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Hypocretin-1 and -2 (Hcrt-1 and -2, also called orexin-A and -B) are newly identified neuropeptides synthesized by hypothalamic neurons. Defects in the Hcrt system underlie the sleep disorder narcolepsy, which is characterized by sleep fragmentation and the involuntary loss of muscle tone called cataplexy. Hcrt neurons project to multiple brain regions including cranial and spinal motor nuclei. In vitro studies suggest that Hcrt application can modulate presynaptic glutamate release. Together these observations suggest that Hcrt can affect motor output and that glutamatergic processes may be involved. We addressed these issues in decerebrate cats by applying Hcrt-1 and -2 into the trigeminal motor nucleus to determine whether these ligands alter masseter muscle activity and by pretreating the trigeminal motor nucleus with aN-methyl-d-aspartate (NMDA) antagonist to determine if glutamatergic pathways are involved in the transduction of the Hcrt signal. We found that Hcrt-1 and -2 microinjections into the trigeminal motor nucleus increased ipsilateral masseter muscle tone in a dose-dependent manner. We also found that Hcrt application into the hypoglossal motor nucleus increases genioglossus muscle activity. Pretreatment with a NMDA antagonist (d-(−)-2-amino-phosphonovaleric acid) abolished the excitatory response of the masseter muscle to Hcrt-1 application; however, pretreatment with methysergide, a serotonin antagonist had no effect. These studies are the first to demonstrate that Hcrt causes the excitation of motoneurons and that functional NMDA receptors are required for this response. We suggest that Hcrt regulates motor control processes and that this regulation is mediated by glutamate release in the trigeminal motor nucleus.
Hcrt-1 and -2 are peptides synthesized by neurons in the lateral hypothalamus (De Lecea et al. 1998; Sakurai et al. 1998; Sutcliffe and De Lecea 1999). Hcrt neurons project widely throughout the brain and spinal cord, including brain stem regions involved in sleep and motor control (Nambu et al. 1999; Peyron et al. 1998; van den Pol 1999). Loss of Hcrt-synthesizing neurons and defects in the Hcrt-2 receptor underlie the sleep disorder called narcolepsy, which is characterized by disrupted sleep homeostasis and sudden loss of muscle tone during wakefulness (cataplexy) (Chemelli et al. 1999;Hara et al. 2001; Lin et al. 1999;Peyron et al. 2000; Siegel 1999;Thannickal et al. 2000).
Intracerebroventricular infusion of Hcrt-1 increases locomotor activity in behaving rats (Hagan et al. 1999), and Hcrt-1 and -2 microinjection into midbrain and pontine regions affects hind limb muscle rigidity in decerebrate rats (Kiyashchenko et al. 2001). While Hcrt affects locomotor activity and muscle tone, it is unclear whether it directly affects motoneurons. The trigeminal (V) motor nucleus innervates masseter muscles, which are consistently affected by sleep-dependent hypotonia and cataplexy (Guilleminault 1976; Pedroarena et al. 1994; Soja et al. 1987). Hcrt neurons project to the V motor nucleus and to the hypoglossal (XII) motor nucleus, which innervates the genioglossus (tongue) muscles (Fung et al. 2001). Like the masseter muscles, the genioglossus muscles incur sleep-dependent reductions in muscle tone, which contribute to obstructive sleep apnea (Horner 1996). Because Hcrt neurons exhibit a state-dependent activity pattern (Estabrooke et al. 2001; Kiyashchenko et al. 2002) and because they project to V and XII motor nuclei, we hypothesize that Hcrt is involved in the normal regulation of motoneuronal excitability across the sleep-wake cycle. To assess the role of Hcrt in muscle tone regulation, we tested the hypothesis that microinjection of Hcrt into the V and XII motor nuclei would excite masseter and genioglossus muscles, respectively.
Hcrt binds to and activates G-protein-coupled receptors to affect postsynaptic neuronal activity (Sakurai et al. 1998); however, it may also act presynaptically. van den Pol et al. (1998) reported that Hcrt-1 increases glutamate release in in vitro hypothalamic slices. Similarly, it is suggested that Hcrt acts on presynaptic, glutamatergic laterodorsal tegmental neurons to increase quanta release probability (Burlet et al. 2002). Recent work from this laboratory demonstrates that systemic infusion of Hcrt-1 strongly increases glutamate release in the amygdala (John et al. 2001). Based on these observations, we suggest that Hcrt may not only act directly but may also act indirectly by causing the release of glutamate. To determine if glutamate mechanisms underlie the muscle tone responses to Hcrt-1 application, we pretreated the V motor nucleus with a N-methyl-d-aspartate NMDA) antagonist [d-(−)-2-amino-phosphonovaleric acid (d-AP5)] prior to the application of Hcrt-1.
These studies are the first to demonstrate that application of Hcrt causes the excitation of cranial motoneurons and that functional NMDA receptors are required for expression of the response. We suggest that changes in Hcrt levels may alter motoneuronal excitability thereby leading to altered muscle tone as seen in cataplexy and during obstructive sleep apnea.
These studies have been presented as a conference abstract (Peever et al. 2002).
Animal preparation
The Animal Care Committee at the University of Los Angeles approved all procedures described herein. A total of 17 decerebrate, adult, female cats weighing between 2.5 and 3.8 kg [3.0 ± 0.1 (SE) kg] were used. They were anesthetized with a halothane-oxygen mixture. When cats no longer responded to a firm foot pinch and blink reflexes were absent, tracheotomy, bilateral carotid artery ligation, and femoral artery cannulation were performed. Cats were then placed in a stereotaxic frame (David Kopf Instruments, Los Angeles, CA) and decerebrated using the following procedure. A midline incision was made along the dorsal surface of the cranium and the skin reflected. The connective tissue covering the parietal bones was removed. The dorsal-medial parietal bones were removed, and the dura cut and reflected. All brain structures rostral to the postmammillary-precollicular level were removed by suction, and the cranial cavity was firmly packed with hot, saline-soaked cotton balls. At this point, anesthesia was terminated. To allow access to the V and XII motor nuclei, the rostral occipital bone covering the cerebellum was carefully removed as was the medial tentorium. All exposed bone surfaces were covered with bone-wax. The dura and pia mater covering the cerebellum and pons were carefully removed, and the exposed brain surface was covered with saline-soaked cotton until experiments began. Rectal temperature was monitored and maintained at 38 ± 0.5°C using a custom-built servo-controlled electric heating-pad. Mean arterial blood pressure was recorded from the femoral artery using a blood pressure transducer (Gould, Model P23ID). Data collected from cats in which mean arterial blood pressure remained between 80 and 150 mmHg were analyzed.
Recording procedures
Bipolar, multistranded, stainless steel electromyographic (EMG) electrodes (∼2-mm uninsulated portions exposed and separated by ∼1 cm; A-M Systems) were carefully inserted into left and right masseter and genioglossus muscles. EMG signals were amplified (Grass EEG Amplifier, Model 7P511K) and filtered between 30 Hz and 10 kHz. EMG signals were calibrated using a built-in microvolt calibrator. Blood pressure signals were amplified (Grass Low Level DC Amplifier, Model 7P122E) and calibrated using a syphygmo-manometer (Labtron). EMG and blood pressure signals were monitored, digitized (Spike 2 Software, 1401 Interface, CED, Cambridge, UK), and stored on a computer (Dell, OptiPlex GX100). EMG signals were integrated off-line in 2-s epochs using a specially written Spike 2 program.
Hcrt-1 and -2 (Peptide Institute) were prepared at the beginning of each experiment by dissolving them in artificial cerebral spinal fluid (ACSF, Harvard Apparatus). We used 1, 10, and 100 μM concentrations because it has been shown that they produce measurable changes in muscle tone when injected into the locus coeruleus of rats (Kiyashchenko et al. 2001). d-AP5 andN-methyl-d-aspartic acid (NMDA) were purchased from Tocris Cookson (St. Louis, MO), and methysergide maleate (methysergide) was obtained from Sigma RBI (St. Louis, MO). These drugs were dissolved in fresh ACSF to make solutions of the following concentrations: 50 mM d-AP5, 1 mM methysergide, and 10 mM NMDA. These concentrations were chosen because previous studies demonstrate that 50 mM d-AP5 are sufficient to block NMDA channels (Lai and Siegel 1988, 1991), 1 mM methysergide blocks the effect of serotonin application onto XII motoneurons (Kubin et al. 1996), and 10 mM NMDA induces changes in muscle tone when injected into the pontine reticular formation (Lai and Siegel 1991).
Experiments began ≥1 h after decerebration. Blood pressure and left/right masseter and genioglossus EMG signals were monitored and recorded during all experimental conditions. A beveled, 25 gauge, 1 μl Hamilton microsyringe (Hamilton, Reno, NV) secured in a micromanipulater (David Kopf instruments) was used to make all microinjections. The tip of the microsyringe was aimed at either the V or XII motor nuclei (Berman 1968). It was considered to be located within the motor nucleus if it caused an increase in baseline EMG activity of the corresponding ipsilateral muscle (see Fig.1 A); post hoc histological analysis identified a tract mark within the motor nucleus (see Fig. 2). After probe insertion, ≥10 min elapsed before microinjections were made. If more than one microinjection of Hcrt was made into the same motor nucleus, ≥2 h elapsed before another microinjection was made. When NMDA or serotonin antagonists was applied before Hcrt, they were microinjected into the motor nucleus at the same stereotaxic coordinates at those for Hcrt.
To test our hypotheses, the following manipulations were performed. To verify that microinjection per se had no effect on basal masseter muscle activity, ACSF (0.5 μl) was injected into the V motor nucleus. To demonstrate the excitatory effects of Hcrt-1 and -2 on putative V and XII motoneurons, we unilaterally microinjected 0.5 μl of 100 μM Hcrt-1 or -2 into either the V or XII motor nucleus while monitoring masseter and genioglossus EMG activity. To demonstrate that Hcrt actions were mediated by neurons in the motor nuclei, Hcrt injections were made outside the motor nucleus. To determine whether Hcrt-related glutamate release mediates changes in muscle activity, we unilaterally microinjected 0.5 μl of the glutamate antagonist, d-AP5 (50 mM) into the V motor nucleus immediately prior to microinjection of 0.5 μl of 100 μM Hcrt-1. To demonstrate that the excitatory effects of Hcrt-1 microinjections could be actively reversed, we applied 0.5 μl of 50 mM d-AP5 into the V motor nucleus immediately after the application of 0.5 μl of 100 μM Hcrt-1. To validate that Hcrt-related glutamate release specifically mediates changes in muscle activity, we unilaterally microinjected 0.5 μl of the serotonin antagonist, methysergide into the V motor nucleus immediately before microinjection of 0.5 μl of 100 μM Hcrt-1.
At the end of each experiment, an iron deposit marked the location of microinjection sites. It was made by positioning a bipolar stimulating electrode at the same stereotaxic coordinates as those for microinjections and then passing a DC current through it for 20 s. Cats were then killed with a overdose of pentobarbital sodium (Nembutal, 50 mg/kg iv). Once a heartbeat could no longer be detected, the brain stem was rapidly dissected and placed in a 100 ml solution of 10% formalin and 30% sucrose in distilled water for ≥3 days. A microtome (Leica, Model SM 2400) was used to cut the brain tissue into 50-μm-thick slices that were stained with Neutral Red and counterstained with potassium ferrocyanide, which permitted detection of iron deposits.
Data analysis
To analyze changes in masseter and genioglossus muscle activities, integrated, bilateral muscle activity was quantified during the following conditions: baseline, that is, 60 s before microinjection; immediately after the completion of microinjection; and for 60 s after the response returned to baseline (see following text). Response latency was characterized as the period between microinjection and the point at which integrated EMG activity exceeded 2 SD of the baseline mean. Response duration was determined by calculating the period of time that integrated EMG activity remained 2 SD above the baseline mean. Integrated EMG activity returned to baseline conditions levels when it fell below 2 SD of the baseline mean. The percentage change of integrated EMG activity was calculated by dividing the difference of baseline and evoked increase by baseline values and multiplying this factor by 100.
For all comparisons, raw data were used, and differences between groups were considered statistically significant at P < 0.05 using two-tailed paired t-test (parametric) or Wilcoxon's match-pairs sign-ranked tests (nonparametric). When ANOVA was performed, post hoc comparisons using either the Bonferronit-test (parametric) or Student-Newman-Keuls method (nonparametric) were used to infer statistical significance. Parametric or nonparametric analysis of samples depended on whether the data were normally distributed. The statistical processes used to analyze data are included in the text. All data are expressed as means ± SE Statistical analyses were performed using Sigmastat (Jandel Scientific).
Microinjection locations and control injections
Insertion and penetration of a Hamilton microsyringe into the stereotaxcially defined V motor nuclei (4.0–5.2 posterior, 3.0–5.5 lateral, and 3.5–5.0 ventral to the interaural point) caused a transient (<3 min) burst in the ipsilateral masseter muscle EMG activity (Fig. 1) but had no effect on either contralateral masseter or genioglossus muscle activity. This transient burst of ipsilateral muscle activity was used as a preliminary guide to determine whether the microsyringe was correctly placed within the V motor nucleus. The same approach was used to locate the XII motor nucleus. Similarly, we found that placement of the microsyringe into the stereotaxcially defined XII motor nucleus (12.0–15.5 posterior, 0–2.0 lateral, and 6.0–7.5 ventral to the interaural point) caused a temporary increase in genioglossus muscle activity but was without effect on masseter muscle activity.
The precise anatomical location of microinjection sites was confirmed by postmortem histological observations. Figure 1 shows iron deposits located within the V and XII motor nuclei. In all 17 cats, we found that microinjection sites were located within either the V or XII motor nuclei (Figs. 1 and 2).
To verify that microinjection per se had no effect on masseter muscle activity, ACSF was injected into the V motor nucleus. In eight cats, we found that microinjection of ACSF into the V motor nucleus had no effect on ipsilateral masseter muscle activity (pairedt-test: P = 0.281; t = 1.169; df = 7; Fig. 3). Therefore we are confident that changes in muscle activity after application of Hcrt are due to the effects of the applied compounds and not due to the mechanical effects of microinjection.
To demonstrate that excitatory effects of Hcrt microinjections are mediated by motoneurons, Hcrt injections were also made outside of V and XII motor nuclei. A total of 17 Hcrt-1 microinjections were made outside the V motor nucleus (Fig. 2 A), and 7 were made outside the XII motor nucleus (Fig. 2 B). Hcrt microinjections placed outside the anatomical boundaries of V and XII motor nuclei had no effect on either masseter or genioglossus muscle activities. Accordingly, we conclude that motoneurons mediate the changes in muscle activity after application of Hcrt into V or XII motor nuclei.
Hcrt-1 and -2 microinjection into the trigeminal motor nucleus
To determine the effect of Hcrt-1 and -2 on the V motor nucleus, we unilaterally microinjected 0.5 μl of 1–100 μM Hcrt-1 or -2 while monitoring masseter and genioglossus muscle activities. A total of 38 Hcrt-1 microinjections were made unilaterally into the V motor nucleus in 11 decerebrate cats. Figure 4shows how bilateral masseter muscle activity changed after microinjection of 100 μM Hcrt-1 into the V motor nucleus. Microinjection of Hcrt-1 into the V motor nucleus caused a significant increase in ipsilateral masseter muscle activity that had no effect on either contralateral masseter (Fig. 4) or bilateral genioglossus muscle activities.
Twenty-four Hcrt-2 microinjections (1–100 μM) were made unilaterally within the V motor nucleus in six cats. Hcrt-2 microinjections into the V motor nucleus caused a significant increase in ipsilateral masseter muscle activity (Fig. 4) that had no effect on either contralateral masseter or genioglossus muscle activities.
Hcrt-1 and -2 microinjections into the V motor nucleus increased masseter muscle activity in a dose-dependent manner. After microinjection of 1, 10, and 100 μM of Hcrt-1 into the V motor nucleus, integrated ipsilateral masseter muscle activity significantly increased from baseline levels by: 8.1 ± 3.2% (Wilcoxon's match-pairs sign-ranked test: P = 0.031,T = 2, df = 5), 43.2 ± 23.7% (P ≤ 0.001, T = 7, df = 11), and 81.5 ± 28.1% (P ≤ 0.001, T = 37, df = 19), respectively (Figs. 4 and5). Similarly, Hcrt-2 microinjections of 1, 10, and 100 μM into the V motor nucleus caused integrated ipsilateral masseter muscle activity to increase by: 26.9 ± 18.8% (paired t-test: P = 0.038,t = 2.776, df =3), 61.5 ± 31.8% (P = 0.031, T = 2, df = 5), and 74.1 ± 10.4% (P ≤ 0.001, T = 12, df = 13), respectively (Figs. 4 and 5). The latency of the response also varied in a dose-dependent manner; it changed from 17.5 ± 7.5 s (1 μM, n = 6), 17.7 ± 6.4 s (10 μM, n = 12), and 11.9 ± 2.3 s (100 μM, n = 20) for Hcrt-1 and from 15.3 ± 8.6 s (1 μM, n = 4), 13.5 ± 5.5 s (10 μM, n = 7), and 7.0 ± 2.5 s (100 μM,n = 14) for Hcrt-2 (Fig. 5). The duration of the response also had a dose-dependent time course; it changed from 175.8 ± 61.3 s (1 μM, n = 6), 316.6 ± 87.0 s (10 μM, n = 12), and 1,080.7 ± 255.0 s (100 μM, n = 20) for Hcrt-1 and from 194.8 ± 101.6 s (1 μM, n = 4), 203.7 ± 76.4 s (10 μM, n = 6), and 581.9 ± 29.5 s (100 μM, n = 14) for Hcrt-2 (Fig. 5). We did not detect any significant differences between the action of equimolar concentrations of Hcrt-1 and -2 on masseter muscle activity changes for either percent increase of EMG activity or latency to response (2-way ANOVA: P = 0.255 and P= 0.240, respectively). However, application of 100 μM Hcrt-1 increased ipsilateral masseter EMG activity for a longer duration than 100 μM Hcrt-2 did (2-way ANOVA: P = 0.023,F = 2.62, df = 19, 13).
Hcrt-1 microinjection into the hypoglossal motor nucleus
To demonstrate the excitatory effects of Hcrt-1 on motor activity, we unilaterally microinjected 0.5 μl of 100 μM Hcrt-1 into the XII motor nucleus while monitoring masseter and genioglossus EMG activity. A total of 12 Hcrt-1 microinjections were made into XII motor nucleus unilaterally in six decerebrate cats. Figure6 shows how bilateral genioglossus muscle activity changed after microinjection of 100 μM Hcrt-1 into the XII motor nucleus. After microinjection of Hcrt-1 into the XII motor nucleus, ipsilateral genioglossus muscle activity increased by 41.1 ± 9.7% above baseline values (Bonferroni t-test:P < 0.05, t = 2.447, df = 5). The latency and duration of the response were 10.0 ± 2.7 and 231.8 ± 108.7 s, respectively. Compared with pretreatment values, contralateral genioglossus muscle activity was unaffected by Hcrt-1 application (paired t-test: P = 0.185,t = 1.440, df = 5; Fig. 6). The change in genioglossus muscle activity elicited by application of 100 μM Hcrt-1 into XII motor nucleus was not statistically different from the response elicited by application of 100 μM Hcrt-1 into V motor nucleus (Mann-Whitney rank sum test: P = 0.563,U = 58, df = 19,5).
NMDA antagonist into the trigeminal motor nucleus
To determine whether Hcrt-mediated glutamate release regulates motor nucleus excitability and hence changes in masseter muscle activity, the glutamate antagonist, d-AP5 was microinjected into the V motor nucleus immediately prior to microinjection of Hcrt-1. In five cats, eight unilateral microinjections of d-AP5 (0.5 μl) into the V motor nucleus had no significant effect on integrated ipsilateral masseter muscle activity (1-way ANOVA:P = 0.489, F = 1.00, df = 7, 7; Fig. 7). Unlike Hcrt-1 application alone, 100 μM Hcrt-1 microinjection did not increase ipsilateral masseter muscle activity after NMDA channels were blocked by prior application of d-AP5 (1-way ANOVA: P = 0.285,F = 1.64, df = 7, 7; Fig. 7).
To demonstrate that the excitatory effects of Hcrt-1 microinjections could be actively reversed, we applied 0.5 μl of 50 mMd-AP5 into the V motor nucleus immediately after the application of 0.5 μl of 100 μM Hcrt-1. In three cats, three microinjections of 100 μM Hcrt-1 into the V motor nucleus significantly increased basal masseter muscle activity by 115.0 ± 37.1% (Bonferroni t-test: df = 2; t = 1.080; P < 0.05; Fig.8). This effect was reversed by application of d-AP5; within 103.3 ± 5.2 s of applying d-AP5 ipsilateral masseter muscle activity returned to within baseline levels (Fig. 8). Application ofd-AP5 caused a significant reduction in the duration of the Hcrt-1 response compared with Hcrt-1 application alone (Mann Whitney rank sum test: P = 0.025; U = 50, df = 19,3). Application of 100 μM Hcrt-1 alone caused ipsilateral masseter muscle tone to increase for 1,080.7 ± 255.0 s (see Fig. 5); however, with application of d-AP5, the Hcrt-1 response only lasted 410.0 ± 94.4 s (Fig. 8).
To demonstrate that glutamate increases muscle activity in a similar manner to Hcrt-1 and that its excitatory effects could be reversed with glutamate antagonists, we applied 10 mM of the glutamate agonist, NMDA (0.5 μl) into the unilateral V motor nucleus, and then immediately applied 50 mM d-AP5 to reverse its effects. In four cats, seven microinjections of NMDA caused integrated ipsilateral masseter muscle activity to significantly increase by 252.3 ± 69.7% (Student-Newman-Keuls method: P < 0.05, df = 6). Application of d-AP5 reversed this excitation; within 55.7 ± 14.3 s, ipsilateral muscle activity returned to baseline levels (Student-Newman Keuls method: P > 0.05, df = 6; Fig. 8).
Serotonin antagonist into the trigeminal motor nucleus
To validate that Hcrt-dependent glutamate release mediates muscle activity with some specificity, we unilaterally microinjected methysergide into the V motor nucleus immediately prior to microinjection of Hcrt-1. In three cats, five microinjections of 1 mM methysergide unilaterally into the V motor nucleus had no effect on integrated masseter muscle activity (Fig.9). Unlike glutamate antagonists, which blocked the effects of Hcrt-1, application of methysergide had no effect on the Hcrt-1 response. We found that 0.5 μl microinjection of 100 μM Hcrt-1 caused integrated ipsilateral masseter muscle activity to increase significantly by 105.9.5 ± 54.2% (Student-Newman-Keuls method: P < 0.05, df = 4; Fig. 9). The latency and duration of the response were 9.8 ± 5.7 and 442.6 ± 251.9 s, respectively. Pretreatment with methysergide had no statistical effect on the magnitude (Mann-Whitney rank sum test:P = 0.209, U = 67, df = 19, 5), duration (unpaired t-test: P = 0.240,t = 1.319, df = 23) or latency (Mann-Whitney rank sum test: P = 1.0, U =67, df =19, 5) of the Hcrt-1 response alone (comparisons were made between Hcrt-1 alone and Hcrt-1 after methysergide application).
Using a decerebrate cat preparation, we demonstrate that application of Hcrt-1 and -2 unilaterally into the V motor nucleus caused a dose-dependent increase in ipsilateral masseter muscle tone and that Hcrt-1 caused a similar increase in genioglossus muscle tone when applied to the XII motor nucleus. However, blockade of NMDA channels abolished the excitatory response to Hcrt-1 application. We conclude that Hcrt exerts a facilitatory effect on muscle tone when applied to these motor nuclei and that functional NMDA receptors are required for the expression of this effect.
Hypocretin and motor output
Our findings demonstrate that Hcrt facilitates excitatory processes within motor nuclei. Four lines of evidence support this claim. First, our histological observations clearly show that Hcrt microinjections were made within V or XII motor nuclei. Second, microinjections of Hcrt into brain structures immediately adjacent to the V or XII motor nuclei had no effect on masseter or genioglossus activity. Third, Hcrt application unilaterally into the V motor nucleus only affected ipsilateral masseter muscle activity and was without affect on either contralateral masseter or genioglossus muscle activities. The pontine inhibitory area and locus coeruleus are motor-related areas that are in close proximity to the V motor nucleus. Chemical and electrical stimulation of these areas consistently produces bilateral muscle activity changes (Lai and Siegel 1988; Lai et al. 1989). If Hcrt microinjections spread to these motor-related areas, then they would undoubtedly alter muscle tone bilaterally and would also affect both masseter and genioglossus muscle activities. Because such a response was never observed, we conclude that microinjections only affected neurons within the target area. Four, because careful electrophysiological studies demonstrate that Hcrt-1 and -2 depolarize neurons in multiple brain regions, including hypothalamus (van den Pol et al. 1998), locus coeruleus (Ivanov and Aston-Jones 2000), basal forebrain (Eggermann et al. 2001), and laterodorsal tegmental nucleus (Burlet et al. 2002), we propose that Hcrt also depolarizes V and XII motoneurons.
Anatomical tracing data illustrate that in cats, Hcrt neurons make synaptic connections with V and XII motoneurons (Fung et al. 2001). In rats, in situ hybridization histochemistry demonstrates the presence of Hcrt receptor mRNA expression in brain stem regions that correspond to V and XII motor nuclei (Marcus et al. 2001). Furthermore, Volgin et al. (2002)found that identified XII motoneurons express mRNA that encodes the Hcrt-2 receptor. Given Hcrt projections to cranial motoneurons and receptor expression on them, in combination, with the results presented here, we purpose that Hcrt plays a permissive role in regulating motoneuronal excitability.
We found no consistent difference in the masseter muscle tone response to Hcrt-1 compared with Hcrt-2, although the effects of Hcrt-1 lasted longer than Hcrt-2 did but only at the highest dosage (100 μM). In decerebrate rats, Kiyashchenko et al. (2001) reported that Hcrt-1 and -2 microinjections into the locus coeruleus produced similar increases in muscle tone. There are two identified Hcrt receptors: HcrtR1 and HcrtR2; however, other as yet unidentified subtypes could exist. In rats, Marcus et al. (2001)reported that HcrtR1 is expressed in the V motor nucleus and HcrtR2 in the XII motor nucleus. HcrtR1 is 30 times more selective for Hcrt-1, whereas HcrtR2 is nonselective (Sakurai et al. 1998). Hence, the expression of HcrtR1 in the V motor nucleus may explain why the duration of muscle tone increase was significantly longer at 100 μM for Hcrt-1 than for Hcrt-2. Furthermore, steep concentration gradients produced by microinjection techniques may attenuate the effects produced by relatively small differences in receptor response.
Interaction of glutamate and hypocretin
Application of Hcrt-1 caused an increase in masseter muscle tone when applied to the V motor nucleus. This response, however, was blocked with pretreatment of d-AP5, and was actively reversed by d-AP5 application. Based on these observations, we suggest that functional NMDA channels are required for the expression of the Hcrt response. These are the first data to demonstrate a functional link between the excitatory effects of Hcrt and glutamatergic processes. Indeed, blockade of NMDA receptors within V motor nuclei nullifies the excitatory Hcrt response on masseter muscle activity, indicating that glutamatergic pathways are critical for Hcrt function. We propose that Hcrt-1 may act on presynaptic receptors located on glutamatergic axons and modulate motoneuronal activity by presynaptic glutamate release. Two lines of evidence support this contention. First, both Hcrt and glutamate-containing presynaptic terminals are found within the V motor nucleus (Bae et al. 1999; Fung et al. 2001). Second, Hcrt has been shown to modulate amino acids release. In in vitro hypothalamic slices, van den Pol et al. (1998) reported that in the absence of synaptic transmission, Hcrt application increases the release of glutamate. In anesthetized rats, intravenous administration of Hcrt-1 alters glutamate release in the amygdala, which receives dense Hcrt projections, but has no affect on glutamate release in the cerebellum, a region virtually devoid of Hcrt projections (John et al. 2001). Similarly,Kodama and Kimura (2002) demonstrate that systematic Hcrt-1 application increases glutamate release within the locus coeruleus in behaving rats. The most parsimonious explanation of these findings would be that Hcrt modulates the presynaptic release of glutamate. We suggest that Hcrt binds to presynaptic receptors to liberate glutamate, thus activating NMDA receptors on V motoneurons to cause motoneuronal excitation and increased masseter muscle activity.
While the response to Hcrt-1 was blocked and reversed by glutamate antagonists, the broad-spectrum serotonin antagonist, methysergide did not neutralize the muscle tone response to Hcrt-1. Accordingly, we suggest that Hcrt processes are not mediated or dependent on serotonin receptors at the level of the V motor nucleus. Furthermore, we are confident that the dosage of methysergide was sufficient to fully block serotonin receptors and that this could not explain that lack of effect. We used higher methysergide concentrations than those previously reported to block serotonin activity in both the V and XII motor nuclei (Kubin et al. 1992; Okabe and Kubin 1996; Ribeiro-do-Valle et al. 1991). We propose the Hcrt acts on presynaptic glutamatergic terminals within the V motor nucleus to regulate glutamate release onto motoneurons, thus altering their excitability via NMDA receptors.
Hypocretin and motor control regulation
The extensive distribution of Hcrt projections throughout the CNS, coupled with recent behavioral studies, suggests that Hcrt probably regulates multiple physiological processes. Indeed, the Hcrt system is implicated in variety of homeostatic processes like feeding, energy metabolism and sleep function (Siegel 1999); however, compounding evidence strongly links the Hcrt system with motor regulation. Recent work from this laboratory demonstrates that there is a pronounced association between CSF Hcrt concentration and motor activity in behaving dogs. Wu et al. (2002)reported that CSF Hcrt concentrations are highly correlated with motor activity levels. They also reported that sleep deprivation leads to increased CSF Hcrt concentrations; however, it is tightly correlated with the level of motor activity during the deprivation procedure rather than with the amount of sleep loss.
Obstructive sleep apnea is a major sleep disorder in which muscle tone plays a key role. It is caused by collapse of the upper airways due, in part, to sleep-dependent reductions in pharyngeal muscle tone (Kubin et al. 1996). Sleep-dependent reductions in muscle tone occur because sleep-related neurons project to motoneurons and by active inhibition and disfacilitation reduce their excitability (Horner 1996). Hcrt neurons project to both the V and XII motor nuclei, which innervate upper airway related muscles affected by sleep hypotonia. Hcrt neuronal activity appears to vary as a function of arousal state. Estabrooke et al. (2001)reported that Hcrt neurons are relatively more active in wakefulness than in sleep, and we recently found that Hcrt concentrations in the lateral hypothalamus and in basal forebrain are greater during wakefulness than during slow-wave sleep (Kiyashchenko et al. 2002). Therefore withdrawal of Hcrt neuronal inputs during slow-wave sleep may lead to disfacilitation of motoneuronal excitability and reduced pharyngeal muscle tone, thus contributing to obstructive sleep apnea during this state. Hcrt administration may have important clinical effects; it might be useful in the treatment of obstructive sleep apnea and cataplexy because it could minimize the loss of muscle tone associated with these conditions. Indeed,John et al. (2000) demonstrate that systemically administered Hcrt-1 produced a dose-dependent reduction in cataplexy in canine narcoleptics.
In summary, we suggest that the Hcrt system is intimately involved in motor regulation, and it contributes to cataplexy and sleep-dependent muscle atonia. We provide the first evidence that Hcrt alters motoneuronal excitability in a glutamate-dependent manner. This latter observation is of physiological importance because it indicates that a major function of Hcrt may be to regulate presynaptic glutamate release.
We thank B. Nienhuis and O. Lyamin for technical advice.
This work was supported by the Medical Research Service of the Department Veterans Affairs and National Institutes of Health Grants NS-14610, HL-41370, and HL-60296. J. H. Peever holds a postdoctoral fellowship sponsored by the National Sleep Foundation.
Address for reprint requests: J. H. Peever, Neurobiology Research 151A3, VAGLAHS, Sepulveda Campus, 16111 Plummer St., North Hills, CA 91343 (E-mail: JHPeever{at}UCLA.edu).
- Copyright © 2003 The American Physiological Society


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Four arrested in shake-and-bake meth operation
Fri, 27 Jan 2012 15:39:49 GMT —
Four Keokuk residents were arrested on Thursday on charges related to a shake-and-bake methamphetamine operation.
Kathy Sue Crowell, 56, Shawn Michael Stark, 25, Christen Mitchell Stark, 26, and Chad Lawrence Stark, 21, all of Keokuk, Iowa were arrested Thursday on felony and misdemeanor drug charges, the Lee County Narcotics Task Force said.
Each is charged with conspiracy to manufacture more than five grams of methamphetamine within 1,000 feet of a city park. The charge carries an additional five-year sentence if they are convicted. The four are also charged with manufacturing the drug in the presence of a minor, which also carries a five year sentencing enhancement.
If convicted, each faces up to thirty-seven years in prison.
Shawn Stark was also charged with child endangerment. If convicted he faces up to an additional five-years prison term.
Field Supervisor Adam Cates said he expects more arrests to stem from the ongoing investigation.

subset: commoncrawl


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United Hospital Center in Bridgeport has announced plans to become the controlling organization for St. Joseph's Hospital in Buckhannon.
UHC CEO Bruce Carter said on Thursday that the hospital has signed a letter of intent and hopes to reach a definitive agreement by November.
The Pallottine Missionary Sisters, a Catholic order, approached UHC about the transfer, according to Carter.
"Their reasoning was there are less sisters in the order and they're aging," he said. "They feel as though they're not going to be able to properly manage these missions in the long-term."
The hospital will no longer be affiliated with the Catholic Church but its day-to-day operations will be unchanged "to honor the legacy of the sisters and everything they've done in Buckhannon over more than 75 years," according to Carter.
The Pallottine sisters recently made a similar announcement with regard to St. Mary's Medical Center in Huntington, which is exploring a merger with Cabell Huntington Hospital.


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|Job Title
|Director of Policy and Communications - EXPIRED
|Contract Type
|£50k - 55k per year
|Job Published
|16 Sep 2016
|Contact Name
|Executive Team
|Contact Email
TPP are working with a leading membership organisation for health professionals, and are supporting the search for a new Director of Policy and Communications.
In this senior leadership role, you work to successfully influence policy at a national and UK level, engaging and informing members and stakeholders of the organisation's work, vision, mission and charitable objects. The organisation has an ambitious membership engagement and growth agenda and your marketing and communications expertise will provide leadership for this work.
You will lead a small team of staff with responsibility for policy, public affairs and parliamentary engagement, undertake strategic analysis to inform and advise policy development, advocate organisational policy and successfully influence partners, senior civil servants and stakeholders. You will also represent the charity in the media, manage communications and PR activity (including digital media), manage the organisation's suite of publications, and develop and implement a clear marketing plan to support organisational targets.
In order to be considered, you will have a proven and successful track record of policy influence at the highest level; experience of partnership working and network development; as well as strategic marketing and communications expertise.
This role represents an exciting opportunity for an experienced professional to make a significant impact to influence health policy at a time of significant change and challenge. This is a fast moving role, so if you are interested, please send an updated CV through in response to this advert ASAP. Alternatively, please contact Matt Adams on TPP's Senior Appointments team for a confidential discussion.


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When their wealthy father dies, three slacker brothers learn that only one of the will earn the inheritance. In a video will, their father states that the first brother to find true love and marry will earn the inheritance.
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10 years earlier 10 years later 80s action Adaptation adventure Animation Based on Animated Series based on book based on comic based on comic book based on tv series Based on video game batman biopic Book comedy comic adaptation comic book crime Crossover DC DC Comics Disney drama family fantasy History horror Idea-for-TV kids Live Action martial arts Marvel Marvel Comics Musical mystery reboot remake romance Sci Fi sci-fi science fiction scifi Sequel Superhero supervillain suspense teens thriller videogame adaptation war western


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Late last week I announced that I was looking for some prizes for my next group writing project. Due to the timing of the post calling for them I've had feedback that a number of people didn't get enough notice to put a pitch together. So I'll extend the deadline for submissions by 24 hours. So at 5pm tomorrow (Tuesday – Melbourne time) I'll stop taking submissions for prizes.
If you'd like to pitch an idea please do so after reading the following full post at Prizes Needed – Sponsor ProBlogger's Next Group Writing Project
Thanks to all those who've sent in ideas – once again there are some great ones (although no more cash prizes please! Never thought I'd hear myself saying that!).


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THE sharp decline in India's current account deficit in the third quarter of the fiscal (October-December) to 0.9pc of GDP may lead to a cut in import duty on gold.
Last year, the government raised import duty on gold to 10pc, as the Indian currency plunged following a widening current account deficit (CAD). The deficit shot up to a record $88bn last fiscal (2012-13), accounting for 4.8pc of the GDP. Finance minister P. Chidambaram, who recently presented his interim budget, is confident that the CAD would decline to $45bn for this fiscal, which ends on March 31.
Last week, Chidambaram promised to take a call on easing duties on gold imports after the CAD figures were released. Hours later, the Reserve Bank of India (RBI), the central bank, revealed that the CAD for the third quarter was down to $4.2bn (0.9pc of GDP) as against $31.9bn (6.5pc of GDP) in Q3 of the previous fiscal. This was the lowest CAD in eight years.
The deficit for the nine-month period of the fiscal (April-December) narrowed to 2.3pc of the GDP (or $31.1bn), as compared to 5.2pc ($69.8bn) for the same period in the previous fiscal. "The lower CAD was primarily on account of a decline in the trade deficit as merchandise exports picked up and imports moderated, particularly gold imports," said the RBI.
Worried over the widening deficit and the plunging rupee, the government last year raised the import duty on the yellow metal from 2pc to 10pc. It also introduced a new, 80:20 scheme, where it allowed nominated agencies to import gold only if they exported 20 per cent of the metal.
Gold imports have fallen sharply after these twin measures were initiated by the government. According to the World Gold Council (WGC), China overtook India to emerge as the world's top importer of gold in 2013.
While demand in India continued to be strong, official imports dipped slightly in 2013. The WGC estimates that domestic demand for gold in India was at 975 tonnes in 2013. Somasundaram PR, managing director, WGC India, estimates that nearly 200 tonnes of gold might have been smuggled into the country last year. Unofficial imports have almost doubled in 2013 as compared to the previous year, feels the council.
Official imports of gold fell to just $3.1bn in the last quarter of calendar 2013, as against $17.8bn a year ago. India's official imports of gold were more than 160 tonnes last May. But this has reduced to a trickle of just 20 to 30 tonnes a month towards the end of the year.
According to RBI figures, merchandise imports fell by 14.8pc to $112.9bn in the third quarter of the fiscal, as against an increase of 10.4pc in Q3 of the previous financial year. Overall, the balance of payments was also positive, resulting in a net accretion of $19.1bn in the foreign exchange reserves towards the end of Q3.
THERE is a growing pressure on the United Progressive Alliance (UPA) government, now in the final weeks of its second term (last week the Election Commission announced a nine-phase voting process beginning April 7; the results would be announced on May 16) to ease the curbs on gold imports.
In fact, in January, UPA chairperson and Congress president Sonia Gandhi had asked the government to consider easing the curbs including the 80:20 rule, and called for a reduction in duties. Gold and jewellery traders have also been demanding the withdrawal of import duties.
But despite the clamour for liberalising gold imports, the government has been tightening the screws on the trade. The India Bullion and Jewellers Association alleges that government agencies are raiding their members' offices and shops, asking them to reconcile the gold bars with their imports.
The association has called for a nationwide strike this week to protest against the spot checks and the import curbs and the general harassment of bullion dealers and jewelers by government agencies. Mohit Kamboj, president of the association, claims that jewelers are being unfairly targeted and harassed.
Bullion dealers and jewelers are also eagerly awaiting the outcome of the general elections. The Associated Chambers of Commerce and Industry of India (Assocham) notes that gold prices may shoot in case there is instability in Delhi after the elections. "Gold prices in India may increase beyond Rs32,000 per 10 grams in the coming few months in case voters throw up a highly fractured mandate leading to an unstable government at the centre," says an Assocham study, 'Golden Connect of Indian Elections.'
But if a stable and decisive government is formed, even if it is a coalition of many parties, investors will switch over to equities and real estate, resulting in a fall in demand for gold.
"At the moment, three important factors are driving the global gold market: concerns over the Chinese economy, uncertainty over the pace of the US economic recovery and the anxiety around the Indian general elections," notes the Assocham study. "India and China are competing with each other for retaining the slot of being the number one consumer of the yellow metal. The demand in these two markets is going to increase should the two economies witness political or economic uncertainties."The trend of investors shifting again to gold as a safe haven is already being witnessed, claims the trade body. Gold prices have risen by over 10pc so far this year largely because of these reasons and the investor interest in bullion-backed exchange traded funds has returned.
D.S. Rawat, secretary-general, Assocham, adds: "While global factors will certainly weigh on gold prices, the Indian market as a consumer of the yellow metal and for the equities would be surely affected by the unfolding developments."


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Coach Kelley Hartley Hutton said being able to secure a spot in the four-team conference tournament on Nov. 16-17 in Fargo, N.D., has been one of the top goals for IPFW (22-5, 11-3 Summit League) this entire season.
"It's huge," Hutton said. "All summer these kids are working out and in August in two-a-days that's what we are going for, to compete for a championship. Going out to Fargo in a few weeks is exactly why we're here."
IPFW in its sweep out-hit Omaha .318 to .130, including holding the Mavs (6-20, 1-13 Summit League) to a match-low zero attack percentage in the second game.
The Mastodons' 15-point win in the second game was also their largest margin of victory in a conference match this season.
IPFW libero Tessa McGill led all players with 18 digs against Omaha. The defensive performance also moved McGill into third place in school history for the most digs in a single-season with 643.
Outside attacker Emily Spencer had a match-high 15 kills in the victory. In addition, middle attacker Jessie Manwaring had eight kills, while outside attacker Kendall Wienkes added seven kills.
Hutton said she was pleased with the way her team was able to run a balanced offense. She also said that is something the Mastodons will need to continue to do as they enter the final weeks of the season.
"We played smart volleyball," the coach said. "When things got a little crazy — and it does, that's our sport — we were really smart with what we did with the volleyball."
With this victory, IPFW remains tied with in-state rival IUPUI (19-9, 11-3 Summit League) for first place in the Summit League entering the final week of the regular season.
The two schools also stay on pace to play defacto regular season championship match when IPFW travels to IUPUI in their regular season finale Saturday.
"It's awesome that Indiana is representing the Summit League, and it's really exciting and good for our league," Hutton said.
IPFW before that potential regular season title match will play a road match against Western Illinois on Friday, while IUPUI will play Oakland on Friday.
Hutton said not having the team's conference tournament seeding clinched yet could be a good thing for this team because it will prevent the players from looking too far ahead at the conference tournament.
"Everyone is excited about this tournament but we do have two matches in front of us. Important ones and they're on the road," Hutton said. "We are excited that we clinched a seed, but we need to continue to play good volleyball and continue to get better. If we are looking too far ahead I think it will be very difficult to do that."


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That said, (ang haba ng intro) can I just share a photo of these pumps that I recently got from TLTSN?
Nice no? These are made of synthetic suede. And did you notice the heel height? They are barely 2" high, which makes them very sensible. I especially like that these shoes have a vintage feel to them. "Feel" being the qualifier to my opinion because I sure as hell don't want to wear shoes already worn by someone in the 1950s.
The second little thing that I got last week are these -
Anthology Kyotos. They don't show well in the photo above but the right one has a violet upper while the left one has a blue upper. Very weird. Here's a photo from the Anthology website -
As always, the detailing on Anthology shoes speaks well of Filipino (Marikina)-made products. I own another pair of Anthology shoes that have been through close to 2 years of abuse and they still look fine. Note that Anthology shoes are not true to size though. I should order one size up next time.
By the way, the above were bought on sale. So, No, mother. I haven't been squandering money again. Besides, these would be all this month.
I hope. Toodles.
- posted via BlogPress for iPad


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Kathy Pasquini and Gary Pasquini, both of Southampton, announce the engagement of their son, Benjamin Pasquini, to Robin Ulrick, of Southampton. The bride-to-be is the daughter of Bonnie and Ken Roukey, of Easthampton.
The future bridegroom graduated from Smith Vocational High School in Northampton and is employed with Palmer Paving Corp. of Palmer. He is also the owner of Ben's Stump Grinding.
The bride-to-be is a graduate of Gateway Regional High School in Huntington and attends Holyoke Community College. She is employed with the Silver Spoon Restaurant.
An October wedding is planned at The Red Barn at Hampshire College in Amherst.


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It's a 'myth' Facebook can't make money on mobile – Mark Zuckerberg
Mark Zuckerberg has said he hopes Facebook has dispelled the 'myth' it cannot make money through mobile platforms after posting a 32 per cent rise in third quarter revenue.
Although the social networking site's revenue was up to $1.26billion (£785million) from $954million (£595million) it recorded an overall loss of $59million (£37million) between July and September, compared to earnings of $227million (£142million) in the comparative period last year when Facebook was privately owned.
But Facebook's stock rose 9.7 per cent following yesterday's earnings announcement after it emerged 14 per cent of its advertising revenue came from mobile.
'I want to dispel this myth that Facebook can't make money on mobile,' Facebook founder and chief executive officer Mark Zuckerberg said.
'This may (have seemed) true earlier this year because we hadn't started trying yet.'
Advertising revenue overall was up 36 per cent to $1.09billion (£680million), representing 86 per cent of total revenue.
In the same period the site's user base grew 26 per cent to 1.01billion, with 60 per cent of users accessing Facebook via a mobile device.
'People who use our mobile products are more engaged, and we believe we can increase engagement even further as we continue to introduce new products and improve our platform,' Mr Zuckerberg continued.
'At the same time, we are deeply integrating monetization into our product teams in order to build a stronger, more valuable company.'
Facebook's stock had not traded above its initial public offering price since it was first listed.


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San Jose-based Mi Pueblo Foods has emerged from Chapter 11 bankruptcy reorganization with founder Juvenal Chavez as board chairman and Javier Ramirez as the new chief executive officer.
The Hispanic grocery chain, which filed Chapter 11 last July, received $56 million in financing from Chicago-based Victory Park Capital as part of the restructuring. After the filing, stores continued to operate under agreements with vendors and creditors, according to a news release.
Mi Pueblo Foods, founded in 1991, has 21 stores in Northern California.
Ramirez has nearly 20 years of experience in the Hispanic food and grocery industry, according to the company.
"We have already started to implement aggressive initiatives designed to reposition Mi Pueblo as a profitable entity and as a strong contributor to our local Hispanic communities," he said in the release.
Ramirez's post-bankruptcy plans include enhancing the company's Hispanic product offering, improving customer service and ensuring competitive prices.
"We will be introducing several new employee benefit programs for our colaboradores as well as several new initiatives focused on supporting our local communities," he said. The company employs about 3,200.
In the bankruptcy claim, the company's top 20 unsecured creditors included OK Produce, Fresno, Calif., with $225,000 owed; Premier Valley Produce Inc., Scottsdale, Ariz., with $243,000 owed; and West Pak Avocado Inc., Murrieta, Calif., with $149,000 owed. Total assets were listed at between $10 million and $50 million, as were total liabilities.


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If one Louisiana legislator has his way, the state's dairy industry will have a new Dairy Development Fund to help dairy sustain itself. Rep. Francis Thompson (D-Delhi) has proposed legislation to create the account that would be funded by a 1 percent fee on all dairy products sold in the state.
It would be administered by the agriculture commissioner, and could grow by as much as $10 million annually. Legislative analysts are working on estimates of how much the proposal would truly bring into the fund's coffers. Thompson says he wants the fund to be used for a wide variety of projects to prevent further erosion of Louisiana's dairy industry.
However, opponents of the bill, like the Louisiana Retailers Association, say it will increase consumer cost for dairy products because grocery store owners will pass the price hike along to their customers.
The state's ag commissioner indicates that the monies will actually be used for new in-store milk and dairy inspections, not for dairy promotions or financial awards to individual producers. Furthermore, he doesn't think the fund will bring in tens of millions of dollars.
Still, according to a recent report by the Louisiana Dairy Industry Task Force, the state's dairy industry needs all the help it can get. And this bill is just one of several aimed at providing economic incentives and relief to the Louisiana dairy business.


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Thursday, January 26, 2012
Explore Japan by Rail: JR Pass Rates January 26 2012
The Japan Rail Pass, which is issued by the JR (Japan Railway) Group, offers travelers excellent value for money and convenience. The Rail Pass enables the almost unlimited use of JR trains and its affiliated bus and ferry services within various areas of Japan. The Japan Rail Pass can also be used for the Tokyo monorail to Haneda Airport and the Narita Express to Narita Airport.
The Japan Rail Pass is available only to people from abroad who wish to travel to Japan as "temporary visitors" for sightseeing. The pass must be purchased before entering Japan.
Japan Rail Pass exchange rate for January 26th 2012 through February 1st 2012 - 1 USD =77.1 JPY
JR Pass prices are updated for the current exchange rate every Thursday.
See http://www.nakastrav … l.com/rail-pass.html for details and current pricing.
Japan's four major islands, Honshu, Hokkaido, Kyushu and Shikoku are covered by an extensive and reliable network of railways. About 70 percent of Japan's railway network is owned and operated by the Japan Railways (JR), while the remaining 30 percent belongs to dozens of other private railway companies, especially in and around metropolitan areas.
The Japan Railways Group, more commonly known as JR Group (JRグループ), is made up of six regional passenger railway companies, which are JR Hokkaido, JR East, JR Central, JR West, JR Shikoku, and JR Kyushu, and one nationwide freight railway company, JR Freight. Together they operate a nationwide network of urban, regional and inter-regional train lines, night trains and shinkansen (bullet trains).
Wednesday, January 4, 2012
Kama'aina Discount for 2012 South Pacific Solar Eclipse Cruise
If the winter solstice has you in a celestial state of mind, Celebrity Cruises is set to host one cruise itinerary in 2012 that's sure to be out of this world. The 19-night South Pacific Solar Eclipse Cruise, aboard the 1,950-passenger Celebrity Millennium, is due to embark on November 2, 2012, from Honolulu en route to Sydney. Given that one of the best places to view the total solar eclipse will be from the southern Pacific Ocean, cruising is just about your best bet for viewing this cosmic phenomenon firsthand.
Port calls on the lengthy voyage will include exotic stops like Hilo, Hawaii; Pago Pago, American Samoa; Suva, Fiji; and a trio of locales in New Zealand: Tauranga, Auckland, and the Bay of Islands. Given the repositioning nature of this transpacific sailing, you can expect a substantial amount of time spent at sea, with at least a dozen days spent in transit, including November 14, the date of the solar eclipse.
Happily, the Celebrity Millennium will be fittingly "Solsticized" ahead of the occasion in May 2012, meaning that it will be retrofitted and refreshed with many of the venues, experiences, and design elements that have made the line's Solstice class of ships so popular. Expect AquaClass spa-inspired accommodations, a Celebrity iLounge, new Specialty Restaurants, and Ice-Topped Martini bar, Cellar Masters Wine Bar, and more.
Special Kama'aina Rates for the solar eclipse-themed sailing start at just $2,009 per person ($106/night), for inside cabins; upgrade to oceanview from $2,269 ($119/night) or a balcony for $2,709 ($143/night).
Special offer: Book between January 9 - February 5, 2012 and receive a $300 discount per stateroom!
Contact Naka's Travel Service for more information, book a Celebrity Cruise online now or see more cruising options on the Cruise with Naka's page.


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New details about elderly man shot by Pine Bluff police
New information out concerning the 107-year-old man killed in a standoff in Pine Bluff over the weekend.
According to police reports, 107-year-old Monroe Isadore told officers back in June that they would, "have to shoot him or throw him in jail before he went back home with his son-in-law." Police say Isadore had jumped out of a car that he and his son-in-law were in.
And even before that, police were very familiar with the elderly man and his condition. Reports from 2008 reveal officers investigating a robbery at his home, where they note, Isadore "is close to deaf in both ears and very hard to understand."
Police shot and killed Isadore Saturday after reports that he'd threatened family members with a gun, and he opened fire on police.
Meanwhile, police say an officer involved in the shooting has been placed on paid administrative leave.


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Renee Binder, M.D., Chair
Meeting of March 20, 2001
PRESENT: Chair Binder, Vice-Chair N. Oppenheimer, D. Perry, P. Robertson, S. Norberg, J. Barbaccia, S. Eisendrath
ABSENT: G. Gregory, J. Howley, C. Harrington
The meeting of the Committee on Faculty Welfare was called to order by Chair Binder at 12.05 p.m. on March 20, in room S-226. A quorum was present.
Announcement from the Chair
Chair Binder introduced all attendees, and welcomed Michele French from the Office of the President.
Chair Binder invited S. Norberg to the next meeting to make a special presentation on the definition of "disability" in short-term and long-term disability plans available to UCSF faculty and staff. S. Norberg accepted this invitation.
Special Presentation by Michele French, Director of Workforce Planning, Office of the President on Mental Health Benefits and Health Plans Available to UCSF Staff and Faculty.
M. French distributed a table which summarized different insurance plan vendors and their different provisions for mental health care. The Committee reviewed this table, and raised the following points of discussion:&Mac183;
In response to these points, M. French made the following observations:
ACTION: M. French agreed to add member-to-provider ratios and helpline numbers to the table. She will email this table to Senate staff E. Langdon-Gray who will distribute it via email to the committee.
Review of Systemwide UCFW Activities – R. Binder, Chair
R. Binder announced to the Committee that:
Report of Chancellor's Housing Committee – N. Oppenheimer, Vice-Chair
The Housing Committee will meet on March 22. A survey designed to collect data from faculty regarding their current housing situations was sent out at the end of January. Many faculty did not receive this survey, and it will be resent in the near future.
The meeting was adjourned at 1.02 p.m.
Senate staff:
Elizabeth Langdon-Gray
Senate Analyst
Tel. 476.1307


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HiHi everybody , I been single for six years now
deleted 26-30 5 Responses 2 Jan 10, 2013
i so understand that u do sound really good i would love to know u more plz
whats the rush take your time and find the right person
and you won't let people add you ???
Sorry to hear that. Hope you find someone soon XXXX
do u wantsex with me and my husband?


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Detail Information
- Learning through public involvement in environmental assessment hearingsPatricia Fitzpatrick
Department of Geography, University of Waterloo, Waterloo, Ont, Canada N2L 3G1
J Environ Manage 67:161-74. 2003..Understanding the existing scope of critical education within a panel review provides the foundation for identifying opportunities for expanding the capacity of the existing EA process to facilitate learning by participants...
- Steady-state free-precession (SSFP) cine MRI in distinguishing normal and bicuspid aortic valvesTadhg G Gleeson
Department of Radiology, Mater Misericordiae University Hospital, Dublin, Ireland
J Magn Reson Imaging 28:873-8. 2008..To assess the diagnostic sensitivity and specificity of double-oblique true fast imaging with steady-state precession (SSFP) cine MRI in distinguishing normal and bicuspid aortic valves...
- Image quality in low-dose multidetector computed tomography: a pilot study to assess feasibility and dose optimization in whole-body bone imagingTadhg G Gleeson
Department of Radiology and Diagnostic Imaging, Mater Misericordiae University Hospital, Dublin, Ireland
Can Assoc Radiol J 61:258-64. 2010....
- Environmental impact assessment under the Mackenzie Valley Resource Management Act: deliberative democracy in Canada's North?Patricia Fitzpatrick
Department of Geography, University of Winnipeg, 515 Portage Ave, Winnipeg, MB, Canada, R3B 2E9
Environ Manage 42:1-18. 2008..However, many of these positive results occurred through nonmandated technical sessions. The absence of participant funding also limits the deliberative potential of the MVRMA...


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On Mon, 2009-09-14 at 14:48 -0700, C Storm wrote: > In this linux mag article (http://www.linux-mag.com/cache/7516/1.html) > the author describes a performance problem > brought on by using the noapic boot time kernel option. Has anyone > investigated whether postgres performs better > with/without the noapic option? It probably depends a lot on how your devices are arranged on the PCI and PCIe bus(es) and how the kernel/bios assigns interrupt lines. If busy/active devices share interrupts with other devices, especially if those devices take significant work to poll when an interrupt is received, it could have a nasty effect on performance. On the other hand, if your high-load devices like NICs and disk controller(s) don't land up sharing interrupts, AFAIK it may not make much difference. I don't know how much difference the local APIC(s) and IO-APIC make as compared to the 8259 PIC when shared interrupts aren't an issue. Then again, I'm surprised any modern machine can run without an IO-APIC. Isn't it required for SMP or multi-core operation? This article might help provide some information. While it's about Windows and is on MSDN, the principles it describes about how the local APIC(s) and IO-APIC(s) help should apply equally well to Linux and other systems. http://www.microsoft.com/whdc/archive/io-apic.mspx I don't think the issues with synchronization primitives really apply on *nix systems, but the issues with interrupt latency certainly do. As you can see from the article, having a working system of local and I/O APICs should dramatically reduce wasted bus I/O resources and CPU time required to service interrupts especially on highly shared interrupt lines. Consider one of the servers here: $ cat /proc/interrupts CPU0 CPU1 0: 90 0 IO-APIC-edge timer 1: 16 0 IO-APIC-edge i8042 4: 1368 0 IO-APIC-edge serial 6: 3 0 IO-APIC-edge floppy 8: 0 0 IO-APIC-edge rtc0 9: 0 0 IO-APIC-fasteoi acpi 14: 0 0 IO-APIC-edge ide0 15: 0 0 IO-APIC-edge ide1 28: 64040415 0 IO-APIC-fasteoi 3w-xxxx 48: 668225084 0 IO-APIC-fasteoi eth1000 See how the highly active 3Ware 8500-8 (3w-xxxx) disk controller and the Intel EtherExpress 10/100/1000 (eth1000) have their own private interrupt lines on interrupts 28 and 48 ? Without APICs they might be forced to share, or at least be placed on the same interrupt as (eg) a USB controller, a PATA disk controller, or whatever. That might force the OS to do work for those devices too when it receives an interrupt on that IRQ line. Not ideal. (Interestingly, this is a real dual-CPU system but all interrupts are being serviced by the first CPU. Whoops. apt-get install irqbalance). -- Craig Ringer
Next: From: Richard Henwood Date: 2009-09-17 12:55:07 Subject: optimizing for temporal data behind a view Previous: From: Richard Huxton Date: 2009-09-17 07:58:35 Subject: Re: Possible causes of sometimes slow single-row UPDATE with trivial indexed condition?


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What are we looking for?
Dividend stocks with an extra sweetener of share buybacks.
More on today's screen
Companies can choose at least two ways to reward investors. One is by increasing dividends (which puts money directly into shareholders' pockets); another is by buying back shares (which benefits shareholders indirectly by reducing the number of shares outstanding, thus spreading future profits among a smaller group of investors).
There's evidence that companies that buy back shares on a regular basis do better than the broad market. There's also evidence that companies that grow their dividends do better than those that don't. Companies that do both would therefore seem well positioned for further gains.
How we did it
Allan Meyer and Sean Pugliese at Wickham Investment Counsel in Hamilton used Morningstar CPMS to screen their database of more than 700 firms for TSX-listed companies that have done a share buyback over the last year, and also increased their dividends.
What we learned
MacDonald Dettwiler was the winner in the share buyback category, shrinking its number of shares by 22.6 per cent over the past year. The company also announced a dividend increase of 30 per cent (from $1 to $1.30) for a dividend yield of 2.9 per cent.
Other firms that have done share buybacks and sport yields of more than 4 per cent are Nordion, Rogers Communications and GMP Capital. It is interesting to note that the payout ratio for all of the securities listed is below 50 per cent, indicating that they are in a good position to raise dividends.
You should, of course, do your own research before buying any stock. But if you're searching for firms that are rewarding their investors in multiple ways, this list is a good place to start your hunt.


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Second arrest made in Futrell Drive homicide
Sun, 02 Jan 2011 18:27:38 GMT —
Myrtle Beach Police arrested Michael Quantrel Barr, 20, in connection with a shooting.
Police say Damian Pickett, 21, was killed at a home on Futrell drive in Myrtle Beach around 11 p.m. Thursday, December 30th.Barr, who was arrested at 3340 Mustang St, Myrtle Beach on Sunday, is being charged with Accessory / Accessory After The Fact To Felony.Myrtle Beach police arrested Kendrix Corbitt, 18, of Myrtle Beach on January 1st. Corbitt is charged with murder and possession of a firearm during the commission of a violent act.
The investigation continues. Anyone with information is asked to call Myrtle Beach police at 843-918-1382.


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Flower Mound Police are investigating the shooting death of a Justin man Wednesday.
Officers responded to an investigation of possible gunshots in the 500 block of Flower Mound Road at 10:45 p.m. Tuesday, police said.
Lamont Darnell White, 54, was found with multiple gunshot wounds, including one to his head, sitting inside a white Mazda sedan in a parking lot, police said.
White was transported by CareFlite air ambulance to Methodist Dallas Medical Center in critical condition.
"We learned he was dead at 4:45 a.m. this morning [Wednesday] from the hospital," said police Capt. Kurt Labhart.
In light of national recent sparks of random violence, Flower Mound Police Department officials said they want to assure the community the incident didn't fall into that category.
"We don't feel this is a random act of violence," Labhart said. "The preliminary investigation shows the killer had some type — we don't know what — affiliation with the victim."
White's body is currently awaiting a full autopsy with the Dallas County Medical Examiner's Office.
Labhart urges anyone with information about this investigation to contact the Flower Mound Police Department at 972-539-0525 or the Anonymous Crime Tip Line at 972-874-3307.
MEGAN GRAY can be reached at 940-566-6885. Her e-mail address is email@example.com .


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User talk:BarkingFish
Tok Pisin[edit]
I have been quite active on Tok Pisin and there's some new stuff you might be interested in. Here's a list of Tok Pisin terms we have that lack etymologies, because I haven't been able to find them or figure them out. If you know the etymologies of any words on that list, you can add them to the entries and pull them off the list.
Also, there are a few Tok Pisin entries at the bottom of WT:RFV that I can't find citations for - if you can, that would be great! Thanks! --Μετάknowledgediscuss/deeds 22:49, 20 July 2012 (UTC)
- I'm actually working on the RFV's now, Metaknowledge - so if you want to check, you're welcome to. There is a very comprehensive list of words on the net that I'm aware of, by two well respected linguists, Terry and Sylvia Barhorst (the latter has worked for the BBC as a producer of educational language programmes). The link is here - it is part of something they undertook called the Human Language Project or HLP - link here. I'm picking through things as I get to them :) BarkingFish (talk) 22:53, 20 July 2012 (UTC)
- Thanks for the link! Please note that, according to WT:CFI, we need "durable" citations, from books, usually. That website is great for verifying, but we also need to cite. Currently, I'm working on that by using
{{tpi-cite-bible}}in conjunction with
{{LDL}}- to see how it works in real life, take a look at an entry like skai. Thanks! --Μετάknowledgediscuss/deeds 23:00, 20 July 2012 (UTC)
- Thanks for the link! Please note that, according to WT:CFI, we need "durable" citations, from books, usually. That website is great for verifying, but we also need to cite. Currently, I'm working on that by using
Both the English and Tok Pisin sections need to be reviewed by an editor who has experience in PNG society. I think the definitions are a bit off. Can you improve them? --Μετάknowledgediscuss/deeds 00:08, 21 July 2012 (UTC)
- A couple more things: do I have the def for pikinini bilong kaikai right? Or does it mean seed? Also, what does en mean in Tok Pisin? Thanks --Μετάknowledgediscuss/deeds 05:15, 21 July 2012 (UTC)
- Right, you're in the target area with fruit, the correct term is pikinini bilong diwai (child of tree) - i can find no reference in my material at the moment to a word for seed, I would suspect pikinini bilong prut (child from fruit). As for en, that's quite a tricky one. I will consult Iketsi, my bud at tpi.wikipedia, and get back to you on that. I can tell you however, that most people mistake it for "and", which is actually "na" - "Mi go wokabaut long bus long tripela wik, na mi kam bek long haus." -
- OOPS: Forgot to deal with wantok - the definitions there look pretty spot on to me, basically a wantok is anyone from your local community, or someone who speaks your language - it's similar in usage to the colloquial term "Bro" or "Brother" in American English - you're identifying a strong bond with that person or member of your own community. "Gude wantok" can be looked at as "Hey bro!" BarkingFish (talk) 12:38, 21 July 2012 (UTC)
- Thanks! It's really great to have someone at this project who actually knows more tpi than me. How involved are you planning on being or interested in being in Wiktionary? There are some Tok Pisin tasks sitting around that I can't do, so if you want them, I can give you the links. Also, please see my response in the thread above this one. Tenkyu tru! --Μετάknowledgediscuss/deeds 15:41, 21 July 2012 (UTC)
Sorry to bother you again - can you also ask what wantu means? I found it in a quote but I don't understand it. --Μετάknowledgediscuss/deeds 23:20, 21 July 2012 (UTC)
- Splitting the two parts up, it seems to be a compound word, Metaknowledge. Wan (from one) and tu (meaning also) - could you link me to the quote where you found it, or maybe paste it here so I can see the context in which it's used, please? BarkingFish (talk) 22:11, 22 July 2012 (UTC)
- Also, could you possibly let me have a copy of that list of jobs and things you wanted doing in relation to Tok Pisin on here please? I haven't got much to do over the next few days, it'd be nice to have something to work on. Thanks again :) BarkingFish (talk) 22:17, 22 July 2012 (UTC)
Definitely! I'm really glad you want to help! Here's a list off the top of my head of stuff in Tok Pisin that needs to be done:
- The quote is at wantu#Tok Pisin. If you can check the etymology and replace
{{rfdef}}with the correct definition, that would be great.
- WT:RFD is where we go to put words that don't fit our inclusion criteria. There's one Tok Pisin term there, at WT:RFD#bilong husat, that appears to be SOP (sum of parts; it is not an independent term but just bilong + husat). If you can weigh in, that would be great.
- At Category:Translation requests (Tok Pisin), there is a list of English terms which a user has requested a Tok Pisin translation for, that I can't provide. Would death adder be snek bilong dai?
- At User:Metaknowledge/Tok Pisin without etymology, there is a list of Tok Pisin terms that need an etymology section. If you could find the etymologies for any of them, I would be very appreciative. (You can learn how to add etymologies at WT:Etymology.)
Anyhow, you don't have to do any of this if you don't want to, but if you can, it would really help. If you want more to do, just drop me a line. Tenkyu tru tru! --Μετάknowledgediscuss/deeds 04:34, 23 July 2012 (UTC)
Please note the changes I made to your etymology at kirapim. It's minor stuff, but using
{{term}} and linking to -im do help. By the way, when you write an etymology, take the word off the list. Thanks! --Μετάknowledgediscuss/deeds 00:46, 24 July 2012 (UTC)
- Hi :) Sorry, I've been having issues getting on the net over the last couple of days. I have managed to get at least one of the definitions you wanted, which you spoke to me about - wantu (one, two) - in this case, it means "instant" or in an instant. Looking at the bible verse, which was quoted, it refers to the eating of the fruit from the tree of knowledge, which God forbids - his warning is clear, that if you eat the fruit from the tree, wantu, yu bin dai - literally, you will die instantly. - Compare it to the english version of Genesis 2:17 - "...but you must not eat from the tree of the knowledge of good and evil, for when you eat from it you will certainly die." - I just have to sort the other one out now, and I'll get back to you with that as soon as possible :) BarkingFish (talk) 01:54, 27 July 2012 (UTC)
- Tenkyu tru! Sapos yu i ken raitim mi nem bilong E-mel bilong Iketsi (poroman bilong yu), orait mi i givim yu planti tenkyu. (Please correct my grammar!) --Μετάknowledgediscuss/deeds 05:29, 27 July 2012 (UTC)


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Do you follow the CG routine or a modified version of it?
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Friday, March 11, 2005 at 02:03AM
I had very slight waves in my hair all of my life. I actually used to get perms to have curly hair and then one day I realized that either my last perm had lasted for about 4 years or it was now natural.
I always used pretty decent products and washed every other day but conditioned everyday. I used gel and mostly air dried like I do now. If I blew it dry I used a diffuser.
The only thing that's changed is I use even better products now, wash less often and with sulfate free shampoos and do DT's more often. I did used to get split ends sometimes and I haven't had any now since I found nc.com.
2b/3a, primarily use Jessicurl and DevaCurl products, Curls Hair Tea conditioner and various gels. I'm modified CG-ish since 5/04.


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James J. Ruggiero, Jr., Esq., AEP
Ruggiero Law Offices
Paoli, Pennsylvania 19301
As Benjamin Franklin once said, "You may delay, but time may not." No truer are these words than in the case of estate planning. The average person allows 10-to-15 years to elapse before revising his or her estate plan. Life's ups and downs, and the impending estate tax law changes, present the opportunity to protect your legacy.
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How could that happen, you ask? Well, in 2006, 46 percent of the general public had a will; however, in 2007, that percentage dropped to 37.
Actually, estate planning is about more than having a will. Four basic documents encompass a good estate plan: a Last Will and Testament, a General Durable Power of Attorney, a Healthcare Power of Attorney, and a Living Will.
Each of us needs an updated Living Will
The recent celebrity case involving Gary Coleman provides a clear example of the ills that can occur without an updated estate plan. In 2006, Coleman created a healthcare directive that gave his then-wife power to make medical decisions if he became incapacitated. It apparently included a statement to prolong his life for as long as possible. After divorcing and failing to revise his healthcare directive, Coleman suffered a head injury and was admitted to the hospital, diagnosed with a brain hemorrhage. Coleman's ex-wife decided to take Coleman off life support only one day after he was admitted.
In some states, divorce fails to nullify a healthcare directive. If you have been through a divorce, it is wise to review your estate documents to ensure they continue to reflect your wishes.
Form your own dynasty
Although problems can arise due to neglecting to update healthcare directives, preserving wealth is perhaps the greatest concern. Too often, we underestimate the size of our estate, not realizing the problems this can cause after we have gone. Trusts provide a viable option for ensuring that your heirs do not pay excessive estate taxes upon your death. Different types of trusts are available to meet your needs and the needs of your loved ones.
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Create a "heir" style that works for you
When is a good time to update your estate plan? While it is always good to maintain a current estate plan, significant life events mandate a revision. If you've recently started a business, you may need to update your estate plan. Crucial aspects, such as business succession planning, guarantee that the wealth you've worked so hard to build is passed on to those you love or designate. Additionally, our changing economy can result in loss of a job or early retirement, both invoking the need for a review. Similarly, a spouse that is re-entering the work force or changing from full- to part-time status, necessitates re-evaluating your assets.
Changes in family may dictate a change in your estate plan. If a son or daughter should marry someone you would prefer not to include as an heir, inevitably, you would want to take a second look at your estate planning. You would find it important to avoid the risk that your wealth could end up in the hands of a former son- or daughter-in-law.
Indeed, even if you like your in-laws, other life events can trigger an update to your estate plan. Have you recently moved into Pennsylvania? Or, are you planning a move to another state? If so, it is good advice to learn about the laws of your new locale to make sure that your plans are protected. Even marriages, births, and other happy events in our lives should awaken the notion that our estate plans need to be re-examined.
Perhaps you have a domestic partner who you would wish to one day become your heir. Pennsylvania does not recognize same sex or common law marriages. Thus, in this Commonwealth, a same sex or opposite sex non-related individual inheriting from you will be taxed at a rate of 15 percent. Don't let him or her experience a bad heir day. Trusts and other estate planning, such as beneficiary designations on financial accounts, can play an important role in preserving the assets of your domestic partnership.
Most of us put estate planning on the back burner. It's easier to choose to wait for tomorrow. By contrast, we go to the barber or beauty salon on a regular basis because we defy being caught having a bad hair day! Applying mousse, gel and spray guarantees we will have a good hair day. Similar protection in the form of a good estate plan can be applied so that a bad heir day is likewise avoided.
Have your estate plan updated today, and do wonders for your heir!
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A WOMAN has died following a two vehicle collision on the A48 near Castleton.
South Wales Police arrived at the scene at 6.36am this morning and are currently still in attendance.
The collision involved two vehicles on the A48 between Marshfield Road and B4487 Newport Road/ St Mellons Roundabout.
Emergency services are attending to the collision near to Blooms Garden Centre where a woman who was the driver of one of the vehicles has died.
The road is closed in both directions and will remain closed while police are investigating.