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Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters
M.V. Fogaça1, S.F. Lisboa1, D.C. Aguiar2, F.A. Moreira2, F.V. Gomes1, P.C. Casarotto1 and F.S. Guimarães1
1Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
2Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
Correspondence and Footnotes ]]>
This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a 'fine-tuning' regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.
Key words: Endocannabinoid; Anandamide; Nitric oxide; Endovanilloid; TRPV1
The periaqueductal gray matter (PAG) is a midbrain structure that surrounds the Sylvius aqueduct and has been implicated in the modulation of cardiovascular and motor control, nociceptive information and defensive responses (1,2). In laboratory animals, stimulation of the dorsal parts of the PAG leads to full-blown escape responses accompanied by sympathetic arousal (3). These escape reactions are attenuated by serotonin reuptake inhibitors (SSRIs) (4), first choice drugs in the treatment of several anxiety disorders.
The involvement of the PAG in defensive behaviors has also been supported by clinical studies. Electrical stimulation of the deep layers of the superior colliculus and periaqueductal gray matter in neurosurgery patients causes intense fear and a feeling of imminent death accompanied by autonomic changes such as increased blood pressure and heart rate (5). These responses are similar to those described for animals facing an imminent, proximal threat such as a predator. Accordingly, recent neuroimaging studies in healthy volunteers have shown that the dorsal part of the PAG is activated during the presentation of proximal threats (6).
On the basis of the similarity between these reactions and panic attacks, as well as on the pharmacological response to SSRIs, stimulation of the PAG has been proposed as a model of panic attack (4). Several lines of evidence support this proposal, indicating that the PAG, particularly its dorsal part, is a crucial structure in the defensive system (7).
Classical neurotransmitters, the PAG and defensive behaviors]]> Several neurotransmitters are present in the PAG, interacting in a complex way to control defensive responses in this region (8-11). The main excitatory input to the PAG is glutamatergic, and glutamate receptors are widely distributed throughout this region (12). There is a vast literature demonstrating that intra-PAG administration of glutamate or an N-methyl-D-aspartate (NMDA) glutamate receptor agonist promotes defensive responses (13,14). On the other hand, direct injections of NMDA and non-NMDA receptor antagonists into the dorsal PAG (dPAG) induce anxiolytic-like effects in animal models such as the elevated plus maze (EPM) and the Vogel conflict test (VCT) (15-17). Metabotropic glutamate receptors (mGluR) in the dPAG could also play a role in anxiety modulation. For example, intra-dPAG administration of a group I and II mGluR agonist induced flight reactions, an effect attenuated by pretreatment with mGluR1 and mGluR5 antagonists (18).
Besides glutamatergic neurotransmission, drugs that mimic or enhance the effects of the inhibitory neurotransmitter γ-amino-butyric-acid (GABA), such as the GABA-A agonist muscimol or benzodiazepine receptor agonists, as well as those that facilitate serotoninergic transmission through the activation of 5-hydroxytryptamine-1A (5-HT1A) or 5-HT2 receptors, attenuate the aversive consequences of dPAG electrical stimulation and produce anxiolytic-like effects in animal models of anxiety (19-21). Moreover, whereas the intra-dPAG injections of serotonergic antagonists have no effect on defensive responses, the microinjection of GABA-A antagonists elicits, by itself, explosive escape reactions (21) similar to those induced by local electrical stimulation. These data suggest that GABAergic mechanisms tonically inhibit the PAG network that controls defensive behaviors, whereas serotonin exerts a phasic inhibition of this network.
Several neuropeptides have also been implicated in the generation and elaboration of defense responses mediated by the dPAG. For example, direct injections of corticotrophin-releasing hormone (CRH), substance P or cholecystokinin (CCK) into the dPAG produce anxiogenic-like effects (22-24).
Atypical neurotransmitters
Several key discoveries made during the 80s and the early 90s have established the concept of atypical neurotransmitters. These substances, contrary to classical neurotransmitters, are produced 'on demand' in and released from the postsynaptic neuronal membrane. Being highly liposoluble, they can act presynaptically to modify neurotransmitter release (25,26). The two main atypical neurotransmitters are nitric oxide (NO) and the endocannabinoids (eCBs). NO is a short-lived gas produced from the amino acid l-arginine by a family of enzymes called NO synthases (NOS) (25). The neuronal NOS (nNOS) isoform is constitutive in the central nervous system (CNS) and located in specific brain regions. It is related to glutamate NMDA receptors and activated postsynaptically by calcium influx through these receptors (26).
The eCBs were isolated following the identification of a cannabinoid receptor now named CB1 and the subsequent search for endogenous ligands. The first recognized cannabinoid receptor agonist was arachidonoyl-ethanolamide, or anandamide (AEA) (27). Since then other endogenous CB1 agonists have been isolated. They include 2-arachidonoyl glycerol (2-AG), N-arachidonoyl dopamine, noladine, and virodhamine (27), all of them arachidonic acid derivatives (27).
Several lines of evidence indicate that these atypical neurotransmitters can modulate defensive behavior. For example, systemic administration of drugs that act on NO- or eCB-mediated neurotransmission modify anxiety-like behavior in different animal models (28,29). Moreover, both the nNOS enzyme and CB1 receptors have been located in key brain areas related to defensive behaviors, including the PAG (28-30).
NO, PAG and defensive behavior
In the PAG, nNOS-containing neurons are located specifically in the dorsolateral column (30). Local injections of NOS inhibitors or NO scavengers into this region induce anxiolytic-like effects in distinct animal models of anxiety that include the EPM, VCT and predator exposure (29,31-33). In contrast, NO donors injected into the dorsolateral PAG (dlPAG) induced flight responses (34,35) (Table 1). Additionally, studies using cFos immunohistochemistry as a tool to reveal neuronal activation show that different aversive conditions such as exposure to an EPM, restraint stress or a predator or ethanol withdrawal activates NOS-positive neurons in this region (36-39).
In the CNS, the effects of NO are exerted mainly through the activation of the soluble guanylate cyclase (sGC) enzyme leading to increased levels of cGMP (25). Accordingly, defensive behaviors induced by NO donors in the dlPAG depend on activation of local sGC, since these effects are attenuated by previous local injection of ODQ, a GC inhibitor (34). Moreover, a cGMP analogue (8-bromo-cGMP) injected into the dlPAG also induced fight/flight behavior similar to NO donors, with GC inhibitors inducing anxiolytic-like effects in animals exposed to the EPM and VCT (28,33). In agreement with these results, Chiavegatto et al. (40) showed that exposure to a live cat increases the production of citrulline (an indirect index of NOS activity) and cGMP in the dlPAG in rats. Taken together, these results indicate that the effects of NO on the dlPAG are probably mediated by the sGC/cGMP pathway.]]> Since NO is a diffusible gas, it can modulate the effects of several neurotransmitters such as glutamate, GABA, 5-HT, CCK, and cannabinoids (25) that have been related to the control of defensive behaviors in the PAG. As mentioned before, in the CNS there is reciprocal regulation between glutamate and NO, since activation of nNOS is dependent on Ca2+ influx induced by activation of NMDA receptors (25). Electrophysiological data showed that excitatory postsynaptic potentials induced by NO in dPAG slices are reduced by antagonists of ionotropic glutamate receptors (41). Reinforcing the possibility that NO effects in the PAG depend on facilitation of glutamate-mediated neurotransmission, we showed that local pretreatment with AP7, an NMDA receptor antagonist, blocked the aversive-like reaction induced by linsidomine chlorhydrate (SIN-1) (42) and reduced the activation of NOS neurons induced by predator exposure (36). More recently, we determined if the defensive reactions induced by NMDA in the dlPAG would depend of endogenous NO. Our experiments, performed with rats, showed that the escape responses induced by NMDA in the dlPAG are independent of endogenous NO (31). However, in mice these responses were prevented by a selective nNOS inhibitor (43,44). This difference may be related to the different species or the doses of NMDA employed.
The aversive reactions of NO donors in the dlPAG could also be modulated by 5-HT neurons, which are known to inhibit panic-like responses (21). Local injections of 5-HT2A receptor agonists reduced the escape reaction induced by SIN-1, a nitric oxide donor (45). Moreover, intradorsal raphe nucleus administration of the 5-HT1A receptor agonist, 8-OH-DPAT, which inhibits the activity of 5-HT neurons, favored the expression of escape induced by SIN-1 in the dPAG (46). The effects of 5-HT on flight responses induced by SIN-1 may involve indirect GABAergic facilitation, since 5-HT2 receptors are co-expressed in GABAergic neurons (8). In agreement with these results, defensive-like responses induced by intra-dlPAG administration of SIN-1 were attenuated by midazolam, a benzodiazepine receptor agonist (47).
It is also possible that the effects of NO on the PAG involve a direct interference with GABA-mediated neurotransmission, since GABA-expressing neurons in the dlPAG are co-expressed with nNOS-positive neurons (8). Moreover, electrophysiological studies performed in dlPAG slices showed that NO can potentiate the synaptic release of GABA (48).
eCB, PAG and defensive behavior
In the PAG, eCBs, similar to NO, modulate the release of several neurotransmitters that regulate defensive behaviors (29,53). CB1 receptors and the fatty acid amide hydrolase (FAAH) enzyme, responsible for AEA degradation, are complementarily expressed along the PAG (54). Moreover, systemic or intracerebroventricular administration of CB1 agonists increases cFos expression in the PAG (55) and AEA and 2-AG levels increase in this region after exposure to aversive footshock stress (56). Taken together, these lines of evidence indicate that eCBs could also be related to defensive reactions in this region. Accordingly, local administration of the synthetic cannabinoid HU210 attenuated defensive behaviors induced by either intra-dPAG injection of excitatory amino acid or by ultrasound exposure (57,58) and intra-PAG administration of drugs that increase eCB-signaling potentiates stress-induced analgesia (56).
In an attempt to better understand the involvement of eCBs in defensive behaviors controlled by the dlPAG, our group showed that local injection of AEA induces anxiolytic-like effect in animals exposed to the EPM through activation of CB1 receptors (59). Anxiolytic-like effects were mimicked by arachidonoylchloroethanolamide (ACEA), a selective CB1 agonist, and potentiated by the inhibitor of AEA transport, AM404. However, as frequently observed after systemic injections, AEA and ACEA produced a bell-shaped dose-response curve, with the higher doses being ineffective (59). Moreover, intra-dlPAG-administered AM404 by itself failed to cause any effect in the EPM (59) (Table 2).
These anxiolytic-like effects of AEA in the dlPAG were subsequently confirmed in two other animal models of anxiety, the VCT and contextual fear conditioning test (CFC) (60,61). Different from the EPM, however, in these studies drugs that inhibit AEA uptake/metabolism induced anxiolytic-like effects. One possible interpretation for this discrepancy is that the eCB system in the PAG is more intensely recruited under higher stress situations, such as those that involve aversive electrical shocks like the VCT and CFC. Accordingly, in CB1 knockout mice the light intensity in the behavioral test room was shown to be a crucial factor to determine the levels of anxiety of the animals (62).
The role of the eCB system in defensive behaviors mediated by the PAG was more recently investigated in two panic models, predator (cat) exposure and electrical stimulation of the dPAG. As observed previously in anxiety models, intra-dlPAG injection of AEA induced antiaversive effects in both models (63, and Lisboa SF and Guimaraes FS, unpublished results). Taken together, these results strongly suggest that eCBs play an important modulatory role in the defensive behaviors mediated by the PAG. This role could involve regulation of glutamate-mediated neurotransmission, since cannabinoid agonists have been shown to inhibit glutamatergic synaptic transmission in this region (64). Interaction with mGluR could also be important. In the PAG activation of mGluR, subtype 5 (mGluR5) induces the release of eCBs, which, in turn, activate presynaptic cannabinoid CB1 and cause analgesia (65).
eCBS can also change GABAergic neurotransmission in the PAG. Local blockade of GABA receptors attenuates cannabinoid-induced sympathoexcitation and pressor responses, suggesting that eCBs could facilitate sympathetic activation by disruption of GABAergic neurotransmission in the PAG (66). It remains to be confirmed if interference with GABA-related mechanisms is involved in the bell-shaped dose-response curves observed when CB1 agonists are injected into the PAG (59).
Endovanilloids, PAG and defensive behaviors]]> Initially identified in the periphery as a receptor for the pungent ingredient of red-hot chili peppers, capsaicin, the transient receptor potential vanilloid type-1 channel (TRPV1) is also expressed in the CNS, where it can elevate calcium levels and potentiate synaptic transmission (29). Anandamide, together with N-arachidonoyldopamine, N-oleoylethanolamine and hydroperoxyeicosatetraenoic acids, has been proposed as one of its putative endogenous agonists, called endovanilloids (29).
The dual action of AEA as an agonist of CB1 and TRPV1 receptors has been related to the dual effects of this and other cannabinoids in several areas, including the PAG (63,70). TRPV1 receptors are expressed in this and other regions related to the control of defensive responses (71). In the PAG, electrophysiological studies have shown that capsaicin, a TRPV1 receptor agonist, facilitates the release of glutamate by a presynaptic mechanism, indicating that these receptors are functional in this region (72). Several other studies, however, have also indicated a postsynaptic localization of TRPV1 receptors in forebrain limbic regions (73).
Although there are few studies in the literature investigating the effects of TRPV1-selective agonists on PAG-mediated defensive behaviors, direct microinjection of antagonists into this region suggests that the endovanilloid system plays an important role in modulating these behaviors (see Table 2). For example, intra-dPAG injection of TRPV1 antagonists such as capsazepine and SB366791 caused anxiolytic- and panicolytic-like effects, respectively, in different animal models (63,64).
These results suggest that TRPV1 receptors are tonically activated by endovanilloids such as anandamide, facilitating vanilloid-mediated defensive responses. However, another possibility to explain these results is an interaction between the endovanilloid and endocannabinoid systems, in a way that the presence of TRPV1 antagonists allows for a selective anandamide effect, redirecting its action entirely to CB1 receptors (63).
Supporting this proposal, activation of TRPV1 receptors has been related to the bell-shaped dose-response curves usually produced by cannabinoid compounds. It was demonstrated, for example, that whereas the anxiolytic-like effect of intra-dPAG administration of the anandamide analogue ACEA is mediated by CB1 receptors, the loss of this response seen with higher ACEA doses is reversed when the animals are pretreated with TRPV1 antagonists (63). Similar effects were demonstrated for the synthetic cannabinoid WIN55,212-2 (that can also activate CB1 and TRPV1 receptors) and the non-psychotomimetic phytocannabinoid cannabidiol (67,68). Although the latter compound has a complex pharmacology, at high doses it can activate TRPV1 receptors (67).
Contrasting with these results, dlPAG-injection of the TRPV1 agonist capsaicin induced anxiolytic-like effects in rats submitted to the EPM and VCT (64). Studies in peripheral tissues, however, have shown that this drug can induce a rapid desensitization of TRPV1 receptors (74). At present it is still unclear, however, if a similar mechanism occurs in the PAG.
Possible interactions between atypical neurotransmitters in the control of defensive behaviors
Several in vitro studies (75-78) have suggested a functional interaction between the cannabinoid and nitrergic systems in the CNS and peripheral tissues. This possible interaction involves different components of these two systems. For example, studies with endothelial cells and synaptosomes derived from rat brain, as well as an ex-vivo model of blood-brain barrier, suggest that NO can control the activity of the proposed AEA transporter (77).
Stimulation of CB1 receptors by different cannabinoid agonists enhances nNOS activity, increasing the production of cGMP (75,76). This effect is involved in some in vivo cannabinoid effects such as AEA-induced inhibition of depolarization-evoked dopamine release in leech ganglia and stimulation of neuropeptide release from the mammalian median eminence (77,79). Also, the usual development of tolerance to the acute hypothermic and cataleptic effects observed with cannabinoid agonists such as WIN55,212-2 is prevented by repeated administration of L-NAME, a non-specific NOS inhibitor (80). Corroborating this finding, some acute effects of tetrahydrocannabinol (THC), including hypolocomotion and hypothermia, are decreased in nNOS knockout mice. This same study demonstrated that several nNOS-positive neurons co-express CB1 receptors in the caudate-putamen and hypothalamus, two brain regions related to motor and temperature control, respectively (81).
Although these studies indicate that CB1 activation can induce NO production, opposite results have been reported. For example, the potent CB1 agonist CP-55,940 was able to decrease NO release in microglial cells stimulated with an endotoxin (82) and L-NAME increased the central hypothermic effect of the CB1 agonist WIN55,212-2 in rats (83). In addition, in cultures of rat cerebellar granule cells, depolarization-induced Ca2+ influx and subsequent NOS activation were reduced by WIN55,212-2 through inhibition of voltage-gated Ca2+ channels (84). Moreover, animals that lack the CB1 gene present an increase in NOS activity in the cerebral cortex, suggesting that CB1 is required to inhibit this activity (85). These results suggest that the interaction between CB1 and NOS activation is complex, with the former, under certain conditions, counteracting some effects of NO.]]> In the dlPAG, as mentioned earlier, NOS inhibitors, NO scavengers and sGC inhibitors cause anxiolytic-like effects in animal models (28), whereas NO donors induce flight reactions (28,34). The latter responses are prevented by local pretreatment with NMDA and non-NMDA glutamate receptor antagonists, suggesting, as shown elsewhere (25), that the effects of NO donors in the dlPAG are mediated by facilitation of glutamate release. As seen, CB1 receptors are also present in the PAG (54) where they can decrease glutamate release (64). This mechanism could explain the similar anxiolytic effects found after intra-dlPAG administration of CB1 receptor agonists (59-61) and glutamate ionotropic receptor antagonists (15,16).
Since NO and eCBs can regulate, usually in opposite directions, the release of neurotransmitters such as glutamate and GABA, and based on the several lines of evidence discussed above indicating that these two systems regulate defensive responses, we determined if they interact in the dlPAG to modulate these responses. In agreement with this proposal, low doses of AEA or an FAAH inhibitor administered into the dlPAG attenuated the flight responses induced by an NO donor, suggesting that activation of CB1 receptors could decrease NO-induced glutamate release. Also, the CB1 receptor antagonist AM251 not only prevented the effects of AEA but also increased the effect of NO (86). The latter effect could involve TRPV1 receptors since, as discussed before, in the PAG CB1 and TRPV1 receptors can be simultaneously activated at a given synapse to modulate defensive-like responses (63). Activation of TRPV1 has also been shown to promote NO formation in endothelial cells and in the placenta (87,88) and capsazepine was able to decrease the defensive reactions induced by an NO donor effect in the dlPAG (Aguiar DC and Guimaraes FS, unpublished results).
In the PAG activation, presynaptic TRPV1 receptor has been shown to increase glutamate release (72). However, it is possible that postsynaptic receptors are also involved. This has been recently observed by Zschenderlein et al. (89) in another brain region related to defensive responses, the lateral amygdala. They showed that, after high frequency stimulation, capsaicin activates postsynaptic TRPV1 receptors. This could activate nNOS and increase NO production by facilitating Ca2+ entry, resulting in presynaptic glutamate release and enhancement of long-term potentiation (LTP). At low frequency stimulation, on the other hand, postsynaptic TRPV1 activation could induce AEA synthesis, which in turn activates presynaptic CB1 receptors, reducing glutamate release and inhibiting LTP. It remains to be determined if similar mechanisms occur in the PAG.
The studies reviewed above clearly indicate that, in addition to classical neurotransmitters such as glutamate, GABA, serotonin, and neuropeptides, atypical transmitter molecules can also regulate defensive responses in the dlPAG.
Since these transmitters, which include NO, endocannabinoids and endovanilloids, exert most of their effects by modulating the release and/or effects of these classical neurotransmitters, they also play a 'fine-tuning' regulatory role in these responses. Several pharmacological results obtained in this region, together with a few electrophysiological and microdialysis data, indicate that this 'fine-tuning' role involves glutamate-mediated neurotransmission. At low doses AEA could activate CB1 receptors and attenuate defensive behaviors by decreasing glutamate release, while at higher doses it becomes ineffective or even increases these responses by also activating TRPV1 receptors and facilitating glutamate release. NO, on the other hand, may also participate in this fine-tuning role by increasing glutamate release. In addition, NO formation would also be modulated in a dual way by AEA through activation of CB1 and TRPV1 receptors.
Although these results have mostly focused on glutamate, based on what has been described in other brain regions, it is most reasonable that other neurotransmitters such as GABA and serotonin are also involved in the effects of these atypical transmitters. This issue needs to be further investigated in future studies.
Table 1. Effects of nitric oxide-related drugs on defensive behavior when injected into the intradorsal periaqueductal gray region.
[View larger version of this table (148 K JPG file)]
|Table 2. Effects of cannabinoid- and vanilloid-related drugs on defensive behavior when injected into the intradorsal periaqueductal gray region.
[View larger version of this table (152 K JPG file)]]]>
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43. Miguel TT, Nunes-de-Souza RL. Defensive-like behaviors and antinociception induced by NMDA injection into the periaqueductal gray of mice depend on nitric oxide synthesis. Brain Res 2006; 1076: 42-48. [ Links ]
44. Miguel TT, Nunes-de-Souza RL. Anxiogenic-like effects induced by NMDA receptor activation are prevented by inhibition of neuronal nitric oxide synthase in the periaqueductal gray in mice. Brain Res 2008; 1240: 39-46. [ Links ]]]>
45. Moreira FA, Guimaraes FS. Role of serotonin receptors in panic-like behavior induced by nitric oxide in the rat dorsolateral periaqueductal gray: effects of chronic clomipramine treatment. Life Sci 2005; 77: 1972-1982. [ Links ]
46. Miguel TL, Pobbe RL, Spiacci Junior A, Zangrossi Junior H. Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter. Behav Brain Res 2010; 213: 195-200. [ Links ]
47. Moreira FA, Guimaraes FS. Benzodiazepine receptor and serotonin 2A receptor modulate the aversive-like effects of nitric oxide in the dorsolateral periaqueductal gray of rats. Psychopharmacology 2004; 176: 362-368. [ Links ]
48. Xing J, Li DP, Li J. Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons. Neuropharmacology 2008; 54: 734-744. [ Links ]
49. Calixto AV, Duarte FS, Moraes CK, Faria MS, De Lima TC. Nitric oxide involvement and neural substrates of the conditioned and innate fear as evaluated in the T-maze test in rats. Behav Brain Res 2008; 189: 341-349. [ Links ]]]>
50. de-Oliveira RW, Guimaraes FS. Anxiolytic effect of methylene blue microinjected into the dorsal periaqueductal gray matter. Braz J Med Biol Res 1999; 32: 1529-1532. [ Links ]
51. Carvalho-Netto EF, Gomes KS, Amaral VC, Nunes-de-Souza RL. Role of glutamate NMDA receptors and nitric oxide located within the periaqueductal gray on defensive behaviors in mice confronted by predator. Psychopharmacology 2009; 204: 617-625. [ Links ]
52. Morato GS, Ortiga RM, Ferreira VM. Involvement of nitric oxide-dependent pathways of dorsolateral periaqueductal gray in the effects of ethanol in rats submitted to the elevated plus-maze test. Behav Brain Res 2004; 153: 341-349. [ Links ]
53. Moreira FA, Aguiar DC, Campos AC, Lisboa SF, Terzian AL, Resstel LB, et al. Antiaversive effects of cannabinoids: is the periaqueductal gray involved? Neural Plast 2009; 2009: 625469. [ Links ]
54. Egertova M, Cravatt BF, Elphick MR. Comparative analysis of fatty acid amide hydrolase and cb(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 2003; 119: 481-496. [ Links ]]]>
55. McGregor IS, Arnold JC, Weber MF, Topple AN, Hunt GE. A comparison of delta 9-THC and anandamide induced c-fos expression in the rat forebrain. Brain Res 1998; 802: 19-26. [ Links ]
56. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 2005; 435: 1108-1112. [ Links ]
57. Finn DP, Jhaveri MD, Beckett SR, Kendall DA, Marsden CA, Chapman V. Cannabinoids modulate ultrasound-induced aversive responses in rats. Psychopharmacology 2004; 172: 41-51. [ Links ]
58. Finn DP, Jhaveri MD, Beckett SR, Roe CH, Kendall DA, Marsden CA, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology 2003; 45: 594-604. [ Links ]
59. Moreira FA, Aguiar DC, Guimaraes FS. Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology 2007; 52: 958-965. [ Links ]]]>
60. Lisboa SF, Resstel LB, Aguiar DC, Guimaraes FS. Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test. Eur J Pharmacol 2008; 593: 73-78. [ Links ]
61. Resstel LB, Lisboa SF, Aguiar DC, Correa FM, Guimaraes FS. Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats. Psychopharmacology 2008; 198: 405-411. [ Links ]
62. Jacob W, Yassouridis A, Marsicano G, Monory K, Lutz B, Wotjak CT. Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav 2009; 8: 685-698. [ Links ]
63. Casarotto PC, Terzian AL, Aguiar DC, Zangrossi H, Guimaraes FS, Wotjak CT, et al. Opposing roles for cannabinoid receptor type-1 (CB(1)) and transient receptor potential vanilloid type-1 channel (TRPV1) on the modulation of panic-like responses in rats. Neuropsychopharmacology 2012; 37: 478-486. [ Links ]
64. Vaughan CW, Connor M, Bagley EE, Christie MJ. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol 2000; 57: 288-295. [ Links ]]]>
65. Palazzo E, de Novellis V, Marabese I, Cuomo D, Rossi F, Berrino L, et al. Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 2002; 439: 69-75. [ Links ]
66. Dean C. Cannabinoid and GABA modulation of sympathetic nerve activity and blood pressure in the dorsal periaqueductal gray of the rat. Am J Physiol Regul Integr Comp Physiol 2011; 301: R1765-R1772. [ Links ]
67. Campos AC, Guimaraes FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 2008; 199: 223-230. [ Links ]
68. Campos AC, Guimaraes FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1517-1521. [ Links ]
69. Terzian AL, Aguiar DC, Guimaraes FS, Moreira FA. Modulation of anxiety-like behaviour by transient receptor potential vanilloid type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray. Eur Neuropsychopharmacol 2009; 19: 188-195. [ Links ]]]>
70. Moreira FA, Aguiar DC, Terzian AL, Guimaraes FS, Wotjak CT. Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety-two sides of one coin? Neuroscience 2011; [http://dx.doi.org/10.1016/j.neuroscience.2011.08.046]. [ Links ]
71. Cristino L, De Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 2006; 139: 1405-1415. [ Links ]
72. Xing J, Li J. TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. J Neurophysiol 2007; 97: 503-511. [ Links ]
73. Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, et al. Polymodal activation of the endocannabinoid system in the extended amygdala. Nat Neurosci 2011; 14: 1542-1547. [ Links ]
74. Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51: 159-212. [ Links ]]]>
75. Carney ST, Lloyd ML, MacKinnon SE, Newton DC, Jones JD, Howlett AC, et al. Cannabinoid regulation of nitric oxide synthase I (nNOS) in neuronal cells. J Neuroimmune Pharmacol 2009; 4: 338-349. [ Links ]
76. Jones JD, Carney ST, Vrana KE, Norford DC, Howlett AC. Cannabinoid receptor-mediated translocation of NO-sensitive guanylyl cyclase and production of cyclic GMP in neuronal cells. Neuropharmacology 2008; 54: 23-30. [ Links ]
77. Maccarrone M, Fiori A, Bari M, Granata F, Gasperi V, De Stefano ME, et al. Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells. Thromb Haemost 2006; 95: 117-127. [ Links ]
78. Thors L, Fowler CJ. Effect of nitric oxide donors on membrane tritium accumulation of endocannabinoids and related endogenous lipids. Eur J Pharmacol 2009; 621: 10-18. [ Links ]
79. Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, et al. Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. Brain Res 1997; 763: 63-68. [ Links ]]]>
80. Spina E, Trovati A, Parolaro D, Giagnoni G. A role of nitric oxide in WIN 55,212-2 tolerance in mice. Eur J Pharmacol 1998; 343: 157-163. [ Links ]
81. Azad SC, Marsicano G, Eberlein I, Putzke J, Zieglgansberger W, Spanagel R, et al. Differential role of the nitric oxide pathway on delta(9)-THC-induced central nervous system effects in the mouse. Eur J Neurosci 2001; 13: 561-568. [ Links ]
82. Waksman Y, Olson JM, Carlisle SJ, Cabral GA. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther 1999; 288: 1357-1366. [ Links ]
83. Rawls SM, Tallarida RJ, Gray AM, Geller EB, Adler MW. L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6 H-pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia. J Pharmacol Exp Ther 2004; 308: 780-786. [ Links ]
84. Hillard CJ, Muthian S, Kearn CS. Effects of CB(1) cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity. FEBS Lett 1999; 459: 277-281. [ Links ]]]>
85. Kim SH, Won SJ, Mao XO, Ledent C, Jin K, Greenberg DA. Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis. J Pharmacol Exp Ther 2006; 319: 150-154. [ Links ]
86. Lisboa S, Magesto AC, Resstel LB, Guimarães FS. Functional interaction between anadamide and neuronal nitric oxide synthase in the dorsolateral periaqueductal grey of rats induces complex modulation of anxiety-like behavior. Neuroscience Meeting 2011. Washington: 2011. p 123 (Abstract). [ Links ]
87. Cella M, Leguizamon GF, Sordelli MS, Cervini M, Guadagnoli T, Ribeiro ML, et al. Dual effect of anandamide on rat placenta nitric oxide synthesis. Placenta 2008; 29: 699-707. [ Links ]
88. Ching LC, Kou YR, Shyue SK, Su KH, Wei J, Cheng LC, et al. Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1. Cardiovasc Res 2011; 91: 492-501. [ Links ]
89. Zschenderlein C, Gebhardt C, von Bohlen Und Halbach O, Kulisch C, Albrecht D. Capsaicin-induced changes in LTP in the lateral amygdala are mediated by TRPV1. PLoS One 2011; 6: e16116. [ Links ]
We thank FAPESP and CNPq for financial support.
Correspondence and Footnotes
Address for correspondence: F.S. Guimarães, Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, USP, Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brasil. E-mail: email@example.com
Presented at the III Fórum em Neurobiologia do Estresse, Araraquara, SP, Brazil, September 8-10, 2011.
Received December 17, 2011. Accepted February 23, 2012. Available online March 9, 2012. Published April 9, 2012.
The Brazilian Journal of Medical and Biological Research is partially financed by
|All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License


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Laufen Palace sanitary ware was designed with the ergonomics of a bathroom space in mind. The soft basin rim draws you in visually along its smooth ceramic edges.
The Palace double white wall hung basin was soft lines inside and out, but still remains a touch modern in its unique design with refined septum to divide the two basins. The generous basin measures 1500 x 510 x 165 mm and provides enough space for your modern day couple to interact in the bathroom space. Each bowl has its own waste in the centre and an overflow in the rear, along with the tap hole.
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text:
CRTAUTL. This command should have PUBLIC *EXCLUDE. You will need to have authority to this command or *allobj authority
Secure the AUTL (CHGOBJOWN to QSECOFR, PUBLIC *EXCLUDE).
Set security on system objects using the desired AUTL.
Add User Accounts to the AUTL (WRKAUTL and Option 2 to change/add/delete). Using Group profiles is my recommendation whenever possible.
I can't think of any reason why CRTAUTL should be restricted as *PUBLIC *EXCLUDE.
Certainly, *PUBLIC *EXCLUDE is a likely authority to assign as a user entry on an *AUTL. There seems to be no reason ever to grant higher than *PUBLIC *USE on any *AUTL. If higher authority is given to *PUBLIC, then there's probably no point in using the *AUTL for whatever is being done.
Note that objects that are added to the *AUTL should usually also have *PUBLIC *AUTL assigned in order to direct authority to the *AUTL.
An Authority List (*AUTL) object is a way of assigning authorities for a list of objects to a list of users. The "lists" may contain just a single object or user. Authorities are set against /each/ user for /all/ objects on the list.
One user might have *USE authority while a different user could have *CHANGE. The authority for a user is associated with every object on the list. I.e., you can't use an *AUTL to give a particular user *USE authority to one object and *CHANGE authority to a different object.
*AUTLs are not the solution for everything. They can provide an administrator with a single interface point for potentially many users and objects. A given object can appear on only one *AUTL.
The list of users will often consist mostly of group profiles. The list of objects will often consist of objects from within a particular application. Users can appear on many *AUTLs.
Often, a single *AUTL might be created for a given application. However, you might create a couple *AUTLs for each application; you might see a reason to put particular users on one *AUTL with *CHANGE authority and *USE on a second *AUTL that lists a few other objects.
By listing group profiles, you effectively are granting members of the groups the authorities that are on the *AUTL. (You can list a particular user on the same list that the user's group is on. The individual's entry will be checked first. In this way, you can restrict an individual or elevate an individual while maintaining general group authority.
Listing a few groups lets you control all of the members with minimal effort. When a new user is added to the group, all authorities of the group become effective for that user. There's no need to to put the user on any of the *AUTLs nor to assign authority object by object.
You can create *AUTLs, create a few profiles, place the profiles on the list with authorities and add objects to the list. As long as the profiles are not in use (no one logs on with them here are no members), the *AUTLs would have no effect. This gives you a way to phase object-level authority into a site that currently isn't controlled. Whatever authorities are in place for users and objects will still be in place in addition to whatever is assigned on the new *AUTLs.
Register Hereor login if you are already a member
GRTOBJAUT OBJ( MyFile ) OBJTYPE(*FILE) AUTL( MYAUTL )


text: A history of the Great War Mark Burger November 16, 2018 Editor's picks, Literature, News Comments Off on A history of the Great War Views : 690 0 PERSHING'S TANKERS: PERSONAL ACCOUNTS OF THE AEF TANK CORPS IN WORLD WAR I. Edited by Lawrence M. Kaplan. Published by University Press of Kentucky. 312 pages. $50 retail. In light of Veterans Day and the 100th ... Read More


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Free the Animation VR / AR
Play to reveal 3D images and 3D models!
Demonstration A-Frame / Multiplayer
vlrPhone / vlrFilter
Project of very low consumption, radiation and bitrate softphones, with the support of the spatial audio, of the frequency shifts and of the ultrasonic communications / Multifunction Audio Filter with Remote Control!
For other uses, see Black Beauty (disambiguation).
Black Beauty First edition, F. M. Lupton Publishing Company, New YorkAuthor Anna SewellCountry United KingdomLanguage EnglishGenre Children's literaturePublisher Jarrold & SonsPublication date 24 November 1877Pages 255Text Black Beauty at Wikisource
Black Beauty is an 1877 novel by English author Anna Sewell. It was composed in the last years of her life, during which she remained in her house as an invalid.[1] The novel became an immediate best-seller, with Sewell dying just five months after its publication, but having lived long enough to see her only novel become a success. With fifty million copies sold, Black Beauty is one of the best-selling books of all time.[2]
While forthrightly teaching animal welfare, it also teaches how to treat people with kindness, sympathy, and respect. In 2003, the novel was listed at number 58 on the BBC's survey The Big Read.[3] It is seen as a forerunner of the pony book.Contents
".... there is no religion without love, and people may talk as much as they like about their religion, but if it does not teach them to be good and kind to man and beast, it is all a sham...."— Black Beauty, Chapter 13, last paragraph.
Anna Sewell was born in Great Yarmouth, England, and had a brother named Philip, who was an engineer in Europe. At the age of 14, Anna fell while walking home from school in the rain and injured both ankles. Through mistreatment of the injury, she became unable to walk or stand for any length of time for the rest of her life. Disabled and unable to walk, she began learning about horses, spending many hours driving her father to and from the station from which he commuted to work. Her dependence on horse-drawn transportation fostered her respect for horses.[2] Sewell's introduction to writing began in her youth when she helped edit the works of her mother, Mary Wright Sewell (1797–1884), a deeply religious, popular author of juvenile best-sellers.
Anna Sewell never married or had children. In visits to European spas, she met many writers, artists, and philanthropists. Her only book was Black Beauty, written between 1871 and 1877 in her house at Old Catton. During this time, her health was declining, and she could barely get out of bed. Her dearly-loved mother often had to help her in her illness. She sold the book to the local publishers, Jarrold & Sons. The book broke records for sales and is the "sixth best seller in the English language."[4] By telling the story of a horse's life in the form of an autobiography and describing the world through the eyes of the horse, Anna Sewell broke new literary ground.[5]
Sewell died of hepatitis or tuberculosis on 25 April 1878, only five months after the novel was published, but she lived long enough to see its initial success. She was buried on 30 April 1878 in the Quaker burial-ground at Lammas near Buxton, Norfolk, where a wall plaque marks her resting place. Her birthplace in Church Plain, Great Yarmouth, is now a museum.
Sewell did not write the novel for children. She said that her purpose in writing the novel was "to induce kindness, sympathy, and an understanding treatment of horses"[1]—an influence she attributed to an essay on animals she read earlier by Horace Bushnell (1802–1876) entitled "Essay on Animals".[6] Her sympathetic portrayal of the plight of working animals led to a vast outpouring of concern for animal welfare and is said to have been instrumental in the abolition of the cruel practice of using the checkrein (or "bearing rein", a strap used to keep horses' heads high, fashionable in Victorian England but painful and damaging to a horse's neck).[5] Black Beauty also mentions the use of blinkers on horses, concluding that this use is likely to cause accidents at night due to interference with "the full use of" a horse's ability to "see much better in the dark than men can."Plot summary
The story is narrated in the first person as an autobiographical memoir told by the titular horse named Black Beauty—beginning with his carefree days as a colt on an English farm with his mother, to his difficult life pulling cabs in London, to his happy retirement in the country. Along the way, he meets with many hardships and recounts many tales of cruelty and kindness. Each short chapter recounts an incident in Black Beauty's life containing a lesson or moral typically related to the kindness, sympathy, and understanding treatment of horses, with Sewell's detailed observations and extensive descriptions of horse behaviour lending the novel a good deal of verisimilitude.[1]
The book describes conditions among London horse-drawn taxicab drivers, including the financial hardship caused to them by high licence fees and low, legally fixed fares. A page footnote in some editions says that soon after the book was published, the difference between 6-day taxicab licences (not allowed to trade on Sundays) and 7-day taxicab licences (allowed to trade on Sundays) was abolished and the taxicab licence fee was much reduced.Analysis
Sewell uses anthropomorphism in Black Beauty. The text advocates fairer treatment of horses in Victorian England. The story is narrated from Black Beauty's perspective and resultantly readers arguably gained insight into how horses suffered through their use by human beings with restrictive technical objects like the "bearing rein" and "blinkers" as well as procedures like cutting off the tails of the horses. For instance, Ginger describes the physical effects of the "bearing rein" to Black Beauty, by stating, "... it is dreadful... your neck aching until you don't know how to bear it... its hurt my tongue and my jaw and the blood from my tongue covered the froth that kept flying from my lips".[7] Tess Coslett highlights that Black Beauty's story is structured in a way that makes him similar to those he serves. The horses in the text have reactions as well as emotions and characteristics, like love and loyalty, which are similar to those of human beings. Coslett emphasises that, while Black Beauty is not the first book written in the style of an animal autobiography, it is a novel that "allows the reader to slide in and out of horse-consciousness, blurring the human/animal divide".[8]Reception
Upon publication of the book, many readers related to the pain of the victimised horses, sympathised and ultimately wanted to see the introduction of reforms that would improve the well-being of horses. Two years after the release of the novel, one million copies of Black Beauty were in circulation in the United States.[9] In addition, animal rights activists would habitually distribute copies of the novel to horse drivers and to people in stables.[10] The depiction of the "bearing rein" in Black Beauty spurred so much outrage and empathy from readers that its use was not only abolished in Victorian England, but public interest in anti-cruelty legislation in the United States also grew significantly. The arguably detrimental social practices concerning the use of horses in Black Beauty inspired the development of legislation in various states that would condemn such abusive behaviours towards animals.[11] The impact of the novel is still very much recognised today. Writing in the Encyclopedia of Animal Rights and Animal Welfare, Bernard Unti calls Black Beauty "the most influential anticruelty novel of all time".[12] Comparisons have also been made between Black Beauty and the most important social protest novel in the United States, Uncle Tom's Cabin, by Harriet Beecher Stowe, on account of the strong degree of outrage and protest action that both novels triggered in society.[11]Characters Horses
The book has been adapted into film and television several times, including:
Black Beauty was adapted for the stage in 2011 by playwright James Stone. The play was perform at the Broughton Hall Estate, North Yorkshire and Epsom Racecourse, Surrey. The production was a critical success and was performed around the UK in 2012.[13]Influence upon other works This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (November 2017) (Learn how and when to remove this template message)


text:
Chugwater Chili
Got a crowd to feed? A batch of Chugwater Chili is a satisfying meal in itself or a great accompaniment to you next BBQ served over hot dogs, hamburgers or french fries. Our award-winning gourmet blend is sure to compliment your own recipe as well, just add three tablespoons of Chugwater Chili Gourmet Chili Blend and enjoy!
Check out our easy step by step instructions
Also great for use as a Taco Seasoning
- No MSG
- No Preservatives, All Natural
- Gluten Free
- Product of USA


text:
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Flowers, green leaves are elements incorporated to create the most beautiful designs. In order to complete your task that are a few things to include.
Abstract Circles Cute Patterns in Watercolor Effect
Very similar to the examples that are shown above. It includes dots, circles with stripes and lines around them. Almost unreal.
Cute different vector seamless patterns tiling White, red and blue color
Have you ever wondered, what would it be like if a collection of seamless cute patterns are put together? For this reason, we have put all these together into a collage of designs.


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Your guide to the best bike rides on the Gold Coast
The Gold Coast is famous for its long sandy beaches, surfing and theme parks, but there are also many paths off the beaten track – perfect for those seeking adventure on two wheels!
Home to national parks, rainforests, ridges, valleys and picturesque backdrops, the Gold Coast is not just a paradise for surfers. It's a great destination for cyclists too.
Get out of the surf and into the saddle, and experience another side of the Gold Coast.
1. Nerang (hard and easy loops)
Nerang offers two great rides through the native Eucalyptus forest, suitable for beginner to expert cyclists. The first is the Casuarina Grove Track, which is ideal for novice cyclists. The track features gradual ascents and descents and paths are clearly marked.
The second loop is for advanced riders and serious thrill-seekers. With intense climbs and descents, this adrenalin-pumping ride takes you deep into the forest. It's easy to lose your path, but that's all part of the fun!
Total ride time will vary depending on which loop you choose, but they're both about 14 kilometres. More information.
2. Boondall to Kedron Brook
Escape the hustle and bustle of the city on this peaceful, smooth ride. Start by discovering the diverse wildlife of the Boondall Wetlands, home to an incredible variety of mammals, birds, frogs and vegetation. If you're the lunching type, finish up with a picnic at Kedron Brook. It's one of the largest catchment areas in Brisbane.
This pleasant beginner (green level) ride takes one to two hours. It is 20 kilometres long. More information.
3. Main Beach to the Spit
This beachside ride departing from the Southport Lifesaving Club leads you to the sand pumping jetty either via bushland or along the ocean. From there, continue under the jetty until you reach the Southport Spit wall.
This one- to two-hour ride is great for sight-seeing, stunning scenery and taking in the fresh sea breeze. You can even stop to taste some fresh prawns from the fishing trawlers on the way. The cycle is only five kilometres and is suitable for all level cyclists. More information.
4. Little Nerang Dam to Springbrook
This picturesque ride reaps great rewards. From Little Nerang Dam, enjoy a relaxed downhill cruise before commencing a challenging climb on Gold Coast Springbrook Road. The timber bridges can be slippery, but it's worth it when you reach the cliff edge and are rewarded with stunning views over Springbrook National Park.
Be well-prepared for this half day cycle. It's 24 kilometres and is recommended for intermediate (blue level) cyclists. More information.
5. Mount Tamborine, Canungra loop ride
Warning: you may have 'jelly legs' at the end of this ride! Starting from the town of Canungra, pass horse-riding studs and vineyards before beginning the climb to the volcanic mass, which was formed around 20 million years ago.
There's a tourist hub full of antique stores and home-made treats at the top of the mountain. The perfect place to refuel! This ride is suited to advanced (black level) cyclists. It takes half a day and is about 43 kilometres. More information.
6. Tweed Coast
Looking for a short, laidback ride? This route runs along the coastline between two beachside towns. The best part: near-constant sea views. Bikes paths are mostly good quality, and there are great cafes and bakeries on the way.
This is an easy ride for beginner (green level) cyclists that can be completed in one to two hours (17kms). More information.
7. Redland Bay (Mount Cotton)
Starting from Redland Bay, meander by the charming Moreton Bay, taking in the unspoilt Southern Bay islands of Russell, Lamb, Macleay and Karragarra. It's also worth mentioning that Redland Bay, known for its fertile iron-rich soil, has many great cafes for hungry cyclists.
This is a pleasant ride for intermediate (blue level) cyclists and takes one to two hours (36kms). More information.
8. O'Reilly's Rainforest Retreat
Keen for an adventure? This is an arduous ride that also starts at Canungra. You'll pass grazing farm-land before beginning a two-and-a-half-hour incline through ancient Gondwana rainforest.
After you've caught your breath, prepare for an adrenalin rush with an exciting downhill ride (easy on the brakes!).
The 70km ride takes half a day and is best suited to advanced (black level) cyclists. More information.
If you're looking for adventure on the Gold Coast, you won't be disappointed. These incredible rides offer diverse landscapes. From coastlines to forests, there's a route for everyone and all cycling abilities!
Which rides are you tempted to try? For more of the Gold Coast's best bike rides, check out CycleLifeHQ's complete list of bike rides for the Gold Coast.


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Weatherford, TX - A Parker County grand jury indicted Calvin Wilson Graves, 64, of Springtown, on Nov. 7 for continuous sexual abuse of a young child and aggravated sexual assault of a child.
On Aug. 15, the Springtown Police Department took a report of sexual abuse of a child after the victim made an outcry that Graves touched her inappropriately.
The child went to the Children's Advocacy Center of Parker County on Aug. 16 for a forensic interview where she described multiple incidents — the first occurring in July of 2013 — in which Graves had touched her in a sexual manner at his home in Springtown.
"Mr. Graves' indictment charges two felony offenses. The continuous sexual abuse of a young child count is a first-degree felony punishable by 25 to 99 years or life in prison. The aggravated sexual assault of a child count is also a first-degree felony, but is ...
Philadelphia, PA — In Philadelphia, a recent trend in crimes against children is taking a toll on those charged with investigating them. After seven murders and two horrific abuse cases, the Philadelphia Police Department is utilizing counselors and pleading for the violence to end.
"Our folks are hurting," Acting Police Commissioner Christine Coulter said.
For Coulter, Friday marked her 32nd year with the department and she says never in that time has she experienced a wave of child tragedy like this.
"Even those folks who have done it for years are impacted more drastically by the death and continued death of young children," Coulter said.
Coulter spoke of the pain after providing an update on a homicide investigating involving yet another toddler. The department's Employee Assistance Program, or EAP, is stepping in more frequently.
"We normally had employee assistance as folks make appointments. They are now dispatching to the scene ...
Creek County, OK - An Oklahoma police officer is accused of multiple sex crimes of children, according to KFOR and other media outlets.
Bradley Don Goodin, 45, is charged with "three counts of lewd molestation and two counts of child sexual abuse in separate cases filed Thursday in Creek County District Court," Tulsa World.com reported.
An affidavit obtained by Tulsa World alleges "a parent of one of the victims walked into a bathroom on Oct. 5 while Goodin had his hand down the pants of a 9-year-old girl." When Goodin was confronted, he threatened to physically harm the child's mother, the affidavit said.
Goodin is also accused of touching an 11-year-old girl inappropriately on multiple occasions, the Sapulpa Times said.
"The third time the defendant explained what happened," an investigator wrote in the affidavit obtained by Tulsa World. "He said his watchband that he wears on his left wrist ...
Philadelphia, PA - U.S. Immigration and Customs Enforcement (ICE) has arrested an illegal alien who was previously jailed for alleged rape and other criminal charges.
Jesus Romero-Bisos was released by the Philadelphia Police Department on October 17 even though ICE had placed an immigration detainer. Philadelphia police had arrested Romer-Bisos "or the criminal offenses of rape, involuntary deviate sexual intercourse by forcible compulsion, unlawful contact with a minor/sex offense ...
Braidwood, IL - A female high school teacher engaged in a sexual relationship with a 14-year-old boy with whom she also traded nude photos, a Will County prosecutor said.
On Wednesday, Dayna Chidester, 50, of the 25400 block of O'Connel Lane in Manhattan declared her intention to resign from her position as a teacher with Reed-Custer High School in Braidwood after being confronted with allegations of exchanging text messages about ...
Victoria, TX — A man on Texas top 10 Most Wanted Sex Offenders list was captured and arrested Friday in Victoria, Texas.
Steve Garcia Lopez, 53, has been on the wanted list since August 2018 after he left his last known address in Abilene. He is wanted for failure to register as a sex offender.
In 1999, Lopez was convicted of aggravated sexual assault involving a 10-year-old child and sentenced to ...
Bedford County, VA -- The Bedford County Sheriff's Office said a Bedford County man has been arrested on child porn and sexual assault charges.
They said this isn't his first time.
The sheriff's office said investigators assigned to the Southern Internet Crimes Against Children Task Force began an investigation into an alleged sexual assault of a minor and possession/manufacture of child pornography on November 2.
They said ...
Georgetown, OH - New details are emerging about what prosecutors say is years-long neglect and abuse of an 11-year-old girl found in a squalid Georgetown home in September.
According to the search warrant affidavit, the girl was starved, beaten, video-taped, confined and threatened with her life.
A recording obtained during the search depicts the girl being whipped by her foster mother, Margaret Breeze, 47, who became the girl's legal guardian ...
- Joseph McCann accused of multiple counts of rape and abduction
- Victims aged between 11 and 17 allegedly linked to McCann
- McCann accused of raping victims during two-week rampage
- Suspect told police: "If you caught me for the first two, the rest would not have happened"
- McCann stole mountain bike and climbed a tree in a desperate bid to evade police
London, England - A court heard today how a man accused ...
California, USA - Watch the video: It turns out that while he might be slightly off base, it's mostly true. The California penal code lists eating on public transport property as a "miscellaneous crime" in section 635-652.
(2) This section shall apply only to acts committed on or in a facility or vehicle of a public transportation system.
(b) (1) Eating or drinking in or on a system facility or ...
Chesterfield County, VA -- Police arrested a 51-year-old Lyft driver accused of sex crimes against a passenger.
"At about 9 a.m. on November 3, an adult female went to a local hospital and reported that she was sexually assaulted several hours earlier by a Lyft driver during a ride," a Chesterfield Police spokesperson said.
The assault, according to police took place earlier that morning on Queens Grant Drive in Midlothian ...
Folsom, CA - A Sacramento man working as a nurse at a rehab facility was arrested last week by Folsom police for alleged sex crimes involving a patient in January, authorities say.
Gregory Harms, 61, was arrested Friday and is "accused of sexual conduct with a patient," the Folsom Police Department said in a news release. One of the charges faced by Harms alleges that the victim was under anesthesia or ...
Rutherford County, TN - Middle Tennessee State football player Reginald Ezekiel Cobb was arrested on Monday on two counts of rape, according to the Rutherford County Sheriff's Office.
The charges stem from a Sept. 1, 2018, assault, according to court documents.
Cobb, known as Zeke, is being held at the Rutherford County Adult Detention Center on a $60,000 bond, according to the indictment filed Nov. 6 in Circuit Court ...
Montgomery County, MD - Montgomery County Democratic Executive Marc Elrich "silently" and partially reversed the sanctuary policy after sex crimes allegedly committed by illegal aliens skyrocketed.
The Community Trust Executive Order, signed by Elrich himself in July, prohibited ICE agents from accessing Montgomery County jails in Maryland to detain illegal aliens before they were released, Fox News reported.
"Last month, Montgomery County Executive Marc Elrich ordered the county's agencies not ...
America USA - If he were to win the presidency, socialist Democrat Bernie Sanders said he would put a stop to all deportations of illegal immigrants who are being detained by the U.S. government.
Sanders' order to halt deportations would include for illegals convicted of murder, sex offenses, and drunk drivers.
"In any given year, more than 6,600 convicted murderers and sex offenders are arrested by ICE and placed ...
New York, NY — U.S. Immigration and Customs Enforcement's (ICE) Enforcement and Removal Operations (ERO) deportation officers arrested Irvin Acaphelus Cespedes, 41, Wednesday, Oct.16. Cespedes, an illegally present Jamaican national who has pending attempted murder charges, was released three times between April and October 2019 from local law enforcement custody with an active detainer because of New York City's sanctuary policies.
"ICE in New York has repeatedly ...
Cumming, GA - Authorities say that a local man has been charged with child molestation by the Forsyth County Sheriff's Office.
Tonis Divan Benitez-Pineda, 25, of Cumming, was charged with one felony count of child molestation on Tuesday, Nov. 5, a sheriff's office spokeswoman said on Thursday.
Benitez-Pineda is being held in the Forsyth County Jail under no bond.
As we find more news, we will post it.
Memphis, TN (AP) — Prosecutors say a Michigan man has been charged in the rape of a Memphis woman 15 years ago.
Shelby County prosecutors said Friday that 62-year-old Ferlin Scott is being held in jail after he was taken into custody last week. Scott is a former resident of Memphis, Tennessee. His last known address was in Detroit.
Investigators say that a woman who was walking in a Memphis neighborhood ...
North Las Vegas, NV - A father and daughter have been accused of kidnapping and sexually assaulting a Las Vegas woman, before binding her with duct tape and leaving her to die in the desert.
Stanley Alfred Lawton, 54, and Shaniya Poche Lawton, 22, are being held on bail of $4.5 million and $3.5 million, according to the Los Angeles County District Attorney's Office. Stanley Lawton is scheduled ...
Marblehead, MA - A youth hockey coach accused of sexually assaulting eight boys under 14 will be released on bail due to rulings by the state's highest court, according to Essex District Attorney Jonathan Blodgett.
At a hearing Thursday in Salem Superior Court, Judge Thomas Drechsler set bail at $15,000 for Christopher Prew.
Prew, 33, of Winthrop has been indicted on one count of rape of a child aggravated ...


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In this paper, a novel structure of dynamic optical arbitrary waveform generation (O-AWG) with amplitude controlled by interference of two fiber Bragg grating (FBG) arrays is proposed. The FBG array consists of several FBGs and fiber stretchers (FSs). The amplitude is controlled by FSs through interference of two FBG arrays. The phase is controlled by FSs simultaneously. As a result, optical pulse trains with various waveforms as well as pulse trains with nonuniform pulse intensity, pulse spacing and pulse width in each period are obtained via FSs adjustment to change the phase shift of signal in each array.
©2012 Optical Society of AmericaFull Article | PDF Article
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Opt. Express 23(9) 12161-12173 (2015)


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These are a few of the comments received from the Music for Youth mentors on the day:
"You carried us along with your scintillating performance" Mentor – MFY
"Great start – eye catching – original – good way to get everyone on stage in an interesting way. (Well done violinist soloist) Well done percussion section – nice and even and precise. Our feet were soon tapping with your enthusiastic playing – well done cellos – you did a great job."
"A terrific opening – unusual, musical, original – percussion – be sure you can hear the violin solo all the time. Nice arrangement of this classic. All watching your conductor."
Jamaican Rhumba
"Excellent start – dance like and jaunty – Well done kit – Very well done"
"Lots of Caribbean sunshine here – you're playing with joy and we can hear it! Hurrah for the crescendo – it makes a big difference – you managed the changes of tempo well – they add interest to the performance – fun to see you moving. You've worked very hard on this and it shows – A terrific orchestra – well done"
Check here for more information on playing with the Southwark Youth Orchestra and the new half term dates.


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....which language is it, and what does it mean?
The context is in chapter 16 of Olivia Manning's novel "The spoilt city" and it runs like this:
"....and [Despina] said that when a peasant, recognizing her as Hungarian, had refused to serve her, she had shouted 'Sitie kiansinlai blogi!' and overthrown his basket of tomatoes".
A search on translate.google.com could not locate this, neither as Rumanian (the novel is set in Bucharest) nor as Hungarian. It is maybe misspelt, Olivia Manning is known to have had more than a little Rumanian to her name, but no Hungarian at all.
Thanks to any expert for your help!


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Quality is our number one priority
Every property is checked before your arrival to ensure the best possible stay.
Every property is checked before your arrival to ensure the best possible stay.
Key collection is arranged by our helpful staff. Available 24/7 or on-site service to help you with all your questions, e.g.: tips and insights for your holiday destination and your booked accommodation.
Be your own boss, eat whenever you want and make the most of plenty of space for all your friends and family.
2-room apartment 42 m2, on the ground floor. Object suitable for 2 adults + 2 children. Simple and cosy furnishings: living/sleeping room with 2 wall-trunk beds (90 cm, length 200 cm), dining nook and cable TV (flat screen), radio. Exit to the loggia. Sleeping alcove with 1 x 2 bunk beds. Open kitchen in the entrance (4 hot plates, oven). Bath/WC. Balcony, south facing position and, east facing position. Balcony furniture. Side view of the countryside. Facilities: Internet (WiFi, free). Maximum 1 pet/ dog allowed.House/Residence
Flachau: Only 500m from the lake. Apartment block "Dachstein". In the district of Reitdorf, in a sunny position, 1.5 km from the skiing area, in the countryside. For shared use: large garden with lawn for sunbathing. In the house: sauna (extra). Storage room for skis, washing machine, tumble dryer (for shared use, extra). Parking at the house. Supermarket 950 m, restaurant 800 m, bakery, café 300 m, bus stop 200 m, thermal baths "Therme Amadé" 3.2 km, bathing lake "Reitecksee" 500 m. Golf course (18 hole) 8 km, riding stable 800 m, walking paths from the house 10 m, cycle lane 50 m, mountain railway 1.5 km, ski rental 1.5 km, ski bus stop 200 m, ski school 1.5 km, cross country ski track 20 m. Nearby attractions: Eisriesenwelt Werfen 30 km. Well-known ski regions can easily be reached: snow space Flachau 2 km, Flachauwinkl-Zauchensee 10 km. Hiking paths: Grießenkar, Lackneralm. Please note: ski bus (free of charge). Free ski bus service to the ski region Flachau/Flachauwinkl. Please note: motorway close by.
Prior to your departure, you will receive the key collection information for your stay, along with your travel documents.
Show all apartments in this house/residence
856 - 2'140 m a.s.l. >>Well-known, family-friendly holiday centre, in a convenient position, 60 km south from Salzburg. In the resort: shops, bakery, post office, restaurant, bar, disco. Climbing, hiking, fitness centre, sauna, solarium, massage. Sights Hermann Maier FIS Rennstrecke, Cultural events FIS Skiweltcup, StrongmanRun im Juli, BikeNight Flachau im August, lakes nearby, kids' animation, toboggan run, leisure park. Access: motorway E55, exit number "Flachau".
Bathing lake. Diving, canoeing, river rafting, canyoning. Tennis, golf course 18 hole in Radstadt 6 km. Minigolf. Riding. Fitness course. Fishing. Summer tobbogan run, floodlit, long 1.1 km climbing park, high rope course. 2 chair lifts, mountain hikes, climbing, children's hiking paths. Bicycle paths, mountain bike routes, bicycles and mountain bikes for hire.
Ski-region Sportwelt Amadé, total of 270 lifts. Total 760 km ski runs, snowboard slope, snow park. Ski school (downhill), snowboard school, children's ski school, ski kindergarten. 220 km cross country ski tracks in the region, winter walking paths. Toboggan runs, partially floodlit. Curling. Ski bus (free of charge).
Click on your desired arrival date in the calendar and select the duration of your stay using the drop down menu. It takes less than two minutes to make your reservation online.
Every property is checked before your arrival to ensure the best possible stay.
Key collection is arranged by our helpful staff. Available 24/7 or on-site service to help you with all your questions, e.g.: tips and insights for your holiday destination and your booked accommodation.
Be your own boss, eat whenever you want and make the most of plenty of space for all your friends and family.
It has never been easier to find your perfect holiday. Do you want to explore new travel destinations? There is no better way than doing it in a holiday home: Enjoy "la dolce vita" in Italy, feel the charming lifestyle of the French Riviera or the Spanish way of life. Be inspired by our travel ideas and book online - quick, easy, and secure with Interhome.
Your stay in a holiday house or a holiday apartment offers plenty of advantages: spend your time exactly as you want. No disturbance from other guests or hotel staff, just spend your holiday according to your own rules. Whether you are looking for a city trip, a relaxing holiday with your family or with friends. Simply enjoy lots of room, flexibility and freedom in your holiday home.


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First Aid Beauty Ultra Repair Hydra-Firm Sleeping Cream
First Aid Beauty Ultra Repair Hydra-Firm Sleeping Cream
Product Description
An antiaging overnight facial cream for smooth, deeply hydrated skin.
What it is formulated to do:
Sleep your way to a more youthful-looking complexion. Drawing on the healing and intense moisturizing power of Ultra Repair, this super charged blend combats key signs of visible aging during skin's nightly repair phase. The unique formula includes a powerful peptide blend to support natural collagen and smooth the appearance of fine lines and wrinkles, glutaline-in-tense to firm, and niacinamide to improve skin's elasticity and revive skin's healthy tone and texture. Sodium hyaluronate, colloidal oatmeal, and conditioning butters and waxes repair and deeply hydrate for healthy, supple skin. This weightless, buttery cream seamlessly envelops skin with impressive nourishment and locks in vital moisture throughout the night. Appropriate for all skin typeseven the most sensitive skinapply nightly before bedtime to wake up to a renewed complexion with firmer, smoother, and moisturized skin.
What it is formulated WITHOUT:
- Parabens
- Sulfates
- Phthalates
What else you need to know:
All products are allergy-tested, free of artificial fragrances, dermatologist-recommended, and safe for even the most sensitive skin.
Research results:
A clinical and consumer study demonstrated:
- 41% improvement in skin elasticity over 8 weeks of twice-daily use
- 90% softer, smoother, and more supple skin after 4 weeks of continued use
- Significant improvement in skin firmness over 8 weeks of twice-daily use
Suggested Usage:
-Apply nightly to clean, dry skin.
-May be used alone or over your favorite serum.
-Glutaline-In-Tense: Encourages skin firmness and smooths the look of fine lines and wrinkles.
-Niacinamide: Improves skin elasticity and revives its healthy tone and texture.
-Sodium Hyaluronate: Plumps the look of skin for a more youthful appearance.
-Colloidal Oatmeal: Eliminates flakiness, redness, and calms the skin.
Water, Glycerin, Caprylic/Capric Triglyceride, Butyrospermum Parkii (Shea) Butter, Dimethicone, C10-18 Triglycerides, Ethylhexyl Palmitate, Glyceryl Stearate, Lactobacillus Ferment, Jojoba Esters, Acacia Decurrens Flower Wax, Acrylates/C10-30 Alkyl Acrylate Crosspolymer, Algae Extract, Butylene Glycol, Camellia Sinensis Leaf Extract (Green Tea), Carbomer, Ceteth-20, Cetyl Alcohol, Chrysanthemum Parthenium (Feverfew) Extract, Colloidal Oatmeal, Glycyrrhiza Glabra (Licorice) Root Extract, Helianthus Annuus (Sunflower) Seed Wax, Hydroxypropyl Cyclodextrin, Niacinamide, Palmitoyl Tetrapeptide-7, Palmitoyl Tripeptide-1, Palmitoyl Tripeptide-38, Peg-75 Stearate, Phenoxyethanol, Polyglycerin-3, Polysorbate 20, Sodium Hyaluronate, Sodium Hydroxide, Spilanthes Acmella Flower Extract, Steareth-20, Tetrasodium Edta, Xanthan Gum.
Shipping & Returns
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Shop with confidence. Read our full, common sense


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Help with paying for childcare
For funding purposes, childcare falls into 2 categories:
- Registered childcare is provided by people or organisations who are childcare providers registered with your local council. They may be childminders, nurseries, after school clubs or day-care centres.
- Unregistered childcare is provided by people who are not registered as childcare providers.
Some students may use both registered and unregistered childcare, in which case you may need to apply for financial help from more than one source. However, there is generally more financial help available for registered childcare costs. This page gives you information on the different sources you may be able to apply to. International and EU fee only funded students cannot apply for help towards childcare costs.
Please note: Only days timetabled to attend GCU or placement will be considered for an award from the Childcare Funds.
Since funds are limited, any award made may not cover your full costs.
Payments towards childcare costs only cover one trimester, therefore you may need to apply more than once over the academic year.
All childcare providers are contacted by the Student Funding Team to check attendance and payments.
If you would like advice on applying for help towards childcare costs or completing the application form contact us.


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MMMaybach Music.
Following the impressive rollout of Rozay Week, the Maybach Music Empire looks to be getting back on track as Meek Mill takes full advantage of the new found momentum generated by Rick Ross in his "Preach" freestyle. This is the Meek we know and respect so much, just spitting tough bars over hot beats. Back to the basics and we love it.
Check it out below and catch a few lines that will shock you during his last visit to Sway in the Morning afterwards.


text: Connections is our weekly communication bulletin handed out each week during Sunday service at 9:30 am. We also upload the weekly Connections to our website, and send it out to those who request an emailed copy. Please let us know if you would like to be added to our email list, or have a submission request, by filling out a request under the Connect/Stay Connected Tab.


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Day 15 and getting to house exchange 2 turns out to be a bit more complicated that we had originally planned. After leaving La Tuilerie, we set off for house exchange 4 (yes – that's right – no 4) for an overnight stay. You see, house exchange 4 is on our way to house exchange 2, and will allow us to break up the journey — and to meet our hosts for no 4.
This is the easiest leg so far – it only takes a couple of hours to reach Annick and Keith in a small village some 50 km or so south of La Rochelle. It seems that one person is nicer than the next on this journey – and Annick and Keith are no exception, as they welcome us to their house and village with great hospitality (and fluent English!). In fact, Keith is Scottish and this immediately creates a bond between us all.
WeeR is only out of the car 5 minutes, and he is in his swim shorts again – delighted to find a hot tub in the garden of our no 4 exchange – this is something we will look forward to in September as the weather cools.
Keith and Annick's is a most varied and interesting life – and we enjoy tales of their lives spent in exotic destinations like Madagascar and Morocco over an amazing Moroccan feast under vines in the garden, with some local brew called Pineau.
These are people we could listen to and talk with for much longer than an evening, and we are glad to spend the next day with them and to share another fine meal with friends – another Scotsman, would you believe!
But instead of leaving this haven of Scots folk, fine food and tales of far flung place to head north to house exchange 2, we are extended an invitation by our French friends Antony and Adeline to stay with them in Bordeaux for a day or two. This means heading back down the A62 for a couple of hours, but it will be great to see them again — and weeR is keen on their swimming pool — so we decide it is worth while! The sun is fierce now, and the sky is an amazing azure – untroubled by clouds.
More French hospitality and I do worry for my waist line. Adeline informs me that after their recent vacation in Corsica, she is aiming for a 'green' week, so I am not to be too scared. There are lots of vegetables – and even the cake is healthy! These are good people, and we enjoy practicing more French – asking "What's the French for?" every 2 minutes. They decide we know more than we let on, so they will only speak in French from herein. Thankfully, they're not too strict…and we make it through 2 evenings with lots more English and laughter.
Day 18 and we head off a couple of hours later than planned – in the searing heat – to house exchange 2 in the north of France. Doris (the GPS) has the address in her memory and we follow her every instruction. The journey is probably an hour longer than we had expected, but we arrive at a small house with wooden shutters and greet the lady hanging out the front window with a friendly "Bonjour!". She must be the friend of the people from house no 2 (whom we know have arrived safely at our place in Scotland).
Thankfully we don't take the suitcases straight out the car – it becomes apparent we are not expected. Lots of rapid French and we are none the wiser. We thrust the piece of paper on which we have written the address on in front of Madame, and she nods her head and shakes her head! She goes off to find her daughter – she speaks some English and may be able to shed light on the matter.
AnnSophie is home on vacation from Paris(lucky for us) and her English is very good. It appears we have the correct address, but this family is not exchanging houses. I begin to worry that we have been given a false address and the house exchange no 2 has been arranged by some fraudsters. Madame invites us intot her beautiful home and offers drinks and food. We politely accept some water and try not to appear too worried.
We have a phone number to call – the family from exchange 2 had arranged for their friends to hand over their keys. AnnSophie takes the number and speaks rapidly to the friend. It seems there has only been a small misunderstanding, and although the house number, street address and postal code were correct – and the same as the house we had arrived at – we were in the wrong town! We should have been in a small village 7km away… Sandrine – the friend with the key – is to come and rescue us – and we can follow her to the correct destination.
Lots of laughter and kisses and bonne vacances and kisses and good lucks and farewells, and we are on the road again…my faith in people across the globe is renewed, and we marvel at our good luck.
Finally we arrive at our destination. This is a lovely modern house – very similar in fact to our own. WeeR is thrilled to find a television for his computer games, and we are delighted with the office and internet connection, which works immediately.
A whole new region to explore. A whole new kitchen to get familiar with. How will the next two weeks fare? We unpack, eat some pasta and flop into our beds, too tired to think about much at all… Phew – it's hot in here…
Wish you were here…
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Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis.. J Psychiatry Neurosci. 39(1):31-9.. 2014.
Changes in memory performance over a 12-month period in relation to achieving symptomatic remission after a first-episode psychosis.. Schizophr Res. 153(1-3):103-8.. 2014.
Cortical thinning in temporo-parietal junction (TPJ) in non-affective first-episode of psychosis patients with persistent negative symptoms.. PLoS One. 9(6):e101372.. 2014.
Functional magnetic resonance imaging study of external source memory and its relation to cognitive insight in non-clinical subjects.. Psychiatry Clin Neurosci. 68(9):683-91.. 2014.
Neurocognition: clinical and functional outcomes in schizophrenia.. Can J Psychiatry. 59(1):5-12.. 2014.
Investigation of white matter abnormalities in first episode psychosis patients with persistent negative symptoms.. Psychiatry Res. 233(3):402-8.. 2015.
Relational Memory as a Possible Neurocognitive Marker of Schizophrenia.. JAMA Psychiatry. 72(9):946-7.. 2015.
Age-related cortical thickness trajectories in first episode psychosis patients presenting with early persistent negative symptoms.. NPJ Schizophr. 2:16029.. 2016.