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Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk. To address this, we analyzed data from 100 small molecules to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package. These models range from the assessment of in-vitro binding and functional profiles at receptors or transporters typically associated with abuse through in-vivo models including locomotor activity, drug discrimination, and self-administration in rodents. Data from subjective report assessments in humans following acute dosing of compounds were also included. The predictive value of each model was then evaluated relative to the scheduling status of each drug in the USA. In recognition of the fact that drug scheduling can be influenced by factors other than the pharmacology of the drug, we also evaluated the predictive value of each assay for the outcome of the human subjective effects assessment. This approach provides an objective and statistical assessment of the predictive value of many of the models typically applied within the pharmaceutical industry to evaluate abuse potential risk. In addition, the impact of combining information from multiple models was examined. This analysis adds to our understanding of the predictive value of each model, allows us to critically evaluate the benefits and limitations of each model, and provides a method for identifying opportunities for improving our assessment and prediction of abuse liability risk in the future.

The quality demands of the pharmaceutical industry require prescription medicines to be consistent in their active ingredient content. Achieving this, using raw cannabis as a feedstock, is especially challenging. The plant material is extremely inhomogeneous, and the ratios of active ingredients are affected by a range of factors. These include the genetics of the plant, the growing and storage conditions, the state of maturity at harvest, and the methods used to process and formulate the material. The reasons for this variability are described, with particular emphasis on the botanical considerations. To produce the complex botanical medicine Sativex®, which contains the cannabinoids Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) and a range of other ingredients, GW Pharmaceuticals had to manage these variables. This medicine, for the treatment of spasticity due to multiple sclerosis, is the first cannabis-based medicine to be approved in the UK. The company's methodology for producing this and other chemotypes is described.

We detail the production of metallic spherules in laboratory oblique shock impact experiments, and their applicability (1) to textures in a partly shock-melted chondritic meteorite and (2) to the occurrence of palaeomagnetically important fine iron or iron alloy particles in the lunar regolith. Samples recovered from 29–44 GPa, 800 ns, experiments revealed melting and textures reminiscent of metallic spherules in the Yanzhuang H-chondrite, including “dumbbell” forms and other more complex morphologies. Our experiments demonstrate that metallic spherules can be produced via oblique impact sliding at lower velocities (1.85 km s^(−1)) than are generally assumed in previous work associated with bulk-shock melting, and that oblique impact sliding is a viable mechanism for producing spherules in shock-induced veins in moderately shocked meteorites. Significantly, our experiments also produced fine metallic (iron alloy) spherules within the theoretical narrow size range (a few tens of nanometers for slightly ellipsoidal particles) for stable single-domain (SSD) particles, which are the most important palaeomagnetically, since they can record lunar and planetary magnetic fields over geological time periods. The experiments also produced spherules consistent with superparamagnetic (SP) and multidomain (MD) particle sizes. The fine SSD and SP particles on the lunar surface are currently thought to have been formed predominantly by space weathering processes. Our experiments suggest that oblique shock impact sliding may be a further means of producing the SSD and SP iron or iron alloy particles observed in the lunar regolith, and which are likely to occur in the regoliths of Mercury and other planetary bodies.

The development of diet-induced obesity (DIO) can potently alter multiple aspects of dopamine signaling, including dopamine transporter (DAT) expression and dopamine reuptake. However, the time-course of diet-induced changes in DAT expression and function and whether such changes are dependent upon the development of DIO remains unresolved. Here, we fed rats a high (HFD) or low (LFD) fat diet for 2 or 6 weeks. Following diet exposure, rats were anesthetized with urethane and striatal DAT function was assessed by electrically stimulating the dopamine cell bodies in the ventral tegmental area (VTA) and recording resultant changes in dopamine concentration in the ventral striatum using fast-scan cyclic voltammetry. We also quantified the effect of HFD on membrane associated DAT in striatal cell fractions from a separate group of rats following exposure to the same diet protocol. Notably, none of our treatment groups differed in body weight. We found a deficit in the rate of dopamine reuptake in HFD rats relative to LFD rats after 6 but not 2 weeks of diet exposure. Additionally, the increase in evoked dopamine following a pharmacological challenge of cocaine was significantly attenuated in HFD relative to LFD rats. Western blot analysis revealed that there was no effect of diet on total DAT protein. However, 6 weeks of HFD exposure significantly reduced the 50 kDa DAT isoform in a synaptosomal membrane-associated fraction, but not in a fraction associated with recycling endosomes. Our data provide further evidence for diet-induced alterations in dopamine reuptake independent of changes in DAT production and demonstrates that such changes can manifest without the development of DIO.

A previous study has shown that allicin produces changes in aqueous humor dynamics, and this study was conducted to examine possible cellular mechanisms. In rabbit nonpigmented ciliary epithelial cells, basal levels of [Ca 2+ ], were determined to be 164 ± 34 nM. Allicin, a sulfhydryl-reactive agent, induced Ca 2+ transients at 0.01 mM and at 0.2 mM, the Ca 2+ transient peaked at 732 ± 35 nM. Allicin-induced Ca 2+ transients were prevented by pretreatment with dithiothreitol which did not affect the basal Ca 2+ levels. Allicin had only a slight, insignificant, effect on L-type Ca 2+ currents, and allicin-induced Ca 2+ transients were also present under extracellular Ca 2+ -free conditions. These data suggest that intracellular Ca 2+ stores are the most probable source of allicin's effect. Pretreatment of cells with ryanodine, an inhibitor of Ca 2+ -induced-Ca 2+ -release, inhibited allicin-induced Ca 2+ transients, but the basal Ca 2+ levels were unaffected by ryanodine. Thus, allicin-induced Ca 2+ transients are most likely mediated through ryanodine-sensitive intracellular Ca 2+ stores.

(1996). Democratisation and the environment: NGOs and deforestation policies in India (Karnataka) and Indonesia (North Sumatra) The Journal of Commonwealth & Comparative Politics: Vol. 34, NGOs and Environmental Policies: Asia and Africa, pp. 9-37.

Oxymetazoline, an alpha 2 agonist, was active in lowering intraocular pressure in normal and sympathetically denervated rabbit eyes. Ocular hypotension was accompanied by decreased aqueous humor inflow. Topical pretreatment with rauwolscine, an alpha 2 antagonist, reduced the oxymetazoline-induced hypotensive effect more in contralateral than in ipsilateral eyes indicating the possible involvement of central alpha 2 adrenoceptors. Efaroxan, a relatively selective imidazoline antagonist, and diclofenac, a cyclooxygenase inhibitor, failed to inhibit the oxymetazoline-induced ocular hypotensive response. Oxymetazoline induced mydriasis in treated eyes at all doses. In in vitro studies, oxymetazoline inhibited isoproterenol-stimulated cAMP production in rabbit iris-ciliary bodies and cultured rabbit nonpigmented ciliary epithelial cells. The inhibition of cAMP accumulation induced by oxymetazoline was antagonized by rauwolscine or by BRL-44408, a relatively selective alpha 2A-adrenoceptor antagonist. These data indicate that oxymetazoline lowered intraocular pressure by activating alpha 2A receptors (ciliary epithelium) and that the ocular hypotensive effect was not totally dependent on intact sympathetic nerves. Results suggest that mechanisms involving centrally mediated effects of oxymetazoline are probable and this possibility is currently under investigation.

To examine ocular actions by rilmenidine, an imidazoline1 and alpha 2 adrenoceptor agonist.Intraocular pressure was measured in normal and sympathetically denervated rabbits by pneumatonometry. Electrically stimulated 3H-norepinephrine release from sympathetic nerves was determined in isolated, perfused rabbit iris-ciliary bodies. cAMP levels were evaluated in rabbit iris-ciliary bodies by radioimmunoassay. Ca2+ concentrations were measured in rabbit transformed nonpigmented ciliary epithelial cells by fluorescence ratio microscopy.Topical, unilateral administration of rilmenidine produced hypotensive responses in normal rabbits which were antagonized by either bilaterally administered efaroxan, an imidazoline receptor antagonist or rauwolscine, an alpha 2 receptor antagonist. Sympathectomy also eliminated the ocular hypotensive response. Rilmenidine (0.001, 0.01, 0.1, 1 microM) caused 5 +/- 1%, 18 +/- 5%, 35 +/- 10%, and 48 +/- 9% inhibition, respectively, of 3H-norepinephrine overflow whereas 10 microM efaroxan or rauwolscine caused enhancement of norepinephrine release by 102 +/- 23% or 86 +/- 25%, respectively. Furthermore, pretreatment with efaroxan or rauwolscine partially antagonized the inhibition of norepinephrine release induced by rilmenidine. In other experiments, rilmenidine (1 microM) inhibited isoproterenol-stimulated cAMP accumulation in rabbit iris-ciliary bodies by 43 +/- 9% which was antagonized by 10 microM efaroxan or rauwolscine. Rilmenidine induced large increases in [Ca2+]i in rabbit nonpigmented ciliary epithelial cells which were effectively antagonized by efaroxan or rauwolscine.These in vivo and in vitro data suggest that the ocular hypotensive activity induced by rilmenidine is due, in part, to suppression of sympathetic neuroeffector function in the rabbit ciliary body and that alpha 2 adrenergic receptors and/or imidazoline1 receptors are involved.

This study was performed to examine some ocular actions of an opioid agonist. Experiments were performed to evaluate the effects of a delta opioid agonist, DPDPE ([D-pen2, D-pen5]enkephalin (where pen = penicillamine)), on: 1) intraocular pressure (IOP) in rabbits; 2) cAMP accumulation in rabbit iris ciliary bodies (ICBs). Unilateral, topical administration of DPDPE caused bilateral depression of IOP. Intravitreal injection of DPDPE caused a greater IOP decrease than intravitreal injection of NaH2PO4 (vehicle). Topical administration of naloxone partially inhibited the effect of DPDPE on IOP in normal rabbits. In other experiments, DPDPE suppressed both basal and isoproterenol (ISO)-stimulated cAMP accumulation in ICBs. The presence of naltrindole (NTI), a delta receptor antagonist, did not prevent the suppression of cAMP levels by DPDPE. The conclusions drawn from the findings suggest that the lowering of IOP by DPDPE is mediated, in part, by actions at postjunctional (ciliary body) sites and may involve an atypical opioid receptor.

Geothermal energy has the potential to reduce both the production costs and greenhouse gas emissions associated with oil sands production in the Western Canada sedimentary basin (WCSB) in Northern Alberta. This is currently being investigated through the Helmholtz-Alberta Initiative, which is a research collaboration between the Helmholtz Association of German Research Centres and the University of Alberta. The primary area of interest is in the Athabasca oil sands where the WCSB is relatively thin and the Phanerozoic sedimentary succession is thinning toward the northeast and subcropping onto the Canadian shield. Beneath the Athabasca oil sands, the Precambrian basement is at a depth of 0.5 km (0.31 mi) and can be studied by the analysis of the geophysical logs and core and rock chip samples from a deep 2.4 km (1.49 mi) well drilled into the granitic basement rocks. A second study area is located around Peace River, where the WCSB is about 2 km (1.24 mi) thick, and data from the Phanerozoic section are being analyzed. The research is focused on an evaluation of potential heat sources for oil-sands processing in areas with existing leases. Revised maps of the temperature at the top of the Precambrian basement confirms that temperatures greater than 60C could be found within the sedimentary strata in the Peace River oil sands area. This temperature will be found in the crystalline Precambrian basement beneath the Athabasca oil sands. Extraction of heat will require the development of engineered geothermal systems with artificial porosity created and fluids circulated at depth. The economics of this process appear favorable, and additional research will define the feasibility of this type of heat production in more detail.

Microfluidic technology provides a unique means of interfacing known analytical methods for embryo developmental physiology and molecular phenotypes in real time. Proof of concept devices have been demonstrated for quantitation of all relevant biological parameters, with commercial translation more prevalent for genomic and proteomic detection, wherein microfluidic devices might form the next generation of PGS technologies. While poly(dimethyl)siloxane devices are amenable to culture and microscopic visualization of growing embryos, there is still no easily implemented substitute for standard incubation techniques, although there is the very real prospect of integration of a microfluidic device for morphokinetic analysis, as an adjunct to time-lapse imaging. It may still be some time before the wealth of experimental concepts in microfluidic sciences are translated into a clinically relevant diagnostic tool for IVF, but these should provide a gateway to future devices with more automation and less user intervention, to systematize assisted reproductive technology laboratories. An ideal device could be an active, continuous culture platform with integrated time-lapse imaging and metabolomic or secretomic endpoints, providing real-time physiological outputs as the embryo develops, as well as sampling for interface with more detailed molecular analyses.

A series of environmental samples, comprising fly ash, caustic wash water from regeneration of a petrochemical reforming catalyst, fish homogenates, soil, and pulp mill sludge, were analyzed for dioxin-like compounds by an assay involving competitive binding of a reference radioligand and an extract from the sample to mouse hepatic Ah receptor ; the results were compared with GC/MS. The bioassay generally gave higher TEQ values than GC/MS. Further analysis by GC/MS in most cases identified much of the additional Ah receptor-active material as coplanar PCBs and PAHs.

These experiments sought to: (1) determine if alpha 2/I1 agonists that are topically active on the eye have similar effects on intraocular pressure when applied to the CNS and (2) ascertain whether these agents lower IOP, in part, via central alpha 2 receptors and/or imidazoline (I1) receptors. New Zealand White rabbits were fitted with chronic indwelling stainless-steel guide cannulas in several brain regions including the lateral ventricle, third ventricle (3V), or medullary intermediate reticular zone. Animals were allowed 5 days' recovery time prior to experiments measuring the effects of drugs on IOP via applanation pneumatonometry. Some animals were also pretreated with 400 micrograms of 6-hydroxydopamine injected into the lateral ventricle to determine the site of action of these alpha 2/I1 agonists. In initial experiments involving microinjection into the lateral ventricle, UK-14,304-18 evoked ocular hypotension that was inhibited by the alpha 2-antagonist rauwolscine but not by the I1-receptor antagonist efaroxan. Conversely, moxonidine and oxymetazoline were preferentially inhibited by efaroxan rather than by rauwolscine. Subsequently, experiments have shown that moxonidine and oxymetazoline, but not UK-14,304-18 will lower intraocular pressure when microinjected into the medullary intermediate reticular zone region and that efaroxan, but not rauwolscine, will inhibit ocular hypotension induced by moxonidine and oxymetazoline. Pretreatment with 6-hydroxydopamine (48 hours) completely eliminated the ocular hypotension induced by moxonidine. These preliminary data demonstrate that alpha 2- and I1-receptors in the brain mediate ocular hypotension induced by UK-14,304-18 and moxonidine/oxymetazoline, respectively. Moreover, the medullary intermediate reticular zone area of the brain stem is the probable presynaptic site mediating ocular hypotension induced by moxonidine and oxymetazoline.

Human services are increasingly regarded as a discrete field of study and an area of public concern. However, little work has been done outside the USA in determining the make‐up of knowledge in the field. This paper presents an initial attempt to study what constitutes the knowledge base for the child care profession in the UK. To do this the citations of five British child care journals were analysed for 1993. Reference type, country code and self‐citations of journals and authors were recorded and analysed. Comparisons were drawn with an earlier citation study of social work. The study confirmed a 1:1 relationship between books and journals and showed the diffuseness of the sources upon which child care professionals draw. Although books were the most cited category individual books were rarely cited multiply. A core of journals was identified but child care journals were only fifth in frequency of citations after books, other journals, grey literature and other child‐orientated journals. This suggests that the child care profession in the UK is outward‐looking, although almost wholly dependent on the English language. Pointers for further research are suggested.

Chemicals that bind to protein may cause immunological responses that include allergic contact hypersensitivity mediated by T cells. Various animal models have been used to predict chemical-mediated contact sensitization. One assay that has recently been developed utilizes the proliferation response induced in the draining auricular lymph node after exposure to contact sensitizers. This assay has been modified to a simpler method that results in the more rapid processing of samples with greater reproducibility. Isothiazolones are chemicals used as biocides in various applications which at greater than use concentrations may cause allergic contact hypersensitivity. The mouse auricular lymph node cell proliferation assay has been used to examine the potential of various isothiazolones to induce contact sensitization. The extent of lymph node cell proliferation was dependent on the concentration of isothiazolone, the vehicle used in the application, and the ability of isothiazolone to bind to protein. Kathon biocide contains two isothiazolones: 5-chloro-2-methyl-4-isothiazolin-3-one (CMI)2 and 2-methyl-4-isothiazolin-3-one (MI). In vivo studies have shown that protein binding correlates with auricular lymph node cell proliferation and an increase in auricular lymph node size. CMI, which binds to protein, induced an auricular lymph node cell proliferation response while MI, which poorly binds to protein, neither stimulated a proliferative response nor induced an increase in lymph node size at concentrations similar to CMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemicals that bind to protein may cause immunological responses that include respiratory hypersensitivity mediated by IgE antibodies. The BALB/c mouse model has been used to characterize chemicals that induce an IgE antibody response. This model may be a useful predictive tool for the evaluation and classification of chemicals that induce IgE antibody production in humans. Total serum IgE content was determined after dermal exposure to various concentrations of isophorone diisocyanate (IPDI), diphenylmethane-4,4'-diisocyanate (MDI), toluene diisocyanate (TDI), 2,4-dinitrochlorobenzene (DNCB), trimellitic anhydride (TMA), formaldehyde (FA), and glutaric dialdehyde (GA). Chemicals were generally administered in acetone:olive oil on Days 1 and 7. Mouse serum was collected 14 days after the initial administration and subsequently total IgE antibody content was evaluated by an enzyme-linked immunosorbent assay. Mice treated with TMA, IPDI, MDI, and TDI had statistically (p < 0.01) higher concentrations of serum IgE antibodies than control animals. Total serum IgE content was examined at various times after TMA or TDI administration. Mice treated with a total of 37.5 mg TMA or 3 mg TDI had elevated IgE antibodies for 8-41 days after initial administration. In other studies where various concentrations of TDI were administered 15 times over a 3-week period or 30 times over a 6-week period, the apparent TDI threshold for IgE antibody production significantly increased with an increase in the number of TDI applications.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent work has shown the potential usefulness of magnetic susceptibility and hysteresis techniques in assessing the impact of fine grained hematite on permeability in red and white sandstone samples (Potter et al. 2009; Ali and Potter, 2011b). The present study demonstrates that hematite cementation is a major controlling factor on permeability in a deep tight gas reservoir in the North Sea. Magnetic susceptibility measurements undertaken on core plugs in this reservoir showed a strong correlation with probe permeability performed on the same plug samples. Moreover, samples with a higher content of hematite exhibited lower permeability values. Thin section analysis revealed the presence of a thin (approximately 10-15µm) rim of hematite cement surrounding quartz grains, which block pore connections and reduce permeability. Magnetic hysteresis measurements on some representative samples indicated a very similar paramagnetic clay content in both the low and high permeability samples suggesting that the clay (mainly illite) is not the dominant controlling factor producing the variations in permeability that we observed. Since samples with higher hematite content exhibit lower permeability it appears that hematite is a major control on the permeability variations seen in this reservoir. Whilst the paramagnetic clays undoubtedly have an influence on the absolute permeability value, since increasing paramagnetic clay content has previously been shown to correlated with decreasing permeability (Potter, 2007), small amounts of hematite cement can significantly further reduce the permeability. Analysis of the magnetic hysteresis parameters on a Day plot indicated that the permeability was essentially independent of the hematite particle size for the fine particle sizes observed in this study.

Because alpha-2 (alpha 2) adrenoceptor-mediated inhibition of signal transduction mechanisms is regulated, in part, by inhibitory G (Gi) protein, we studied the effects of pertussis toxin (PTX) pretreatment on alpha 2 adrenergic agonist, UK 14,304-18 (UK; brimonidine)-induced: (1) changes in intraocular pressure (IOP) and aqueous flow rate of rabbits; (2) modulation of 3H-norepinephrine (NE) overflow of rabbit iris-ciliary bodies (ICBs) and (3) accumulation of cyclic AMP in rabbit ICBs and cultured non-pigmented ciliary epithelial (NPE) cells. Results showed that UK (50 micrograms) lowered the IOP of normal rabbits by 8 +/- 1 mmHg (n = 8) at 3 hr when treated topically and that the reduction of IOP was accompanied by a decrease in aqueous humor inflow (35%, n = 5). Therefore, it was postulated that these UK-induced effects involve activation of a Gi protein linked to alpha 2 adrenoceptors. In PTX-pretreated (2.5 micrograms kg-1, i.a.) rabbits, hypotensive responses to UK were reduced by 50% and 70% (n = 8) at days 4 and 7 post PTX treatment, respectively. The suppression of aqueous humor inflow induced by UK was also prevented by the PTX treatment. In isolated, perfused rabbit ICBs, UK (1 microM) caused 50% inhibition of 3H-NE overflow from electrical field stimulation. Pretreatment with PTX (150 ng ml-1, 4 hr) partially prevented UK-induced inhibition of NE overflow. In in vitro assays of postjunctional alpha 2 adrenoceptor activity, UK (1 microM) inhibited isoproterenol (ISO, 1 microM)-stimulated cAMP accumulation by 45% and 48% in ICBs and NPE cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The physics of mineral grain sliding, which occurs upon dynamic compression of rocks, is investigated by shock loading single crystals of corundum (Al_2O_3) and periclase (MgO) in contact obliquely in impact experiments. Energy dispersive X-ray analysis and X-ray diffraction studies of samples recovered from 26–36 GPa, 800 ns experiments indicated that under certain conditions a spinel phase of composition MgAl_2O_4 and thickness ≤20 µm was produced at the interface between the two crystals. Although the computed shock (continuum) temperatures were below those necessary to melt the initial oxides, the spinel nonetheless appears to have formed as a result of localised melting, via grain boundary sliding friction, followed by rapid quenching. Scanning electron microscopy (SEM) revealed some evidence for such melting. Moreover, the timescale of the experiments is too short for solid state diffusion (during the shock state) to explain the observed spinel thickness, although defect enhanced solid state diffusion, subsequent to loading and unloading, remains a possibility. The results also reinforce other recent observations and theories of heterogeneous deformation in minerals.

Assessment principles and methodologies are applied to a framework for implementing a learner-focused internal program review process.

Solid-phase microextraction (SPME) was investigated as a solvent-free alternative method for the extraction and analysis of nonpolar semivolatile analytes. Analytes were extracted into a polymeric phase immobilized onto a fusedsilica fiber. The fiber was then inserted directly into the injector of a gas chromatograph, and the analytes were thermally desorbed. This new technique allows sampling directly from the source (lake, drinking fountain, etc.) and, therefore, eliminates the loss of analytes through adsorption onto container walls and saves transport costs

Background Repeated exposure to drugs of abuse and stress increase dynorphin, a κ opioid receptor (KOR) ligand, in the nucleus accumbens (NAc). Acute KOR activation produces dysphoria that might contribute to addictive behavior. How repeated KOR activation modulates reward circuitry is not understood. Methods We used intracranial self-stimulation (ICSS), a method that provides a behavioral index of reward sensitivity, to measure the effects of repeated administration of the KOR agonist salvinorin A (salvA) (2 mg/kg) on the reward-potentiating effects of cocaine (5.0 mg/kg). In separate rats, we measured the effects of salvA on activation of extracellular signal regulated kinase (ERK), cyclic adenosine monophosphate (cAMP) response element binding protein, and c-Fos within the NAc. Results SalvA had biphasic effects on reward: an immediate effect was to decrease the rewarding impact of ICSS, whereas a delayed effect was to increase the rewarding impact of ICSS. Repeated salvA produced a net decrease in the reward-potentiating effects of cocaine. In the NAc, both acute and repeated salvA administration increased phosphorylated ERK, whereas only acute salvA increased c-Fos and repeated salvA increased phosphorylated cAMP response element binding protein. The KOR antagonist nor-binaltorphimine (20 mg/kg) blocked the immediate and delayed effects of salvA and prolonged the duration of cocaine effects in ICSS. Conclusions Repeated salvA might trigger opponent processes such that "withdrawal" from the dysphoric effects of KOR activation is rewarding and decreases the net rewarding valence of cocaine. The temporal effects of salvA on ERK signaling suggest KOR-mediated engagement of distinct signaling pathways within the NAc that might contribute to biphasic effects on reward sensitivity.

PURPOSE. Mice deficient in the secreted protein Norrin or its receptor Frizzled-4 (FZD4) exhibit incomplete vascularization of the neural retina. However, because of early retinal vascular defects in the knockout models, it has not been possible to study FZD4 contribution in ocular neovascular disease. To further understand the role of this signaling pathway in physiological and pathologic angiogenesis, the authors generated a monoclonal antibody that neutralizes FZD4 function in vivo. METHODS. Antibodies were generated by immunizing Fzd4 knockout mice with the cysteine-rich domain of FZD4. A monoclonal antibody (1.99.25) was discovered that antagonizes Norrin- and WNT3A-induced β-catenin accumulation in vitro. 1.99.25 and an isotype-matched negative control antibody were evaluated in models of developmental retinal angiogenesis, oxygen-induced retinopathy, and retinal angiomatous proliferation. The authors also investigated the role of FZD4 in maintaining the blood-retina barrier in normal adult mice. RESULTS. Administration of 1.99.25 inhibited physiological and pathologic sprouting angiogenesis within the retina. Inhibition of FZD4 in developing retinal vascular networks caused the upregulation of PLVAP, a protein normally associated with fenestrated, immature endothelium in the CNS. In the adult neural retina, the administration of 1.99.25 induced PLVAP expression in the deep capillary bed and enabled extravasation of small and large molecules through the blood-retina barrier. CONCLUSIONS. These results demonstrate that FZD4 is required for physiological and pathologic angiogenesis in the retina and for regulation of retinal endothelial cell differentiation. The authors also show that FZD4 is critical for maintaining the integrity of the mature blood-retina barrier.

In vitro metabolism studies have indicated that the tumorigenic environmental pollutant 1,6-dinitropyrene has the potential to bind covalently to DNA and to induce oxidative DNA damage. We have determined if 1,6-dinitropyrene treatment will cause both types of DNA damage in vivo. Female Sprague-Dawley rats were given a single intraperitoneal injection of 1,6-dinitropyrene, and covalent DNA adduct formation, as indicated by the presence of N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, and oxidative DNA damage, as indicated by increases in 5-hydroxymethyl-2′-deoxyuridine and 8-hydroxy-2′-deoxyguanosine, were assessed at 3, 12, 24 and 48 h after dosing. 32P-postlabeling analyses of DNA isolated from liver, mammary gland, bladder and nucleated blood cells indicated the formation of N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, with the levels being highest in the bladder. 5-hydroxy-methyl-2′-deoxyuridine was detected in DNA from each of these tissues, and the levels of this oxidized nucleoside were higher in the mammary glands and livers of 1,6-dinitropyrene-treated rats. 1,6-Dinitropyrene dosing did not affect the levels of 8-hydroxy-2′-deoxyguanosine in these two tissues. These results indicate that exposure to 1,6-dinitropyrene can result in increased levels of 5-hydroxymethyl-2′-deoxyuridine in addition to covalent DNA adduct formation.

An octahydrobenzo[f]quinoline compound, Ha117, was examined for activity on: (1) intraocular pressure and in normal, sympathectomized and water loaded rabbits and aqueous flow rate in normal and sympathectomized rabbits, respectively; (2) contractions of the cat nictitating membrane elicited by electrical stimulation of cervical sympathetic nerves; (3) cAMP accumulation in the isolated rabbit iris root-ciliary body preparation. Ha117 lowered intraocular pressure and aqueous flow rate in normal but not in sympathectomized rabbits. Elevated intraocular pressure produced by water loading was suppressed by Ha117 and pretreatment with metoclopramide antagonized the inhibitory effect of Ha117. Neuronally mediated contractions of the nictitating membrane were inhibited in a dose-related fashion by Ha117, and inhibitory effects were antagonized by domperidone. Ha117 and an analog, Ha118, did not suppress isoproterenol- and vasoactive intestinal peptide-induced accumulation of cAMP in the rabbit iris root/ciliary body. In vivo results in rabbit and cat models suggest that the ocular hypotensive effect of Ha117 is mediated by an action on prejunctional dopamine (DA2) receptors. In vitro data in the rabbit iris root/ciliary body suggest that Ha117 and Ha118-induced lowering of intraocular pressure does not involve postjunctional suppression of cAMP accumulation.

The intent of this work was to examine the actions of allicin on 1) intraocular pressure (IOP) in normal and unilaterally sympathectomized (SX) rabbits; 2) cAMP accumulation in the rabbit iris-ciliary body (ICB) and cultured nonpigmented epithelial (NPE) ciliary body cells; and 3) 3H-norepinephrine (NE) release by calculating fractional tritium overflow in response to electrical field stimulation (EFS, 5 Hz, 12 V/cm) in isolated, perfused rabbit ICBs. Allicin, one of the active compounds produced by garlic, was evaluated on IOP and it was determined that allicin (1, 2.5, or 10 micrograms), topically, but not the precursor, alliin (10 micrograms), lowered the IOP unilaterally in normal rabbits. Allicin (10 micrograms) reduced the IOP by 6 +/- 1 mmHg (n = 4) in normal rabbits at 2 hrs (maximum response) whereas no change occurred in sympathectomized rabbit eyes. Moreover, allicin (0.01, 0.1, or 1 microM) caused 40, 40, or 52% inhibition, respectively, of 3H-NE overflow in response to EFS. Isoproterenol (ISO, 1 microM) stimulated cAMP accumulation by 3.6 and 9 fold in isolated rabbit ICB and cultured NPE cells, respectively. Allicin (1 microM) had no effect on basal cAMP level while it inhibited ISO-stimulated cAMP accumulation by 40% and 23% in ICB and NPE cells, respectively. This study suggests that allicin lowered IOP, in part, by dual actions at the neuroeffector junction.

Alpha-2 and DA2 adrenoceptor agonists produce ocular hypotension in cats, rabbits, monkeys and humans. In this study, the effects of topical, unilateral administration of medetomidine (MED), an alpha-2 agonist, and Ha-118 (HA), a DA2 agonist, were compared on intraocular pressure (IOP) in normal, unilaterally sympathectomized (SX), and ocular hypertensive (oral water loaded) Dutch Belted (DB) and New Zealand White (NZW) rabbits. MED (75 micrograms) produced bilateral ocular hypotensive effects in both DB and NZW normal rabbits; however, HA (250 micrograms) lowered IOP unilaterally in NZW rabbits only. MED (25 micrograms) inhibited the rise in IOP caused by oral water loading in both DB and NZW rabbits; HA, on the other hand, was effective only in NZW rabbits. Topical bilateral pretreatment with metoclopramide, a DA2 antagonist, inhibited the ocular antihypertensive effect of HA in NZW rabbits. The IOP lowering effects of MED were absent in the SX eyes of DB and NZW rabbits, but hypotensive responses to MED were present in normal (contralateral) eyes of both strains. In contrast, HA was effective only in the treated, normal eyes of SX NZW rabbits. These data support pharmacodynamic roles for alpha-2 and DA2 receptors in modulating IOP. The lack of activity by HA in DB rabbit eyes suggests a possible absence of DA2 receptors or excessive binding of HA to pigment in the anterior segment of DB rabbit eyes.

Our recent work on deep tight gas reservoirs containing red and white sandstones (Potter et al., 2009) has shown that the presence of small amounts of hematite in reservoir samples has a dramatic effect on permeability. Such conclusions were made using laboratory based low and high field magnetic susceptibility measurements on reservoir rock samples and by comparing these measurements with the permeability data. These rapid, non-destructive magnetic measurements have previously been applied in clastic reservoir samples (Potter, 2005, 2007; Ivakhnenko, 2006; Ivakhnenko and Potter, 2006, 2008; Potter and Ivakhnenko 2007, 2008) and carbonate reservoir samples (AlGhamdi, 2006; Potter et al 2008). However, such laboratory based analyses are not representative of the downhole in-situ conditions, especially in deep gas reservoirs where temperature can reach quite high values. Typical tight gas reservoir depths can reach to about 4000m (Abu-Shanab et al 2005) and 6000m (Jianming et al 2008) and the equivalent temperatures would measure 131 °C and 192 °C respectively (Mayer-Gurr, 1976). This paper investigates the in-situ magnetic properties of permeability controlling reservoir minerals (hematite and illite in this case) via laboratory experiments to model downhole conditions. We perform magnetic hysteresis measurements at various temperatures in order to 1) quantify mineralogy and 2) to show changes in the magnetic behaviour of these minerals at in-situ downhole conditions. From these measurements, we are able to show whether the mineralogy and/or domain state of these permeability controlling minerals is likely to change with temperature in the deep gas reservoirs. This can have a major impact on permeability. We also show some results from another red and white tight gas reservoir where there is a strong correlation between core permeability and magnetic susceptibility data. In this particular reservoir, the presence of siderite in the white sections of the core greatly improves permeability. Once again for this reservoir, the permeability is low in red sections of the core due to the presence of hematite.

Reaction between low molecular weight highly functionalized maleic anhydride grafted polyethylene and several diamines were carried out using xylene as a reaction media. The influence of varying the amine to maleic anhydride (NH2/MAH) molar ratio and chain length of diamine on reaction was investigated. It was shown that the reactions of these materials cannot be followed by FTIR measurements alone. In these examples, colorimetric titrations were used to assess residual acid/anhydride content that was not detected by FTIR. The reaction between anhydride and amine was observed to be fast. The degree of reaction and crosslinking in the reactor was observed to depend on the concentration of the reaction mixture and the NH2/MAH molar ratio. In some cases, a gelatinous insoluble mass was produced in the reactor and this material was not easily processed for further characterization. All soluble reaction products obtained were observed to be thermoplastic and could be melt processed at elevated temperatures. However, further reaction and crosslinking of these materials occurred during processing to produce thermosets, as demonstrated by rheological measurements and sintering experiments. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Solid-phase microextraction (SPME) is combined with gas chromatography-ion trap mass spectrometry (GC-IT-MS) for the analysis of benzene, toluene, ethyl benzene and xylene isomers (BTEX) in water. SPME is a recent technique for extracting organics from an aqueous matrix into a stationary phase immobilized on a fused-silica fiber. The analytes are thermally desorbed directly in the injector of a gas chromatograph. The wide linear dynamic range (five orders of magnitude) and pg sensitivity of the ion trap mass spectrometer in its full scan mode is an ideal detector for identifying and quantifying the analytes extracted with an SPME device. The combined method SPME-GC-IT-MS, using fibers coated with a 100-microns polydimethylsiloxane coating, showed a limit of quantitation (LOQ) of 50 pg/ml benzene in water. This corresponds to 5 pg of benzene absorbed onto the fiber. The limit of detection (LOD) was 15 pg/ml benzene. For o-xylene spiked at 50 pg/ml in water 50 pg were absorbed by the fiber indicating an LOQ and LOD 10 times better than for benzene. The detection limits obtained exceed the requirements of both the United States Environmental Protection Agency method 524.2 and the Ontario Municipal/Industrial Strategy for Abatement program, which range from 30 to 80 pg/ml and 500 to 1100 pg/ml, respectively. The linearity of the method extended over five orders of magnitude. Relative standard deviation ranged from 2.7 to 5.2% for 15 ng/ml BTEX in water and from 5.5 to 7.5% for 50 pg/ml BTEX in water. SPME-GC-IT-MS was used to evaluate the contamination level in laboratory, potable and wastewater sources.

Ethyl acrylate is a monomer used extensively in polymer manufacturing. Although ethyl actylate is toxic at high concentrations, it is metabolized and detoxified rapidly at low concentrations. In the current studies, in vitro experiments have demonstrated that [ 14 C]ethyl acrylate reacts with both glutathione (GSH) and protein to give either [ 14 C]3-(glutathion- S -yl)ethylpropionate or covalently bound protein adducts, respectively. The second-order rate constant for [ 14 C]ethyl acrylate conjugation with GSH was determined by quantification of [ 14 C]3-(glutathion- S -yl)ethylpropionate using an HPLC system equipped with a flowthrough radioactive detector. The rate constant for conjugation was 32.8 M −1 min −1 . Additionally, the apparent second-order rate constants were determined for [ 14 C]ethyl acrylate binding to the protein fraction of 14 whole tissue homogenates. Estimation of total protein binding sites was performed by reacting tissue homogenates with high concentrations of [ 14 C]ethyl acrylate, while rates of binding were determined by reacting tissue homogenates with 200 μM [ 14 C]ethyl acrylate at 37°C for various periods of time. Apparent second-order rate constants for ethyl acrylate binding to protein homogenates were similar to that observed for GSH reacting with ethyl acrylate. The role of GSH-transferase in catalyzing 3-(glutathion- S -yl)eth-ylpropionate formation also was evaluated with whole tissue homogenates. In most tissues, the GSH-transferases poorly catalyzed the conjugation reaction. However, a significant increase in 3-(glutathion- S -yl)ethylpropionate formation was observed with liver homogenate.

rn Solid-phase microextraction (SPME) is applied to the analysis of benzene, toluene, ethyl benzene, and xylenes in groundwater. The inexpensive SPME method reduced the sample preparation time by 3-7-fold when compared to purge and trap methods. The relative standard deviation ranged from 3 to 5% for the single-operator relative standard deviation using a methyl silicone fiber. Limits of detection of 1-3 ppb (w/v) were obtained when using a fiber coated with 56-pm methyl silicone film and FID detection. The linear range extended from 15 to 3000 ppb (w/v). Solvents have been completely removed from the sample preparation step.

Blends of monodisperse polystyrene were recovered from chloroform solutions and dried. Large variations in the mean entanglement molecular weight and in the zero shear viscosity were observed. The steady state compliance was dependent only on sample polydispersity and did not vary with sample history. The results could be rationalized using a modification of the theory of Kavassalis and Noolandi. It is concluded that the prior treatment of the polymers alterd the the entanglement spacing. This may be the result of a change in the spatial dimensions of the polymer moleculs in the bulk

Space weathering is now generally accepted to modify the optical and magnetic properties of airless planetary regoliths such as those on the Moon and Mercury. Under micrometeorite and ion bombardment, ferrous iron in such surfaces is reduced to metallic iron spheres, found in amorphous coatings on almost all exposed regolith grains. The size and number distribution of these particles and their location in the regolith all determine the nature and extent of the optical and magnetic changes. These parameters in turn reflect the formation mechanisms, temperatures, and durations involved in the evolution of the regolith. Studying them in situ is of intrinsic value to understanding the weathering process, and useful for determining the maturity of the regolith and providing supporting data for interpreting remotely sensed mineralogy. Fine-grained metallic iron has a number of properties that make it amenable to magnetic techniques, of which magnetic susceptibility is the simplest and most robust. The magnetic properties of the lunar regolith and laboratory regolith analogues are therefore reviewed and the theoretical basis for the frequency dependence of magnetic susceptibility presented. Proposed here is then an instrument concept using multi-frequency measurements of magnetic susceptibility to confirm the presence of fine-grained magnetic material and attempt to infer its quantity and size distribution. Such an instrument would be invaluable on a future mission to an asteroid, the Moon, Mercury or other airless rocky Solar System body.

Purpose In nonocular systems, activation of opioid receptors has been shown to ameliorate tissue damage induced by ischemic stress. The current study was an investigation of whether opioid receptors activated by endogenous or exogenous agonists can ameliorate ischemic retinal injury. Methods In an investigation of whether endogenous opioid receptor-activation reduces ischemic injury, the effects of the opioid antagonist naloxone (3 mg/kg; IP) on retinal neuroprotection induced by ischemic preconditioning (IPC) were evaluated. Whether exogenous opioid administration can reduce ischemic retinal injury was determined by pretreating rats with morphine (0.01-10 mg/kg) before injury. Morphometric and electroretinogram (ERG) analyses were used to assess the differences in retinal structure and function. The expression of opioid receptor subtypes was evaluated by Western blot and immunohistochemical analyses. Results In control animals, 7 days after ischemic retinal injury, ERG a- and b-wave amplitudes were significantly reduced (23% and 41%, respectively). In addition, degeneration of the inner retina resulted in a 34% reduction in overall retina thickness. In animals receiving IPC before ischemic injury, ERG wave forms and retinal morphology were preserved. Pretreatment with naloxone reversed both the functional and structural retinal protection induced by IPC. In animals treated with morphine 24-hours before ischemic injury, ERG waveforms were preserved in a dose-dependent fashion (ED(50) = 0.18 mg/kg), and this protective response was reversed by naloxone pretreatment. Immunohistochemical and Western blot data demonstrated that the delta-, kappa-, and mu-opioid receptor subtypes are expressed in the retina. Conclusions These data provide evidence that activation of one (or more) opioid receptor(s) facilitates the development of IPC within the retina and can reduce ischemic retina injury.

Historians have a habit of explaining the important decisions of the past in terms of principles. On this basis, it is easy to say that the Republicans rejected compromise because they were committed to the principle of antislavery and that they rejected secession because they were committed to the principle of union. But in the realities of the historical past, principles frequently come into conflict with other principles, and those who make decisions have to choose which principle shall take precedence. When principles thus conflict, as they frequently do, it is meaningless to show merely that a person or a group favors a given principle: the operative question is what priority they give to it. For instance, before the secession crisis arose, there were many Northerners who believed in both the principle of antislavery and the principle of union, but who differed in the priority which they would give to one or the other: William Lloyd Garrison gave the priority to antislavery and proclaimed that there should be “no union with slaveholders.” Abraham Lincoln gave, or seemed to give, the priority to union and during the war wrote the famous letter to Horace Greeley in which he said: “My paramount object is to save the Union and it is not either to save or to destroy slavery. What I do about slavery and the colored race, I do because I believe it helps to save the Union, and what I forbear, I forbear because I do not believe it would help to save the Union.”

Monodispersed polystyrenes were precipitated from chloroform solutions and dried. Residual solvent was present only in trace quantities. Large variations were observed in the mean molecular weight between entanglements and in the zero-shear viscosity. The steady-state compliance was not affected by sample history. Trends predicted by reptation scaling laws were indeed observed, but the data for all the samples did not fit a unique curve. The data could be resolved into a single plot by using a modification of the theory of Kavassalis and Noolandi. It is concluded that the prior treatment of the polymer altered the entanglement spacing as well as the nature of the entanglements

OPIUM IS AN EXTRACT derived from the poppy plant, Papaver somniferum, which, for many centuries, has been used to produce analgesia and alleviate pain. Opium contains several important alkaloid constituents, which vary markedly in their pharmacologic actions. Some of these alkaloids, such as morphine and codeine, are useful therapeutically. In 1806, Serturner isolated morphine from opium; this was a major advancement in opioid research.1 The term opioid was coined by Acheson2 to denote compounds with morphine-like properties despite their chemically diverse structures. However, it was not until 167 years later that the pharmacology of opioids was defined at the receptor level.3 Although morphine is the most widely used analgesic clinically, it produces several undesirable side effects, including nausea, constipation, respiratory depression, and addiction. Chemists have successfully synthesized other forms of opioid molecules in a continuing effort to make analogs with greater selectivity and fewer side effects. The first reports of morphine’s clinical use were provided by a second-century Greek physician, Galen, who administered opium for the relief of pain and to reduce anxiety in those suffering from asthma and congestive heart failure. About A.D. 1000, an Arabic physician, Avicenna, prescribed opium for diarrhea and diseases of the eye.4 In addition to producing analgesia, numerous studies suggest that endogenous opioids are mediators/modulators of: the stress response; immune/inflammatory events; cardiovascular, gastrointestinal, endocrine, and respiratory control; neuronal events related to behavior, learning, memory, perception, and emotion; and regulation of cellular proliferation and survival. Thus, in addition to being effective analgesics, opioids can produce a myriad of pharmacologic actions that might have application in a variety of diseases of the eye. To date, numerous studies have suggested modulatory roles for the opioidergic receptors in neuronal, cardiac, gastrointestinal, endocrine, and immune systems. For example, the ability of opioids to elicit protection against ischemia and other insults has been demonstrated unequivocally in the heart, brain, kidney, and liver of laboratory animals.5,6 Moreover, some investigators have proposed that endogenous opioids should be considered messenger molecules (cytokines) at the crossroads of the inflammatory/immune responses.7 These diverse types of pharmacologic actions of endogenous and exogenous opioid ligands have not been investigated sufficiently in the eye. This review provides an overview of the complexity of opioid receptor-mediated pharmacologic actions in the eye and compares it to reports of similar effects in nonocular systems. Based on existing literature and current data, evidence suggests that opioidergic ligands have the potential to protect against retinopathies, particularly those associated with glaucoma. In this regard, it

A rapidly ageing society and the rise of an invigorated non-profit sector have been parallel trends in Japan in the last two decades. As the central and prefectural governments have begun to realize their economic and administrative limitations in coping with demographic change, localities and non-profits are called upon to fill in policy gaps. This chapter surveys Non-Profit Organization (NPOs) engaged in service provision for the elderly in Japan's 47 prefectures. It examines opinion polls and government policy pronouncements to identify public expectations about NPO roles in coping with ageing population. The chapter attempts to measure the degree of NPO involvement in elderly care provision and examines the kinds of activities that NPOs themselves define as elderly care. It concludes by assessing to what degree NPO activities reflect public expectations about their roles. Keywords: ageing society; elderly care; government policy; Non-Profit Organization (NPO)

The application of alternating (AF) or direct (DF) magnetic fields to two weakly anisotropic rock specimens which remain static, significantly alters their measured low-field anisotropy of magnetic susceptibility (AMS) by superimposing an anisotropy which has the form of an ellipsoid of revolution with its unique axis aligned along the field axis. Previous AF history is also shown to influence the acquisition of isothermal remanent magnetization (IRM). These effects can be quite substantial and thus it is essential that rocks should not be used for low-field AMS analysis or for IRM anisotropy studies if they have previously been subjected to static AF demagnetization. AMS studies should also not be carried out on rocks which carry a significant remanence (e.g., an IRM acquired in ≥5 mT). The field-impressed effects were also strongly dependent upon whether the ferrimagnetic particles in the rocks were predominantly multidomain (MD) or uniaxial single-domain (SD). The results were consistent with our recent work on synthetic specimens (containing magnetite, titanomagnetite or magnemite) and add support to our suggestion that these effects could provide a rapid, nondestructive, means of determining the predominant domain state (MD or uniaxial SD) of ferrimagnetic particles in rocks.

Prejunctional adrenoceptor activity of N-0437, 2[N-n-propyl-N-2-(thienylethyl-amino)-5-hydroxytetralin], was investigated by means of the cat nictitating membrane (CNM) preparation. Intra-arterial (i.a.) administration of N-0437 produced a dose-related inhibition (ED50 = 14 micrograms) of the CNM contractions elicited by electrical stimulation of pre- and postganglionic sympathetic nerves of the superior cervical ganglion. Pretreatment with domperidone i.a., a relatively selective DA2 receptor antagonist, markedly attenuated the CNM response to racemic N-0437 (ED50 = 6.7 x 10(2) micrograms). However, pretreatment with rauwolscine i.a., a relatively selective alpha 2-receptor antagonist, did not alter the CNM responses to racemic N-0437. Evaluation of the (R)-(+) and (S)-(-) enantiomers showed that only the (S)-(-) enantiomer was active in suppressing the contractions in the CNM preparation. These results demonstrate that N-0437 is a potent agonist for prejunctional DA2 dopamine receptors on peripheral sympathetic nerves in the CNM and that these peripheral DA2 receptors appear to be enantioselective.