP gene expression in BNST neurons and if so the time taken for testosterone to exert its effect. We found that exposure to supraphysiological concentrations of testosterone for 6-12 days caused an exponential, 50-fold increase in the number of cells that expressed AVP mRNA in the BNST in hpg mice. The action of testosterone is "all-or-none" in that the level of AVP mRNA in the AVP-positive cells was similar at all times after testosterone implantation and also similar or less than that in the few AVP-positive cells in animals not treated with testosterone. The relatively long time taken for testosterone to exert its effect on AVP mRNA in BNST neurons is comparable to its effects on AVP immunoreactivity in the LH and LS and on behaviour and suggests that the action of testosterone may be mediated by indirect or slow intracellular transduction mechanisms.