Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Targeting mutant fibroblast growth factor receptors in cancer

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.

Central Queensland Mining Supplies Pty Ltd v Columbia Steel Casting Co Ltd

In Central Queensland Mining Supplies Pty Ltd v Columbia Steel Casting Co Ltd [2011] QSC 183 Applegarth J considered complaints made by the defendant about the approach the plaintiff had taken in its endeavour to comply with its disclosure obligation under r 211 of the Uniform Civil Procedure Rules 1999 (Qld). The judgment also provides an indication of the direction the court is taking in relation to disclosure and document management in matters involving large numbers of documents.

Just do it : action's central role in venture creation

This study examined the effect that venture creation action has on the outcomes of nascent entrepreneurship. A theoretical model was developed which proposes action as a fundamental mechanism in venture creation. Thus, action should rightly be considered as a means rather than an end in itself. In this respect, action transmits the effects of venture resource endowments on to venture creation outcomes. This conceptual model was empirically supported in a random sample of nascent ventures. Ventures with higher levels of human or social capital tend to be more active in venture creation. In turn, more active venture attempts are more likely to achieve improved results.

Limestone and speleothem trace element geochemistry as tools for palaeoclimatic reconstruction, Mount Etna region, central-coastal Queensland

This study investigated potential palaeoclimate proxies provided by rare earth element (REE) geochemistry in speleothems and in clay mineralogy of cave sediments. Speleothem and sediment samples were collected from a series of cave fill deposits that occurred with rich vertebrate fossil assemblages in and around Mount Etna National Park, Rockhampton (central coastal Queensland). The fossil deposits range from Plio- Pleistocene to Holocene in age (based on uranium/thorium dating) and appear to represent depositional environments ranging from enclosed rainforest to semi-arid grasslands. Therefore, the Mount Etna cave deposits offer the perfect opportunity to test new palaeoclimate tools as they include deposits that span a known significant climate shift on the basis of independent faunal data. The first section of this study investigates the REE distribution of the host limestone to provide baseline geochemistry for subsequent speleothem investigations. The Devonian Mount Etna Beds were found to be more complex than previous literature had documented. The studied limestone massif is overturned, highly recrystallised in parts and consists of numerous allochthonous blocks with different spatial orientations. Despite the complex geologic history of the Mount Etna Beds, Devonian seawater-like REE patterns were recovered in some parts of the limestone and baseline geochemistry was determined for the bulk limestone for comparison with speleothem REE patterns. The second part of the study focused on REE distribution in the karst system and the palaeoclimatic implications of such records. It was found that REEs have a high affinity for calcite surfaces and that REE distributions in speleothems vary between growth bands much more than along growth bands, thus providing a temporal record that may relate to environmental changes. The morphology of different speleothems (i.e., stalactites, stalagmites, and flowstones) has little bearing on REE distributions provided they are not contaminated with particulate fines. Thus, baseline knowledge developed in the study suggested that speleothems were basically comparable for assessing palaeoclimatically controlled variations in REE distributions. Speleothems from rainforest and semi-arid phases were compared and it was found that there are definable differences in REE distribution that can be attributed to climate. In particular during semiarid phases, total REE concentration decreased, LREE became more depleted, Y/Ho increased, La anomalies were more positive and Ce anomalies were more negative. This may reflect more soil development during rainforest phases and more organic particles and colloids, which are known to transport REEs, in karst waters. However, on a finer temporal scale (i.e. growth bands) within speleothems from the same climate regime, no difference was seen. It is suggested that this may be due to inadequate time for soil development changes on the time frames represented by differences in growth band density. The third part of the study was a reconnaissance investigation focused on mineralogy of clay cave sediments, illite/kaolinite ratios in particular, and the potential palaeoclimatic implications of such records. Although the sample distribution was not optimal, the preliminary results suggest that the illite/kaolinite ratio increased during cold and dry intervals, consistent with decreased chemical weathering during those times. The study provides a basic framework for future studies at differing latitudes to further constrain the parameters of the proxy. The identification of such a proxy recorded in cave sediment has broad implications as clay ratios could potentially provide a basic local climate proxy in the absence of fossil faunas and speleothem material. This study suggests that REEs distributed in speleothems may provide information about water throughput and soil formation, thus providing a potential palaeoclimate proxy. It highlights the importance of understanding the host limestone geochemistry and broadens the distribution and potential number of cave field sites as palaeoclimate information no longer relies solely on the presence of fossil faunas and or speleothems. However, additional research is required to better understand the temporal scales required for the proxies to be recognised.

Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine : involvement of adenosine and dopamine receptors

Purine compounds, such as caffeine, have many health-promoting properties and have proven to be beneficial in treating a number of different conditions. Theacrine, a purine alkaloid structurally similar to caffeine and abundantly present in Camellia kucha, has recently become of interest as a potential therapeutic compound. In the present study, theacrine was tested using a rodent behavioral model to investigate the effects of the drug on locomotor activity. Long Evans rats were injected with theacrine (24 or 48 mg/kg, i.p.) and activity levels were measured. Results showed that the highest dose of theacrine (48 mg/kg, i.p.) significantly increased locomotor activity compared to control animals and activity remained elevated throughout the duration of the session. To test for the involvement of adenosine receptors underlying theacrine's motor-activating properties, rats were administered a cocktail of the adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA; 0.1 mg/kg, i.p.) and A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.2 mg/kg, i.p.). Pre-treatment with theacrine significantly attenuated the motor depression induced by the adenosine receptor agonists, indicating that theacrine is likely acting as an adenosine receptor antagonist. Next, we examined the role of DA D₁ and D₂ receptor antagonism on theacrine-induced hyperlocomotion. Both antagonists, D₁R SCH23390 (0.1 or 0.05 mg/kg, i.p.) and D₂R eticlopride (0.1 mg/kg, i.p.), significantly reduced theacrine-stimulated activity indicating that this behavioral response, at least in part, is mediated by DA receptors. In order to investigate the brain region where theacrine may be acting, the drug (10 or 20 μg) was infused bilaterally into nucleus accumbens (NAc). Theacrine enhanced activity levels in a dose-dependent manner, implicating a role of the NAc in modulating theacrine's effects on locomotion. In addition, theacrine did not induce locomotor sensitization or tolerance after chronic exposure. Taken together, these findings demonstrate that theacrine significantly enhances activity; an effect which is mediated by both the adenosinergic and dopaminergic systems.

Neuronal nicotinic acetylcholine receptors : neuroplastic changes underlying alcohol and nicotine addictions

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.

Visual sensitivity loss in the central thirty degrees of visual field is associated with diabetic peripheral neuropathy

Aims/hypothesis: Impaired central vision has been shown to predict diabetic peripheral neuropathy (DPN). Several studies have demonstrated diffuse retinal neurodegenerative changes in diabetic patients prior to retinopathy development, raising the prospect that non-central vision may also be compromised by primary neural damage. We hypothesise that type 2 diabetic patients with DPN exhibit visual sensitivity loss in a distinctive pattern across the visual field, compared with a control group of type 2 diabetic patients without DPN. Methods: Increment light sensitivity was measured by standard perimetry in the central 30 degree of visual field for two age-matched groups of type 2 diabetic patients, with and without neuropathy (n=40/30). Neuropathy status was assigned using the neuropathy disability score. Mean visual sensitivity values were calculated globally, for each quadrant and for three eccentricities (0-10 degree , 11-20 degree and 21-30 degree ). Data were analysed using a generalised additive mixed model (GAMM). Results: Global and quadrant between-group visual sensitivity mean differences were marginally but consistently lower (by about 1 dB) in the neuropathy cohort compared with controls. Between-group mean differences increased from 0.36 to 1.81 dB with increasing eccentricity. GAMM analysis, after adjustment for age, showed these differences to be significant beyond 15 degree eccentricity and monotonically increasing. Retinopathy levels and disease duration were not significant factors within the model (p=0.90). Conclusions/interpretation: Visual sensitivity reduces disproportionately with increasing eccentricity in type 2 diabetic patients with peripheral neuropathy. This sensitivity reduction within the central 30 degree of visual field may be indicative of more consequential loss in the far periphery.

Using the collaborative evidence based practice model : a systematic review and uptake of chlorhexidine-impregnated sponge dressings on central venous access devices in a tertiary cancer centre

Background: Greater research utilisation in cancer nursing practice is needed, in order to provide well-informed and effective nursing care to people affected by cancer. This paper aims to report on the implementation of evidence-based practice in a tertiary cancer centre. Methods: Using a case report design, this paper reports on the use of the Collaborative Model for Evidence Based Practice (CMEBP) in an Australian tertiary cancer centre. The clinical case is the uptake of routine application of chlorhexidine-impregnated sponge dressings for preventing centrally inserted catheter-related bloodstream infections. In this case report, a number of processes that resulted in a service-wide practice change are described. Results: This model was considered a feasible method for successful research utilisation. In this case report, chlorhexidine-impregnated sponge dressings were proposed and implemented in the tertiary cancer centre with an aim of reducing the incidence of centrally inserted catheter-related bloodstream infections and potentially improving patient health outcomes. Conclusion: The CMEBP is feasible and effective for implementing clinical evidence into cancer nursing practice. Cancer nurses and health administrators need to ensure a supportive infrastructure and environment for clinical inquiry and research utilisation exists, in order to enable successful implementation of evidence-based practice in their cancer centres.

The causes of sinuous crustal-scale deformation patterns in hot orogens: Evidence from scaled analogue experiments and the southern Central Andes

The cause of upper-crustal segmentation into rhomb-shaped, shear zone-bound domains associated with contractional sedimentary basins in hot, wide orogens is not well understood. Here we use scaled multilayered analogue experiments to investigate the role of an orogen-parallel crustal-strength gradient on the formation of such structures. We show that the aspect ratio and size of domains, the sinuous character and abundance of transpressional shear zones vary with the integrated mechanical strength of crust. Upper-crustal deformation patterns and the degree of strain localization in the experiments are controlled by the ratio between the brittle and ductile strength in the model crust as well as gradients in tectonic and buoyancy forces. The experimental results match the first-order kinematic and structural characteristics of the southern Central Andes and provide insight on the dynamics of underlying deformation patterns in hot, wide orogens.