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Publications (429)1971.75 Total impact
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ABSTRACT: Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that modulating its activity might represent a novel strategy for management of neuropathic pain.Journal of Neuroscience 01/2015; 35(3):1125-1135. · 6.75 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Objective. Telaprevir (TVR)-based triple therapy has substantially improved cure rates of hepatitis C virus (HCV) genotype 1 infection but side effects are frequent and often severe. Therefore, response predictors are needed for early identification of patients not responding to TVR-based triple therapy. Material and methods. Forty-five patients (mean age: 54 ± 13 years; male gender: 60%; treatment-experienced: 82%; cirrhosis: 58%) with HCV genotype 1 infection were treated with a TVR-based triple-therapy regimen. TVR plasma levels were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry at weeks 2, 4, 8, and 12 of antiviral therapy. On-treatment HCV RNA response was assessed at weeks 4, 12, and 24 by real-time polymerase chain reaction. Results. An extended rapid virological response (eRVR) and sustained virological response (SVR) was achieved in 21 of 45 patients (47%) and 36 of 45 (80%) patients, respectively. Mean ± standard deviation TVR plasma levels at week 2 were 3.4 ± 0.2 log10 ng/ml and did not differ over time (when assessed at weeks 4, 8, and 12). TVR plasma levels at week 2 were significantly higher in patients who achieved an eRVR compared to those who did not achieve eRVR (3.5 ± 0.1 vs. 3.3 ± 0.2 log10 ng/ml; p = 0.003) but were neither associated with SVR nor with treatment-related anemia. Conclusion. TVR plasma levels are associated with on-treatment response but not with overall treatment efficacy. Given the high overall response rates to TVR-based triple therapy, our data suggest that TVR trough levels may not be a useful predictor of treatment response, and routine drug-level monitoring is not required.Scandinavian Journal of Gastroenterology 11/2014; · 2.33 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Chemotherapy-induced peripheral neuropathic pain (CIPNP)-a severe adverse effect observed in up to 80% of patients during treatment with antineoplastic drugs-limits the tolerable dose of cytostatics, and can lead to discontinuation of chemotherapy. Many drugs that are approved for the treatment of other neuropathic pain states have shown little or no analgesic effect on CIPNP in large randomized, placebo-controlled clinical trials. Here, we review the known mechanisms of CIPNP induced by the three most commonly used cytostatics: paclitaxel, oxaliplatin and vincristine. These substances have distinct neurotoxic and neuroinflammatory properties, but they also have overlapping contributions to pathogenesis of CIPNP that could potentially be targeted for prevention or treatment of CIPNP. We discuss the failure of previously tested antioxidants, neuroprotective agents, anticonvulsants and antidepressants as therapeutic or preventative strategies, and suggest individualized, mechanism-based therapeutic options for CIPNP associated with each of the three main drug groups. We point out the necessity to assess drug efficacy in CIPNP independently of other neuropathic pain states, and emphasize the need for delineation of subpopulations of patients with CIPNP for more-efficient treatment. Finally, we discuss novel therapeutic strategies and recent progress in treatment of CIPNP, and evaluate the potential benefits of these recent proceedings for future therapies.Nature Reviews Neurology 11/2014; · 14.10 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2,-4, -5 and CerS6 promoter and 3'-UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERα/β) and MDA-MB-231 (ERβ) cells after 17β-estradiol treatment. Only the activities of CerS4 and CerS5 promoter Luc constructs, as well as CerS2- and CerS5 -3'UTR Luc constructs increased after estradiol treatment in MCF-7 cells, and this could be inhibited by the anti-estrogen fulvestrant. Co-transfection with the G protein-coupled estrogen receptor 1 (GPER1) also enhanced CerS2, CerS4 and CerS6 promoter activity whereas CerS5 promoter activity was inhibited in both cell lines. Promoter deletion and mutation constructs from CerS4- and CerS5 promoters revealed that estradiol and GPER1 mediate their effects on both promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos. At least we could show, that cell proliferation induced by estradiol could be blocked by co-treatment with Fumonisin B1, indicating that upregulation of CerS in breast cancer cells by estrogen is important for cell proliferation and possibly tumor development. In conclusion, our data highlight transcriptional and posttranscriptional mechanisms regulating CerS expression in human cells which provide the basis for further studies investigating the regulation of CerS expression and ceramide synthesis after diverse stimuli in physiological and pathophysiological processess.Biochemical Pharmacology 10/2014; · 4.65 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Prostanoids, derivatives of arachidonic acid, are involved in inflammation and immune reactions. To understand the role of prostanoids produced by diverse immune cells, a highly sensitive quantitation method for prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), 6-keto prostaglandin F1α (6-keto PGF1α), prostaglandin F2α (PGF2α), and thromboxane B2 (TXB2) by means of nano-liquid chromatography-tandem mass spectrometry has been developed. It was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of linearity, precision, accuracy, recovery, stability, and lower limit of quantitation (LLOQ). The LLOQ were 25 pg/mL in the injected solution (75 fg on column (o.c.)) for PGE2 and PGD2 and 37.5 pg/mL (112.5 fg on column) for 6-keto PGF1α, PGF2α, and TXB2, respectively. It was successfully applied to murine mast cells isolated from paws after zymosan injection and to CD4(+) and CD8(+) T lymphocytes from blood of sensitized versus non-sensitized mice in context of a delayed type hypersensitivity model. About 5,000 (T cells) to 40,000 (mast cells) cells were sufficient for quantitation. In the mast cells, the production of PGE2 increased at a significantly higher extent than the synthesis of the other prostanoids. The T lymphocytes did not show any difference in prostanoid production, no matter whether they were obtained from sensitized mice or non-sensitized mice.Analytical and Bioanalytical Chemistry 09/2014; · 3.66 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Lipoxins belong to the family of so-called pro-resolving endogenous lipid mediators which are derived from arachidonic acid and play a key role in the counter-regulation of inflammation. Arachidonic acid is also precursor of multiple pro-inflammatory lipid mediators, such as prostaglandins and leukotrienes, which are simultaneously present in biological compartments. The close structural relationship between several of these lipid mediators and the absence of blank matrix samples enormously complicates the unequivocal identification of these compounds. The determination of lipoxin A4 has been accomplished by chromatographic separation using a C18 reversed phase column and tandem mass spectrometry detection. Samples were liquid-liquid extracted with ethyl acetate before injection. Identification of the analyte was done based on three criteria: retention time, ratio of the m/z transitions and MS/MS spectrum. To avoid false positive results due to endogenous interferences, the extracted samples were re-injected into a chiral Lux Amylose-2 chromatographic column. The authors recommend the use of chiral chromatography in the determination of pro-resolving lipid mediators, together with transition area ratio and fragmentation spectra to improve selectivity for identification and quantitation purposes.Talanta 09/2014; 127:82–87. · 3.50 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T cells, CTLA4+ inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial.EMBO Molecular Medicine 09/2014; · 7.80 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Ceramides (Cer) are mediators of inflammatory processes. In a chronic experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we observed a significant elevation of C16-Cer and its synthesizing enzyme, ceramide synthase(CerS)6, in the lumbar spinal cord. In the present study, we have confirmed that C16-Cer and CerS6 are also upregulated in the lumbar spinal cord in a spontanous relapse-remitting EAE model, using SJL mice overexpressing a transgenic T cell receptor (TCR1640). CerS6 was found to be expressed in macrophages, T cells and B cells in EAE lesions. In macrophages, we demonstrated that interferon gamma (IFN-γ)-induced CerS6 upregulation was amplified by 17ß-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-α). Accordingly, CerS6 and TNF-α expression was upregulated predominantly in the spinal cord in female TCR1640 mice, which usually develop the relapse-remitting form of EAE, while male TCR1640 mice showed an attenuated regulation of CerS6 and TNF-α and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-α, which is linked to neuroprotection and remyelination, was also upregulated to a greater extent during EAE in female TCR1640 mice in comparison to male TCR1640 mice. Taken together, our results confirm the upregulation of CerS6 and C16-Cer in an adjuvant-independent, physiological EAE model and further suggest an anti-inflammatory role of CerS6 in the regulation of the disease course in female TCR1640 mice via TNF-α/TNFR2.Biochemical Pharmacology 08/2014; · 4.65 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: CYP inhibitors may reduce opioid analgesia by inhibiting CYP activity dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function and side effects in 21 healthy volunteers, prior and during steady-state concentrations of remifentanil at effect site (CNS) of 1.5 ng/ml and 3 ng/ml, administration of 400 mg/d fluconazole for 8 days in a double-blind, placebo-controlled manner, failed to attenuate opioid effects. Although CYP inhibitors like fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because opioid differences, like e.g. ligand-selective biased signaling at opioid receptors, leave the possibility that brain CYP dependent opioid signaling might be limited to morphine but not remifentanil.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 22 August 2014; doi:10.1038/clpt.2014.169.Clinical Pharmacology & Therapeutics 08/2014; · 6.85 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating NADPH oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRGs) in mice. In response to peripheral nerve injury, Nox2-positive macrophages were recruited to DRGs, and ROS production was increased in a Nox2-dependent manner. Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent and ATF3-induction was reduced in DRGs of Nox2-deficient mice suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRGs contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.Pain 08/2014; · 5.64 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Pro-resolving lipid mediators are a class of endogenously synthesized molecules derived from different fatty acids, such as arachidonic, docosahexaenoic or eicosapentaenoic acid, which are derived into four different product families: lipoxins, resolvins, maresins and protectins. For quantitation of these compounds, a sensitive, selective and robust liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of lipoxin A4, 6-epi-lipoxin A4, lipoxin B4 and lipoxin A5, the D-series resolvins D1 and D2 as well as aspirin-triggered lipoxin A4 and resolvin D1, maresin and protectin and the pathway markers 17(S)-hydroxy-docosahexaenoic acid and 17(R)-hydroxy-docosahexaenoic acid in cell culture supernatants. For this purpose, a chiral column was connected in series with a reversed-phase column to achieve efficient analyte separation and high sensitivity. Sample pre-treatment included a fast and simple liquid-liquid extraction procedure. Limits of quantitation in the range of 0.1-0.5ng/mL cell culture media, absolute recoveries between 90 and 115%, intra- and interday precision of less than 13% and an accuracy of less than 11% were obtained. Stability of the samples after 60 days storage at -80°C, three freeze/thaw cycles and 4h at room temperature has been demonstrated for all analytes. Sample extracts can be stored at 7°C for 24h without degradation of the analytes. Deviations of less than 13% in the accuracy, evaluated in terms of relative error, were obtained. The suitability of the method has been demonstrated in cell culture supernatants of human polymorphonuclear leukocytes, stimulated with 15R-hydroxy-eicosatetraenoic acid and in cell culture media of human polymorphonuclear leukocytes co-incubated with human platelets. From all studied analytes, lipoxin A4 and 6-epi-lipoxin A4 were found in cell culture media under both incubation conditions, while 15-epi-lipoxin A4 was additionally detected in cell culture supernatants of polymorphonuclear leukocytes stimulated with 15R-hydroxy-eicosatetraenoic acid.Journal of Chromatography A 07/2014; · 4.26 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Prostaglandins (PGs) act as potent local hormones in nearly all tissues of the human body and are used for various medical applications. Heterologous expression of PG endoperoxide H-synthase from the alga, Gracilaria vermiculophylla, into E. coli and the application of this strain in biotransformation experiments resulted in a highly efficient conversion of arachidonic acid (ARA) yielding up to 130 mg natural PGs l(-1) in a laboratory scale approach. Detailed analyses of the products and production kinetics were performed, confirming a rapid conversion of ARA to PGs.Biotechnology Letters 07/2014; · 1.74 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Accumulating evidence indicates that various subtypes of purinergic receptors (P2X and P2Y receptor families) play an essential role in the development and the maintenance of neuropathic pain. However, there is only limited data available about the role of P2Y6 receptors in pain processing. Here we detected P2Y6 receptor immunoreactivity in primary afferent neurons of mice and observed an upregulation in response to peripheral nerve injury. However, systemic and intrathecal administration of the P2Y6 receptor antagonist MRS2578 failed to affect the injury-induced neuropathic pain behavior. Our results suggest that P2Y6 receptors, in contrast to other purinergic receptor subtypes, are not critically involved in nerve injury-induced neuropathic pain processing in mice.Pharmacology Biochemistry and Behavior 07/2014; · 2.82 Impact Factor -
Article: Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing.
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ABSTRACT: Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive. Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60-7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry. The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60-7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60-7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues. Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.Anesthesiology 04/2014; · 6.17 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity. Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2). Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced. The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.PLoS ONE 04/2014; 9(4):e95592. · 3.53 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain.PLoS ONE 04/2014; 9(4):e93338. · 3.53 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have a therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.Biochemical and Biophysical Research Communications 04/2014; · 2.28 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Background/AimsRecurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virologic response rates in patients after OLT in combination with pegylated-interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT-patients with IS are unknown. Aim of the present study was to analyze telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS.Methods Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1 infected patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily, and pegylated-interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase-chain-reaction.ResultsMedian (range) telaprevir plasma concentrations of TW 4, 8, and 12 were 3970 (1980-4430) ng/mL and 2520 (1870-8730) ng/mL in patients after OLT and ciclosporin or tacrolimus based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (p=0.3). In one patient with tacrolimus based IS, telaprevir dose had to be adjusted to achieve virologic response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8, and 12 in patients with and without IS.Conclusions Telaprevir drug monitoring may be necessary in patients with tacrolimus based IS in patients with HCV graft infection after OLT.This article is protected by copyright. All rights reserved.Liver international: official journal of the International Association for the Study of the Liver 03/2014; · 4.41 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Inflammatory pain is based on stimulation and sensitization of peripheral endings of sensory neurons (nociceptors) by pronociceptive mediators. These mediators can be released by resident cells, as well as invading immune cells. Although neutrophils are known to release various mediators, which can stimulate or sensitize nociceptors, the extent of their contribution to nociceptive responses is unclear. Here, we studied the contribution of neutrophils to zymosan-induced inflammatory pain, which is characterized by an early recruitment of high numbers of neutrophils. Surprisingly, antibody-mediated neutrophil depletion caused a complete loss of edema formation but had no effect on mechanical pain thresholds. Blockage of the interaction between neutrophils and platelets or endothelial cells using antibodies directed against CD11b and CD162 reduced neutrophil recruitment to the site of inflammation. Again, the treatment decreased zymosan-induced edemas without altering mechanical pain thresholds. Also, HLB-219 mice, which have five to 10 times less platelets than WT mice, showed reduced neutrophil recruitment to the site of inflammation and decreased edema sizes, whereas, again, mechanical thresholds were unaltered. The effects observed in HLB-219 mice were relatively small and not reproduced in vWF-deficient mice or after antibody-mediated blockage of GPIbα. Flow chamber and transmigration assays showed that platelets were not necessary for neutrophil adhesion to endothelial cells but increased their transmigration. Taken together, zymosan-induced mechanical allodynia is, in contrast to edema formation, independent of neutrophils, and recruitment of neutrophils is only partly influenced by interactions with platelets.Journal of leukocyte biology 02/2014; · 4.99 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA. We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.Diabetologia 02/2014; · 6.88 Impact Factor
Publication Stats
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Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Aachen, North Rhine-Westphalia, Germany
University Hospital Frankfurt
Frankfurt, Hesse, Germany
Goethe-Universität Frankfurt am Main
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Frankfurt, Hesse, Germany
University Health Network
Toronto, Ontario, Canada
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Toronto, Ontario, Canada -
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Stadt Bad Nauheim, Hesse, Germany
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Stanford University
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Palo Alto, CA, United States
Friedrich-Alexander Universität Erlangen-Nürnberg
- • Department of Ophthalmology
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Erlangen, Bavaria, Germany
Universitätsklinikum Erlangen
Erlangen, Bavaria, Germany
Hadassah Medical Center
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Jerusalem, Jerusalem District, Israel
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Gratz, Styria, Austria -
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Kensington, New South Wales, Australia
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Ruhr-Universität Bochum
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Bochum, North Rhine-Westphalia, Germany
Max Planck Institute for Biophysical Chemistry
Göttingen, Lower Saxony, Germany


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110544, **EXCLUSIVE** LOS ANGELES, CALIFORNIA – Wednesday December 18, 2013. FLEX THOSE MUSCLES! Danica Patrick gets into a muscle suit to film a Go Daddy Super Bowl commercial. The race car driver wore neon green body shorts and a sports bra over her muscle girl suit. Photograph: KVS, © PacificCoastNews.com **FEE MUST BE AGREED PRIOR TO USAGE** **E-TABLET/IPAD & MOBILE PHONE APP PUBLISHING REQUIRES ADDITIONAL FEES** LOS ANGELES OFFICE: 1 310 822 0419 LONDON OFFICE: +44 208 090 4079
Bracket Breakdown: Big 12 Logjam, Two of Last Year's Final Four in Doubt
Florida and UConn need to do plenty of work.
NFL Media Have Collective Laugh at Roger Goodell Claim To Be Available "Almost Every Day"
Less available than Obama.
UConn Guard Laid Out By Cincinnati Big Man's Screen
Boom goes the guard.
Heisman Trophy Odds 2015: Ezekiel Elliott Opens as 6-1 Favorite
Prescott, Fournette and Boykin among other favorites.

subset: commoncrawl


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General Info
If I built a gloryhole...would you cum?
One day at a time.ï I can go from a one-nighter, quickie with a married dude, to a long term loving relationship.ï I won"t hold out for a specific.ï In the meantime, I"m enjoying the vids being posted.ï Some true hot stuff out there!ï The LTR is my dream though.
Turn Ons
Each day brings a new interest.ï I can go from wanting to be with a young dude [why have the 18 year olds suddenly become hotties?], to being with aïDaddy.ï Love the Hispanics [Mexicans---yummy], Blacks, Trash [the mohawk/tat boys...turn me on], Professional, BlueCollar, chubs, muscle chests, you name it.ï Latest interest has been helping out the married dudes getting off.ï Underwear fetish (Iïalways want to keep theïundies when we"re done).ï
Turn Offs
Fakes and Phoneys.ï Also, not into the blood/scat deal.ï I"ll do a watersport but, not too extreme.ï Typically, getting it from the spout.
Porn (DUH!) [Especially the HorniPapi series], comedies, chick flicks (Believe it or not, I"m a true romantic!),Keanu Reeves flicks, suspense [who done it],horror ONLY if I"m in a man"s arms.
Watching Daddy Mugs vids...Seriously, how does this dude get these hot boys to do what they do?
Nearly any and all. I have several iPods with different settings.ï Depends on whether I"m working out, yard work [yeah, I"m the one jamming while mowing the lawn or tending to fix-ups], cycling, sitting on a train, etc.ï
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Thanks for the FR and add and your nice comments on my vid. Your pics are great
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Thanks for the FR and add and your nice comments on my vid. Your pics are great
Thanks for the comment on my vid - glad you enjoyed it man and love making hot guys such as yourself turned on!
Hey my man, thanks so much for the comments,
It warms my balls that you fav'd my pics, thanks
http://www.xtube.com; Sorry this took so long to get to you. I started sending out before Christmas, but my list is long, and my computer is slow. 500 down, about 1,200 to go - should have started in November.
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If nobody else is going to say it, I will.
Mister Amazing's forum posts
Found a double entry for the Marvel character Stranger:
The Stranger: http://www.comicvine.com/the-stranger/35896/
i would imagine the mutants and some of the metahumans would have a greater advantage in this situation, since they have some form of superhuman ability that they could utilize which a regular human couldn't.
Sure, humans have gotten through disasters before, like you said, but since mutants are higher on the power scale than humans, what makes you think they wouldn't survive just as well?
It appears there is an entry for both D-Man and Demolition Dunphy, which is his wrestling name.
D-Man: http://www.comicvine.com/d-man/19960/
Demolition Dunphy: http://www.comicvine.com/demolition-dunphy/14529/


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Looking for movie tickets? Enter your location to see which movie theaters are playing Australian Rules near you.
Paul Goldman's feature film debut Australian Rules is a sports drama that combines a coming-of-age story with an examination of race relations between Australians and Aboriginals, and a sensitive interracial love story. Gary Black (Nathan Phillips) is a 16-year-old who plays on the local Australian rules football team. His best friend is aboriginal Dumby Red (Luke Carroll), the star of the team. After Dumby wins the big game, the racist coach denies him the credit he deserves. This leads to a series of dramatic confrontations capped off by Gary confronting his racist father. Australian Rules was screened at the 2002 Sundance Film Festival. ~ Perry Seibert, Rovi


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Antennas Directâs Clearstream2 Antenna Available for Pre-Order
clearstream2small.JPGJune 13, 2008: ST. LOUIS, Mo. â St. Louis-based antennas maker Antennas Direct announced its new, ultra-efficient, compact, digital TV antenna, ClearStream2, will arrive June 30. Orders are being taken now.
ClearStream2 is Antennas Directâs latest model of digital TV antennas, which are optimized specifically for the 2009 digital conversion.
âThe ClearStream2, which is the first in a series of ClearStream DTV antennas, is unmatched in size and performance,â? said Antennas Direct President Richard Schneider. âDemand for ClearStream2 is high because of its strength, reliability and small form.â?
The first DTV antenna created with the latest simulation software and test equipment, the ClearStream2 is designed to receive digital, over-the-air broadcasts, with a range up to 50 miles. Its wide, 70-degree beam width allows it to capture signal from towers spaced far apart, and its patented, tapered-loop design is 50 percent smaller than previous models.
âThis represents a breakthrough in antenna design. There hasnât been significant change in TV antenna technology for the past 30 years,â? Schneider said. âAlthough television broadcasts have changed — with the introduction of digital programming — antenna design has been stagnant. Antennas Direct was founded to foster research and development of stronger, more-efficient antennas designed specifically for digital television.â?
After the nationwide switch to digital broadcasting in February 2009, millions of Americans who still rely on over the air broadcasts will lose picture unless they purchase either a converter box or a new digital television.
âSince most antennas on the market were created for a different era, people may require an updated antenna once the 2009 digital transition occurs,â? Schneider said. âWe continually educate the public regarding the type of antenna they will need to receive digital television and how to install it.â?
Antennas Direct provides customers with a 90-day, no-fault return guarantee on all Antennas Direct antennas and a lifetime warranty against failure, corrosion, defects in materials or workmanship.
If youâd like more information about this topic, or to schedule an interview with Richard Schneider, please call Scott Kolbe at 636-379-3895 ext 13 or send an e-mail to firstname.lastname@example.com
About Antennas Direct
Antennas Direct is a St. Louis-based manufacturer and distributor of over-the-air antennas. The company was founded by Richard Schneider in 2003 and has since been widely recognized for superior product design and performance by a number of industry publications and main stream media outlets. Having invested major resources into the discovery and implementation of new technological advances in television antenna design, Antennas Direct continually tests and modifies antenna designs, raising the bar by which antenna performance and appearance are measured. For additional information on Antennas Direct, visit
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By Rick Warren — May 21, 2014
If you've gotten anything at all out of following Christ, if his love has made any difference in your life, if being in a community of the Spirit means anything to you ... agree with each other, love each other, be deep-spirited friends. (Philip. 2:1-2, Msg)
God sent Jesus into the world so that our relationship with God could be restored. Christmas is about restoring relationships and many of us have relationships that need mending.
God wants us to value relationships and make every effort to maintain them instead of discarding them whenever there is a rift, a hurt or a conflict.
In fact, the Bible tells us that God has given us the ministry of restoring relationships. For this reason a significant amount of the New Testament is devoted to teaching us how to get along with one another.
The Apostle Paul taught that our ability to get along with others is a mark of spiritual maturity. Since Christ wants his family to be known for our love for each other, broken fellowship is a disgraceful testimony to unbelievers. This is why Paul was so embarrassed that the members of the church in Corinth were splitting into warring factions and even taking each other to court.
He wrote, "Shame on you! Surely there is at least one wise person in your fellowship who can settle a dispute between fellow Christians." (1 Cor. 6:5, TEV) He was shocked that no one in the church was mature enough to resolve the conflict peaceably. In the same letter, he said, "I'll put it as urgently as I can: You must get along with each other." (1 Cor. 1:10, Msg)
If you want God's blessing on your life and you want to be known as a child of God, you must learn to be a peacemaker. Jesus said, "God blesses those who work for peace, for they will be called the children of God." (Matt. 5:9, NLT)
Notice Jesus didn't say, "Blessed are the peace lovers," because everyone loves peace. Neither did he say, "Blessed are the peaceable," who are never disturbed by anything. Jesus said, "Blessed are those who work for peace" - those who actively seek to resolve conflict.
This Christmas is a good time to actively work toward restoring broken relationships.
Would you like to become all that God intended you to be? You can, but not on your own power. In these messages Pastor Rick shows you how to unlock the promises in God's word to TRANSFORM your life in eight key areas...from the inside out. You'll want to add this life changing teaching to your library of Christian teaching. We'll also send you the Transformed Music CD, a sound track for life-change, featuring eight of today's best worship songs and two original worship songs.
If you're like most people - every new year - you've tried to make positive changes and then given up or slidden back into old destructive patterns. Here's the good news, with God's help you can make and maintain positive changes in every area of your life. Let Pastor Rick show you how unlocking the promises in God's word and following his instructions will TRANSFORM your life in seven key areas...from the inside out.
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With February here, we're pleased to announce that Beth Sanders will be presenting WordPress: More Than a Blog. If you have a business, you have a story to tell. The story of your customers' or clients' needs and challenges and how your product or service helps them meet those challenges. WordPress gives you a key to the Internet, so you can tell your story, in your words, on your schedule.
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Reader comments are listed below. Comments are currently closed and new comments are no longer being accepted.
@ [Alpha November 42] wrote: September 3, 2009 21:09
["Melamine milk, anyone?"]??
Although you can never compensate some losses enough, a crime is a crime and bad guys involved in Melamine case (including some city officials, and never mind that it was a 58:42 % joint venture with New Zealand who came out unscathed) were quickly apprehended and put to trial; and justice was done swiftly to the extent of law in this case.
But I don't think you should beat the dead horse of [Melamine milk, anyone?] again and again like something of a hallmark or trademark every time the topic of Chinese business is brought up.
What's unique in what you said ["What is most shocking and seems unique to China, however, are the lengths corporations will go to in order to maximize profits, with total disregard for the lives of their consumers."] is your statement itself, which in fact discribes wanton disregard and betrayal of consumers' interest that's far more ubiquitous than being nation-unique at all.
The bootlegs, the toxic tampons that killed many American young women years ago and the recently exposed Madoff's long running and painstakingly choreography-ed Ponzi scheme (it kills too) for examples are no less insidious or reckless than the Melamine lacing.
What's fair is fair. What's not is not.
"Wealth is the curse." Sure. My land lord uncle was executed family property all grabbed by the CCP and the villagers when the CCP took over the power in 1949-50. Irony is CCP officials and the smart villagers become the rich land lord the newly corrupted rich themselves. Who will execute them? Oh yes, they execute one another. ha ha ha
Isn't there a saying that goes along the lines of "Behind every great fortune there lies a great crime".
So what's new?
Look at ethical Chinese in Hongkong and Singapore, they don't have the same norms as in mainland China. Why? The system matters.
In China, big successful enterprises are extremely 'close' with the government is not a piece of news. Basically everyone knows it. I major in Business in China. But my parents want me to stay away from business in work place because they know how companies relate to the government, and they know competition in the market is hell unfair. What is more unacceptable, however, is the close and opaque relationship between hospitals, educational institutes, courts and the government. This kills people.
My question is:
How many of the global super-rich earned their money or accumulated their fortunes in an honest, scrupulous and honorable way?
It is most regrettable that a good number of Chinese had amassed their wealth in a highly unfair and dishonest manner. But the same can easily be applied to many around the world.
These utterly ugly and greedy people!
The majority of businessmen are honest, that includes most Chinese businessmen. I think most Chinese businessmen earned their money honestly within the Chinese context.. Because bribery is common in China like in most developing country, most businessmen have to pay something to get things done. The relationship between the government official is temporary. I think the vast majority of businessmen don't depend on the government or government officials to survive.
I think the melamine milk, lead in toys are exceptional cases that people hype up to scare people. I don't blame Western journalist, they are objective compared to some of the Chinese press outside China like in Taiwan or Hong Kong. If you read the stories coming out of Hong Kong you would think the majority of mainland Chinese are ingesting poison on a daily basis. The Western press only covers the tip of the iceberg when it comes to health issues compared to the Hong Kong and Taiwanese press.
The so-called "original sin" tied to wealth of entrepreneurs in China were primarily driven by the government and the malformed economic systems. In other words, no one can become a successful entrepreneur in China without breaking the past and ongoing regulations / policies. You will find the only way to run a profitable business in China is to circumvent or even violate those outrageous regulations imposed by the government. One born in U.S. cannot imagine how a Chinese businessman can survive such a heavily-governmental-controlled market, with private companies given little access to bank credit while state-owned firms monopolizing all valuable resources.
Given such circumstances, are the Chinese entrepreneurs really evil? if yes, are they evil innately or forcedly?
In a wooden board of standing nails, the only tallest nail has to be Beijing. In Chinese history any individual or movement that went above 'ordinary height' got nailed down 'flat'.
In this story, the concluding sentence is crucial. The entrepreuners are not the only ones who 'played dirty'. The government officials also 'played dirty', also got rich.
I bet the remaining 98% of China's tycoons are paying off government officials, to 'simply stay where they are'.
That is where the difference is with other democratic countries with better rule of law.
'Watching China' is right about the unethical practices of many Western enterprises but their relationship with government officials in their countries is different. More over, the facts s/he cites are all from media exposes and court cases. Thalidamide, for example, was brought to book through investigative reporting and government officials pressing the company for facts as to what scientific results were recorded by the company before deciding to market it to the public.
China's story is different.
My view on the key issues here are two folds: (1) during the past 30 years the Chinese society evolves too fast (avg 8% to 10% growth?), the law and regulatory environment can not keep up. Therefore, all laws tend to be "broad stoke", leaving the details intepreted by officials, which is the root of unfair power and corruption. (pls note that there is only tradeoff here, no solution) (2) in the earlier years of opening-up (80s and 90s), officials using this power to help relatives and friends (as they intepret the law) which is the source of the so said "original sin".
However, getting into 21st century, we see more and more professionals and entrepeneurs getting rich, and I expect 10 years from now, there will be a lot less discussions on "original sin".
@ bidor wrote:September 5, 2009 2:39
U said: ["Many evidences suggest that the central government knew the problem in July 2008 but they suppressed the news until Olympic is over.]???
That's rather irresponsible and loose way of salvo-ing heavy charges of allegation, unless being substantiated by convincing evidence thereof which went missing in your posting.
I do not know why people keep questioning on other rich men's sin around the world. Their commitment to crimes does not make Chinese corrupt entrepreneurs any more justifiable by any means.
About the food poisoning scandals, the first to notice these things in China were the Chinese press in Hong Kong and Taiwan. They have been talking about dangerous mainland products and food ad nauseum ever since China started reforming their economy. Alot of it is like the stuff you would find in the National Enquirier. Western journalist have only picked up the big stories and only in the past 3-4 years. Much of it they got first from the Hong Kong press.
Tribute to Hong Kong's ICAC.
They really are learning how to become American! Maybe some of our unemployed can go over there and dynamite passageways for their new high speed rail systems.
The truth that explains everything:
"Everyone (or country) seeks their own benefits and justify what they do"
I won't be surprised if Economist decide to publish my comment if I claim to be Huang Guangyu, former chairman of Gome and say that the CCP government framed me with fictitious allegations because it wants to swallow my billions of assets. I can even claim to be chained up like a dog and sexually abused by female GIs...ops I mean cadres.
How good or bad our government is? Who knows?
1.If goverment will somewhat take your wealth in the end, any individual desires to be rich?
2.Making social connections without breaking the law is the same rule for a thriving business all over the world.
In graphics: Explaining Thailand's volatile politics
Graphic detail
The view from Buenos Aires: Justice in the dock
The Americas
Johnson: Accents: The last acceptable prejudice
Ebola in graphics: The toll of a tragedy
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Catholic education in Northern Ireland: Faith of their fathers
Air safety: A crash course in probability
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As credit spreads have tightened on a nearly continuous trend over the past year, they are becoming richly valued relative to their historical average.
Corporate credit spreads are fairly valued--albeit at the tight end of the range that we view as fairly valued.
The corporate bond market will probably struggle to return much above break-even in 2014.
Widening investment-grade credit spreads and rising interest rates lead to losses.
Rising interest rates have taken their toll, but as the Fed delays dialing back on stimulus, investors are poised to recapture some of their losses.
Get our sector-by-sector take on the bond market, plus our five best bond ideas.
Each specialty retail segment is not like the others; our analysts have scoured the industry's credit offerings to find the best deals.
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An idea so contrarian that few ETFs exist to capitalize on it.
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Native Plants
Q. Who is Mr. Smarty Plants?
A: There are those who suspect Wildflower Center volunteers are the culpable and capable culprits. Yet, others think staff members play some, albeit small, role. You can torture us with your plant questions, but we will never reveal the Green Guru's secret identity.
Did you know you can access the Native Plant Information Network with your web-enabled smartphone?
Ask Mr. Smarty Plants is a free service provided by the staff and volunteers at the Lady Bird Johnson Wildflower Center.
Need help with plant identification, visit the plant identification page.
rate this answer
Friday - March 19, 2010
From: North Myrtle Beach, SC
Region: Southeast
Topic: Shrubs
Title: Shrubs for North Myrtle Beach, South Carolina
Answered by: Janice Kvale
What shrubs can I plant on the west-facing side of my home? The way the house sits, these shrubs will only get 2-3 hours of sun, but those 2-3 hours are end-of-the-day hot! Thanks!!ANSWER:
There are so many options for you to choose from, you may want to do some research on your own in our Plant Database. Here is how you do that: Go to our Plant Database Combination Search. Enter your location (South Carolina), enter shrub, and perennial. Then indicate the amount of sunlight your site receives daily (part shade which is 2-6 hours daily sun) and the moisture content of the soil (dry). You may indicate if you want flowering shrubs. This previous answer may apply to your situation or this one. Be sure to check out the details of the shrubs that interest you, such as the soil specifications, disease resistance, anticipated size of the shrub, and birds or butterflies the shrub may attract. Do that by clicking on the name of the plant in any of our lists. The North Carolina Native Plant Society also has a list of native plants for North and South Carolina that may meet your specifications. The suggestions below are just a sample of the shrubs you may consider.
After you have made your selection(s), find suppliers in your area from our list. Thank you for letting Mr. Smarty Plants do a bit of research for you. The research part is fun, so enjoy! The hard work comes later.
Castanea pumila (chinkapin) may grow to 30 feet tall, but any of these should prune to a desired height.
Ilex vomitoria (yaupon) 12 to 45 feet tall, popular densely growing landscape plant
Diervilla sessilifolia (southern bush honeysuckle) 3 to 5 feet tall. Thrives in hot, sunny places.
Physocarpus opulifolius (common ninebark) 3 to 10 feet tall. Looks a bit like spirea.
More Shrubs Questions
Evergreen, flowering hedge shrub for GA.
February 12, 2009 - Hi, there! I am looking for a shrub for planting as a hedge in Decatur, GA. I have hard acidic clay and I would like an evergreen flowering shrub to line the edges of my backyard to separate it from...
view the full question and answer
Trimming of Pineapple Sage and Salvia Greggii
October 07, 2007 - I live in Central Austin. My question is: When is the
best time to trim back Pineapple Sage and Salvia Gregii? How far back should these plants be trimmed?
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Plants for a sandy slope at a weekend cabin in central WI.
June 30, 2009 - I have a cabin in central Wisconsin where the soil is equivalent to a sandy beach. There are some areas that are nearly impossible to mow because of how steep the incline is. Could you recommend som...
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Evergreen hedge for constant rain
June 24, 2008 - We live in Washington State up north by Canadian border. We need a hedge that will survive the constant rain. We have tried cedar. They seem to turn brown and die,one at a time so we keep replacing th...
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Problems with non-native Cleyera and Red-tip photinia
June 01, 2008 - I planted a row of Cleyera in a bed that receives sunlight for about 3 hours during the middle of the day. My problem is that a number of the plants are dying. It begins with the leaves on one small...
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Support the Wildflower Center by Donating Online or Becoming a Member today. Mr. Smarty Plants wants you to be his Facebook friend. Click the Facebook icon to add yourself to Mr. Smarty Plants list of friends. |


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Announcing the winners of the DBJ's Best Real Estate Deals
- Steven R. Thompson
- Associate Editor- Dallas Business Journal
- Email | Twitter | Google+ | LinkedIn
The winners of our annual Best Real Estate Deals awards were honored at the Hilton Anatole Thursday night.
Real estate professionals, economic development agency workers and company representatives gathered to celebrated some of the biggest and most complex and impactful deals in North Texas in 2012.
Below are the winners, as well as in the slideshow above. Click here to see the finalists.
Deal of the Year
The combined State Farm transactions
Commercial Property Deal
Encana Regional Headquarters
Community Impact Deal (tie)
Klyde Warren Park
Perot Museum of Nature and Science
Green Deal
Panda Power Funds - Sherman Power Plant
HQ/Campus Deal
Christus Health
Industrial Deal
Quaker Sales & Distribution Build to Suit
Land Deal
KDC Richardson Project
Lease Renewal
Neiman Marcus downtown Dallas
Medical Deal
Baylor Medical Center at McKinney
Mixed-use Deal
3700M West Village
Most Creative Financing Deal
NYLO South Side
Rehab/Reuse Deal
Digital Dallas Campus
Retail/Restaurant Deal
Trinity Groves
Single-family/planned community
Light Farms Celina
Suburban Multifamily
Britain Way Apartments
Suburban Office Deal
State Farm - 190/Plano Road in Richardson
Urban Office Deal
Reel FX - Deep Ellum Headquarters
Urban Multifamily
The Alexan
Steve produces the Dallas Business Journal's special publications.
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CALL Available 7 days and evenings Yorkie CharacteristicsSize Grooming Requirements Friendly with Other Pets Exercise Requirements Watchdog Ability My family and I are so excited to have our Bailey (formally known as Heath) home with us. He is the cutest puppy ever and we couldn't be Karen Daisy is now 1 year almost 2 months and no more than 3 pounds. She has taken over our home, hearts, bed and checkbook. She is the best thing we ever bought and better than we ever imagined. She ... Dawn I wanted to let everyone at Purebred Breeders know how happy we are with (Alisha) her new name is Lil' Miss Dexi Reigh, Dexi for short. She is adapting quite well to her new home and she already ... Terri |


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IMAX Theatre To Open In Time For Superman Returns: An IMAX 3D Experience
Toronto, Canada – May 10, 2006 – IMAX Corporation (NASDAQ: IMAX; TSX: IMX) and O'Neil Theatres, an exhibitor based in Slidell, Louisiana, today announced an agreement to open an IMAX® theatre in a multiplex located in Covington, Louisiana. The new IMAX location will open in June, in time for the release of the highly anticipated Superman Returns : An IMAX 3D Experience, the world's first live-action Hollywood feature to include segments converted from 2D to IMAX ® 3D.
The deal marks the Company's fourth commercial theatre agreement in North America for 2006, for a total of seven theatres, which exemplifies the growing interest in the IMAX theatre business from North American exhibitors looking to differentiate multiplexes by offering a unique experience that consumers cannot replicate at home.
"As residents of New Orleans continue to recover from Katrina, we are excited to include an IMAX theatre in a building that has been successfully remodelled following the hurricane," said Tim O'Neil, President of O'Neil Theatres. "The new IMAX theatre will offer North Shore audiences a whole new way to experience Hollywood movies – in the most powerful and immersive way available to consumers anywhere throughout the world. "This announcement further demonstrates the traction IMAX is gaining in North America , as more exhibitors seek ways to differentiate themselves from competitors and keep audiences returning to multiplexes." said IMAX co-Chairmen and co-CEOs Richard L. Gelfond and Bradley J. Wechsler. "We are pleased to partner with O'Neil Theatres, an exhibitor committed to delivering the best out-of-home movie going experience to residents of Louisiana ."
O'Neil's IMAX theatre will feature an IMAX MPX® system. The IMAX MPX theatre system was designed specifically to enable multiplex operators to more cost effectively enter into the IMAX theatre business, either by retrofitting an existing stadium-seating auditorium or via an economical new build. The new IMAX theatres will be capable of playing Hollywood event films that have been digitally re-mastered into the unparalleled image and sound quality of The IMAX Experience ® , as well as original IMAX productions in 2D and IMAX ® 3D. IMAX's 2006 film slate is stronger than any other in its 35-year history.
Currently, there are six Hollywood event titles scheduled to be released simultaneously to IMAX and conventional theatres. Four of the titles will feature IMAX 3D. The slate includes: Poseidon : The IMAX Experience (May 12), Superman Returns : An IMAX 3D Experience (June 30), The Ant Bully : An IMAX 3D Experience (August 4), Open Season : An IMAX 3D Experience (September 29), and Happy Feet : An IMAX 3D Experience (November 17). Currently playing in IMAX theatres is Warner Bros. Pictures' V for Vendetta : The IMAX Experience and the studio's second original IMAX 3D film Deep Sea 3D.
About O'Neil Theatres
O'Neil Theaters, established in 1968, opened its first theater in Slidell , LA and presently operates theaters in four southern states. Its objective is to bring to the public the ultimate in motion picture entertainment. By partnering with IMAX Corporation, O'Neil Theatres delivers the complete venue to accomplish this objective.
About IMAX Corporation
Founded in 1967, IMAX Corporation is one of the world's leading entertainment technology companies and the newest distribution window for Hollywood films. IMAX delivers the world's best cinematic presentations using proprietary IMAX, IMAX 3D, and IMAX DMR ® technology. IMAX DMR (Digital Re-mastering) makes it possible for virtually any 35mm film to be transformed into the unparalleled image and sound quality of The IMAX Experience. The IMAX brand is recognized throughout the world for extraordinary and immersive entertainment experiences. As of March 31, 2006, there were 266 IMAX theatres operating in 36 countries. This press release contains forward looking statements that are based on management assumptions and existing information and involve certain risks and uncertainties which could cause actual results to differ materially from future results expressed or implied by such forward looking statements. Important factors that could affect these statements include the timing of theatre system deliveries, the mix of theatre systems shipped, the timing of the recognition of revenues and expenses on film production and distribution agreements, the performance of films, the viability of new businesses and products, and fluctuations in foreign currency and in the large format and general commercial exhibition market. These factors and other risks and uncertainties are discussed in the Company's Annual Report on Form 10-K for the year ended December 31, 2005.
Source: IMAX Corp. Press Release
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WWE and ECW legend Paul Heyman: The Malcolm McLaren of professional wrestling
How the former ECW man - a man full complexity and contradictions - has kept up with the times
London, England, 1975. A former art student turned clothes shop owner named Malcolm McLaren saw the future. His aptly named Kings Road boutique 'Sex', which he ran with fashion designer Vivienne Westwood was attracting interest from all over the world. The clothing they sold was a shock to most onlookers, with their fetish and bondage wear a world away from the flares and feather cuts that most of the capital city rocked.
His concept was simple.
"There are two rules I've always tried to live by: turn left, if you're supposed to turn right; go through any door that you're not supposed to enter. It's the only way to fight your way through to any kind of authentic feeling in a world beset by fakery."
McLaren's shop was a haven to waifs and strays who travelled from far and wide just to be seen as something different. Realising that a counterculture was waiting for a change, McLaren found that the best way to get across his message was via music.
In an attempt to break up the monopoly of prog rock and awkward dancing on Top Of The Pops, he formed the Sex Pistols, who within three years had inspired punk culture, changed the mind-set of a nation, released a number one album, and then imploded in spectacular fashion.
Malcolm McLaren knew that punk was more than just a musical movement; it was an inclination to be adhered to at all times. For every chime of Anarchy In The UK, for every New Rose or London Calling, there was thousands of people who were inspired to change their lives as a result of the ethos.
"I always said punk was an attitude. It was never about having a Mohican haircut or wearing a ripped T-shirt. It was all about destruction, and the creative potential within that."
Philadelphia, America, 1993. A former wrestling photographer and manager named Paul Heyman saw the future. He had just taken over a fledgling wrestling promotion called Eastern Championship Wrestling, and was looking to make a change.
Heyman had big ideas for the wrestling business, having recently left another company named World Championship Wrestling, which was struggling to come to terms with the new decade.
In 2005 the WWE released a DVD entitled The Rise And Fall OF ECW. Early on in the documentary, Heyman remarked on how he set out on his plans for greatness. Just like McLaren, he saw how culture transformed through music, and how every generation needed to evolve to avoid becoming stagnant.
"I thought that the business, the industry, the presentation needed to change in the same way music had changed. Because music was all about Poison and Mötley Crüe and Winger and all these hair bands, and then along came Nirvana and *BAM*! The whole industry changed. So in the same way, I thought wrestling needed to change, in that wrestling had become the equivalent of hair bands, and we needed wrestling's version of Nirvana to come along and just shake everything up."
Soon, Heyman, and his company which was renamed Extreme Championship Wrestling (ECW) became a haven for both fans of wrestling, and the wrestlers themselves. Heyman realised that wrestling had become drab and boring, and became an almost evangelical figure, who inspired devotion - and derision by his supporters and detractors.
Within a few years, his company rose from a tiny regional promotion, to one with network television, regular Pay-Per-Views, and an exciting, diverse roster of talent that was regularly poached by other companies.
A dynamo on the mic, Paul Heyman laughs in the face of adversity
As punk had transformed from dozens in the 100 Club to an ideal of living, the ECW brand at one point transcended pure wrestling, and became a higher entity.
"I was on 57th Ave. in New York City and there was a three-car pileup and a bunch of people looked at the car wreck and started chanting 'ECW'. It's become part of the country's lexicon. It's an accepted, acknowledged phrase" commented Heyman.
Just like punk though, the good times couldn't last forever, and 2001 saw ECW go out of business. The money had run out, and the organisation ceased to exist, despite a still rabid fan base. Within weeks, many of their talent signed to the then World Wrestling Federation, including, to the surprise of many, Paul Heyman himself.
Many wouldn't have taken that leap into the world of WWF, especially when they had been a direct competitor mere months before. But Heyman believed in himself, and refused to accept that his day was done.
Over the last 13 years Heyman has been in a key ingredient in the success of the now World Wrestling Entertainment (WWE).
He has been a commentator, a manager, a writer, and has even competed in the ring as a wrestler for the company.
Many WWE stars have benefited from his tutelage, including Brock Lesnar who, with Heyman by his side, was the man chosen to end the WrestleMania streak of The Undertaker.
Brock Lesnar - a man who has benefited from Paul Heyman's tutelage
Despite a near six year gap from WWE in the middle of the 2000s, Heyman has managed to remain one of the greatest interviews in wrestling, and in 2005 he helped bring back his old company ECW for a glorious one night stand, which eventually became a (watered down) television show again for a couple of years.
Away from the ring, Heyman has maintained a close relationship with the aforementioned Brock Lesnar, and wrote Lesnar's 2011 autobiography. He has created the highly successful Heyman Hustle website, plus an advertising agency which has created content for WWE and UFC, among others.
A 2011 song called Wrestler by British dance band Does It Offend You, Yeah? sampled a Heyman speech from seminal wrestling documentary Beyond The Mat.
That same year, former WWE star CM Punk, in a passionate interview declared himself to be a 'Paul Heyman guy', a phrase which has become a genuine phenomenon, and even a t-shirt.
After more than 30 years in the wrestling business, WWE are releasing a feature length documentary on Heyman entitled 'Ladies and Gentleman, my name is Paul Heyman', on August 5th.
The boy who was running a celebrity and sporting memorabilia mail order service at 11-years-old, is now the subject of praise from many corners of the entertainment business.
How has Heyman managed to remain both contemporary and reassuringly vintage in this frequently fast moving world? Just like punk evolved into post-punk, to new wave, to hardcore and to pop-punk, Heyman has reinvented himself as a brand, from generic wrestling manager, to a sporting savant whose opinion is coveted by everybody from MMA fighters like Chael Sonnen to aspiring lingerie models.
Despite Malcolm McLaren's relative lack of mainstream success after Johnny Rotten uttered the immortal 'ever get the feeling you've been cheated' line after the last Sex Pistols concept, he never stopped trying to believe in change.
"I was taught that to create anything you had to believe in failure, simply because you had to be prepared to go through an idea without any fear. Failure, you learned, as I did in art school, to be a wonderful thing. It allowed you to get up in the morning and take the pillow off your head."
Over twenty five years later, Paul Heyman closed The Rise And Fall Of ECW DVD with a similarly philosophical statement.
"You cannot achieve success without the risk of failure. And I learned a long time ago, you cannot achieve success if you fear failure. If you're not afraid to fail, man you have a chance to succeed but you're never gonna get there unless you risk it all the way. I was a failure. Sometimes half the fun is failing, learning from your mistakes, waking up the next morning and saying, okay watch out, here I come again. A little bit smarter, licking my wounds and really not looking forward to getting my ass kicked the way I just did yesterday. And now I'm just a little more dangerous."
A 90 minute documentary will never truly encapsulate the complexity and contradictions of a man like Paul Heyman, but if you're a fan of the triumph of the human spirit, of facing adversity in the face and laughing maniacally at its distorted appearance, treat yourself to a couple of hours of insight into one of the greatest minds any creative industry has ever seen.
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When you think about buying Japan Rail Pass, you may compare the price of Japan Rail Pass and a single fare. But it is very hard to get an exact fare because the fare rule of Japan Railway is so complicated. So I will give you some examples and consider which way has greater value.
Narita airport to Kyoto for round trip
Base Fare: 18060yen
Surcharge: 3220yen (Narita Airport-Tokyo), 10480yen (Tokyo-Kyoto)
Total Cost: 31760yen
As long as you travel within 7 days, Ordinary 7 days pass (28300yen) is cheaper than a regular fare.
Narita airport to Sendai for round trip
Base Fare: 13660yen
Surcharge: 3220yen (Narita Airport-Tokyo), 9620yen (Tokyo-Sendai)
Total Cost: 26500yen
Ordinary 7 days pass (28300yen) is more expensive, but I go for the pass. Because the pass can be used during staying in Tokyo and Sendai. And also there are some popular sightseeing spots, such as Matsushima or Yamadera, around Sendai. You can use your pass to travel to these spots.
Narita airport to Hakata (Fukuoka) for round trip
Base Fare: 25320yen
Surcharge: 3220yen (Narita Airport-Tokyo), 16560yen (Tokyo-Hakata)
Total Cost: 45100yen
It is exactly same price as Ordinary 14 days pass. If your trip is in 7 days, of course 7 days pass is a great deal!
Even if you travel more than 8 days, the pass is much easier to handle. And also you may have an extra trip.
Anyway if you go to Kyushu island, the pass recover your cost easily.
Narita airport to Sapporo for round trip
Base Fare: 25880yen
Surcharge: 3220yen (Narita Airport-Tokyo), 12000yen (Tokyo-Hachinohe), 2400yen (Hachinohe-Hakodate), 3030yen (Hakodate-Sapporo)
Total Cost: 46530yen
Ordinary 14 days pass is much better choice obviously. If you have an itinerary that includes Hokkaido island, choose the pass.
Fare standard of major sections
I show you some base fares. Please use these fares to compare to the price of Japan Rail Pass. But this is just standard fare. If you have Multi-city travel, the fare may be cheaper. These following fares are based on Shinkansen and daytime limited express trains. (As of April 2012)
station | Tokyo | Osaka | Nagoya |
Sapporo | 23270 | 32400 | 30180 |
Aomori | 16870 | 26110 | 26250 |
Akita | 16810 | 26250 | 24030 |
Sendai | 10390 | 21390 | 19170 |
Yamagata | 11030 | 21830 | 19930 |
Niigata | 10720 | 21390 | 19170 |
Nagoya | 10580 | 6180 | - |
Takayama | 13300 | 10310 | 5870 |
Kanazawa | 12710 | 7440 | 8280 |
Osaka | 13750 | - | 6180 |
Hiroshima | 18050 | 9950 | 13430 |
Fukuoka (Hakata) | 21720 | 14590 | 17530 |
Kumamoto | 24750 | 18320 | 20450 |
Kagoshima | 28030 | 21600 | 23730 |
station | Hakodate | Kushiro | Abashiri | Asahikawa |
Sapporo | 8590 | 9120 | 9640 | 4520 |
station | Nagasaki | Yufuin | Beppu/Oita | Kumamoto | Miyazaki | Kagoshima-Chuo |
Fukuoka | 4580 | 4430 | 5420 | 4990 | 9140 | 10170 |
Tokyo station
Haneda airport
Tokyo Disney Resort
Furano, Biei
Abashiri, Shiretoko
Kawaguchiko (Fuji)
(Kyoto station
Gion, Higashiyama
(JR Osaka, Umeda
Namba, Shinsaibashi
Kansai airport
Kobe, Arima
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82 Comments to "Compare Japan Rail Pass and regular fare. Which one has a greater value or cheap?"
Hi, I intend to move around Kyushu for 15 days but Kyushu pass only comes in 3 Days and 5 Days.
Can a 14 JR pass be used in Kyushu? -
Hi Takeshi,
I plan to travel to Japan in the coming December. Below is my itinerary
Day 1 – arrived Kansai – Osaka
Day 2 – Osaka
Day 3 – Osaka
Day 4 – Kyoto
Day 5 – Kyoto
Day 6 – Takayama
Day 7 – Takayama
Day 8 – Tokyo
Day 9 – Tokyo
Day 10 – Hakone
Day 11 – Hakone
Day 12 – Tokyo
Day 13 – Tokyo
Day 14 – Tokyo- Narita AirportI plan to buy 7 days JR Pass to use from day 6 to day 12. Is this worthy to do so?
You seem very knowledgeable on the difference between the JR rail pass and the single tickets. Unfortunately I have missed the opportunity to receive the jr rail pass in time before my departure. Could you please describe the expected cost of my trip taking public transportation:
1) 10/3/2014: NRT to Shibuya
2) 10/5/2014: Shibuya to Mt. Fuji
3) 10/5/2014: Mt. Fuji to Kyoto
4) 10/6/14: Kyoto to Hiroshima
5) 10/6/14: Hiroshima to TokyoThank you very much.
Hello Takeshi,
Thank you for all the informative posts! I read through most of the reviews but is still confused if I should get a JR pass. Did a rough calculations using HyperDia for this coming Christmas/New Year period and it doesn't seem like a big saving. Would love to hear your kind opinion on my itinerary below.
Day 1: Arriving Kansai (Osaka) airport at 6:00 am. Stay a night at Umeda area
Day 2: Kyoto and stay a night
Day 3: Nagano/Yudanaka to see snow monkeys
Day 4: Hakuba
Day 5: Hakuba
Day 6: Hakuba
Day 7: Tokyo (Ueno area)
Day 8: Depart from Narita airportThank you!
Dear Mr. Takeshi,
I am travelling to Kobe on the 14th of October, but most of my travelling will be during the week, starting on the 18th as follows-
18- travelling to Kyoto from Kobe
21- travelling back to kobe from Kyoto
23- travelling from Kobe to Hiroshima and back again to Kobe (round trip)
24- travelling from Kobe to Tokyo (one way)My question is whether you would recommend that I purchase the JR rail pass for 7 nights (ordinary) or whether I should purchase each ticket separately. I admit that I am confused by all the information,
Many thanks,
Hi Mr Takeshi,
I am planning to travel to Japan from 20 – 28 Dec. My itinerary as follow:
Day 1: Arrive in Tokyo Narita
Day 2: Nagano – Asama 513
Day 3: Matsumoto – Ltd Exp (Wide View) Shinano 8
Day 4-5: Takayama (Shirakawago and Takayama Old town) Matsumto – Takayama Express Bus
Day 6: Tokyo
Day 7-8: Mt Nokogiriyama (JR Uchibo Line)My main aim is Takayama but I thought Matusomoto is along the way so we are thinking of heading there as a base to Takayama. I am thinking of taking JR Pass for 7 days. Do you think it is appropriate and is Matusomoto a good base for exploring Takayama? Thanks
Leave a Reply
I always welcome your comment. But before you leave a comment, please remember these following:
- This is not an official website. This website, JPRail.com is a private website. I don't sell any tickets or passes.
- I am not a travel agent. Please do not ask me to make an itinerary. I can check your itinerary and give you suggestion. I think making an itinerary is a part of your travel. Please try to make it by yourself. Enjoy! :)
- If you need access information to your hotel, please don't ask me but ask your hotel.
- If you are looking for the information about timetable, please refer Japan Railway's timetables.
- If you are looking for the information about the fare, please refer Fare Calculation.
- If you are looking for the information about reservation, please refer, How to reserve seat.
- If you want to post, please comment to relate to the post. I will delete any unrelative comment to the post without notice.
If you still have a question, of course I can answer your question.
Please don't ask a question about other than train travel. :)
*If you are the first time vistor, your comment will not be shown before I approve.