Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Simulating NIRS and MRS measurements during cerebral hypoxia-ischaemia in piglets using a computational model.

We present a group analysis of the changes in cerebral haemodynamics, and the oxidation state of cytochrome-c-oxidase measured using broadband near-infrared spectroscopy (NIRS) and intracellular pH measured by phosphorous ((31)P) magnetic resonance spectroscopy (MRS) during and after cerebral hypoxia-ischaemia (HI) in 15 piglets. We use a previously published computational model of cerebral metabolism in the piglet [1] to integrate these measurements and simulate HI. We successfully simulate changes in cellular metabolism including shifts in intracellular pH observed in the piglet brain during HI. In this process, we optimise physiological parameters in the model identified through sensitivity analysis (such as the rate of glucose metabolism and intracellular lactate concentration), to fit simulated and measured data. The model fits the data reasonably and suggests a 20 % drop in glucose consumption, a ~65 % increase in lactate concentration and ~35 % drop in the cerebral metabolic rate of oxygen (CMRO2) during HI.

Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy.

BACKGROUND: Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy ((31)P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and (31)P metabolite peak-area ratios during and after transient cerebral hypoxia-ischemia (HI) in the newborn piglet. METHODS: Twenty-four piglets (aged<24 h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~20 min). Whole-brain (31)P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by (31)P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp=exchangeable phosphate pool=Pi+PCr+2γ-NTP+ß-NTP). RESULTS: During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between (31)P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48 h related to recovery of Δ[oxCCO] and (31)P ratios 1h post-HI (survived: 1-h NTP/epp 0.22 ± 0.02, Δ[oxCCO] -0.29 ± 0.50 µM; died: 1-h NTP/epp 0.10 ± 0.04, Δ[oxCCO] -2.41 ± 1.48 µM). CONCLUSIONS: Both lowered Δ[oxCCO] and NTP/epp 1h post-HI indicated mitochondrial impairment. Animals dying before 48 h had slower recovery of both Δ[oxCCO] and (31)P ratios by 1 h after HI.

Participatory scenario development for environmental management: a methodological framework illustrated with experience from the UK uplands.

A methodological framework is proposed for participatory scenario development on the basis of evidence from the literature, and is tested and refined through the development of scenarios for the future of UK uplands. The paper uses a review of previous work to justify a framework based around the following steps: i) define context and establish whether there is a basis for stakeholder engagement in scenario development; ii) systematically identify and represent relevant stakeholders in the process; iii) define clear objectives for scenario development with stakeholders including spatial and temporal boundaries; iv) select relevant participatory methods for scenario development, during initial scenario construction, evaluation and to support decision-making based on scenarios; and v) integrate local and scientific knowledge throughout the process. The application of this framework in case study research suggests that participatory scenario development has the potential to: i) make scenarios more relevant to stakeholder needs and priorities; ii) extend the range of scenarios developed; iii) develop more detailed and precise scenarios through the integration of local and scientific knowledge; and iv) move beyond scenario development to facilitate adaptation to future change. It is argued that participatory scenario development can empower stakeholders and lead to more consistent and robust scenarios that can help people prepare more effectively for future change.

Professional allies: the storying of allies to LGBTQ students on a college campus.

This article details the narratives of faculty and staff involved in a lesbian, gay, bisexual, transgender, and queer (LGBTQ) ally organization at a large southeastern state university. We illustrate how interview participants diverged from organizational literature on how to be an ally by offering a different narrative, one of professional responsibility to a diverse student body. We expound upon how this notion of professional responsibility differs from most models for understanding ally development and action. We suggest that from an organizational standpoint, these professional ally self-concepts make sense and should be taken into account when building ally organizations in educational settings.

Epigenetic modification of vomeronasal (V2r) precursor neurons by histone deacetylation.

Vomeronasal neurons undergo continuous neurogenesis throughout development and adult life. These neurons originate as stem cells in the apical zone of the lumen of the vomeronasal organ (VNO) and are described as nestin-expressing glia-like progenitor cells (Murdoch and Roskams, 2008). They then migrate horizontally along the basal zone where they differentiate into functional VNO neurons (Kaba et al., 1988). We harvested progenitor cells from the adult VNO and, after 3-6 months of invitro culture, these VNO neurons remained in a stable undifferentiated state expressing nestin, beta-tubulin III and vomeronasal type 2 (V2r), but not vomeronasal type 1 (V1r) receptors. Application of histone-deacetylase inhibitors induced development of a neural phenotype that expressed V2r receptors, a down-regulation of nestin expression and no change in any specific genetic markers associated with glial cells. Treatment with valproic acid induced extensive changes in gene expression in the axon guidance pathway. The adult VNO is known to functionally adapt throughout life as a consequence of changes in both a mouse's physiological status and its social environment. These pluripotent cultured neurons may provide valuable insights into how changes in both physiology and environment, exert epigenetic effects on vomeronasal neurons as they undergo continuous neurogenesis and development throughout the life of a mouse.

Mother-infant bonding and the evolution of mammalian social relationships.

A wide variety of maternal, social and sexual bonding strategies have been described across mammalian species, including humans. Many of the neural and hormonal mechanisms that underpin the formation and maintenance of these bonds demonstrate a considerable degree of evolutionary conservation across a representative range of these species. However, there is also a considerable degree of diversity in both the way these mechanisms are activated and in the behavioural responses that result. In the majority of small-brained mammals (including rodents), the formation of a maternal or partner preference bond requires individual recognition by olfactory cues, activation of neural mechanisms concerned with social reward by these cues and gender-specific hormonal priming for behavioural output. With the evolutionary increase of neocortex seen in monkeys and apes, there has been a corresponding increase in the complexity of social relationships and bonding strategies together with a significant redundancy in hormonal priming for motivated behaviour. Olfactory recognition and olfactory inputs to areas of the brain concerned with social reward are downregulated and recognition is based on integration of multimodal sensory cues requiring an expanded neocortex, particularly the association cortex. This emancipation from olfactory and hormonal determinants of bonding has been succeeded by the increased importance of social learning that is necessitated by living in a complex social world and, especially in humans, a world that is dominated by cultural inheritance.

Oceans and human health: Emerging public health risks in the marine environment.

There has been an increasing recognition of the inter-relationship between human health and the oceans. Traditionally, the focus of research and concern has been on the impact of human activities on the oceans, particularly through anthropogenic pollution and the exploitation of marine resources. More recently, there has been recognition of the potential direct impact of the oceans on human health, both detrimental and beneficial. Areas identified include: global change, harmful algal blooms (HABs), microbial and chemical contamination of marine waters and seafood, and marine models and natural products from the seas. It is hoped that through the recognition of the inter-dependence of the health of both humans and the oceans, efforts will be made to restore and preserve the oceans.

Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory.

Sheep form an olfactory recognition memory for their lambs within 2 h of parturition and will subsequently reject the approaches of any strange lamb and protest vocally. In this study we report that following olfactory memory formation, ewes exposed to either their own or a strange lamb show c-fos mRNA expression in the medial frontal cortex, although levels of expression in the pyramidal output cell layer V were significantly higher in ewes that rejected strange lambs. Reversibly inactivating this region by the retrodialysis of the anaesthetic tetracaine before birth reduced aggressive motor responses towards lambs but not protest vocalisations. Similar treatment during the critical period for olfactory memory formation and lamb recognition (0-4 h post-partum) had no effect on ewes maternal behaviour towards their own lambs. It did, however, prevent the normal selective expression of aggressive rejection, and reduced protest vocalisation behaviours directed towards strange lambs. These rejection behaviours did appear 1 h after the termination of tetracaine infusions despite the ewes not being given the opportunity to interact with their own lambs during this time. Therefore, tetracaine blockade of the medial frontal cortex prevents animals from responding with motor aggression, but not vocal aggression, to odour cues from strange lambs, but has no effect on the formation of an olfactory recognition memory for their own lambs. Both pre- and post-partum aggressive rejection of strange lambs was associated with increased concentrations of dopamine, serotonin, glutamate and GABA. When these behaviours were inhibited by the tetracaine infusions, extracellular concentrations of these neurotransmitters were all increased by the anaesthetic but did not change in response to lambs. These findings suggest that a functional medial frontal cortex is not required for the formation of an olfactory recognition memory or for mediating pro-active maternal behaviours. It is however required for the mediation of motor but not vocal aspects of aggressive rejection responses directed towards aversive odour cues from strange lambs.

Sex differences in the influence of mothers on the sociosexual preferences of their offspring.

The extent to which "nurture" as opposed to "nature" determines behavior and sociosexual preferences in mammalian species is controversial although most recent interest has focused on genetic determinants. We report here that if sheep and goats are cross-fostered at birth, but raised in mixed-species groups, their play and grooming behavior resembles that of their foster rather than genetic species. There are no sex differences in effects on these behaviors, and other species-specific behavior patterns such as aggression, browsing, climbing, and vocalizations are unaffected. In adulthood, cross-fostered males strongly prefer to socialize and mate with females of their foster mother's species, even if raised with a conspecific of their own species. Castration within 2 days of birth slightly reduces the level of this altered social preference but mating preference following short-term testosterone treatment is the same as for gonadally intact animals. Cross-fostered females also show significant preference for socializing with females and mating with males of their foster mother's species, although this effect is weaker than that in both gonadally intact and castrated males. When cross-fostered animals are placed in flocks containing members of only their genetic species for 3 years, male social and mating preferences for females of their mother's species remain virtually unaffected. Females change to display an exclusive mating preference for members of their genetic species in 1-2 years although they still retain some social interest in female members of their foster species. Thus, there are clear sex differences in the impact of the emotional bond between a mother and her offspring in these mammals. Effects on males are strongest and irreversibly maintained even after altering their social environment, whereas those on females are weaker and mating preferences are clearly adaptable in the face of altered social priorities. These sex differences are presumably caused by pre-, or early postnatal, organizational effects of sex hormones on the brain.

Is right hemisphere specialization for face discrimination specific to humans?

Patterns of neural activation during face recognition were investigated in sheep by quantifying altered c-fos mRNA expression in situations where faces (sheep vs. human) can (faces upright) and cannot (faces inverted) be discriminated. Exposure to upright faces selectively increased expression significantly more in the right inferior temporal cortex than in the left, and active choice between upright faces additionally increased expression bilaterally in basal amygdala and hippocampus (CA1-4). Exposure to inverted faces did not lead to enhanced activation in the right inferior temporal cortex, amygdala or hippocampus but instead increased expression levels in the diagonal band of Broca, parietal and cingulate cortices. These results show that discrimination of upright faces in sheep preferentially engages the right temporal cortex, as it does in humans, and that performance of active choices between such faces may additionally involve the basal amygdala and hippocampus.

CLIMATE: The Ethiopia Food Crisis-Uses and Limits of Climate Forecasts.

Post-cold war investment in science--particularly in the case of seasonal to interannual climate forecasting--is increasingly justified by the goal of demonstrating explicit societal benefit. A review of the 2000 food crisis in Ethiopia and the state of the science of seasonal forecasting is sobering and underscores the need to foster more realistic expectations among both policy-makers and scientists about the uses and limits of climate forecasts in alleviating complex social problems.

Previous maternal experience potentiates the effect of parturition on oxytocin receptor mRNA expression in the paraventricular nucleus.

In sheep, central oxytocin release at parturition induces maternal behaviour which is thought to be mediated by changes in the expression of central oxytocin receptors. The distribution, effects of parturition, previous maternal experience and hormonal status on the distribution of an oxytocin receptor was investigated using immunocytochemistry and in situ hybridization. In ewes with no previous maternal experience, parturition induced significant increases in oxytocin receptor mRNA expression in the anterior olfactory nucleus, medial preoptic area, ventromedial hypothalamus, lateral septum, medial amygdala, bed nucleus of the stria terminalis and diagonal band of Broca. In maternally experienced ewes, parturition induced additional increases in two areas, the paraventricular nucleus and the Islands of Calleja. The changes in progesterone and oestrogen that occur during late pregnancy and parturition appear to contribute to increases in expression in the anterior olfactory nucleus, Islands of Calleja, medial preoptic area, ventromedial hypothalamus, bed nucleus of the stria terminalis and diagonal band of Broca, but not in the paraventricular nucleus, lateral septum and medial amygdala. These results demonstrate that progesterone and oestrogen priming enhance oxytocin receptor mRNA expression in a number of regions in the olfactory system, hypothalamus and limbic brain. These effects appear to be independent of maternal experience. Parturition increases oxytocin receptor mRNA expression in all the areas influenced by hormonal priming and the lateral septum, medial amygdala and paraventricular nucleus. Maternal experience also enhances expression of oxytocin receptor mRNA in the paraventricular nucleus and the Islands of Calleja. Because the paraventricular nucleus is the main source of oxytocin release in the brain, this upgrading of autoreceptors as a result of maternal experience may serve to enhance release of this peptide in projection sites regulating maternal behaviour.

Sex hormones enhance the impact of male sensory cues on both primary and association cortical components of visual and olfactory processing pathways as well as in limbic and hypothalamic regions in female sheep.

Differential activation of neural substrates was investigated in female sheep exposed to a male when they were in oestrus, and sexually receptive and attracted to males, as opposed to anoestrus when they were not. Changes in neuronal activation were visualized in ovariectomized, hormone-treated ewes by quantifying changes in cellular expression of c-fos messenger RNA by in situ hybridization histochemistry. Results showed that, while oestrus induction had no significant effects on c-fos expression per se, a 5-min exposure to a male significantly increased it in a number of primary and association cortical regions (the mitral and granule cell layers of the olfactory bulb, visual, somatosensory, orbitofrontal, piriform, cingulate and temporal cortices), the limbic system (CA1 region of the hippocampus, subiculum, lateral septum, lateral and basolateral amygdala, bed nucleus of the stria terminalis) and hypothalamus (mediobasal hypothalamus, medial preoptic area and paraventricular nucleus) as well as the nucleus accumbens and mediodorsal thalamus. Intromissions did not contribute significantly to these c-fos changes however. In anoestrus females, exposure to a male only produced a small significant increase in c-fos messenger RNA expression in the temporal cortex inspite of receiving similar amounts of visual and olfactory cues from him and a number of mating attempts. These results clearly demonstrate that changes in sexual motivation markedly alter the neural processing of sensory cues from males. They also show that the hormonal induction of sexual attraction to males cues and the resultant stimulation of sexual behaviour is due not only to altered responsiveness of oestrogen-sensitive brain regions involved in mediating behavioural responses towards the male, but also to changes in primary and secondary/tertiary somatosensory, olfactory and visual processing regions which relay sensory information to them.

Formation of olfactory memories mediated by nitric oxide.

Sheep learn to recognize the odours of their lambs within two hours of giving birth, and this learning involves synaptic changes within the olfactory bulb. Specifically, mitral cells become increasingly responsive to the learned odour, which stimulates release of both glutamate and GABA (gamma-aminobutyric acid) neurotransmitters from the reciprocal synapses between the excitatory mitral cells and inhibitory granule cells. Nitric oxide (NO) has been implicated in synaptic plasticity in other regions of the brain as a result of its modulation of cyclic GMP levels. Here we investigate the possible role of NO in olfactory learning. We find that the neuronal enzyme nitric oxide synthase (nNOS) is expressed in both mitral and granule cells, whereas the guanylyl cyclase subunits that are required for NO stimulation of cGMP formation are expressed only in mitral cells. Immediately after birth, glutamate levels rise, inducing formation of NO and cGMP, which potentiate glutamate release at the mitral-to-granule cell synapses. Inhibition of nNOS or guanylyl cyclase activity prevents both the potentiation of glutamate release and formation of the olfactory memory. The effects of nNOS inhibition can be reversed by infusion of NO into the olfactory bulb. Once memory has formed, however, inhibition of nNOS or guanylyl cyclase activity cannot impair either its recall or the neurochemical release evoked by the learned lamb odour. Nitric oxide therefore seems to act as a retrograde and/or intracellular messenger, being released from both mitral and granule cells to potentiate glutamate release from mitral cells by modulating cGMP concentrations. We propose that the resulting changes in the functional circuitry of the olfactory bulb underlie the formation of olfactory memories.

Olfactory memory and maternal behaviour-induced changes in c-fos and zif/268 mRNA expression in the sheep brain.

In sheep maternal behaviour and the formation of the selective olfactory, ewe/lamb bond are induced by feedback to the brain from stimulation of the vagina and cervix during parturition. In the present study, we have used in situ hybridization histochemistry to quantify changes in cellular expression of two immediately-early genes, c-fos and zif/268, in order to identify activated brain regions during the induction of maternal behaviour and olfactory bonding as well as regions where plastic changes are occurring during with the formation of the olfactory memory associated with bonding. Three different treatment groups were used. One group gave birth normally, became maternal and were allowed to interact with their lambs for 30 min. A second group received exogenous treatment with oestradiol and progesterone to induce lactation and then received a 5-min period of artificial stimulation of the vagina and cervix (VCS) which reliably induces maternal behaviour but could not interact with lambs. A final control group received exogenous hormone treatment but no VCS or interaction with lambs. Compared to the control group, post-partum animals and animals that had received VCS showed increased c-fos expression in a number of cortical regions (cingulate, entorhinal and somatosensory), the mediodorsal thalamic nucleus and the lateral habenula, the limbic system (bed nucleus of the stria terminalis, lateral septum, medial arnygdala, dentate gyrus and the CA3 region of the hippocampus) and the hypothalamus (medial preoptic area, mediobasal hypothalamus, paraventricular nucleus, supraoptic nucleus and periventricular complex). The group that gave birth and had contact with their lambs for 30 min had significantly enhanced c-fos mRNA expression in the cingulate cortex compared to those receiving VCS and additionally showed significantly increased c-fos mRNA expression in olfactory processing regions (olfactory bulb, piriform cortex and orbitofrontal cortex). Expression of zif/268 was significantly increased in the entorhinal cortex, orbitofrontal cortex and dentate gyrus of the parturition group compared to either the control or the VCS alone groups. These results show a clear differentiation between neural substrates controlling the expression of maternal behaviour and those involved in the olfactory memory process associated with selective recognition of offspring although at the level of the hippocampus and cingulate cortex there may be some degree of overlap. Alterations in zif/268 at tertiary processing sites for olfactory information (orbitofrontal cortex) and the entorhinal cortex and dentate gyrus may reflect plastic changes occurring during the early stages of olfactory memory formation.

Neural control of maternal behaviour and olfactory recognition of offspring.

In terms of reproductive success the quality and duration of maternal care exhibited by any particular species is of paramount importance, and yet compared with the amount of research studying the control of reproductive cycles, sexual behaviour, and fertility, it has historically received considerably less attention. However, we are now beginning to understand how the brain is organised to mediate this complex behaviour and how its expression is orchestrated by different hormonal and neurochemical factors. This review summarises a series of neuroanatomical, electrophysiological, in vivo sampling and behavioural neuropharmacological experiments carried out in sheep. These have attempted to define the neural circuitry and hormonal neurotransmitter systems involved both in the control of maternal behaviour per se and in the selective olfactory recognition of lambs, which is the basis of an exclusive emotional bond between mother and offspring.

Changes in content of mRNA encoding oxytocin in the pig uterus during the oestrous cycle, pregnancy, at parturition and in lactational anoestrus.

The aim of this study was to show that the pig uterus synthesizes oxytocin. Uteri were obtained from 2-7 pigs at regular intervals during the oestrous cycle, throughout pregnancy, at parturition and in lactational anoestrus. Localization of mRNA encoding oxytocin was by in situ hybridization and oxytocin concentrations were measured by radioimmunoassay. As reproductive status changed, mRNA encoding oxytocin varied significantly (P < 0.05). Uterine tissue type was a significant factor in determining synthesis of mRNA encoding oxytocin (P < 0.001). In luminal epithelia, concentrations of mRNA encoding oxytocin were greater at oestrus than during day 14 of the luteal phase (P < 0.01) or at any stage of pregnancy (P < 0.05), with concentrations minimal at parturition. This trend was also exhibited in uterine circular muscle. In longitudinal muscle, concentrations of mRNA encoding oxytocin were lower during late pregnancy than at oestrus (P < 0.05) or during the luteal phase (P < 0.05). Concentrations were minimal at parturition. The oxytocin content in endometrial and myometrial tissue was positively correlated across reproductive status (P < 0.02, r = 0.402, n = 35). These data are the first indication that the uterine endometrium and musculature of the pig express mRNA encoding oxytocin. The luminal epithelium of animals at oestrus was particularly rich in mRNA encoding oxytocin, whilst late pregnant and parturient animals did not show a rise in mRNA encoding oxytocin. Local uterine synthesis of oxytocin may therefore be more important in control of the oestrous cycle than in pregnancy or at parturition in pigs.

Perceptions of ganja and cocaine in urban Jamaica.

This article, based on ethnographic research, discusses the dynamic relationship between ganja (marijuana) and cocaine in five areas within Montego Bay, an urban-tourist center in Jamaica, West Indies. The focus is on the contrasting and conflicting social perceptions related to the current role of each substance in the society, as well as the interrelationship between these two substances. Of particular interest in the analysis of use and distribution patterns of each substance is the seemingly conflicting moral versus economic dilemma surrounding the drug trade; perceptions related to the effects of these two substances on the body and mind; and perceptions related to the role these substances play in local crime and physical violence. Community-level social perceptions will be compared to official discourse and actions regarding demand reduction, prevention, and enforcement of "drug" laws.