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Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days' antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs.
Citation: Zhang XR, Wang YX, Zhang ZJ, Li L, Reynolds GP (2012) The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat. PLoS ONE 7(4): e33247. doi:10.1371/journal.pone.0033247
Editor: Xiang Yang Zhang, Baylor College of Medicine, United States of America
Received: August 13, 2011; Accepted: February 13, 2012; Published: April 13, 2012
Copyright: © 2012 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the National Basic Research Program of China (973 Program, 2010CB529602), National Natural Science Foundation of China (No. 30900482 and F040805), and JiangSu Province Natural Science Foundation of China (BK2009280). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect, which is gaining increasing attention within the past decade. Sexual dysfunction has important implications for satisfaction with sexual life and overall quality of life [1], [2]. It is one of the major reasons for treatment noncompliance and inevitably affects overall clinical outcome and treatment success [3], [4], [5].
The mechanism of antipsychotic drug-induced sexual dysfunction is complex and remains unclear. Generally, the sensory information related to sexual behaviour is processed at various brain nuclei, which balance the inhibitory and excitatory influence on spinal sympathetic and parasympathetic centres, and then determine the functional state of the sexual effector organ [6]. Antipsychotics might act both centrally and peripherally to induce sexual dysfunction. We have shown that some antipsychotics change NOS activity and expression in penile tissues [7], as well as demonstrating functional effects on male sexual behaviour in the rat [8], [9]. Research directly investigating the central mechanisms of antipsychotic-induced sexual dysfunction is particularly rare. Understanding of these mechanisms is mostly theoretical, deriving from general knowledge of sex physiology and psychopharmacology, and is generally unverified by basic or clinical investigation.
The medial preoptic area (MPOA) and the paraventricular nucleus (PVN) are two critical brain structures for male sexual behaviour. These nuclei receive direct and indirect input from every sensory modality and send projections to extra-hypothalamic brain areas for the initiation and patterning of copulation [10], [11]. The MPOA and PVN also have mutual connectivity [12], [13]. Neuroanatomical studies further indicated that the MPOA could be divided into several sub-regions, which have different roles in the regulation of sexual function. Lesion studies have inferred that the caudal MPOA could impair copulation more severely than the rostral MPOA while the dorsal MPOA (anterodorsal preoptic nucleus, ADP) may be more important than the medial and other MPOA regions for copulatory behaviour [14], [15].
Previous studies have indicated that dopamine and nitric oxide (NO) might be two of the most important neuromodulators with facilitative effects on sexual function in both the MPOA and the PVN [16]. A direct dopamine D2 receptor antagonist effect has been proposed as the primary underlying mechanism of sexual dysfunction after antipsychotic drug administration [17]. Haloperidol, a dopamine D2 receptor antagonist, has been found to impair sexual behaviour after acute microinjection into the MPOA [18] and the PVN [11]. However, the role of dopamine D2 antagonism has not been tested with other antipsychotic drugs, notably the newer atypical drugs.
The importance of NO in sexual function has been demonstrated by the observation that a NO precursor (L-arginine) facilitates male sexual function, while a NOS inhibitor (L-nitroarginine methyl ester, L-NAME) injected into either the MPOA [10] or the PVN [19], reduces it. An early study suggested that haloperidol could inhibit neuronal nitric oxide synthase (NOS) activity by preventing electron transfer [20], while apomorphine, a mixed D1/D2 agonist, increased NO production in the PVN, which was correlated with penile erection. Acute haloperidol (0.5 mg/kg i.p.) prevented apomorphine's effect on both NO2− concentration and penile erection [21]. Therefore, the NO pathway might also be involved in the development of antipsychotic-induced sexual dysfunction.
The current study investigated the expression of neural NOS (nNOS) and the dopamine D2 receptor in the MPOA and PVN after chronic systemic administration of the typical antipsychotic haloperidol, and the atypical antipsychotics risperidone and quetiapine, in which haloperidol and risperidone, but not quetiapine are associated with a high incidence of sexual dysfunction in both humans [22], [23] and rats [9].
3-month-old male Sprague-Dawley rats (Shanghai Laboratory Animal Centre, China) were used. After being quarantined for 1 week, animals were housed five or six to a cage with free access to food and water, at an ambient temperature of 18–22°C and 60% humidity with a 12-h light/dark cycle (lights on 7.00AM – 7.00PM). The animals were handled daily. All procedures in animal experiments were approved by the Animal Study Committee of Southeast University, China (ethics approval number 2006ZDLL009.0).
Drug Administration and Experimental Design
Four groups of 3-month-old male Sprague-Dawley rats (n = 7 in each group) received intraperitoneal injection of haloperidol (0.5 mg/kg), risperidone (0.25 mg/kg), quetiapine (20 mg/kg) or vehicle (saline) once daily for 21 days. The haloperidol dose was chosen to obtain effective receptor occupancy (Wadenberg et al, 2001); does for risperidone and quetiapine were chosen on the basis of their relative clinical potency (Jibson and Tandon, 1998). Risperidone (Sigma, Poole, UK), haloperidol (Seranace liquid, 2 mg/ml) and quetiapine (AstraZeneca, Macclesfield, UK) were dissolved in a few drops of glacial acetic acid, diluted with distilled water and buffered back with NaOH to pH 6.0. The vehicle was saline previously acidified to pH 6.0. The experiment was performed three times for immunocytochemistry, gene expression and protein expression.
Immunohistochemistry of nNOS
At the end of the drug administration, the rats were sacrificed by deep anaesthesia with 30 mg/kg pentobarbital i.p. followed by transcardial perfusion with 4% paraformaldehyde (PFA) in 0.1 M phosphate buffered saline (PBS). Brains were removed and fixed in 4% PFA for 4 days before being embedded in wax. Three sections (7 µm) from MPOA between Bregma −0.30 and −0.40 mm, determined using the rat brain stereotaxic atlas [24], were mounted onto slides coated with 3-aminopropyltriethoxysilane (APES) (Sigma). PVN sections were taken from Bregma −1.60 to – 1.88 mm. Avidin-Biotin Complex (ABC) method was used to stain for nNOS immunoreactivity. Briefly, following clearing in xylene and rehydration in graded alcohol, sections were incubated in hydrogen peroxide solution to inhibit endogenous peroxidase activity and a microwave treatment protocol was employed to aid antigen retrieval. Sections were then blocked with 10% normal horse serum diluted in 0.01 M PBS. The sections were incubated with a mouse anti-rat polyclonal primary antibody raised against the C-terminal of nNOS protein (1095–1289) (Product NO 610308, BD Transduction Laboratories, USA) at a dilution of 1∶6000 in antibody dilution buffer (10% normal serum in 0.01 M PBS) overnight at 4°C, followed by incubation with biotinylated secondary antibody (anti-mouse IgG) (Vector Laboratories, Burlingame, CA) at a dilution of 1∶200 for 2 h at room temperature. Sections were then incubated for 2 h at room temperature with ABC solution (Vectastain elite kit, Vector Laboratories, Burlingame, CA) and peroxidase was stained by incubation with 3,3′-diaminobenzidine (DAB) solution containing nickel chloride. No immunoreactivity could be detected in control sections, in which the primary antibody was omitted from the staining protocol.
The composite images containing total left and right MPOA and PVN were captured using a RGB JVC solid-state camera connected to an Olympus BH2 microscope at 10-fold objective magnification fitted with a motorized stage. Then two immunohistochemical parameters, the neural positive cell density and integrated optical density (IOD), were analysed using Image-pro plus software (version 4.1, Diagnostic, Inc.) in three horizontal sections (28 µm apart) in each structure. The quantification processes were set blind to section code until the analysis was finished. Two sub-nuclei, anterodorsal preoptic nucleus (ADP) and medial preoptic nucleus (MPN), were investigated in the MPOA, with ADP and MPN defined by a 0.2 × 0.3 mm2 and 0.4 × 0.6 mm2 rectangle area respectively [25]. The PVN field area was defined by the area within its clear border after DAB staining. Stained neurons were counted using a manual counting option, and then calculated as neuronal density (cells/mm2). Integrated optical density (IOD) is the summation of total pixel optical density in the sub-nuclei [26], [27], [28], [29].
nNOS and DRD2 mRNA Measurement
Brains from each animal were immediately frozen in liquid nitrogen and then allowed to thaw slightly on ice. The MPOA slice was made by cutting between the anterior and posterior edges of the optic chiasm. The tissue containing the MPOA was isolated by cutting laterally to the lateral sulcus and to the depth of the anterior commissure [30]. The PVN slice was made by cutting rostral to the optic chiasm and again 2 mm posterior to the first cut. The tissue containing the PVN was dissected out by cutting 1.5 mm lateral to the median line and undercutting at a depth of 3 mm [31]. The tissues were finally stored at −80°C until analysis.
Total RNA was isolated from the tissue after homogenization using phenol- chloroform TRIzol (Sigma, USA). Genomic DNA contaminants were removed by treatment of the tissue extract with RNase-free DNase (Promega, USA). First-strand cDNA was then synthesized from 2 µg total RNA by incubating with Oligo(dT)15 Primer and M-MLV Reverse Transcriptase according to the manufacturer's protocol (Promega, USA).
The expression level of nNOS and DRD2 mRNA was examined by a quantitative real-time PCR method using an ABI Prism 7000 Sequence Detector (Applied Biosystems, USA). β-actin was used as the endogenous control. Rat-specific oligonucleotide primers were designed and synthesized by Invitrogen (China) as following: nNOS: FWD 5′-TCA AAG CCA TCC AGC GCA TA-3′, REV 5′-GCG GTT GGT CAC TTC ATA CGT TC-3′; DRD2: FWD 5′-AGA CGA TGA GCC GCA GAA AG -3′, REV 5′-GCA GCC AGC AGA TGA TGA AC-3′; β-actin: FWD 5′-GGA GAT TAC TGC CCT GGC TCC TA-3′, REV 5′-GAC TCA TCG TAC TCC TGC TTG CTG-3′. A final 20 µl reaction was prepared with 10 µl SYBR Green Premix Ex Taq (TaKaRa, Japan), 0.4 µl ROX Reference Dye, 0.8 µl primer pairs, 6.8 µl sterile water and 2 µl cDNA sample. Samples were analysed in triplicate, while a negative control using water as template was included for each primer pair. The PCR reaction was started with an initial enzyme activation step at 95°C for 10 seconds followed by 40 cycles of denaturation at 95°C for 5 seconds and annealing/extension at 62°C for 34 seconds. Data were evaluated by the relative quantification method with efficiency calibrated mathematical model using the control group as a calibrator for comparison of every unknown sample gene expression level [32]. The conversion between Ct and relative gene expression level is n fold induction 2-Ct relative to β-actin.
Western Blotting Measurement of nNOS and DRD2
The isolated samples were homogenized in lysis buffer (containing 50 mM Tris-HCl, 150 mM NaCl, 0.02 NaN2, 1 mM PMSF, 1 µg/mL Aprotitin and 1% Triton X-100) in the presence of protease inhibitors (5 µL/mL of protease inhibitor cocktail, Sigma). After centrifugation (12,000g, 25 min, 4°C), protein concentration of the supernatant was estimated by the method of Bradford. About 50 µg total protein was then boiled in sample buffer for 5 min and separated by SDS-PAGE using 10% polyacrylamide gels. After electrophoresis, the proteins were transferred to PVDF membranes (Millipore) for 120 min. The membranes were treated with a blocking buffer (5% nonfat dry milk with 0.1% Tween-20) and incubated with primary nNOS and DRD2 antibody respectively (mouse monoclonal antibody against nNOS 1∶500, Transduction Laboratories, Lexington, KY; Rabbit polyclonal antibody against DRD2 1:200, Chemicon International Inc., Temecula, CA) at 4°C overnight. The blots were incubated with a peroxidase-conjugated anti-mouse IgG (Santa Cruz). The reactive bands were detected with an enhanced chemiluminescence method (ECL; Amersham Biosciences). Quantitation of protein bands was carried out by optical densitometry. β-tubulin was used as a control.
Statistical Analysis
Positive cell density, integrated optical density and mRNA expression were expressed as mean ± s.e.means and were analysed by one-way ANOVA followed by post-hoc Dunnett's t-test. p<0.05 was considered statistically significant.
Immunohistochemistry of nNOS
nNOS positive cell density.
The effects of antipsychotic drugs on nNOS positive cell density in the MPOA and PVN are shown in Figure 1. One-way ANOVA showed no significant effect of antipsychotic drug on nNOS positive cell density after three weeks' administration in the MPN [F(3, 24) = 0.081, p = 0.970] but revealed a significant between-groups effect on nNOS positive cell density in ADP [F(3,24) = 3.743, p = 0.024]. Individual comparisons with the vehicle group revealed that nNOS positive cell density in the ADP was significantly reduced by haloperidol (p = 0.033), but not by risperidone (p = 0.668) or quetiapine (p = 0.997). No significant effect of antipsychotic drug on nNOS positive cell density was found in the PVN [F(3, 24) = 0.812, p = 0.500].
nNOS immunostaining in the MPOA (A) and the PVN (D); Quantitative analyses of nNOS positive cell density in the MPOA (B) and the PVN (E), Haloperidol significantly decreased the nNOS positive cell density in the ADP; Quantitative analyses of nNOS IOD in the MPOA (C) and the PVN (F). Haloperidol significantly decreased nNOS IOD in MPN and ADP, and risperidone inhibited the nNOS IOD in the ADP. 3 v: third ventricle; ac: anterior commissure; ADP: anterodorsal preoptic nucleus; ox: optic chiasma; IOD: integrated optical density; MPN: medial preoptic nucleus. Scale bar:200 µm. *p<0.05 vs Vehicle.
Integrated optical density of nNOS staining.
The effects of antipsychotic drugs on nNOS integrated optical density (IOD) in the MPOA and PVN are shown in Figure 1. One-way ANOVA revealed a significant between groups effect in the MPN [F(3,24) = 3.125, p = 0.045]. Individual comparisons with the vehicle group revealed that IOD of nNOS staining was significantly reduced by three weeks' administration of haloperidol (p = 0.015), but not by risperidone (p = 0.212) or quetiapine (p = 0.320). A significant effect was also seen in the ADP [F(3, 24) = 4.016, p = 0.019]. Individual comparisons with vehicle group revealed that IOD of nNOS staining in the ADP was significantly reduced by three weeks administration of haloperidol (p = 0.038) and risperidone (p = 0.049), but not by quetiapine (p = 0.989). No significant effect of antipsychotic drug on IOD was found between groups in the PVN [F(3, 24) = 1.089, p = 0.373].
Relative Gene Expression of nNOS and DRD2
The effects of antipsychotic drugs on nNOS mRNA expression in the MPOA and PVN are shown in Figure 2. One-way ANOVA revealed a significant effect of antipsychotic administration on nNOS mRNA expression [F(3,24) = 4.213, p = 0.016] in the MPOA. Individual comparisons with the vehicle group revealed that nNOS mRNA expression in the MPOA was significantly reduced by administration of haloperidol (p = 0.006) but not by risperidone (p = 0.374) and quetiapine (p = 0.644). No significant effect of antipsychotic drug on nNOS mRNA expression was found between groups in the PVN [F(3, 24) = 1.089, p = 0.373].
nNOS mRNA in the MPOA but not the PVN was significantly decreased by haloperidol. Data were relative to β-actin mRNA. *p<0.05 vs Vehicle.
The effects of antipsychotic drugs on DRD2 mRNA expression in the MPOA and the PVN were shown in Figure 3. One-way ANOVA revealed a significant effect of antipsychotic administration on DRD2 mRNA expression [F(3,24) = 23.691, p<0.001] in the MPOA. Individual comparisons with vehicle group revealed that DRD2 mRNA expression in the MPOA was significantly increased by three weeks administration of haloperidol (p<0.001) and risperidone (p = 0.001), but not by quetiapine (p = 0.929).
One-way ANOVA also revealed a significant effect of antipsychotic administration on DRD2 mRNA expression [F(3,24) = 6.947, p = 0.002] in the PVN. Individual comparisons with vehicle group revealed that DRD2 mRNA expression in the PVN was significantly increased by administration of haloperidol (p = 0.001) and risperidone (p = 0.013), but not by quetiapine (p = 0.412).
Haloperidol and risperidone increased DRD2 mRNA expression in both the MPOA and the PVN. Data were relative to β-actin mRNA. *p<0.05 vs Vehicle.
Protein Expression of nNOS and DRD2
The nNOS monomers display sizes corresponding to approximately 155 kDa, whileβ-tubulin has a size of approximately 55 kDa. One-way ANOVA revealed a significant effect of antipsychotic administration on nNOS expression in the MPOA [F(3,24) = 18.115, p<0.001] but not the PVN [F(3,24) = 0.027, p = 0.994]. Individual comparisons with vehicle group revealed that nNOS protein expression in the MPOA was significantly decreased by administration of haloperidol (p<0.001) but not risperidone (p = 0.999) or quetiapine (p = 0.619) (Figure 4).
The calculated ODs of nNOS (B) and DRD2 (D) protein bands were normalized to each β-tubulin OD and expressed as a ratio. nNOS protien in the MPOA but not the PVN was significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 protien expression in both the MPOA and the PVN. Lanes: 1 = Vehicle; 2 = haloperidol; 3 = risperdone; 4 = quetiapine. Data are means ± s.e.means and expressed in arbitrary units. *p<0.05 vs Vehicle; **p<0.001 vs Vehicle.
The DRD2 immunoreactivity identified a protein band corresponding to approximately 48 kDa. One-way ANOVA revealed a significant effect of antipsychotic administration on DRD2 expression in both the MPOA [F(3,24) = 13.976, p<0.001] and the PVN [F(3,24) = 30.737, p<0.001]. Individual comparisons with vehicle group showed that DRD2 protein expression was significantly decreased by administration of haloperidol (MPOA: p<0.001; PVN: p = 0.01) and risperidone (MPOA: p<0.001; PVN: p = 0.002) but not quetiapine (p>0.05) (Figure 4).
The present study evaluated a possible relationship between chronic antipsychotic drug administration and the expression of nNOS in regions of the hypothalamus implicated in sexual function. nNOS catalyzes the synthesis of neuronal NO from L-arginine. Behavioural and neurochemical studies indicate that neuronal NO plays a key role in the central mechanism of sexual function. Originally nNOS was considered a constitutively expressed enzyme but accumulating evidence demonstrates that nNOS expression is highly susceptible to regulation by various physiological or pathological conditions [33]. Previous studies indicated that nNOS expression could also be affected by antipsychotic medication, while the reported effects varied widely with different antipsychotic drugs and different brain regions (as summarised in [7]). Our current study is consistent with those previous findings in that haloperidol and risperidone, but not quetiapine, decreased immunopositive neuron density and IOD of nNOS in the ADP and the MPN to different extents.
Along with the inhibitory effect of haloperidol on nNOS immunoreactivity, chronic treatment with haloperidol decreased levels of nNOS mRNA and protein in the MPOA. These findings indicate that haloperidol might suppress nNOS gene transcription and protein expression, which then reduces the production of neuronal NO in the MPOA and finally lead to sexual dysfunction. The mechanism underlying down-regulation of nNOS synthesis following haloperidol administration remains unclear. nNOS is regulated by Ca2+ influx through L-type voltage-sensitive Ca2+ channels [33], while haloperidol has been demonstrated to inhibit the L-type Ca2+ channel at micromolar concentrations [34]. Wu et al., (2000) reported that haloperidol but not risperidone (both 10 uM) could significantly reduce the amplitude of L-type Ca2+ current in vitro [35]. Collectively, these studies provide a possible mechanism underlying the effect of haloperidol on nNOS expression. However, these inhibitory effects occurred at relatively high concentrations, and extrapolation to the in vivo situation should be undertaken with caution.
Risperidone also showed an effect on nNOS expression in the MPOA, indicated by a suppression of nNOS IOD in the ADP, although nNOS-immunopositive neuron density was not significantly changed. Risperidone did not significantly influence nNOS mRNA and protein levels in the MPOA; however differences restricted to individual sub-nuclei may not be detectable in this analysis as they may not be robust enough to influence the result in the whole nucleus.
In the hypothalamus, dopamine D2 receptor density is rich in both the MPOA and the PVN [36], [37]. Sexual function was noticeably inhibited after infusions of haloperidol to the MPOA or the PVN [11], [18]. D2 receptor expression in the brain is increased after chronic treatment with antipsychotic drugs [38], [39], while continuous infusion of the dopamine D2 agonist quinpirole can cause a significant down-regulation of striatal D2 dopamine receptors [40]. The alterations of D2 receptor expression also parallel dopamine-mediated behaviours, such as stereotypy and locomotor behaviour [40]. Although the increase in D2 receptors is not always accompanied by an increase in D2 mRNA [41], higher doses and more prolonged exposure to antipsychotic drugs do elevate D2 mRNA [42], [43]. We find that haloperidol and risperidone increased the DRD2 mRNA and protein expression in the MPOA and the PVN. This is the first study providing direct evidence for dopamine D2 receptor alteration induced by antipsychotic drugs in those two neural sites. Our study also provides strong support for the hypothalamic dopamine D2 receptor antagonism hypothesis of antipsychotic drug-induced sexual dysfunction. This hypothesis is also supported by our previous observation of an association of D2 receptor polymorphisms with sexual dysfunction in male subjects receiving antipsychotic treatment [44].
While the current study is limited by using only single dose regimes, these were chosen to be equivalent to clinically-effective doses on the basis of inducing substantial and effective dopamine D2 receptor occupancy. Previous studies from this laboratory have investigated the effects of a range of doses of these three drugs in rat sexual behavior; the doses chosen here were at (haloperidol) or below (risperidone and quetiapine) the threshold dose that impaired aspects of male sexual function [9].
As reviewed by Hull and Dominguez [10], chemosensory information activates the MPOA neurons, resulting in Ca2+ influx and NOS activation. The resultant NO production may increase dopamine neurotransmission to facilitate sexual function via D2-like receptors. The incerto-hypothalamic dopaminergic neuron terminals from the MPOA release dopamine in the PVN and then activate NOS production in the oxytocin-containing neurons of the PVN, which in turn facilitates penile erection [11], [19]. According to our current findings, antipsychotic drugs might impair sexual function through the following various mechanisms: 1) down-regulation of nNOS expression, thereby decreasing production of NO and consequently synaptic dopamine in the MPOA and/or 2) blocking the postsynaptic D2 receptor directly in the PVN and consequently inhibiting sexual behaviour. These central effects might be involved in sexual dysfunction induced by certain antipsychotic drugs. These differences of sexual dysfunction induced by various antipsychotic drugs observed in clinical medication are likely because of the different pharmacological properties of these antipsychotics.
Author Contributions
Conceived and designed the experiments: XRZ ZJZ GPR. Performed the experiments: XRZ YXW LL. Analyzed the data: XRZ YXW. Wrote the paper: XRZ ZJZ GPR. Helped to revise the paper: GPR.
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- 35. Wu SN, Jan CR, Li HF, Chiang HT (2000) Characterization of inhibition by risperidone of the inwardly rectifying K(+) current in pituitary GH(3) cells. Neuropsychopharmacology 23: 676–89.
- 36. Gurevich EV, Joyce JN (1999) Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 20: 60–80.
- 37. Meador-Woodruff JH, Mansour A, Healy DJ, Kuehn R, Zhou QY, et al. (1991) Comparison of the distributions of D1 and D2 dopamine receptor mRNAs in rat brain. Neuropsychopharmacology 5: 231–42.
- 38. Jenner P, Kerwin R, Rupniak NM, Murugaiah K, Hall MD, et al. (1983) Long-term adaptive changes in striatal dopamine function in response to chronic neuroleptic intake in rats. J Neural Transm Suppl, 18: 205–12.
- 39. Rupniak MN, Jenner P, Marsden CD (1983) The effect of chronic neuroleptic administration on cerebral dopamine receptor function. Life Sci, 32: 2289–11.
- 40. Chen JF, Aloyo VJ, Weiss B (1993) Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 54: 669–80.
- 41. Fox CA, Mansour A, Watson SJ (1994) The effects of haloperidol on dopamine receptor gene expression. Exp Neurol 130: 288–3.
- 42. D'Souza , U , McGuffin , P , Buckland PR (1997) Antipsychotic regulation of dopamine D1, D2 and D3 receptor mRNA. Neuropharmacology 36: 1689–96.
- 43. Joyce JN (2001) D2 but not D3 receptors are elevated after 9 or 11 months chronic haloperidol treatment: influence of withdrawal period. Synapse 40: 137–44.
- 44. Zhang XR, Zhang ZJ, Zhu RX, Yuan YG, Jenkins TA, et al. (2011) Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes. Pharmacogenomics 12: 1127–36.


text:
See it. Fix it.
Submit your issues using this form. We'll contact your city to try and get it fixed. Read more »
Schooner, mascot for Raye's Mustard, drowns in Boyden Lake
By Dawn Gagnon on Dec. 10, 2016, at 3:06 p.m.
Schooner, one of Raye's Mustard's two canine mascots, drowned Thursday morning after getting stuck in thin ice on Boyden Lake, one of the company's owners said Saturday.
Another polar vortex is coming, but it's not as scary as it sounds
on Dec. 10, 2016, at 11:56 a.m.
Stay warm, folks.
Skimmer discovered at Bangor Savings Bank in Belfast
By CBS 13 on Dec. 10, 2016, at 11:45 a.m.
If you have used this ATM recently, check your accounts and consider changing your PIN.
House speaker, LePage agree to cooperate on new mental health facility
By Michael Shepherd on Dec. 09, 2016, at 4:31 p.m.
Maine's new House speaker emerged from a meeting with Gov. Paul LePage to say they agreed to a path for legislative leaders to approve a new, privately run mental health facility in Augusta by 2016's end.
Despite higher prices, electricity resellers retain Maine customers
By Darren Fishell on Dec. 09, 2016, at 4:10 p.m.
Companies selling electricity directly to consumers have retained more than one in six Maine households as customers this year, despite charging generally higher prices.
The yeas and nays: How Maine's congressional representatives voted this week
By Targeted News Service on Dec. 09, 2016, at 4:06 p.m.
Here's a look at how area members of Congress voted over the previous week.
Quarry Road Trails 2016-2017 Winter Season Kicks Off
on Dec. 09, 2016, at 4:03 p.m.
Windham high school choral director and Houlton high school grad is a finalist for Grammy educator award
By Jen Lynds on Dec. 09, 2016, at 3:56 p.m.
Richard Nickerson is one of 10 finalists up for the award, created by the Recording Academy and Grammy Foundation.
Bill Townsend, noted Maine lawyer and environmental advocate, dies at 89
By Bill Trotter on Dec. 09, 2016, at 2:50 p.m.
Clinton "Bill" Townsend was best known for his work with many of Maine's most influential environmental advocacy organizations and regulatory authorities.
A Messy Monday Ahead For Maine
on Dec. 09, 2016, at 2:15 p.m.
Here's the route to follow to see the best Christmas lights in Maine
on Dec. 09, 2016, at 11:56 a.m.
Stonewall Kitchen issues voluntary recall on salmonella concerns
By Tony Reaves on Dec. 09, 2016, at 11:30 a.m.
York-based Stonewall Kitchen has announced a recall of three pancake and waffle mixes because of concerns of salmonella contamination in the powdered buttermilk used in those products.
New net aims to help Maine fishermen land fewer cod
By Fred Bever, Maine Public on Dec. 09, 2016, at 8:13 a.m.
It's the kind of innovation that has become prevalent over the last six years, as regulators have deployed a quota system that frequently changes its parameters as one species or another becomes more or less abundant.
The polar vortex is coming. Here's how cold it could get.
By Angela Fritz, The Washington Post on Dec. 09, 2016, at 8:10 a.m.
Much of the northern half of the United States could see frigid weather next week similar to life-threatening cold the polar vortex brought to parts of the country in 2014.
Father killed daughter, then self in Hebron, police say
By Dawn Gagnon on Dec. 09, 2016, at 7:44 a.m.
Police believe a 56-year-old man shot and killed his 27-year-old daughter at their home Thursday before turning the gun on himself.
Toddlers with ties to Houlton die in NYC when radiator bursts
By Laila Kearney, Reuters on Dec. 09, 2016, at 6:29 a.m.
New York City's use of private apartment buildings to house multiple homeless families came under fire on Thursday, a day after two children living in one of the "cluster sites" were killed in a radiator accident.
Caribou Utilities District takes top honors in 30th annual tap water taste-off
By Dawn Gagnon on Dec. 08, 2016, at 7:39 p.m.
This year's judges were Virginia Manuel, state director of USDA Rural Development, WABI TV weatherman Todd Simcox and retired Bangor police Lt. Paul Edwards.
Former Maine man charged in death of 2-year-old daughter
By Dawn Gagnon on Dec. 08, 2016, at 6:37 p.m.
Roger Joseph Dana, 43, is charged with second-degree murder in connection with the death last month of his daughter.
Witnesses testify about alleged crimes before, after Oakfield slayings
By Judy Harrison on Dec. 08, 2016, at 5:43 p.m.
Prosecution witnesses on the third day of the Matthew Davis double murder trial testified about events police have said took place before and after Michael Kitchen, 51, and Heidi Pratt, 49, were killed in the early morning hours of Sept. 23, 2013, in the Oakfield home they shared.
Police: Bodies of man, woman found in Hebron house
on Dec. 08, 2016, at 5:05 p.m.
The bodies were discovered by a neighbor.

subset: commoncrawl


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The Fall are an English post-punk band, formed in 1976 in Prestwich, Greater Manchester. The Fall essentially consists of founder and only constant member Mark E. Smith with an ever-changing lineup; he has said that "If it's me and your granny on bongos, then it's The Fall." First associated with the late 1970s punk movement, the band's music has evolved through numerous stylistic changes, often concurrently with changes in the group's lineup.
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Random Restaurant
0Lively bistro fare, including buffalo wings, crab dip, fat sandwiches and salads, burgers, steaks, and seafood. You can also play foosball and darts and enjoy some live music.
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Berry Berry Frozen Yogurt
Less than $25 (average dinner bill for 2 excluding alcohol)
Self-serve, soft-serve frozen yogurt shop. They use creamy Greek yogurt, and since the owners are Chinese, expect some bubble tea options as well.
The HooK
CUISINEIce Cream
NEIGHBORHOODThe Corner


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$1,347.25 $2,672.05
|In stock
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Casual Dining Room Set
Signature Design by Ashley
Contemporary, Modern
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Danimore 7-Piece Oval Dining Set in Light Brown
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Asia Pulp and Paper
Mechanical Engineers
Deskripsi Pekerjaan
Job Description
Familiar with EPC projects and all aspects including
- Engineering design & management of consultant design, document and drawing review, with knowledge of document handling in projects.
- Procurement: consolidation of materials, BOQs, preparation of PR's and follow up of deliverables, contract & scope of work preparation for main equipment, service contacts, and bulk materials
- Construction: familiar with construction methods, supervision, and quality requirements. Focusing on execution of the construction activities with knowledge of material management, manpower tracking, and field engineering
- Hands on experience in related area
- People management skills and strong leadership
- Pulp & Papper industry expeirence a plus
- Can be based in Serpong site
Ke halaman yang merekrut lowongan ini
Data pekerjaan
|Cibodas, Tangerang, Banten
|Manufaktur / Produksi
|Asia Pulp and Paper lihat lowongan
Deskripsi Perusahaan
As one of the world's largest pulp and paper companies, Asia Pulp and Paper Group (APP) is responsible for delivering quality products to meet the growing global demand for tissue, packaging and paper. On any given day, our products find their way into the hands of consumers in various branded forms from all over the world.Over the years, we have expanded our operations significantly through the acquisition and expansion of several of our pulp and paper mills. It's our commitment to customer satisfaction that enables us to grow our share in paper sales worldwide and broaden our presence through offices in many countries. We believe 'tradition and modernity go hand in hand' which means we value long term relationships as part of our Eastern traditions, while we also are eager to embrace the modern values of innovation and efficiency.
Started in 1972 with Tjiwi Kimia producing caustic soda, now we run operations across Indonesia and China with an annual combined pulp, paper, packaging product and converting capacity of over 19 million tons per annum. Today, APP markets its products in more than 120 countries across six continents.
Mengapa bergabung dengan kami?
Here at APP, we believe that a great company is made by great people. When employees succeed, the business also takes off. This value has driven us to be the world's leading pulp and paper company since our very first operation in 1972 until today. We dedicate our time and resources to find talented individuals to join us and become our next future leader. ARE YOU THE ONE ?
Ke halaman yang merekrut lowongan ini
lowongan kerja rekomendasi
Marketing Analyst
Mobile Marketing Analytics Lead
Annalyst Programmer
Admin Penjualan
Manager Stores and Warehouse
MIS Manager


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Foursquare © 2016 Lovingly made in NYC & SF
People tend to check in during these times:
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5040 San Fernando Rd
"I love their hotdogs."
Virgil's Hardware
520 N Glendale Ave (at E. Doran St.)
"Great local hardware store! Kind and helpful staff. Skip the corporate giants like Home Depot and come here!"
VER (Video Equipment Rentals)
912 Ruberta Ave (San Fernando Road)
"Make sure you bring a book or have lots of games on your phone"
Created by Joe Bohn3 items • 1 follower
My Favorite Places
Created by 😎 Les Halstead 😎46 items
Make sure your information is up to date. Plus use our free tools to find new customers.
Download Foursquare for your smart phone and start exploring the world around you!


text:
4 bus schedules from Glasgow, Scotland to Manchester, England
About Bus - Glasgow x Manchester
Bus24x7 gather and provide all main needed information for you easy find the best and cheap Glasgow bus ticket to Manchester on 9 December 2016.
Here you find a variety of features to help you make the best travel decisions.
Also compare all Glasgow schedules and tickets, bus services and check 183 customers reviews.
This bus route is carried by 1 great bus companies, such as Megabus with 4 bus schedules to Manchester.
The first bus leaves at 08:20 and the last Glasgow departure time is at 23:55.
You'll be able to board at Glasgow, Buchanan Bus Station and get off bus at Manchester, Shudehill Interchange Stand G (except between Midnight and 0400 - use Stand L).
Traveling by bus from Glasgow to Manchester takes around 4h 16m length.
All available Glasgow bus travel tickets to Manchester usually costs from £ 15.00 to £ 16.00 per seat.
These bus fares can vary from onboard bus services, daily promotions and bus seats availability.
Bus24x7 don't sell bus tickets and will easily redirect you to buy online tickets to your bus trip and reserve your seat in advance.


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Theres only one cure.
Highest Rated
I don't know what the fuss is about! People going crazy about an advert! It's funny, maybe not TV material but it's funny...
Those students should go to Some bakery and learn baking toasts rather than producing ads.
This is CRAP. How can you make connect food ads with psycho-hospitals...
Nothing says to me, I really want beans... It says bread want beans.. but thats it.. And if I only get that, I wouldnt get hungry for beans at all, wich means I dont buy the product.
if these are student work, they better quit college and get out or switch college
come on, let's all stop being so overdramatic... the ad says toast goes well with heinz... i've seen worse that all you guys hav praised... itz a different take on a category that has been flooded with creatives... they may not b the best, but they aren't that terrible either...
(the ad says toast goes well with heinz) . There may be a billion more effective and Better ways to execute this message, mr tiny_words. Don't be so emotional about it. Its a blog, every one has the right to express himself here. You have urs.
i know but let's at least try n be objective... it's may not b sooooooo effective but it has its good sides... i may not run it if i were a client but it shows that the creative person actually tried to look for a nu benefit and not just copy sumthin for the internet... n i'm not emotional... just pointin a few thingz out...
I don't know what the fuss is about! People going crazy about an advert! It's funny, maybe not TV material but it's funny...
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Academy of Ancient Music in Ludlow
A BBC-led weekend of over 100 live music events across the UK - from Cornwall to the Shetland Isles and Belfast to Birmingham - launching the nationwide countdown to the London 2012 Festival.
Radio 3 celebrates live music-making all weekend, handing on the baton from concert to concert, featuring a wide range of professional and amateur events and talking to the people who've made it all happen. Presented by Andrew McGregor and Suzy Klein.
Petroc Trelawny introduces a concert by the Academy of Ancient Music and violinist Alina Ibragimova, recorded earlier this evening at the Assembly Rooms in Ludlow.
Alina Ibragimova makes her Academy of Ancient Music debut in a programme which vividly charts groundbreaking developments in the role of the violin as a solo instrument.
The concert begins with Ibragimova alone on the stage, performing what is thought to be the first work for solo violin: Biber's Passacaglia. Then she's joined by a harpsichord for JS Bach's Violin Sonata in E major. Later, the stage bustles with action as the whole orchestra arrives to perform violin concertos by Bach and Vivaldi. As Ibragimova says, 'These works aren't just the start of something. They form their own world, with the full spectrum of colour and emotion - everything that music is about, in fact.'
H. Biber - Passacaglia in G minor from the Mystery/Rosary Sonatas
JS Bach - Sonata for violin and harpsichord in E major, BWV 1016
JS Bach - Violin Concerto in A minor, BWV 1041
Vivaldi - Violin Concerto in D major, RV 234 (L'inquietudine)
Vivaldi - Concerto for two violins and cello in D major, Op. 3 no. 11 (RV 565)
H. Biber - Battalia
JS Bach - Violin Concerto in E major, BWV 1042.


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Today, during dinner with my wife's family, my daughter suddenly yelled, "DADDY TICKLES MOMMY'S BUM BUM!" I don't think I've ever received dirtier glares in my life. FML
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Today, in the middle of a presentation, I fought a shart, but the shart won. FML
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by dead man walking? / 10/04/2015 at 9:21am / United States / Miscellaneous


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Explore More of the Museum
Upper Gallery
Trains In Literature
January – June 2016
Trains have been featured in literature since their invention in the early 19th century. The sense of adventure and mystery they can bring to a story make them a perfect setting for an engaging tale. Using the museum's rich library collection and some special treasures from our friends, this exhibit explores the impact these stories have had in both children's and adult literature.
Black on Track
February – March 2016
Following the Civil War, many African Americans found work with the railroads. Using objects from the permanent collection, this exhibit explores the resulting impact on America such as the evolution of middle class neighborhoods like Denver's Five Points and the Civil Rights Movement.
Trains in Politics: Getting Out the Vote
July – November 2016
Trains have participated in political elections since the early 19th century. Here in Colorado we have seen a number of Presidential candidates making "whistle stops" to sell their candidacy for office. Join us this election year as we revisit the part train travel played in electing those who would hold office.
Voltaw Model Trains
Available Year-Round
Herbert W. Voltaw built a series of 1-inch locomotive and train car models in the 1940s, 50s and 60s using aluminum, steel bar, soft and hard woods, plastic, glass, etc. The Museum displays a number of these intricate works of art in their depot galleries.
Lower Gallery
Eating on the Rails: A Look at Dining on Railroads
April 2016 – July 2017
Food and eating has been an essential part of the train experience since trains first started transporting people. Join the Colorado Railroad Museum as we explore the impact of Butcher Boys, Pullman cars, Fred Harvey and Dining cars on American culture.
Colorado Trains in Building Blocks
May – September 2016
Building block toys like LEGO building bricks spark the imagination.
Some amazing creations focusing on trains, depots and rails will be on display this summer!
Tiny Houses
Opening August 2017.
Telegrapher's Office
This diorama shows a typical telegraph office that could be found at a train depot in the early 20th century. It comes with a working "sounder" encouraging visitors to decode and send messages coming over the wire.
Denver HO Model Railroad Club
Located in the lower level of the main building, the Denver HO Model Railroad Club is one of the oldest and largest model railroad clubs in the Rocky Mountain region. The layout replicates the various types of Colorado mountain railroading in HO and HOn3.
HO scale is a model train that is 1/87th of the real size of standard gauge trains and track. HOn3 is the same scale, but designed for narrow gauge trains and track.
Members of the Denver HO Model Railway Club will operate the model train layout on most Tuesdays 1:00 to 4:00PM. For more information, visit DenverHOModelRRClub.org.


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President and Raleigh Chapter President
Full Member
NCSA and NSA
Member, Burlington Chapter
NCSA and NSA
Captain of the First Responders
Bulletin Committee
Directory Committee
QAR Committee
New Trier High School
Northwestern University
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Thirteen were in attendance for the ...
www.ncsa1947.org [cached]
Thirteen were in attendance for the meeting to hear NCSA Past President Stephen Metelits speak on the new Tangible Property Regulations.
North Carolina Society of Accountants Inc. - Raleigh Chapter - NCSA
www.ncsa1947.org [cached]
Stephen Metelits, President
www.ncsainc.org [cached]
www.ncsa1947.org [cached]
For more information contact
www.ncsa1947.org [cached]
For more information contact Stephen Metelits at firstname.lastname@example.com The Sandhills-Sanford Chapter met on Thursday, September 24that Hickory Tavern in Pinehurst. Lauren Benbow ofthe NC Secretary of State's office spoke to the chapter on Preventing Elder Fraud. Thenext meeting will be on October 22nd at Bay Breeze in Sanford with NCSA Past Presi- dent Stephen Metelits speaking on the new Capitalization of Property and Repair Regulations.
Joel Metelits
Thunderbird Internal Medicine
Melissa Metelits
InVersion Theatre Company
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People's United Bank
Rachel Metelits
Arizona Attorney General's Office
Stephen Metelits
Metelits Allen Tax & Accounting, Inc.


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The Economic and Financial Crimes Commission (EFCC) has re-arraigned the former governor of Adamawa State Murtala H. Nyako and eight others at the Federal High Court Abuja for an alleged money laundering and fraud.
They were arraigned yesterday on 37-count charges which were allegedly committed when Nyako held sway as governor in a suit with file number FHC/ABJ/CR/293/15. They pleaded not-guilty to all the charges at the resumption of the case yesterday.
On August 7, 2015, the EFCC had arraigned the governor alongside his son Abdulaziz Nyako and five firms before the late Justice Evoh Chukwu. The accused persons were alleged to have converted the sum of N29 billion allegedly proceeds of theft of funds belonging to the Adamawa State Government.
The prosecution, led by Mr Rotimi Jacobs (SAN), had called six witnesses before the demise of the late Justice.
The trial judge, Justice Okon Abang, in his ruling, held that the defendants continue to enjoy the bail conditions earlier granted by late Chukwu, following their plea. The request of the prosecutor that the defendants' surety should file a fresh affidavit was refused.
Abang ruled that the prosecutor failed to oppose the oral application of the defence counsel. He also added that the court cannot verify the condition of bail earlier granted and subsequently adjourned the case.
Source: Today Trending News


text:
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Endtown by Aaron Neathery
- February 09, 2011
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I still don't understand why he tossed the gun..
Go, Catboy, Go!
nice to know he is not totally self centred. but your right there will be nothing in the transporter and I doubt if they will all be as friendly as petey. but he is also not thinking. if he did he would have just ran away right?
Wouldn't it be crazy if that was Petey.
Or even better - What if Catboy and Flask hook up together? Wouldn't that be the cat's meow?
you know this could be Petey the cat… Universes and story line do not have to be sequential. this could be what get's our cat friend captured.
If the ones that hunt are called mutts, than the ones you ride must be called… Nags, Dobbins, Mounts, Seabiscuits…
You might have have something there, Doggard. This story line could turn out to be a flashback, with Petey explaining what happened to him.
Uh-uh; Mr. Neathery said no spoilers would be found in this storyline.
Petey was a human - we saw his head and he had a human nose.
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Cottage Pie OAMC
Total Time
Prep 20 mins
Cook 30 mins
Another recipe from "Don't Panic- Dinner's in the Freezer"- with some alterations. The original recipe calls for cheese sprinkled on top and canned veggies. I have always made it without cheese and never missed it- it is very flavorful. I like to use frozen veggies rather than canned whenever possible. I have used frozen corn, and frozen veggie medley but prefer peas in this recipe. This can be made as a large casserole or as individual pot pies.
Ingredients Nutrition
- 1 1⁄4 lbs lean ground beef
- 1 cup onion, chopped
- 1⁄2 teaspoon salt
- 1⁄4 teaspoon pepper
- 2 garlic cloves, minced
- 16 ounces frozen peas
- 1 (10 1/2 ounce) can tomato soup, undiluted
- 1⁄2 cup picante sauce
- 4 cups mashed potatoes
- Brown ground beef with the onions, drain. Add salt, pepper, garlic. Spread beef evenly in bottom of 8 x 8 casserole dish.
- Layer veggies on top of the beef, followed by tomato soup and picante sauce. Top with mashed potatoes.
- OAMC- Allow to cool completely, then wrap and freeze.
- To serve, thaw completely if frozen and bake at 350 degrees for 30 to 45 minutes or until heated through.
Most Helpful
Whoops! I just now noticed that the recipe says 16 oz of peas... I used 6 oz (1.5 cups). Not sure if I would like more than 2-3 cups though so maybe that was a good thing. I have another recipe that is similar to this one but the picante sauce is different. I have a homemade mild salsa that I used. Worked perfect! (Haven't tried freezing it yet. Not really sure how to freeze cassaroles without using disposable aluminum.
Hubby liked this but I didn't care for it much so I'm giving it 3 stars to kind of compromise on both of our reviews of it. Thanks for posting.
Our whole family loved this! I took your advice and didn't use any cheese topping; it was just great without it, and I also used frozen peas as you suggested. The filling was especially good -- mixing the picante sauce with the tomato soup concentrate made a delicious filling and it could be altered to suit one's taste by using different flavors of picante sauce such as mild, medium or hot. I used the medium Pace's picante and it was perfect for us. We'll definitely have this again. It's tasty comfort food at its best!


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Landhotel Adler, Waltenhofen
- Free WiFi
Main amenities
- 30 guestrooms
- Restaurant
- Breakfast available
- Free train station pick-up
- 2 meeting rooms
- Terrace
- Front desk safe
- Conference space
- Multilingual staff
- Barbecue grills
- Limited hour front desk
- Tour/ticket assistance
For families
- Cribs/infant beds (surcharge)
- Rollaway/extra beds (surcharge)
- Sofa bed
- Separate sitting area
- Television
- Terrace
What's around
- Kapuzinerkirche St. Josef (6.6 mi / 10.7 km)
- Museum Hofmuehle (6.8 mi / 10.9 km)
- Allgaeuer Bergbauernmuseum (7 mi / 11.3 km)
- Big Box Kempten (7.1 mi / 11.4 km)
- Baslika St. Lorenz (7.6 mi / 12.3 km)
Landhotel Adler, Waltenhofen
Hotel Info: 866-539-8117
- Double Room (Illertal)
- Single Room (Illertal)
- Double Room Single Use
- Double Room (Grüntenblick)
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For transfers, guests must contact the property 24 hours prior to arrival at the number on the booking confirmation.
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A tax is imposed by the city: EUR 1 per person, per night. This tax does not apply to children under 10 years of age.
Pet deposit: EUR 10,00 per day
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Self parking costs EUR 6 per day
Rollaway beds are available for EUR 25 per stay
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WESTPORT - The Westport Fire Department says no one was hurt when the deck on the back of the house collapsed.
It happened at 61 Silent Grove North yesterday.
The deck hit a propane tank, but did not damage the tank.
Fire officials say the family was able to stay in their home.


text:
Information Morning Cape Breton
Information Morning Cape Breton | Weekdays 6 a.m. to 8:37 a.m. | CBC Radio One
Join Information Morning's host Steve Sutherland and news editor Hal Higgins starting at 6 a.m. on weekdays.
Flood victims 'draining their bank accounts' as they await compensation details
The newly formed Southend Lost Homes Coalition of Sydney wants clarity surrounding compensation for inhabitable homes and is urging a speedier recovery process after members lost everything in the flood on Thanksgiving Day.
SYDNEY FLOOD 4,000 tonnes of flood-soaked debris pile up at Sydney landfill
A specially created section of the municipal landfill in Sydney is now piled high with an untold number of personal and household items destroyed in the Thanksgiving Day flood three weeks ago.
Cape Breton road closed indefinitely after bridge wiped out by flood
It will be several months before Hornes Road, which links two Cape Breton communities, will reopen after Thanksgiving Day floodwaters destroyed a bridge along the local highway.
Information Morning Cape Breton Clips
Thursday December 08, 2016
Audio Mabou Farmers' Market
The Mabou Farmers' Market is a popular spot... for buyers and vendors. And its looking at options to expand. For an update on their plans, we contact Michelle Smith, she's the Secretary of the Mabou Farmers' Market and a vendor.
Thursday December 08, 2016
Audio Opioid Treatment
Less inpatient detox, and more methadone. That's the Nova Scotia Health Authority's plan to tackle opioid addiction. Reporter Angela MacIvor reports on what CBC learned by calling every detox and rehab centre in the province.
Thursday December 08, 2016
Audio Strait Area Transit Update
The Strait Area Transit has become a valuable service for riders. In the new year, the co-operative will take a close look at and review the service. Jim Mustard, Chair of the Board for Strait Area Transit, explains what that could mean for users.
Wednesday December 07, 2016
Audio Cuff on CB Eagle + World Jrs.
A Cape Breton Screaming Eagle looks to swoop in and take a spot on Team Canada at the upcoming World Junior Hockey Championship. Our sports guy Charlie Cuff talks about Pierre Luc Dubois.
Wednesday December 07, 2016
Audio Jim St. Clair - Naming The Beaton Institute
A "Then and Now" about a place dedicated to the "Then and Now" of Cape Breton Island... to learn about our history, the Beaton Institute is the place to start. Jim St. Clair presents a history of the Beaton, and the woman for whom its named.
Tuesday December 06, 2016
Audio Rally For Teachers In Sydney
Yesterday, the talk of the province was school being cancelled by the NS Education Minister. Hundreds of people lined the sidewalks outside the Provincial Building to demonstrate in support of NS teachers. Reporter Joan Weeks spoke with some participants.
Tuesday December 06, 2016
Audio NSTU Update - Liette Doucet
Students in Nova Scotia are heading back to school this morning. Education Minister Karen Casey announced yesterday that the student supervision issue had been clarified. To find out what has changed, we call NSTU President Liette Doucet.
Monday December 05, 2016
Audio NS Education Minister Karen Casey
Your children are NOT going to school today... We ask the NS Minister of Education to elaborate on why students are not in school. Karen Casey explains what happens next in her showdown with the province's teachers.
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text: An American Man of Letters COLLIER COBB Reprinted fiotn The University of North Carolina Magazine October, 1909 The North Carolina Review, October 3, 1909 Digitized by tine Internet Arciiive in 201i witii funding from University of North Carolina at Chapel Hill http://www.archive.org/details/americanmanoflet121cobb \ The University Magazine OCTOBER, 1909 Old Series, Vol. 40 No. J New Series, Vol. 27 AN AMERICAN MAN OF LETTERS Collier Cobb A slave who owned his master; a poet ignorant of the rules of prosody; a man of letters l)efore he had learned to read; a writer of short stories who published in several papers simul- taneously before the day of newspaper syndicates ; an author who supported himself and his family in an intellectual cen- ter liefore authorship had attained to the dignity of a pro- fession in America: such was Geoi'ge Horton, a negro, Ixjrn in North Carolina, in 1798. Like all the members of his race, he was fond of melody and devoted to church going; and to this religious impulse he owed the cultivation of a poetic temperament, and the oppor- tunity to study tlie structure of the short story. My attention was drawn to his Avork several years ago by some verses of his written for a lady's album in 1840, to the authorship of Avhich he had relinquished all claim for twenty- five cents. The quality of the verse and the story of its author led me to look into tlie man's history and to search for his work in the tiles of the newspapers of his day. George was the property of Mr. James Horton, of Chat- ham County. He was a full-blooded black man, something like the type known today as negroid, yet more Aryan than Semitic in features, and more like the natives of India and Northern Africa, than the negro south of the Sahara. He himself, Othello like, boasted of the purity of his black 4 The University Magazine blood. Such is the description I get of his personal appear- ance from old residents of Chapel Hill, who knew him in his prime. George lived on the plantation of his master, where he made a pretense of working on the farm, until he was about thirty-three years old. His time in winter was spent large- ly in fishing and hunting, and in some slight personal ser- vice for his master. His summers were devoted mainly to protracted meetings. He became familiar with the Bible from hearing it read, and Avith the melodies of the Metho- dist hymnal, which were constantly ringing in his ears. From these sources he gained his sole knowledge of stories and of verse. On hearing some verses read from an odd number of the North Carolina University Magazine, he asked his master's permission to visit Chapel Hill and get acquain- ted with the young jnasters who did such work. When he reached the university town, his gift of versifica- tion secured for him ready employment. He composed acrostics on ladies' names, and love songs and other amorous verses for ladies' albums. He was also actively employed in the production of love letters. George found his new ven- ture so profitable that he offered his owner fifty cents a day for his time, which was worth nothing on the farm. Soon his verses appeared in the University Magazine, some of the young masters claiming the authorship. All his lines were written down by others from his dictation, for he had never learned to write. Hie had learned to read, however, by the use of his Wesleyan hymn book, and learned his words before he learned his letters, thus anticipating a method of the new education. The laws of the State forbade the teach- ing of slaves, but George learned to read without a teacher, and his master knew nothing of his accomplishments until he was shown some of his verses. One of George's earlier efforts at Chapel Hill, inspired by the half-dollar of an aspiring Sopliomore, who nightly wan- dered in the neighborhood of Piney Prospect, ran thus: An American Man of Letters 5 At length the silver queen begins to rise, And spread her glowing mantle in the skies, And from the smiling chambers of the east. Invites the eye to her resplendent feast. The poet begged a blue-backed sioelling book, and from this learned his letters, with what assistance no one ever knew. Later he learned to spell by matching the words in his hymnal, which he already knew by heart and by sight, with the words in the spelling book. In this way, he learned to read his Bible. Thus, entirely unaided by instruction, he learned to read and made the acquaintance of grammar and prosody, acquiring a simple straightforward style, and writ- ing good idiomatic English. Dr. Joseph Caldwell, president of the University, was interested in the gifted negro and lent him books, and George was not slow to add to his small store of the best in English literature. About this time, in 1829, Gales and Son printed at Raleigh several of his poems in a pamphlet, entitled "The Hope of Liberty", a collection made up entire- ly from his earlier efforts. From this pamphlet the follow- ing is taken: THE SLAVE'S COMPLAINT ' 'Am I sadly cast aside, On misfortune's rugged tide? Will the world my pains deride Forever? "Must I dwell in Slavery's night, And all pleasure take its flight. Far beyond my feeble sight, Forever? "Worst of all, must hope grow dim, And withhold her cheering beam? Rather let me sleep and dream Forever ! "Something still my heart surveys. Groping through this dreary maze ; Is it Hope?J— then bum and blaze Forever ! 6 The University Magazine "Leave me not a wretch confined, Altogetlier lame and blind, Unto gross despair consigned. Forever! "Heaven! in whom can I confide? Canst thou not for all provide? Condescend to be my guide Forever ! "And when transient life shall end, Oh may some kind eternal friend Bid me from servitude ascend, Forever ! ' ' George never really cared t'i)r more libertj^ than he liad, but he was fond of playing to the grand-stand. It was a common .saying in Chapel Hill that Poet Horton owned Mr. Horton and all but owned the president of the University. The next example of his woik is one of his earlier efforts in that style of verse making which won for him a liveli- hood and reputation at Chapel Hill. It is entitled: LOVE "Whilst tracing thy visage, I sink in emotion, For no other damsel so wond' rous I see ; Thy looks are so pleasing, thy charms so amazing, I think of no other, my true love, but thee. "With heart-burning rapture I gaze on thy beauty. And fly like a bird to the boughs of a tree; Thy looks are so pleasing, thy charms so amazing, I fancy no other, my true love, but thee. "Thus oft in the valley I think and I wonder Why cannot a maid with her lover agree? Thy looks are so pleasing, thy charms so amazing, I pine for no other, my true love, but thee. "I'd fly from thy frowns with a heart full of sorrow — Return, pretty damsel, and smile thou on me; By ev'ry endeavor, I'll try thee forever; And languish until I am fancied by thee. ' ' This, too, was written down from his dictation before its author had learned to write. An American Man of Letters 7 The following stanza is from one of his poems of the same period : "Come melting Pity, from afar, And break this vast euormons bar, Between a wretch and thee ; Purchase a few short days of time, And bid a vassal soar sublime, On wings of Liberty." His work at Chapel Hill and his appeals to the sympathy of the students secured for him a small sum of money, with which he hoped to buy his freedom and a passage to Tiiberia ; but after the death of his patron, Dr. Caldwell, he gave him- self up to drink, and his little savings, with all tliat he could earn or beg, went for liquor. A favorite scheme of his for raising money was to write some verses setting forth the sick- ness and distress of his familj^ and closing with an appeal t(j the students to "lend a helping hand to the old unfortunate bard". This he would take from room to room and read, and his old employers in versification nearly always respond- ed liberally. Dr. Battle tells us in his history of the Univer- sity that "his manner was courteous, his moral character good. Like Byron, Burns, and Poe, he often quenched the divine spark with unpoetic wliiskey." I have on my table as I write a small volume of his poems published in 1838. Earlj'- in the fifties a small duodecimo volume of his verses was published in Boston along with his autobiography. Several short stories and numerous essays of his were also published about this time. He addressed the following verses to Horace G reel 3', and they appeared in the New York Tribune. THE POET'S PETITION "Bewailing 'mid the ruthless wave I lift my feeble hand to thee, Let me no longer be a slave, But drop the fetters and be free. * 'Why will regardless Fortune sleep Deaf to my penitential prayer. 8 The University Magazine Or leave the struggling bard to weep, Alas! and languish in despair? "He is an eagle void of wings Aspiring to the mountain height, Yet in the vale aloud he sings For Pity's aid to give him flight. "Then listen all who never felt For fettered genius heretofore, Let hearts of petrification melt, And bid the gifted negro soar." Horton's versification had often been employed in singing the praises of the ladies, and he had written many an acros- tic and sung many a song in praise of Sally Maxwell, a charming young widow of Warrenton . For this work he re- ceived his highest prices, paid by the lovesick swains of Chapel Hill who spent their senior vacation in that delight- ful village. Miss Cheney of Connecticut, who afterwards be- came Mrs. Horace Greely, was teaching school at Warrenton, and, while making a short stay in New York on her way to North Carolina, met Greel}^ and still further enlisted his in- terest in the negro poet. When George's student employer was willing to pay as much as fifty cents, the poem was generously gushing. Hor- ton continued to live near Chapel Hill until the coming of the United States cavalry in 1865, when he accompanied an army officer to Philadelphia, and lived there until his death at an advanced age. He was fond of writing poems in pairs, matching one against the other. The result of his first effort in this direction was given to a young instructor in the University in recognition of some favor that ths poet had received at his hands : THE PLEASURE OF A BACHELOR'S LIFE O tell. me not of Wedlock's charms, Nor busy Hymen's galling chain, But rather let me fold my arms From pleasures which wiW end in pain. An American Man or Letters § 'Tie true the primogenial flower Arose to please in Eden's grove, But did she not as soon devour The silly bee that sought her love? Then with content remain alone, But still on wings of pleasure soar, The storms of life will soon be gone, Perhaps, and to return no more. Without a surly wife to scold, Or children lo disturb your mind, To pillage o'er your chest for gold. And spend for trifles what they find. PAIN OF A BACHELOR'S LIFE When Adam dwelt in Eden's shade, His state was joyless there ; He then the general scene surveyed. No true delight the world dsiplayed To him witliout the fair. His mind was like the ocean's wave When rolling to and fro ; He seemed a creature doomed to crave, Too melancholy to be brave, AVheii ui) trra pleasure.-: flow. At length a sniiling woman rose, A bone from hi^ own side, The scene of pleasure to disclose An<l lull him into soft repose, The raptni-es of a bride Young bachelor whoe'er thou art Thy pleasures are but rare; A t]iorn will ever pierce thy heart Until fond nature takes its part Of comfort with the fair. His later work showed remotely and in some small meas- ure the influence of tliat group of Elizabethan poets who were wont to meet in tlie clvil»-room of the Mermaid Tavern, and, after he went to Philadelphia, he wrute a number of poems in imitation of Marlowe's "Passionate Shepherd to his Love" and "The Nymph's Reply" by Sir Walter Raleigh. 10 The University Magazine It was in Philadelphia that he developed his gift of story telling, his stories being modelled on the old stories of the East, as he had learned them from his Bible and in many cases being bodily taken from the Scriptures and made modern as to names and places. In this he was even more success- ful than was Benjamin Franklin in his famous paraphrase of the Book of Job. The source (^f Horton's inspiration was alvnys liid from any but tlic closest students of Holy Writ, and even they did not often recognize tlieir old friends in modern dress. In yet another respect this poet would be a paradox in our day. He did very little work before reaching the age of forty, and the most productive period of liis life began when he was sixty-seven years old, continuing lill liis death at the age of eightv-five, in 1883. All the examples of his verse that I have given are selected from his earlier productions, written when he was still an unlettered slave.


text:
200 Canyon Park Dr., Pelham, AL 35124
- $385,000
- 115 Days on site
- Beds: n/a
- Baths: n/a
- Commercial Building
Right off of 31, mostly ready for move in, 1. 5 story with 3034 SF +/- main level and 1517 +/- s/f upstairs. Plenty of parking will meet many business needs. Not for lease, for sale only. A variety of room sizes may meet immediate needs, or build out to your needs. Upstairs has a full bath for added benefit, two large work areas, surrounded by executive offices with windows. Click here to learn more about this listing.
- Commercial Building
- Beds: n/a
- Baths: n/a
Listing Details
- Lot Size
- Approximately 0.47 Acres
Public Facts: As provided by County Assessor and Recorder offices. May not reflect recent additions or improvements. If you see any errors, the best way to get the records updated is to contact your local county records office. If any of the information in this section conflicts with property information provided by a listing agent or broker, agent-provided information should be deemed more reliable.
Local Info
| Median Household Income
| Median Years In Residence
| Median Homeowner Age
| Households with Children
| Percent of Homes Rented
Nearby Elementary Schools
- Valley Intermediate Sch
- 2200 Highway 33
- Valley Elem Sch
- 310 Opportunity Dr
- Helena Elem Sch
- 187 3rd St
Nearby Middle Schools
- Pelham High Sch
- 2500 Panther Cir
- Kingwood Christian School
- 1351 Royalty Dr
- Hoover High Freshman Ctr
- 100 Flemming Parkway
Nearby High Schools
- Pelham High Sch
- 2500 Panther Cir
- Kingwood Christian School
- 1351 Royalty Dr
- Hoover High Sch
- 1000 Buccaneer Dr
These are the closest schools to your requested location. Proximity does not guarantee enrollment eligibility. Please consult your real estate agent or school district to confirm the schools you are zoned to attend.
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**** *** **** * CheckPoint ******* Development **** Cycle ******
Attached: XBIS219 Week 6 CheckPoint - Systems Development Life Cycle (SDLC).zip
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In this paperwork of XBIS 219 Week 6 CheckPoint Systems Development Life Cycle (SDLC) you will find the answers on the next questions:
Review Section 10.3 in the text.
Write a 200-word paper outlining the phases of SDLC and identifying the different personnel that participate in this process.
findings of the study?
Format your paper consistent with APA guidelines. There
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£650 pcm Available Now
Presented to the market is a Three Bedroom, Mid Terrace, Family Home, situated North of Kilbowie Road, Clydebank. LANDLORD REGISTRATION - 380393/395/12471
Property Misdescriptions Act: Please note that these particulars are prepared by us on the basis of information provided to us by our client. We have not tested the electrics, Fixtures, fittings or other appliances that may be within the property, including the Central Heating. Prospective purchasers can make their own enquiry.
This house description is based upon information supplied by the owner, or on behalf of the owner. These property particulars are produced in good faith and do not constitute or form part of any contract. s1homes do not take any responsibility to the accuracy of the information contained in this document.


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CHINA: Thermal Market Heats Up
China is drafting a national standard for the thermal underwear industry in a bid to stop the current chaos in the market, according to the China Knitwear Association. Thermal underwear, introduced to China in 1998, is now a mature market and competition has hit an all-time high. According to X&L Marketing Services, thermal underwear manufacturers have spent at least 140m yuan ($17m) on television advertising during the period between January and October this year, 86 times more than that spent in the same period last year.
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