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Acute stress affects gut functions through the activation of corticotropin-releasing factor (CRF) receptors. The impact of acute stress on pelvic viscera in the context of chronic stress is not well characterized. We investigated the colonic, urinary, and locomotor responses monitored as fecal pellet output (FPO), urine voiding, and ambulatory activity, respectively, in female and male CRF-overexpressing (CRF-OE) mice, a chronic stress model, and their wild-type littermates (WTL). Female CRF-OE mice, compared with WTL, had enhanced FPO to 2-min handling (150%) and 60-min novel environment (155%) but displayed a similar response to a 60-min partial restraint stress. Female CRF-OE mice, compared with WTL, also had a significantly increased number of urine spots (7.3 ± 1.4 vs. 1.3 ± 0.8 spots/h) and lower locomotor activity (246.8 ± 47.8 vs. 388.2 ± 31.9 entries/h) to a novel environment. Male CRF-OE mice and WTL both responded to a novel environment but failed to show differences between them in colonic and locomotor responses. Male WTL, compared with female WTL, had higher FPO (113%). In female CRF-OE mice, the CRF1/CRF2 receptor antagonist astressin B and the selective CRF2 receptor agonist mouse urocortin 2 (injected peripherally) prevented the enhanced defecation without affecting urine or locomotor responses to novel environment. RT-PCR showed that CRF1 and CRF2 receptors are expressed in the mouse colonic tissues. The data show that chronic stress, due to continuous central CRF overdrive, renders female CRF-OE mice to have enhanced pelvic and altered behavioral responses to superimposed mild stressors and that CRF1-initiated colonic response is counteracted by selective activation of CRF2 receptor.
- chronic stress
- colon
- urine
- locomotor activity
- astressin B
- mouse urocortin 2
early on, clinical observations and experimental studies established a link between psychological stress and motor function alterations of gut (1) and bladder (62). Recent studies in humans showed the role of psychosocial factors in the onset or development of functional bowel and bladder diseases, particularly irritable bowel syndrome (IBS) (40) and interstitial cystitis (IC) (55). This led to the notion that the level of chronic life stress predicts the clinical outcome in these patients (6, 19). Numerous studies in rodents have characterized the alterations of motor and mucosal barrier functions in the gastrointestinal and urinary tracts, mainly under acute stress conditions (13, 58, 65).
Persistent elevation of central drive of the hypothalamic-pituitary-adrenal (HPA) axis is one of the distinguishing characteristics of chronic stress in animals and humans (9). Corticotropin-releasing factor (CRF) is a 41-amino acid hypothalamic peptide that initiates HPA axis activation by stimulating the secretion and biosynthesis of pituitary ACTH, which, in turn, causes adrenal glucocorticoid secretion (4). In addition, activation of CRF signaling pathways induces a battery of acute behavioral, autonomic and visceral stress responses (4, 17, 65). Hypersecretion of CRF in the central nervous system has been implicated in stress-related human pathologies, including major depressive disorders (2). The actions of CRF and other related endogenous peptides, urocortin 1 (Ucn 1), Ucn 2, and Ucn 3, are mediated through the activation of two G-protein-coupled receptors, CRF1 and/or CRF2 (4, 21). Convergent reports indicate that acute stress and central injection of CRF and Ucn 1 stimulate propulsive colonic motility, primarily through the activation of brain CRF1 receptors as established by the use of selective CRF1 and CRF2 receptor antagonists in rodents (67) and monkeys (17).
Recent studies also support a role for peripheral CRF receptors in the colonic response to stress in rats (68). Peripheral injection of CRF1/CRF2 agonists such as CRF and Ucn 1 and exposure to stressors such as restraint or water avoidance stimulate motility and increase permeability of the colon. These responses are blocked in rats by peptide CRF antagonists acting peripherally (68). In contrast to CRF and Ucn 1, peripheral injection of selective CRF2 agonists, Ucn 2 or Ucn 3, had no measurable effects on basal colonic function in rats and mice (39, 43). However, emerging evidence points to a role for CRF2 receptors in counterbalancing CRF1-initiated anxiety, stimulation of the pituitary adrenal axis, and visceral hyperalgesia responses to stress, thereby contributing to the restoration of homeostasis (3, 11, 12, 50), although recent studies indicate that brain septal CRF2 plays different roles (anxiogenic or no effect) depending on the level of background stress (25). With regard to the gut, there are recent reports showing that peripheral injection of Ucn 2 inhibits the CRF1-mediated hyperalgesia induced by intestinal distension in rats (42, 44, 47).
CRF injected daily or intermittent exposure to stressors has been used to model a state of chronic stress (26, 33). An alternative strategy is to use transgenic mice that overexpress CRF (CRF-OE) (59). CRF-OE mice were generated by a chimeric CRF transgene comprising the methallothionein promoter driving the rat CRF gene, including introns (59) or the Thy-1 promoter (15, 16). These transgenic mice overexpress CRF primarily in the brain and show several features that parallel those characteristic of chronic stress (12), including the chronic stimulation of pituitary ACTH release and elevated corticosterone levels (16, 59). CRF-OE mice are also a validated model of chronic stress that bear an anxiety-like behavioral profile featuring hypoactivity when placed in a novel environment (60, 72), hyperemotionality and impaired learning (23, 70), and diminished sexual receptivity (22). CRF-OE mice display immunologic alterations (12, 46) and increased body temperature and heart rate during the inactive phase of the diurnal cycle (15). Although CRF-OE mice have been largely characterized to assess the consequences of chronic constitutive CRF overdrive on the endocrine, behavioral, cardiac, and immune systems under basal or acute stress, to date, this model has not been used to explore alterations of pelvic function well known to be susceptible to stress (28, 40, 65).
In the present study, we examined pelvic visceral functions, primarily propulsive colonic motility, and, to a lesser extent, bladder function and locomotor responses in CRF-OE mice after exposure to acute stressors that were superimposed on their life-long CRF overexpression. Studies were conducted in male and female CRF-OE mice and wild-type littermates (WTL) because studies suggest the presence of sex differences in intestinal motor responses to chronic wrap restraint in rats (76), as well as in the prevalence of IBS (24) and IC (10). A link between IBS and overactive bladder has also been suggested (45). The role of peripheral CRF signaling pathways in mediating the pelvic changes induced by exposing CRF-OE mice and WTL to a novel environment stressor was assessed by peripheral pretreatment with the long-acting CRF1/CRF2 peptide antagonist astressin B (54). We also investigated whether acute stress-induced stimulation of pelvic propulsive motor activity in CRF-OE mice is modulated by activation of CRF2 receptors using peripheral injection of Ucn 2.
Adult male and female CRF-OE mice and WTL (Oregon Health and Science University, Portland, OR) and male C57BL/6 mice (Harlan, Indianapolis, ID), aged 3–6 mo, were used. CRF-OE mice were generated as previously detailed (59, 60) with the use of a chimeric CRF transgene comprising the methallothionein protomer driving the rat CRF gene and backcrossed eight generations onto the C57BL/6 mouse strain. Mice were housed in standard plastic cages (outer dimension: 27 × 12 × 16 cm) in groups of three or four of the same sex, in a temperature-, humidity-, and light cycle (lights on 0600)-controlled environment. Mice were provided ad libitum access to water and a commercially available laboratory rodent diet (Prolab RMH 2500-5P14; Purina LabDiet, St. Louis, MO). All of the procedures were approved by the Animal Research Committees at UCLA and Veteran Affairs Greater Los Angeles Healthcare System (Protocols 05058-02 and 11084-03).
Mouse Ucn 2 and astressin B (Peptide Biology Laboratory, The Salk Institute, La Jolla, CA) were synthesized by the solid-phase approach and the Boc strategy as previously described (54) and stored in powder form at −80°C. Immediately before the experiments, astressin B was dissolved in sterile water and Ucn 2 in saline (pH 7.0). Subcutaneous and intraperitoneal injections were performed (in 0.1 ml).
Acute stressors.
Three stressors were used: brief handling, novel environment, and partial restraint. Brief handling consisted of handling for 2 min. The novel environment consisted of transferring mice from their home cage (in <20 s) to a new clean plastic cage (outer dimension: 27 × 12 × 16 cm). The cage floor was lined with filter paper instead of bedding, and each mouse stayed alone in this novel environment for 60 min without food or water. Partial restraint stress consisted of placing the mouse head first into a ventilated 50-ml falcon tube for 60 min, as previously described (38).
Monitoring colon, bladder, and behavioral parameters.
Fecal pellet output (FPO) was recorded as the number of fecal pellets expelled at 2 min for the handling stressor; at 5, 15, 30, 45, and 60 min for the novel environment; and at 15, 30, 45, and 60 min for the partial restraint stressor. Urine voiding was monitored essentially as previously described (14) with some modifications. Mice were placed individually in a new cage with the floor lined with filter paper that was divided with a marker in 12 equal squares of 5.2 × 5.2-cm size. Urine spots left on the filter paper were viewed at the end of the 60-min novel environment with a UV transilluminator and photographed. The number and area of spots were determined with NIH Image software (Scion, Frederick, MD). Locomotor activity was monitored in mice placed individually in a new cage with the floor lined with filter paper that was divided with a marker in 12 equal squares of 5.2 × 5.2-cm size. Locomotor activity was assessed as the number of squares crossed during the first 5, 15, 30, 45, and 60 min, as previously described (5).
CRF receptor gene expression in the colon.
Proximal and distal colon tissue samples were harvested from naive female CRF-OE mice and female WTL to assess CRF receptor gene expression by RT-PCR. For RNA isolation and cDNA synthesis, total RNA was extracted from the proximal and distal colons of CRF-OE female mice (n = 5) and their WTL (n = 3) using RNA-Bee (TEL-TEST, Friendswood, TX), according to the manufacturer's protocol, which included a DNase step. Briefly, the colonic tissue was homogenized in RNA-Bee with the FastPrep system (FP120A homogenizer and lysing matrix D; QBiogene, Carlsbad, CA), 200 μl of chloroform were added, and the solution was centrifuged for 15 min at 4°C. The aqueous layer was precipitated with isopropanol. The RNA pellet was suspended in diethyl pyrocarbonate water and digested for 60 min at 37°C using DNase I (Promega, Madison, WI). The quality and amount of final total RNA yield were estimated based on the ratio of absorbance at 260 to 280 nm by UV spectrophotometer (ND-1000; NanoDrop, Wilmington, DE). Total RNA (5 μg) was denatured at 65°C for 5 min and used to synthesize first-strand cDNA in a total volume of 20-μl reaction by the ThermoScript RT-PCR system (Invitrogen, Carlsbad, CA). The reverse transcription was terminated by incubation at 85°C for 5 min. RNase H was then added to the reaction mixture to remove the total RNA template.
The following specific mouse CRF1, CRF2, and ribosomal protein S16 oligonucleotide primers were used in the PCR: for mouse CRF1, 5′-GGTGTGCCTTTCCCCATCATT-3′ and 5′-CAACATGTAGGTGATGCCCAG-3′ corresponding to nucleotides 740–760 (sense) and 998–1018 (antisense) (74) and the predicted size of the band of 279 bp; for mouse CRF2, 5′-GGCAAGGAAGCTGGTGATTTG-3′ and 5′-GGCGTGGTGGTCCTGCCAGCG-3′ corresponding to nucleotides 957–977 (sense) and 1314–1334 (antisense) (61) and the predicted size of the band of 378 bp; and for ribosomal protein S16, 5′-TGCGGTGTGGAGCTCGTGCTTGT-3′ and 5′-GCTACCAGGCCTTTGAGATGGA-3′ corresponding to nucleotides 369–391 (sense) (75) and the predicted size of the band is 309 bp. PCR reactions were performed in a final volume of 30 ml using the RedTaq system (Sigma-Aldrich, St. Louis, MO). The reaction was predenatured at 95°C for 2 min and then amplified 34 times (94°C, 40 s; 59°C, 40 s; 72°C, 2 min), followed by a 5-min extension at 72°C in Thermal Cycler (PTC-200; MJ Research, San Francisco, CA). S16 was used as an internal control to ensure cDNA quality and equal loading. Negative control contained all reagents, except that 1 μl of H2O was substituted for reverse transcriptase in the RT reaction to exclude the possibility of genomic or other DNA contamination. The agarose gel image of PCR products corresponding to CRF receptors was acquired by the Kodak EDAS 290 system and semiquantified by densitometric measurement using NIH Image software (Scion). All results were normalized by the internal control.
Experimental protocols.
All experiments were performed during the light phase between 0830 and 1200 in nonfasted mice.
Effects of various acute stressors on FPO and urine voiding.
Female CRF-OE mice (22.1 ± 0.9 g) and WTL (21.2 ± 0.3 g) were handheld for 2 min (handling stress), and the FPO during the 2-min handling period was monitored. Female CRF-OE mice (22.6 ± 1.1 g) and WTL (21.7 ± 0.3 g) were restrained for 60 min (partial restraint stressor), and FPO was monitored every 15 min for 60 min. Female (24.7 ± 1.3 g) and male (32.4 ± 2.4 g) CRF-OE mice and female (21.4 ± 0.4 g) and male (31.8 ± 1.0 g) WTL were placed in the novel environment for 60 min (novel environment stressor). FPO and locomotor activity were monitored at 5, 15, 30, 45, and 60 min. Urine output during the 60-min period was determined after the end of experiment. To avoid the confounding effect of pheromone, experiments were conducted in isolated individual cages for each mouse. Male and female mice were not housed together under any circumstances, either for regular housing or during the experiment. The cages used for each study were cleaned and autoclaved at the Animal Facility where experiments were conducted. No single cage was used more than once.
Effects of CRF receptor antagonist on colonic response to acute stressors in female CRF-OE mice and WTL and male C57BL/6 mice.
Astressin B (100 μg/kg) or water was injected subcutaneously 30 min before the 60-min novel environment exposure of female CRF-OE mice (24.2 ± 2.2 g) and WTL (22.1 ± 0.8 g), and FPO, locomotor activity, and urine voiding were monitored for 60 min. A similar injection protocol was used with male C57BL/6 mice (34.3 ± 0.6 g) before the 60-min exposure to partial restraint stress, and FPO was monitored. The dose and route of CRF antagonist administration were selected based on previous experiments in mice and rats that characterized the regimen of injection for astressin B to block peripheral CRF-induced stimulation of distal colonic transit or endocrine response (39, 54).
Effects of Ucn 2 on colonic response to a novel environment in female CRF-OE mice and WTL.
Female CRF-OE mice (28.9 ± 1.7 g) and WTL (23.9 ± 0.5 g) were injected intraperitoneally with vehicle or Ucn 2 (1, 3 and 10 μg/kg) 10 min before exposure to a novel environment for 60 min. The FPO, urine voiding, and behavioral locomotor responses were monitored for 60 min. Doses and route of Ucn 2 administration were chosen on the basis of previous studies on gut functions in rodents (38, 43).
Statistical analysis.
All values are reported as means ± SE. One-way repeated-measures ANOVA followed by the Newman-Keuls multiple comparison test were used to analyze the time courses of FPO and locomotor activity. The number of urine spots and volume were analyzed by one-way ANOVA followed by Student's t-test to compare differences at one time point. Two-way repeated-measures ANOVA was used when two-factor effects, genotype and treatment, were analyzed. A P value of <0.05 was considered statistically significant.
Differential FPO responses to acute stressors in female and male CRF-OE and WTL mice.
Female CRF-OE mice responded to 2-min handling with a higher FPO than female WTL (1.0 ± 0.2 vs. 0.4 ± 0.2 pellets/2 min, respectively, P < 0.05; Fig. 1A). Similarly, female CRF-OE mice exposed to a novel environment for 60 min displayed significantly higher cumulative FPO/h than did the WTL (6.9 ± 0.9 pellets/h, n = 12, vs. 2.7 ± 0.9 pellets/h, n = 11, respectively, P < 0.05; Fig. 1B). Time-course studies showed that the peak FPO in female CRF-OE mice occurred within the first 15 min of the novel environment exposure and was sevenfold higher than that of the corresponding WTL (5.4 ± 0.8 vs. 0.7 ± 1.0 pellets/15 min, respectively, P < 0.05; Fig. 2A). Thereafter, FPO/15 min in female CRF-OE mice remained low and was not significantly different from that of female WTL, with values between 0.6 and 1 pellet/15 min (Fig. 2A). In response to partial restraint, however, both female CRF-OE mice and WTL had similarly high cumulative FPO (12.3 ± 0.4 pellets/h, n = 7, vs. 11.8 ± 1.2 pellets/h, n = 6, respectively, P > 0.05) with a similar peak response at 15 min (5.7 ± 0.6 vs. 5.3 ± 1.0 pellets/min) and significantly decreased plateau response during the remaining 45 min (Fig. 1C). Because the novel environment stressor showed a significant difference between the female CRF-OE mice and WTL, we selected this stressor for all subsequent studies involving CRF-OE mice and their WTL. In male mice exposed to a novel environment, both CRF-OE mice and WTL had a significantly higher FPO score during the first 15 min (7.0 ± 0.5 vs. 4.9 ± 1.1 pellets/15 min, respectively) than that shown in the remaining 45 min, monitored every 15 min (Fig. 3A). However, neither the peak (7.0 ± 0.5 vs. 4.9 ± 1.1 pellets/15 min, P > 0.05) nor the cumulative defecation response (10.9 ± 1.2 vs. 8.6 ± 1.1 pellets/h, P > 0.05) reached significant difference between male CRF-OE mice and WTL (Fig. 3A).
Comparison of the total 60-min FPO to novel environment by sex showed that male WTL mice had significantly higher FPO response (8.6 ± 1.1, n = 7) than did the female WTL (2.7 ± 0.9 pellets/h, n = 11, P < 0.05) (Figs. 1B and 3B). Likewise, male CRF-OE mice tended to have a higher increased FPO to a novel environment than did female CRF-OE mice (10.9 ± 1.2 pellets/h, n = 7, vs. 6.9 ± 0.9 pellets/h, n = 12, P > 0.05) (Figs. 1B and 3B), although the difference did not reach significance. Because the body weight was higher in male than in female mice, FPO per 10 g body wt was computed. Analysis of FPO normalized to body weight yielded similar results. In response to a novel environment, there was no significant difference between male CRF-OE mice and WTL (3.5 ± 0.5 vs. 2.8 ± 0.4 pellets·10 g−1·h−1, P > 0.05), whereas female CRF-OE mice had a significantly higher response than their WTL (2.9 ± 0.5 vs. 1.2 ± 0.4 pellets·10 g−1·h−1, P < 0.05). Male WTL also had a significantly higher response to a novel environment than did female WTL (2.8 ± 0.4 vs. 1.2 ± 0.4 pellets·10 g−1·h−1, P < 0.05). These data argue against body weight as a significant contribution to the observed sex difference in FPO in response to a novel environment in both WTL and CRF-OE mice.
Differential urine output and locomotor activity responses to novel environment between female CRF-OE and WTL mice.
Female CRF-OE mice exposed to the novel environment had a higher number of urine spots than did the WTL (7.3 ± 1.4 vs. 1.3 ± 0.8 spots/h, P < 0.05; Fig. 2B). No significant difference was identified in total area under the curve of the urine spots between female CRF-OE mice (32.2 ± 9.6 cm2, n = 7) and WTL (21.4 ± 9.9 cm2, n = 6, P > 0.05). The urine output response in male mice was not studied.
The ambulatory activity in response to a novel environment, assessed as the total number of squares crossed during the 60-min period, was significantly lower in the female CRF-OE mice than in the WTL (246.8 ± 47.8 vs. 388.2 ± 31.9/h, P < 0.05; Fig. 2C). The time course study showed that the activity of CRF-OE female mice was reduced starting in the first 15 min and continued to be lower than that of the WTL throughout the 60-min period with a significant effect at 30–45 min (Fig. 2C). In male CRF-OE mice, the total number of squares crossed during the 60 min of novel exposure was not different from that of WTL (404.7 ± 99.1 vs. 468.0 ± 27.3/h, respectively, P > 0.05; Fig. 3B). Inspection of the time course of the response showed similar values in both male CRF-OE and WTL mice during the first 45-min period, with a significant reduction in activity during the last 15 min in the CRF-OE mice (Fig. 3B). The ambulatory activity in male CRF-OE mice and WTL tended to be higher than that of female CRF-OE mice and WTL (Figs. 2C and 3B). Because female CRF-OE mice were more responsive to the novel environment than male CRF-OE mice compared with their WTL, further studies were mainly performed in female mice.
Effects of astressin B on acute stress-induced stimulation of pelvic function in CRF-OE and WTL mice.
Female CRF-OE mice injected subcutaneously with vehicle and exposed to a novel environment had a significantly higher FPO than vehicle injected subcutaneously in female WTL (0–30 min: 7.3 ± 0.9 vs. 1.7 ± 1.7 pellets/30 min, P < 0.05; 30–60 min: 2.3 ± 0.6 vs. 0.3 ± 0.2 pellets/30 min, P < 0.05; Fig. 4, A and B) consistent with previous observations in nonpretreated animals. Astressin B (100 μg/kg sc) injected 30 min before exposure to a novel environment did not significantly modify the low defecation score in female WTL but prevented the significant increase in FPO in CRF-OE mice, and values were similar to those observed in astressin B-pretreated female WTL (Fig. 4A). Likewise, astressin B (100 μg/kg sc) injection in male C57BL/6 mice as a 30-min pretreatment significantly inhibited the FPO rise induced by partial restraint stress compared with subcutaneous injection of vehicle (vehicle + restraint: 8.7 ± 0.8 pellets/h, n = 13; astressin B + restraint: 3.8 ± 0.2 pellets/h, n = 5/group, P < 0.05). Astressin B did not significantly influence FPO compared with vehicle-injected control male C57BL/6 mice (2.4 ± 1. 3 pellets/h, n = 7, vs. 1.7 ± 0.9 pellets/h, n = 7; P > 0.05). By contrast, astressin B pretreatment under the same conditions affected neither the number of urine spots (vehicle: 6.3 ± 2.4 spots/h vs. astressin B: 9.0 ± 0.8 spots/h; Fig. 4C) nor the locomotor response (vehicle: 232.0 ± 89.8 entries/h vs. astressin B: 178.0 ± 34.8 entries/h; Fig. 4D) induced by a novel environment in female CRF-OE mice.
Peripheral mouse Ucn 2 blocked FPO response to novel environment in female CRF-OE mice.
CRF-OE mice injected intraperitoneally with saline had a significant 3.1- to 3.3-fold higher FPO score than did the saline-injected WTL during the first 15 or 30 min of novel environment (Fig. 5, A–C). Ucn 2 (1, 3, and 10 μg/kg ip) blocked the novel environment-induced 60-min FPO response in CRF-OE female mice (pellets/h: 4.0 ± 1.5, 3.8 ± 0.8, and 2.6 ± 0.4, respectively, vs. 9.0 ± 2.1 in vehicle, P < 0.05; Fig. 5B). By contrast, Ucn 2 (10 μg/kg ip) did not significantly affect the urine response as shown by the similar spot number in WTL and CRF-OE mice (Fig. 5D). Ucn 2 (10 μg/kg ip) treatment in female CRF-OE mice significantly reduced the novel environment-induced overall locomotor response (106.3 ± 23.5 vs. 218.4 ± 62 entries/h; Fig. 5E) with no significant effect during the first 15 min when the FPO response was maximal (Fig. 5C).
CRF1 and CRF2 gene expression in proximal and distal colons of female CRF-OE and WTL mice.
Using the primers specific for mouse CRF1 and CRF2, we found RT-PCR products for CRF1 and CRF2 with the predicted sizes in all samples of the proximal and distal mice colons that were examined (Fig. 6A). Quantitative analysis of the proximal vs. distal colon for CRF1 signal showed that CRF1 mRNA levels were significantly higher in proximal colon than in distal colon in both WTL (94.2%) and CRF-OE mice (96.1%). CRF1 mRNA levels in CRF-OE mice tended to decrease by 22.6% in the proximal colon and by 48.5% in the distal colon compared with WT mice. In contrast, similar levels of CRF2 expression was found in the proximal and distal colons with increased tendency of CRF2 mRNA level in the proximal colon of CRF-OE mice (21.4%) (Fig. 6B).
Stimulation of colon and bladder motor functions (transit, defecation, urination) is a hallmark of the acute visceral response in rodents exposed to various stressors (38, 63, 65). The present study shows that female CRF-OE mice exposed to a novel environment for 60 min displayed a 6.7-fold peak increase in FPO compared with WTL. The response had a rapid onset and was short lasting. Likewise, female CRF-OE mice responded to handling for 2 min with a significant increase in FPO, compared with their WTL. By contrast, both female CRF-OE and their female WTL mice had a robust FPO response with a similar time course and magnitude during partial restraint stress. Female CRF-OE mice displayed enhanced urine voiding and decreased ambulation during exposure to the novel environment compared with their female WTL. These data are significant because they demonstrate that exposure to a novel environment triggers pelvic and behavioral manifestations of stress in female CRF-OE mice, which are under conditions of chronic central drive of CRF (12). Therefore, female CRF-OE mice provide an experimental model of enhanced pelvic responsiveness to a novel environment in the context of chronically activated stress pathways that may have relevance to stress modulation of functional disorders (19, 40, 55).
The present data also provide evidence that peripheral activation of CRF signaling pathways is part of the underlying mechanisms of acute stress-related activation of motor function in the colon. The CRF receptor antagonist, astressin B (54), prevented the significant increase in FPO of female CRF-OE mice compared with their WTL when exposed to the novel environment stressor. Similarly, in male C57BL/6 mice, the partial restraint-induced 4.1-fold increase in FPO compared with control was prevented by astressin B injected subcutaneously. Consistent with these observations, studies in female and male rats have also shown that the CRF1/CRF2 peptide antagonists, α-helical CRF9–41, or astressin (51, 53) injected intraperitoneally or intravenously prevented wrap restraint or water avoidance stress-induced acceleration of colonic transit and defecation (7, 36, 43, 77).
The blunting of the FPO response to acute stress by subcutaneous astressin B is likely to reflect a peripheral site of action (38, 68). In our study, the subcutaneous injection of astressin B did not influence the decreased locomotor activity in CRF-OE mice exposed to a novel environment. Such a decrease in exploratory activity is part of the anxiety-like behavior in CRF-OE mice, which has been well characterized in different novel environment paradigms, including open field, light-dark exploration, 16-hole board task, and elevated plus maze (35, 60, 70, 72), and shown to be mediated by brain CRF1 receptors (12, 60). CRF injected into the cerebral ventricles in as low as 0.15 nmol was previously reported to decrease locomotion in an open-field test, whereas subcutaneous injection of similar doses of CRF failed to affect locomotion (64). Thus, although there is no immunohistochemical evidence for the overexpression of CRF peptide in the peripheral tissue or elevated CRF levels in the circulation of CRF-OE mice (12, 59), an acute mild stressor superimposed on their chronic central CRF overproduction could engage the peripheral urocortin signaling (20, 31) to contribute to the colonic response.
Although astressin B binds to both CRF1 and CRF2 receptors (52), the astressin B-induced dampening of colonic motor response to a novel environment is likely to occur primarily through peripheral blockade of CRF1 receptors. This has been shown by the blockade of stress or CRF-induced colonic motor stimulation by intraperitoneal injection of astressin and CRF1 receptor antagonists (39) but not by peripheral injection of the selective CRF2 antagonist astressin B (38, 42). In addition, the CRF2 agonists Ucn 2 (6–60 μg/kg ip) and Ucn 3 (6–120 μg/kg ip) did not influence basal distal colonic transit, although they dose-dependently inhibited gastric transit monitored simultaneously in male mice (39). CRF1 receptors are localized at peripheral sites that subserve the regulation of propulsive motor activity in the colon. These include the myenteric neurons in the rat and guinea pig colon, where CRF induced a CRF1-dependent activation (8, 34, 41). We found by RT-PCR that CRF1 receptors are also expressed in CRF-OE mouse and WTL proximal colon and to a lesser extent in the distal colon, consistent with a possible site of action as established in rats. Lastly, female CRF-OE mice injected intraperitoneally with Ucn 2 in doses ranging from 1 to 10 μg/kg no longer displayed a significant increase in FPO during the 60 min of novel environment, whereas vehicle-injected CRF-OE mice did. Collectively, these findings support a role for peripheral CRF1 and not CRF2 receptors in mediating the FPO response to an acute stressor in mice, in line with previous reports in rats (36, 43).
Some of the phenotypic attributes of the CRF-OE mice, particularly those related to immunological abnormalities, derive exclusively from the CRF1-mediated chronic increase in circulating glucocorticoids (12). Other attributes, such as decreased exploratory activity and decreased sexual receptivity in females, are unrelated to the hypercorticosteronemia (12, 22, 23). Existing data do not support a glucocorticoid modulation of the CRF1-mediated colonic motor response in female CRF-OE mice. Hypophysectomy does not alter the stimulation of colonic transit by an acute stressor, and peripheral injection of ACTH or glucocorticoids does not result in colonic motor activation (66). The FPO of female CRF-OE mice was enhanced during exposure to the novel environment compared with WTL but was similar to WTL during the partial restraint stressor, indicative of differential responsiveness between the endocrine (12, 16, 60) and colonic motor changes to acute stressors (present study).
The selective CRF2 receptor agonist, Ucn 2 injected intraperitoneally, prevented the CRF1-initiated colonic motor response to a novel environment in female CRF-OE. Ucn 2 injected intravenously into mice has been reported to reach the brain parenchyma in an intact form at a moderate rate through passive diffusion (27), and a direct or indirect central action could occur. However, intraperitoneal Ucn 2 is likely to act peripherally. First, CRF2 receptors are expressed in the proximal and distal colons of both CRF-OE mice and WTL, as has been observed in rats (8). In addition, intraperitoneal Ucn 2 did not block the decrease in locomotor activity in CRF-OE mice exposed to the novel environment, a response well established to be mediated by CRF receptors in the brain (12, 60). These data support the emerging concept that activation of CRF2 receptors may counterbalance CRF1-initiated endocrine and visceral responses and thereby maintain allostasis (3, 44, 50).
Female CRF-OE mice exposed to a novel environment responded by a 4.6-fold increase in the frequency of urine voiding compared with WTL. CRF-OE mice are reported to have increased water intake (72), which may lead to increased voiding frequency. However, the fact that voiding frequency, but not the total urine output, was increased in CRF-OE mice suggests that the increased spotting in CRF-OE mice is related to an altered voiding and/or guarding reflex rather than factors affecting the overall urine volume (14). A recent review linked disorders of voiding with anxiety (29), and data in conscious rats established an important positive relationship between the state of arousal and micturition (28). The increased number of urine spots from CRF-OE mice, which also display anxiety-like behavior, is in line with the idea that their state of anxiety and/or arousal increased voiding frequency. The Barrington's and sacral parasympathetic nuclei are synaptically linked to modulate motor function in both colon and bladder (56, 57, 71), and CRF serves as a major neurotransmitter in this pathway (56, 73). However, the precise role of CRF in the micturition reflex remains to be clarified. An inhibitory effect of central and spinal CRF on the micturition pathway in conscious and anesthetized male Sprague-Dawley rats (28, 48) and increased micturition frequency and threshold of micturition by intrathecal or intraperitoneal injection of CRF in conscious Wistar female rats have been reported (30). In the present study, astressin B or Ucn 2 injected intraperitoneally at doses that counteracted the FPO response to novel environment did not alter the voiding response in CRF-OE mice. These data suggest that peripheral CRF receptors play little role in triggering or modulating the enhanced voiding frequency under these conditions. The lack of CRF1 receptor expression in the rat bladder under noninflamed conditions (32) may explain the differential effects of peripheral astressin B on colonic vs. bladder responses, since CRF1 receptors are located on myenteric neurons in the colon, where they exert an excitatory action in response to peripheral injection of CRF agonists (8, 34, 41). Clearly, further studies will be needed to address the underlying mechanisms regulating voiding function in CRF-OE mice exposed to novel environments. Whether a reflex response from the possible cross-talk between the colon and bladder contribute to the observed effects is also not known and requires further studies.
The present data suggest that chronically stressed female mice tend to have enhanced behavioral and autonomic responses to a superimposed acute mild stress compared with male. Female CRF-OE mice, compared with their female WTL, displayed higher FPO and anxiogenic-like responses than did male CRF-OE mice, compared with their male WTL, during exposure to the novel cage stressor. Alterations of brain CRF pathways induced by restraint stress during the last week of pregnancy result in a sex difference in the offspring, whereby female offspring display a prolonged HPA axis response and increased anxiety to stressors vs. that shown in the male offspring (49). Such in utero impact of stress may have a bearing on the observed sex difference in our study. The observation that chronic stress enhances the colonic and anxiogenic responses to a superimposed acute, novel stressor, mainly in the female CRF-OE mice has relevance to sex differences observed in chronic disease conditions in humans. It is well documented that women under stress conditions develop functional diseases such as IBS (24), IC (55), and comorbid disorders (6, 78) with anxiety more prevalently than men. Whether estrogen receptors, known to influence the activity of the CRF promoter and transcriptional activity of the urocortin gene (18, 69), play a role in this sex difference warrants investigation.
In summary, the present study established that female CRF-OE mice exhibit enhanced FPO and urine voiding and reduced locomotor activity when submitted to novel environmental stress compared with female WTL. This enhanced pelvic responsiveness of female CRF-OE mice was mainly observed in the context of mild stressors and was sex specific. The present findings also point to differential peripheral mechanisms in the colon vs. bladder of female CRF-OE mice exposed to a novel environment. The FPO response to novel cage and restraint stressors involved primarily peripheral CRF1 and could be blunted by peripheral Ucn 2, strengthening the notion of a possible modulation of CRF1 stimulatory action by CRF2 receptors. By contrast, the enhanced urine spotting was largely independent of peripheral CRF1 receptors and not modulated by intraperitoneal Ucn 2, suggesting the presence of different peripheral or central mechanisms that will require further detailed investigations. The data also add to a possible link between IBS and overactive bladder, as suggested by Monga et al. (45). In view of the enhanced response to acute novel mild stressors in chronically CRF-OE female mice, this model has an important bearing on the understanding of several functional diseases in women, such as IBS and IC, which are known to be linked to chronic stress and for which growing evidence indicates that CRF signaling pathways may be of significant relevance (6, 37).
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R01 DK-33061 (to Y. Taché), R01 DK-57238 (to Y. Taché), R21 DK-068155 (to M. Million), P50 DK-64539 (to Y. Taché, T. Buffington, M. Million), DK-26741 (to J. Rivier), and R01 MH-65689 (to M. Stenzel-Poore).
We thank HongHui Liang for technical assistance. We also thank Teresa Olivas and Debby Doan for editing the manuscript.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2007 the American Physiological Society


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As another disappointing season comes to an end, the Edmonton Oilers will begin the process of self evaluation, trying to figure out exactly what went wrong.
More importantly, once the problems are identified, the club will have to work hard in order to remedy them, having possibly painted themselves into a corner with player personnel.
Heading into this off season, the Oilers have 10 pending free agents on their current roster, seven of which are restricted.
It seems the club has already made a decision on Linus Omark, who has been a healthy scratch for the past four games.
If the Oilers don't see fit to play Omark in meaningless encounters down the stretch this season, it's hard to believe he's in the plans for next year.
Unfortunately for Omark and the Oklahoma City Barons, who will be in the post-season, the Oilers would probably have been better served to leave the Swedish product in the AHL where he could have helped in a playoff drive.
Now the Oilers risk losing Omark if they try to send him down to the minors as he has to clear waivers even after the NHL regular season comes to an end.
"He's in a bit of a logjam with people in front of him, which makes it difficult for him to get in and do what I think he's capable of," said Oilers head coach Tom Renney, late last week. "That being said, it's a bit of a numbers things right now quite honestly."
As a restricted free agent this summer, it's likely the Oilers will qualify Omark before trying to deal him away. The Oilers obviously feel there is a market for the winger or else they would just send him back to Oklahoma City.
But not having been on the roster for most of this season, Omark is the least of the Oilers' concerns moving forward.
They still have Eric Belanger locked in for another two years after this season. The veteran centre was supposed to provide leaderships, stability in the face-off circle and secondary scoring this season.
He has been good in the face-off circle, but has struggled offensively and has seen his role and ice time diminish as the season has gone along.
If the Oilers select Mikhail Grigorenko in the upcoming NHL draft and bring Anton Lander back into the mix, it's likely they'll have to find a trading partner for Belanger, who's in line to make $2 million next season.
Apart from Belanger, the Oilers need to make a decision on Darcy Hordichuk, who saw limited ice time this season but did serve a purpose as a deterrent for those looking to take runs at the Oilers' young talent. And as is the case with most deterrents, their true value can only be measured when they are no longer around.
From there, the Oilers will most likely have a similar look up front next season as they did this year.
Whether Ryan Smyth comes back remains a question. But as someone who wanted to return to Edmonton due to family reasons, his options are limited when it comes to negotiating a new deal. The Oilers can simply tell the veteran to take it or leave it, knowing his role and contribution is expected to decrease in coming seasons.
Outside of Smyth, the Oilers have made a commitment to Ben Eager and Ryan Jones, whose value has increased in the last month, proving he can play a top-six role.
On the back end, the Oilers have four spots accounted for with Ladislav Smid, Jeff Petry, Ryan Whitney and Nick Schultz. They also extended Andy Sutton and Corey Potter, pretty much leaving the fate of Cam Barker and Theo Peckham in doubt.
Nikolai Khabibulin has another year left on his deal, which will likely be used mentoring Devan Dubnyk, who the Oilers have to re-sign as a restricted free agent.
All in all, doesn't leave a lot of wiggle room for a club that once again finished last in their division standings, and will take part in the NHL draft lottery for a third consecutive season.
The upshot is, if the Oilers want to improve their standing next year, they're going to have to do it with essentially the same group that was unable to get the job done this season.

subset: commoncrawl


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Nealand Liquor
letter to Xbox
Thought this was interesting yesterday. Take with grain of salt.
Rumor: Our internal product release schedule from head office dropped yesterday and on Oct 21st an unnamed Sony console will be launched. Fyi all console revisions like the ps360 slims and Wii Mini were listed as ps360 & wii mini. Previously the wiiu, 3ds and vita were also only listed as Nintendo/Sony Console in the product name column.
Disclaimer: I just work at a very large retailer, managing the electronics sales force and nothing more. I have nothing to do with purchasing, nation wide merchandising or shipping. I am not trying to play this off as I have connections at Sony, or I am some sort of insider. It's that just yesterday we received a product release schedule from our head office and I thought this is OT itt. These schedules btw, are for internal use only, designed to allow us time to create our instore merch plans. If the launch date for a product is unknown, it's simply marked TBA. The only time a date is ever included is when we have received confirmation of said date from the product company.
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Process Improvement Presentation
Create an 3 slide MS PowerPoint presentation with detailed speaker notes. Include the following:
Identify which ISO standards apply to Riordan ManufacturingUsing the Six Sigma DMAIC process, develop a new process design for the production of the Riordan electric fans. Be sure to take advantage of any global opportunities available to Riordan, such as lower labor costs. (2 slide)Describe the bottlenecks that may occur in the new process. (1 slide)
Tutor Answer
Brown University
1271 Tutors
California Institute of Technology
2131 Tutors
Carnegie Mellon University
982 Tutors
Columbia University
1256 Tutors
Dartmouth University
2113 Tutors
Emory University
2279 Tutors
Harvard University
599 Tutors
Massachusetts Institute of Technology
2319 Tutors
New York University
1645 Tutors
Notre Dam University
1911 Tutors
Oklahoma University
2122 Tutors
Pennsylvania State University
932 Tutors
Princeton University
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Stanford University
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University of California
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Oxford University
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Yale University
2325 Tutors


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Frequently Asked Questions (FAQ's)
Hopefully here we can answer most of your queries.
Chawton WI are hosting a carol service in Chawton Church, ALL WELCOME!!
Men, families, friends, everyone! Refreshments will be provided.
More details to follow.
Our Christmas event, details to follow.
Free entry day for all to celebrate Jane Austen's Birthday. Join us for a mince pie and a sing song of Christmas Carols around the piano.


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The Zacks Analyst Blog Highlights:IBM, Cisco Systems, NetSuite, Rackspace Hosting and Veeva Systems
Apr 04, 2014, 09:30 ET from Zacks Investment Research, Inc.
CHICAGO, April 4, 2014 /PRNewswire/ -- Zacks.com announces the list of stocks featured in the Analyst Blog. Every day the Zacks Equity Research analysts discuss the latest news and events impacting stocks and the financial markets. Stocks recently featured in the blog include the IBM Corp. (NYSE: IBM-Free Report), Cisco Systems, Inc. (Nasdaq: CSCO-Free Report), NetSuite Inc. (NYSE: N-Free Report), Rackspace Hosting, Inc. (NYSE: RAX-Free Report) and Veeva Systems Inc. (NYSE: VEEV-Free Report).
Today, Zacks is promoting its ''Buy'' stock recommendations. Get #1Stock of the Day pick for free.
Here are highlights from Thursday's Analyst Blog:
Dark Clouds Hover Over These Cloud Stocks
According to a study, cloud-related tech spending is expected to witness an almost three-fold jump from $78.2 billion in 2011 to $235.1 billion in 2017. Multibillion-dollar investments in cloud-based architectures are expected to follow as more and more companies turn to cloud computing to offer online storage, computing, analytics and provisioning services to tackle a proliferation of huge data.
But before joining the bandwagon, companies must realize that technology is just a mere tool and not necessarily the only route to success. It is true that cloud computing can play wonders in transforming a business by offering a competitive edge, but a company requires more than just tools and technologies to succeed in the long run.
As each player in the industry strives to win a greater market share with reduced barriers-to-entry and competitive pricing, the battle gets increasingly murkier. With the global consumer cloud subscription tally projected to rise to 730 million this year from 630 million in 2013, the fight for dominance is understandably fierce. However, not all companies have been able to cash-in on the euphoria and have visibly lagged far behind in the race. Before we zero-in on such stocks that investors should avoid currently, let us have a quick look across the cloud to gauge the movements of the movers and shakers.
Price Wars
As commoditization of cloud services gains steam, service providers are reducing prices to gain more market share. This has led to intense price wars among rivals as one tries to outwit the other.
Key Differentiators
However, not all companies are aggressively following the pack. Price is one of three factors in the decision-making process for availing cloud computing services, the other two being quality and innovation. Experts argue that in order to maintain margins, tech companies will try to offset the price cuts with over-subscription of their services. This is expected to culminate in performance degradation, thereby eroding the financial benefits and leaving the customer at status quo.
Cloud services provider IBM Corp. (NYSE: IBM-Free Report) has resisted itself from across-the-board price cuts and instead introduced special pricing deals for volume customers. Cisco Systems, Inc. (Nasdaq: CSCO-Free Report) further pushed the envelope when it announced an ambitious plan to invest over $1 billion to build the world's largest global Intercloud (a network of clouds) over the next two years. The Cisco global Intercloud is expected to raise the performance bar with an expanded suite of value-added application- and network-centric cloud services to accelerate the Internet of Everything.
3 Cloud Stocks to Avoid
Not all companies are able to capitalize on such positive vibes in the industry. Let's take a closer look at these companies that appear to be falling much behind in the race and are expected to perform abysmally in the short-term.
NetSuite Inc. (NYSE: N-Free Report): Headquartered in San Mateo, CA, NetSuite offers cloud-based financials and enterprise resource planning (ERP) and omni-channel commerce software suites in the U.S. and internationally. This Zacks Rank #3 (Hold) stock has a poor year-to-date return of -8.1% (as of April 2, 2014).
The current Zacks Consensus Estimate for the recently concluded quarter is pegged at a loss of 24 cents, which represents a year-over-year decrease of 43.5%. The earnings estimate for full-year 2014 has also declined by 6 cents or 7.3% in the last 90 days to a loss of 88 cents.
Rackspace Hosting, Inc. (NYSE: RAX-Free Report): Headquartered in San Antonio, TX, Rackspace provides cloud computing services for small and medium-sized businesses through dedicated hardware and multi-tenant pools of virtualized hardware. With a year-to-date return of -15.7%, this Zacks Rank #3 (Hold) stock has witnessed a steady drop in earnings estimates.
The current Zacks Consensus Estimate for the recently completed quarter is pegged at 12 cents, which represents a year-over-year decrease of 39.0%. The earnings estimate for full year 2014 has declined by 12 cents or 16.7% in the last couple of months to 60 cents.
Veeva Systems Inc. (NYSE: VEEV-Free Report): Headquartered in Pleasanton, CA, Veeva provides industry-specific cloud-based software solutions for the life sciences industry in North America, Europe, the Asia Pacific, and Latin America. This Zacks Rank #4 (Sell) stock has a dismal year-to-date return of -18.4%.
Earnings estimate for both the recently completed quarter and the ongoing fiscal have been revised downward. The earnings estimate for fiscal 2015 has declined by 4 cents or 16.7% in the last month to 20 cents.
With such disappointing metrics and grim earnings outlook, investors may be better off if they avoid these stocks.
Today, Zacks is promoting its ''Buy'' stock recommendations. Get #1Stock of the Day pick for free.
About Zacks Equity Research
Zacks Equity Research provides the best of quantitative and qualitative analysis to help investors know what stocks to buy and which to sell for the long-term.
Continuous coverage is provided for a universe of 1,150 publicly traded stocks. Our analysts are organized by industry which gives them keen insights to developments that affect company profits and stock performance. Recommendations and target prices are six-month time horizons.
Zacks "Profit from the Pros" e-mail newsletter provides highlights of the latest analysis from Zacks Equity Research. Subscribe to this free newsletter today.
About Zacks
Zacks.com is a property of Zacks Investment Research, Inc., which was formed in 1978. The later formation of the Zacks Rank, a proprietary stock picking system; continues to outperform the market by nearly a 3 to 1 margin. The best way to unlock the profitable stock recommendations and market insights of Zacks Investment Research is through our free daily email newsletter; Profit from the Pros. In short, it's your steady flow of Profitable ideas GUARANTEED to be worth your time! Register for your free subscription to Profit from the Pros.
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Past performance is no guarantee of future results. Inherent in any investment is the potential for loss. This material is being provided for informational purposes only and nothing herein constitutes investment, legal, accounting or tax advice, or a recommendation to buy, sell or hold a security. No recommendation or advice is being given as to whether any investment is suitable for a particular investor. It should not be assumed that any investments in securities, companies, sectors or markets identified and described were or will be profitable. All information is current as of the date of herein and is subject to change without notice. Any views or opinions expressed may not reflect those of the firm as a whole. Zacks Investment Research does not engage in investment banking, market making or asset management activities of any securities. These returns are from hypothetical portfolios consisting of stocks with Zacks Rank = 1 that were rebalanced monthly with zero transaction costs. These are not the returns of actual portfolios of stocks. The S&P 500 is an unmanaged index. Visit http://www.zacks.com/performance for information about the performance numbers displayed in this press release.
SOURCE Zacks Investment Research, Inc.


text:
One Angled Monitor Isolation Pad
Product Code 43543
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The Primacoustic RX7a Recoil Stabilizer is a unique speaker-mounting platform. The RX7a eliminates disruptive resonant coupling from the loudspeaker to the stand while providing a stable base that reduces the recoil caused by the forward energy of loudspeaker motion.
The RX7a model has a top surface angled at 5° and fits many monitor models (listed below) with a 2.6" height x 13" width x 10.3" depth.
Made from three basic components, the Recoil Stabilizer is essentially a platform for the loudspeaker that features a high-density urethane base that isolates the speaker from the shelf, monitor-bridge or stand. This effectively decouples the loudspeaker to eliminate vibration-borne resonance to the substructure. A heavy laser-cut steel plate is added and sandwiched between the isolation layer and a no-slip neoprene top. The steel plate introduces significant mass to the structure and serves to stabilize the speaker.
By reducing the backward recoil energy as the speaker coil pushes energy forward, initial waveform transients no longer suffer lag and the sharpness of the resulting pulse is more defined. The result is significantly greater detail at all frequencies, with tighter bottom end and improved depth of field.
The RX7a Recoil Stabilizer is available in various sizes and weights to address different speaker designs and may be ordered in both standard and custom angles to precisely aim the loudspeakers for critical listening environments.
0 0
- 5° angled top surface
- Improves transient response
- Widens the sound field for better imaging
- Tightens up the bass response for greater accuracy
- Available in several sizes and firing angles
- High density urethane foam insulator
- Heavy mass laser cut stabilizing deck
- Non-resonating front coupling plate
- Anti-slip neoprene friction pad
- 2.6" (66mm) height x 13" (330mm) width x 10.3" (263mm) depth
- Weight: 44 lbs. (20 kg)
One Unit
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Don't miss your chance to see Unity Tour in Philadelphia! Check out the schedule below for the concert date of your choice, then buy your Unity Tour Philadelphia tickets before they sell out!
Looking for Unity Tour tickets in other cities? View all Unity Tour tickets »
Sorry! We couldn't find any events for Unity Tour in Philadelphia.
If you were searching to see if Unity Tour is coming to Philadelphia, then you're in luck! For their latest tour, Unity Tour will indeed hold a concert in Philadelphia. Have an awesome concert experience when you go to see Unity Tour in Philadelphia. Get your Unity Tour tickets Philadelphia and join fellow fans for a concert to remember!


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Lawler Park
5210 W. 64th St. Chicago, Illinois 60638
(773) 284-7328
Fee: Free
Age Range: Any
The Puppet Place: Hansel and Gretel. This show is a lively version of the classic children's story of a brother and sister who get lost in the woods and find a beautiful candy house inhabited by a nasty witch. It is accompanied by music from the opera by Englebert Humperdinck.


text:
On its surface, Bruner is no different from any other peaceful town in rural northern Wisconsin, but all is not what it seems. In the days and hours before an ominous approaching snowstorm, local sheriff Paul Summers struggles to cope with a strange series of events, including the arrival of a mysterious group of criminals, the suspicious disappearance of a fellow townsperson, and rumors of evil cult activity, not to mention difficulties at home.
As the storm gathers in intensity, so do the twists and turns that bring Paul ever closer to unraveling the big secrets that haunt this small town. In a stunning conclusion, Paul witnesses firsthand the startling power and beauty of heaven's fury.
©2010 Stephen Frey (P)2010 BBC Audiobooks America
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text:
If you are in need of new bakeware, here is a great deal for you.
Today on Amazon you can purchase Rachael Ray Oven Lovin' Nonstick Bakeware Collection for $49.95(originally $100.00) shipped!
Product Details:
- Includes: two 9-inch rounds, 9-inch by 13-inch rectangle, 10×15-inch crispy sheet, 9-inch by 5-inch deep rectangle
- Extra wide handles for a confident grasp
- Comfortable silicone grips add a splash of color
- Long lasting nonstick inside and out
- Oven safe to 500F.
This is a great price for Rachael Ray products. If you can not use these for yourself think ahead to any wedding or house warming presents you may need in the near future. This set would make a great gift.
Order today because Amazon prices can change at any time.


text:
A bungalow - whether it is on the beach, amidst tropical gardens or hovering over a lagoon......is a great choice for a romantic, private or just a quiet holiday away from the maddening crowds.
Most of the bungalow accommodation on our sites are child free and offer a great level of service and facilities. Bungalow holidays are becoming more popular as people move away from big mainstream resorts to smaller more intimate resorts.
Super Travel Sites has carefully chosen several bungalow properties catering to all budgets and tastes.
Fafa Island resort is located on an 18 acres palm covered offshore island 7km north of Nuku'alofa, the capital of Tonga.
It takes approximately 30 from the airport to Nuku'alofa Wharf and then another 30 minutes by boat transfer from Nuku'alofa Wharf to reach Fafa Island Resort
The accommodation on the Resort is like a Polynesian village surrounded by gardens. A small intimate resort with all guests staying in traditional Tongan style fales facing the beach.
The island is guarded by a coral reef ensuring safe swimming and snorkeling in crystal clear blue waters. Deserted sandy beaches invite you to relax and lie in the sun.
A delightful resort with an uncomplicated lifestyle where bungalows have no TV or telephone. Let our local staff entertain you with a weekly Polynesian dance show evening.
Fafa Island offers true island living for all people wanting to get away.


text:
GAINESVILLE -- Jesse Palmer will be Florida's starting quarterback when the Gators' play at Tennessee Saturday, coach Steve Spurrier said Monday.
Spurrier pulled Palmer in the middle of a drive during the second quarter of Florida's 55-0 rout of Middle Tennessee State last Saturday, replacing him with redshirt freshman Rex Grossman.
Grossman completed 9 of 14 passes for 95 yards, three touchdowns and one interception after taking over. Palmer was 15-of-23 for 193 yards, one touchdown and no interceptions. However, he also struggled with timing on deep routes for the second straight week.
After the game, Spurrier said he was not sure who would start against the Volunteers. Monday he said Palmer would start and Grossman would probably see some action.
"Jesse Palmer's our starter, just like the first two games,'' Spurrier said. "Rex is waiting in the wings. Rex probably will play, but we will start with Jesse just like the other games and see how it goes. Rex definitely will get a lot of snaps during practice and hopefully we'll have two ready to play.''
© 2017. All Rights Reserved. Contact Us


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Posted 16 May 2011
Link to this post
Good day, Telerik team!
I'm using RadHtmlPlaceHolder to play and control Flash movies.
SL interacts with Flash using JavaScript and Flash ExternalInterface.
Interaction is like in this article http://www.telerik.com/support/kb/silverlight/htmlplaceholder/htmlplaceholder-javascript.aspx
I have a problem with RadHtmlPlaceHolder after I set its Visibility property to Visibility.Collapsed.
Let's suppose when video playing I'm clicking on a button, on button handler video is paused by calling specified JavaScript function and PlaceHolder's Visibility property is setting to Visibility.Collapsed. Because instead of RadHtmlPlaceHolder I want to show some info. Then I'm clicking on another button (e.g. hide info), and RadHtmlPlaceHolder's Visibility property is settings to Visibility.Visible, and then I want to continue play video by calling another JavaScript function. But when my code reaches "document.getElementById('myID');" I'm getting NullReferenceException.
I looked at Html page in IE debugger and found that when RadHtmlPlaceHolder is collapsed, it's disappears from there.
And then if I ignore IE error message and continue execution, iframe is appears again but in the end of page. With the same Id as before. Look at attached screenshots.
Seems to be my code is calling when iframe is missing from page.
Any suggestions? Can it be solved?
I tried to reset Id:
HtmlElement iframe = HtmlPage.Window.Eval(string.Format(@"document.getElementById('{0}');", "myIFrame" + _id)) as HtmlElement;
if (iframe == null)
((HtmlElement)htmlPlaceholder.HtmlPresenter.Children[0]).SetAttribute("id", "myIFrame" + _id);
It doesn't work.
Here is an example of calling JavaScript
code = string.Format(@"document.getElementById('{0}').contentWindow.continueFLV();", "myIFrame" + _id);
Posted 19 May 2011
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Posted 20 May 2011
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Posted 16 Aug 2011
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Posted 19 Aug 2011
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You can use the sizes (ActualWidth and ActualHeight) of the HTMLPlaceHolder's parent container like so;
sender, RoutedEventArgs e)
.RadHtmlPlaceholder1.Width = (
.RadHtmlPlaceholder1.Height = (
Explore the entire Telerik portfolio by downloading the Ultimate Collection trial package. Get now >>
Posted 24 Aug 2011
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Mac Mrad
Oct. 22, 1927 – Mar. 24, 2014
Mac Mrad, 86 years old from Pacifica, passed away peacefully in loving arms. He was born in Ouled Kacem, Kerkennah Islands, off the east coast of Tunisia, N. Africa.
Mac immigrated to America at the age of 21 by sponsorship from a captain in the United States Army. Seven months later he subsequently joined the Army and a few years later he became an American citizen. During his Army service, Mac fought in the Korean War with the 24th Infantry where he was wounded. He was also stationed in Japan, Germany, San Francisco, and France and reassigned to Korea in the late '60s. He was extremely happy to return to the Presidio in San Francisco where he managed the Officers' Club. He settled down to raise his family in Pacifica, which he called home for the last 50 years. Mac served 20 years in the military, retiring with an Honorable Discharge as Sergeant First Class and spent five years in the civil service. He was very proud to serve his country.
Mac met his wife, Margit, in Germany where their first son, John, was born.
Their second son, James, was born in San Francisco and daughter, Regina, in Paris.
He is survived by his wife, Margit; his son, John (Sallie); son James (Debbie); daughter Regina (James); five grandchildren; two great-grandchildren; one brother; two sisters and a large family who reside in Tunisia; as well as extended family.
Mac's passion was cooking and he volunteered many hours at the Pacifica Moose Lodge cooking dinners; he was happiest when he was planning and preparing a meal for his family. He also had a desire to achieve a college degree, which he attained at the age of 51. Mac enjoyed his daily walks and talking to the neighbors, and his greatest love was for his wife and his expanding family. Mac was the most loving, generous, and supportive father and grandfather. He will be deeply missed by his family and friends and he will always be in our hearts.
A private family memorial will be held in celebration of his life.


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Picture: Swizz Beatz 2011 MTV Video Music Awards held at LA Live - Outside Arrivals Los Angeles, California - 28.08.11
Producer Swizz Beatz surprised his wife Alicia Keys with a very special gift on his own birthday - he gave her a brand new luxury sports car.
The hip-hop star turned 33 on Tuesday (13Sep11) but, rather than sit back and accept gifts from his wife, he decided to turn the tables on Keys and present her with a lavish present instead.
Beatz took to his Twitter.com blog to show off his generosity and posted a photo of the No One hitmaker posing beside her one-of-a-kind, bright red custom Lotus.
In the caption accompanying the picture, he wrote, "The best part of my Bday (sic) today was my gift I made my wife because my Bday is her Bday #love4life :)"
The beatmaker was appointed vice president of creative design at the British car manufacturers last month (Aug11).
The romantic gesture comes as the couple continues to fight back against allegations its one-year marriage is in trouble amid rumours of Beatz's infidelity.
On Monday (12Sep11), Keys brushed off claims her man has been caught exchanging steamy text messages with rising singer Christina Elizabeth, writing in a post on Twitter, "Haaaaaaaaaaa!!!!!!!! Some things are just Laughable!!!!!! Now, Let's Continue to Shine!! Everything else is a waste of time!! Sending love!"
The stars are parents to son Egypt, 11 months.
With a jazz musician for a father, Nasir bin Olu Dara Jones grew up in...


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Were these Tasers or Stun Guns
Tasers work from a distance using electrified projectiles. Stun Guns (and Cattle Prods) require the victim to be touched by the device to receive a shock. So which was it? Stun Guns aren't all that scary to me.
And as for why a regular Joe would need one, have you read this? http://blogs.phoenixnewtimes.com/bella/2010/08/ouch_todays_hard_lesson_on_yel.php


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Gibson is synonymous with guitars, so we had high hopes for the Android app that bears its name. Actually, it's a bit of a mishmash of the other types of apps we review on these pages, but certainly has its uses. See Android Smartphone reviews
There are plenty of dedicated guitar tuners and apps that show you which strings to strum and hold for each chord. Gibson does both these things, with a vertical list of open and barre chords that you click on to view the fingering for. Images were rather fuzzy, denoting an app first made for a smaller screen rather than for a tablet. See Google Android Tablet reviews
The tuner couldn't be simpler: choose between single notes and chromatic tuning and the sort of tuning you need, then press the green start button on the tuner to see how well your guitar strings are tuned. A needle shows you which way to turn your pegs.
The metronome is our most frequent port of call. It has a dropdown list of standard time signatures, a bpm dial and lets you tap out your own tempo. The metronome arm can be set to operate with or without a 'chink'.
The lessons seem like a bolt on to the elements of the app we've just described. They are links to lengthy YouTube videos that Gibson presumably recorded some time ago and deemed useful inclusions in an app. Gibson sells music tuition DVDs separately, so they may be from this.
You need a web connection to stream each video – nowhere near as satisfactory as the Music Makers saxophone app we tried. The lessons are less focused and quite verbose compared with the informative to camera approach of the Jools Holland app series, too.
There's certainly enough in Gibson Guitar for Android, but it's less polished than GarageBand and it's individual elements don't knit together as well as other apps here.
Gibson Guitar app for Android: Specs
- 1.6 and up
- Size: 5.5M
- 1.6 and up
- Size: 5.5M
There's certainly enough in Gibson Guitar for Android, but it's less polished than GarageBand and it's individual elements don't knit together as well as other apps here.


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mea culpa
3 weeks ago
You may think this crazy, but from Canada your post today is like reading something from an exotic foreign land, like a peep into Ali Baba's cave.
The only way I could grow a camphor tree would be in a (very large) greenhouse.
Camphor trees are not often found here, but where they are planted they thrive. My property had several large ones when I bought it.
They are attractive shade trees. The robins feast on the berries in winter. But they also drop a lot of debris, leaves and sticks, and seedlings must be vigilantly uprooted.


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Kaley Cuoco and Johnny Galecki met up with their costars from The Big Bang Theory yesterday for a night of laughs and charity at the A Night at Sardi's gala in Beverly Hills. Kaley wore a strapless blue gown as she mingled with stars like Emmy Rossum, Jason Bateman, and Zachary Levi at the event. She got glammed up after sporting a more casual, but still chic, look when she celebrated Hollywood stylists at an event in LA last week. The Big Bang Theory cast and other funny actors and actresses typically perform skits during the event, which benefits the Alzheimer's Association. We were live on the scene last night, so be sure to check back for more of our red carpet coverage!
Image Source: Getty


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Hospital-insurer bargaining: An empirical investigation of appendectomy pricing
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Volume (Year): 16 (1997)
Issue (Month): 4 (August)
Pages: 417-434
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| Web page: http://www.elsevier.com/locate/inca/505560
References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- J. A. Kregel, 1980. "Introduction," Journal of Post Keynesian Economics, M.E. Sharpe, Inc., vol. 3(1), pages 19-20, October.
- Svejnar, Jan, 1986.
"Bargaining Power, Fear of Disagreement, and Wage Settlements: Theory and Evidence from U.S. Industry,"
Econometric Society, vol. 54(5), pages 1055-1078, September.
- SVEJNAR, Jan, "undated". "Bargaining power, fear of disagreement, and wage settlements: theory and evidence from U.S. industry," CORE Discussion Papers RP 720, Université catholique de Louvain, Center for Operations Research and Econometrics (CORE).
- Svejnar, J., 1984. "Bargaining power, fear of disagreement and wage settlements: theory and evidence from U.S. industry," CORE Discussion Papers 1984037, Université catholique de Louvain, Center for Operations Research and Econometrics (CORE).
- Nash, John, 1953. "Two-Person Cooperative Games," Econometrica, Econometric Society, vol. 21(1), pages 128-140, April.
- Nash, John, 1950. "The Bargaining Problem," Econometrica, Econometric Society, vol. 18(2), pages 155-162, April.
- Staten, Michael & Umbeck, John & Dunkelberg, William, 1988. "Market share/market power revisited : A new test for an old theory," Journal of Health Economics, Elsevier, vol. 7(1), pages 73-83, March.
- Dranove, David & White, William D, 1994. "Recent Theory and Evidence on Competition in Hospital Markets," Journal of Economics & Management Strategy, Wiley Blackwell, vol. 3(1), pages 169-209, Spring.
- Zwanziger, Jack & Melnick, Glenn A., 1988. "The effects of hospital competition and the Medicare PPS program on hospital cost behavior in California," Journal of Health Economics, Elsevier, vol. 7(4), pages 301-320, December.
- Dor, Avi & Watson, Harry, 1995. "The hospital-physician interaction in U.S. hospitals: Evolving payment schemes and their incentives," European Economic Review, Elsevier, vol. 39(3-4), pages 795-802, April.
- Melnick, Glenn A. & Zwanziger, Jack & Bamezai, Anil & Pattison, Robert, 1992. "The effects of market structure and bargaining position on hospital prices," Journal of Health Economics, Elsevier, vol. 11(3), pages 217-233, October.
- Alvin E Roth, 2008. "Axiomatic Models of Bargaining," Levine's Working Paper Archive 122247000000002376, David K. Levine.
- Aumann, Robert J & Kurz, Mordecai, 1977. "Power and Taxes," Econometrica, Econometric Society, vol. 45(5), pages 1137-1161, July. Full references (including those not matched with items on IDEAS)
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