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FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD4+ T cells (TEM cells; CD45RBlowCD44highCD62L−) into severe combined immunodeficiency (SCID) mice and suppresses interferon-γ, interleukin-2, and tumor necrosis factor-α production by LP CD4+ T cells. The numbers of spleen, peripheral blood, mesenteric lymph node, and LP CD4+ T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD4+ TEM cells as well as splenic CD4+CD45RBhigh T cells expressed several spingosine-1-phosphate receptors that are targets for FTY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD4+CD45RBhigh T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases.
- therapy
- migration
- I cell
2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride (FTY720) is a chemical derivative of myriocin (thermozymocidin), a substance found in the fungi Myriococcum albomyces and Isaria sinclairii (1, 2, 5, 6). FTY720 is a potent immunomodulator that has been shown to prevent graft rejection in various animal allotransplantation models (23, 24), autoimmune disease animal models (11, 16, 20), and viral infection animal models (17, 21). Good synergy with cyclosporine and sirolimus has been reported (3, 28, 30). FTY720 elicits a lymphopenia resulting from a reversible redistribution of naïve lymphocytes from the circulation to secondary lymph nodes (4) without evoking a generalized immunosuppression (31). Another study (21) has suggested that low blood lymphocyte counts may reflect reduction in the emigration of effector cells to the periphery.
After naïve lymphocytes enter a secondary lymphoid organ from the blood, they travel to separate subcompartments, where they survey for antigen. In the absence of an antigen encounter, cells leave the organ via the efferent lymphatics or, in the case of the spleen, via the red pulp. Timely egress ensures that the cells travel rapidly to further lymphoid organs to continue their antigen surveillance process. Recent studies (1, 4, 22) have demonstrated that FTY720 blocks the egress of lymphocyte from the lymph nodes, Peyer's patches, and thymus. In vivo, FTY720 is immediately phosphorylated, and in vitro analysis has established that FTY720-phosphate is an agonist for sphingosine-1-phosphate (S1P) receptors (S1P1–S1P5 except for S1P4) (2, 5, 13). The S1P1 ligand, S1P, is present at high concentrations (100–300 nM) within blood and body fluids (26). It has been suggested that the egress-blocking activity of FTY720 can be explained by its S1P1 downmodulating activity in lymphocytes (8, 15).
In inflammatory bowel diseases (IBDs), it is believed that memory T cells are intermittently reactivated in secondary lymphoid organs and thereafter return to inflammatory tissues, such as, in this case, the gut (22). These memory T cells can survive for a long period, and they provide the basis for long-term immunological memory. However, it is little known how memory T cells are controlled by FTY720 in IBDs. In this study, we evaluated the effect of FTY720 using our recently established CD4+CD44highCD62L− effector memory T cell (TEM cell)-mediated chronic colitis model.
Female BALB/c and CB-17 severe combined immunodeficiency (SCID) mice were purchased from Japan Clear (Tokyo, Japan). Mice were maintained under specific pathogen-free conditions in the Animal Care Facility of Tokyo Medical and Dental University. The Institutional Committee on Animal Research of Tokyo Medical and Dental University approved the experiments.
The following monoclonal antibodies were used for the purification of cell populations and flow cytometric analysis: RM4-5, CyChrome- or phycoerythrin (PE)-conjugated anti-mouse CD4 (BD PharMingen; San Diego, CA); 16A, FITC-conjugated anti-mouse CD45RB (BD PharMingen); IM7, PE-conjugated anti-mouse CD44; and MEL-14, PE- or FITC-conjugated anti-mouse CD62L.
T cell reconstitution and FTY720 treatment.
FTY720 (Novartis Pharma; Basel, Switzerland) was dissolved in sterile distilled water (DW). For in vivo treatment, FTY720 was administered via per os gavage. To exclude the possibility that in vivo FTY720 treatment might be cytotoxic for CD4+ T cells, we treated normal BALB/c mice with a single dose of FTY720 (0, 0.3, and 3.0 mg/kg). Seventy-two hours after the treatment, dead and apoptotic cells were detected by annexin V-FITC/propidium iodide (PI) staining (MBL; Nagoya, Japan). As shown in Fig. 1, there were no significant differences in the numbers of dead (PI+ and annexin V+) or apoptotic (PI− and annexin V+) cells between mice treated with each dose. Thus we adopted the 0.3 mg/kg dose of FTY720 in a line of in vivo experiments.
Colitis was induced in CB-17 SCID mice by the adoptive transfer of syngeneic CD4+CD45RBhigh T cells as described previously (10). Briefly, CD4+ T cells were isolated from splenocytes from normal BALB/c mice using the anti-CD4 (L3T4) MACS magnetic separation system (Miltenyi Biotec; Auburn, CA). Enriched CD4+ T cells were labeled with PE-conjugated anti-mouse CD4 monoclonal antibodies and FITC-conjugated anti-CD45RB monoclonal antibodies and the isolated CD45RBhigh (highest staining: 30%) fraction on a FACS Vantage (Becton-Dickinson; Sunnyvale, CA). Each SCID mouse was injected intraperitoneally with syngeneic 3 × 105 CD4+CD45RBhigh T cells. Colitic mice were killed at 5–7 wk after the transfer to isolate the colitogenic lamina propria (LP) memory CD4+ T cells (10). The entire length of the colon was opened longitudinally, washed with PBS, and cut into small pieces. The dissected mucosa was incubated with Ca2+-and Mg2+-free HBSS containing 1 mM DTT (Sigma) for 30 min to remove mucus and then treated with 1 mg/ml collagenase (Worthington Biomedical; Freehold, NJ) and 0.01% DNase (Worthington) for 2 h. Cells were pelleted two times through a 40% isotonic Percoll solution and then subjected to Ficoll-Hypaque density gradient centrifugation (40%/75%). Enriched CD4+ LP T cells were obtained by positive selection using anti-CD4 (L3T4) MACS magnetic beads. The resultant cells, when analyzed by FACS Calibur, contained >96% CD4+ cells. To investigate LP memory CD4+ T cell migration properties and the preventive effect by FTY720, we next induced a colitogenic LP memory CD4+ T cell-mediated colitis as previously described (25). In brief, seven SCID mice from each group were injected intraperitoneally with 200 μl PBS containing 3 × 105 colitic LP CD4+ T cells and were treated with DW or FTY720 (0.3 mg/kg) daily starting 1 day before the transfer over a period of 4 wk. In another experiment, seven SCID mice from each group were injected intraperitoneally with 200 μl PBS containing 3 × 105 normal splenic CD4+CD4RBhigh T cells and were treated with DW or FTY720 (0.3 mg/kg) daily starting 1 day before T cell transfer over a period of 5 wk. SCID mice after transfer were weighed initially and then three times per week thereafter. They were observed for the following clinical signs of illness: hunched over appearance, piloerection of the coat, diarrhea, and blood in the stool. The mice were then killed and assessed for a clinical score, that is, the sum of the following four parameters: hunching and wasting, 0 or 1; colon thickening, 0–3 (0, no colon thickening; 1, mild thickening; 2, moderate thickening; and 3, extensive thickening); and stool consistency, 0–3 (0, normal beaded stool; 1, soft stool; and 2, diarrhea; and an additional point was added if gross blood was noted) (29).
Histological examination and immunohistology.
Tissue samples were fixed in PBS containing 6% neutral buffered formalin. Paraffin-embedded sections (5 μm) were stained with hematoxylin and eosin. Three tissue samples from the middle part of the colon were prepared. Sections were analyzed without prior knowledge of the type of T cell reconstitution or treatment. The area most affected was graded by the number and severity of lesions. The mean degree of inflammation in the colon was calculated using a modification of the previously described scoring system (29).
Flow cytometry.
Flow cytometry three-color analysis was performed. Isolated peripheral blood, spleen, mesenteric lymph node (MLN), peripheral lymph node (PLN; inguinal, axillary, and lateral axillary), and LP cells obtained from FTY720- and DW-treated mice were preincubated with Fcγ receptor-blocking monoclonal antibodies for 20 min followed by an incubation with CyChrome-conjugated anti-mouse CD4, PE-conjugated anti-CD44, and FITC-conjugated anti-CD62L monoclonal antibodies for 30 min on ice. After the cells had been stained, flow cytometry and data analysis were performed using FACS Calibour and CELLQUEST software (BD Biosciencesl San Jose, CA).
Cytokine production assay.
To measure cytokine production, 1 × 105 LP CD4+ T cells were cultured in 200 μl culture medium at 37°C in a humidified atmosphere containing 5% CO2 in 96-well plates (Costar; Cambridge, MA) precoated with 5 μg/ml hamster anti-mouse CD3ε monoclonal antibodies (145-2C11, BD PharMingen) and hamster 2 μg/ml anti-mouse CD28 monoclonal antibodies (37.51, BD PharMingen) in PBS overnight at 4°C. Culture supernatants were removed after 48 h and assayed for cytokine production. Cytokine concentrations were determined by a specific ELISA [interleukin (IL)-10] (R&D; Minneapolis, MN) or a mouse T helper (Th)1/Th2 cytokine bead array kit [IL-2, IL-4, IL-5, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] (BD Biosciences) per the manufacturer's recommendation.
Total cellular RNA was extracted from 7 × 105 cells using the RNeasy Mini Kit (Qiagen; Valencia, CA). Five micrograms of total RNA were reverse transcribed using SuperScript reverse transcriptase (Invitrogen). S1P receptor (S1P1, S1P2, S1P3, S1P4, and S1P5) levels were measured by a QuantiTect SYBER green PCR kit using an ABI7500 real-time PCR system and 7500 system SDS software (Applied Biosystems; Foster city, CA). The following primers were used: S1P1, forward 5′-GTG TAG ACC CAG AGT CCT GCG-3′ and reverse 5′-AGC TTT TCC TTG GGA GAG-3′; S1P2, forward 5′-GGC CTA GCC AGT GCT CAG C-3′ and reverse 5′-CCT TGG TGT AAT TGT AGT GTT CCA GA-3′; S1P3, forward 5′-GGA GCC CCT AGA CGG GAG T-3′ and reverse 5′-CCG ACT GCG GGA AGA GTG T-3′; S1P4, forward 5′-CCT GGA ACT CAC TTT ATA GAC CAG G-3′ and reverse 5′-AGA AAG CGT GCC ATA GGC AG-3′; S1P5, forward 5′-GAG TGC CGG TTA CAG GAG ACT T-3′ and reverse 5′-CGC TGC TGT GTC CTG CC-3′; and glyceraldehyde-3-phosphate dehydrogenase, forward 5′-CTA CTG GCG CTG CCA AGG CAG T-3′ and reverse 5′-GCC ATG AGG TCC ACC ACC CTG-3′. PCR cycling conditions consisted of 95°C for 15 min followed by 45 cycles of 95°C for 15 s, 60°C for 30 s, and 72°C for 40 s. Real-time PCR analysis of S1P receptors was expressed as the relative amount of the indicated mRNA normalized by that of glyceraldehyde-3-phosphate dehydrogenase.
Statistical analysis.
Results are expressed as means ± SD. Groups of data were compared by the Mann-Whitney U-test. Differences were considered to be statistically significant at P < 0.05.
Treatment with FTY720 suppresses the development of colitis induced by adoptive transfer of naïve CD4+CD45RBhigh T cells.
We first tested whether FTY720 suppressed the development of colitis originally induced by the adoptive transfer of splenic CD4+CD45RBhigh T cells from normal BALB/c mice into CB-17 SCID mice (Fig. 2A). Mice were administered daily with FTY720 (0.3 mg/kg) or DW orally starting 1 day before transfer. The control DW-treated mice manifested progressive weight loss from 2 wk after transfer (Fig. 2B) and clinical symptoms of colitis (Fig. 2C) such as diarrhea with increased mucus in the stool, anorectal prolapse, and hunched posture by 3–4 wk. In contrast, FTY720-treated mice appeared healthy with a gradual increase of body weight and without clinical symptoms during the whole period of observation (Fig. 2, B and C). In total, the assessment of colitis by clinical scores showed a clear difference between the control DW-treated mice and FTY720-treated mice (Fig. 2D). Histological examination showed a marked elongation of the villi with a massive infiltration of mononuclear cells in the LP of the colon from control DW-treated mice (Fig. 2E). In contrast, the elongation of the villi was mostly abrogated and only a few mononuclear cells were observed in the LP of the colon from FTY720-treated mice (Fig. 2E). This difference was also comfirmed by the histological scoring of multiple colon sections, which was 0.4 ± 0.8 in FTY720-treated mice versus 4.2 ± 0.8 in control DW-treated mice (P < 0.05; Fig. 2F).
A further quantitative evaluation of CD4+ T cell infiltration was made by isolating CD4+ T cells from each tissue or the peripheral blood. Only a few CD4+ T cells were recovered from the colonic tissue of FTY720-treated mice compared with control DW-treated mice (Fig. 3). The number of CD4+ cells recovered from the colon of control DW-treated mice (23.6 ± 18.4 × 105 cells) far exceeded the number of originally injected cells (3 × 105 cells), indicating extensive T cell migration and/or proliferation in the inflamed colon, which was mostly abrogated in FTY720-treated mice. Similarly, the numbers of CD4+ cells in the spleen, MLN, and peripheral blood from FTY720-treated mice was significantly decreased compared with those from control DW-treated mice (Fig. 3). In contrast, the number of CD4+ cells in the PLN from FTY720-treated mice was comparable with that in DW-treated mice (Fig. 3).
We next examined cytokine production by LP CD4+ T cells from control PBS-treated mice and FTY720-treated mice. As shown in Fig. 4, LP CD4+ cells from FTY720-treated mice produced significantly less TNF-α, IFN-γ, and IL-2 compared with those from control DW-treated mice upon in vitro stimulation. In contrast, the production of IL-4, IL-5, or IL-10 was not significantly affected. These results suggested that FYT720 prevented the development of colitis primarily by promoting the sequestration of naïve CD4+ T cells and/or inhibiting the egress of colitogenic CD4+ T cells in the MLN, followed by inhibiting the development of pathogenic Th1 cells producing TNF-α, IFN-γ, and IL-2.
We further evaluated whether FTY720 affected cell differentiation of the transferred CD4+CD45RBhigh T cells in vivo. As shown in Fig. 5, almost all CD4+ T cells in any tissue and the blood from DW- or FTY720-treated SCID mice had a phenotype of TEM cells, which express CD62L−CD44high, in contrast to the originally transferred CD4+CD45RBhighCD62L+CD44low T cells (data not shown). The results indicated that cell activation/differentiation from naïve T cells to TEM cells in this model was not impaired by FTY720 treatment.
Treatment with FTY720 suppresses the development of colitogenic CD4+ TEM cell-mediated colitis.
Although we found that FTY720 suppressed the development of chronic colitis induced by the adoptive transfer of naïve CD4+CD45RBhigh T cells into SCID mice (Figs. 2–5), it was still unclear how FTY720 controlled the migration property of colitogenic memory T cells in memory T cell-mediated chronic colitis. Because it was possible that the effect of FTY720 in the CD4+CD45RBhigh T cell transfer model was owing to the promotion of the sequestration of naïve CD4+ T cells and/or to the inhibition of the egress of colitogenic CD4+ memory T cells in the MLN, as previously demonstrated by others (3), we used our recently established colitogenic CD4+ TEM cell-mediated chronic colitis model (29) under the condition without impact of naïve T cells. CB-17 SCID mice were injected intraperitoneally with LP CD4+ TEM (CD44highCD62L−; as shown in the inset in Fig. 6A) cells obtained from colitic SCID mice originally induced by CD4+CD45RBhigh T cells and were treated with DW or FTY720 (0.3 mg/kg) daily starting 1 day before transfer over a period of 4 wk (Fig. 6A). As shown in Fig. 6B, control DW-administered mice manifested progressive weight loss from 2–4 wk after the transfer. These mice had diarrhea with increased mucus in the stool, anorectal prolapse, and hunched posture by 4 wk. In contrast, FTY720-treated mice appeared healthy without any clinical signs during the whole period of observation (Fig. 6B). At 4 wk after the transfer, the colon from control DW-treated mice, but not from FTY720-treated mice, was enlarged and had a greatly thickened wall (Fig. 6C). In total, the assessment of clinical scores showed a clear difference between control DW-treated mice and FTY720-treated mice (Fig. 6D). Histological examination showed a marked inflammation in the LP of the colon from control DW-treated mice (Fig. 6E). In contrast, it was mostly abrogated in the LP of the colon from FTY720-treated mice (Fig. 6, E and F).
Furthermore, a few CD4+ T cells were recovered from the colonic tissue of FTY720-treated mice compared with control DW-treated mice (Fig. 7). The numbers of CD4+ cells recovered from the colon of control DW-treated mice (91.4 ± 63.7 × 105 cells) far exceeded the number of originally injected memory cells (5 × 105 cells), indicating extensive T cell migration and/or proliferation in the inflamed colon, which was mostly abrogated in FTY720-treated mice. Similarly, the numbers of CD4+ cells in the spleen and peripheral blood from FTY720-treated mice was significantly decreased compared with control DW-treated mice (Fig. 7). Somewhat at odds, the numbers of CD4+ cells in the MLN from FTY720-treated mice was comparable with that from DW-treated mice (Fig. 7). Unlike the CD4+CD45RBhigh T cell-transferred model, transferred colitogenic LP CD4+ TEM cells could not be detected in the PLN.
Cytokine production by LP CD4+ T cells from control PBS- or FTY720-treated mice transferred with colitogenic LP CD4+ TEM cells was assessed. As shown in Fig. 8, LP CD4+ cells from FTY720-treated mice produced significantly less TNF-α, IFN-γ, and IL-2 compared with control DW-treated mice upon in vitro stimulation. In contrast, the production of IL-4, IL-5, or IL-10 was not significantly affected.
We further determined whether FTY720 affected the cell differentiation of transferred CD4+CD62L−CD44high TEM cells in vivo, because we initially speculated that memory T cells residing in lymph nodes preferentially express CD62L, which is termed as central memory T (TCM) cells. As shown in Fig. 9, however, almost all CD4+ T cells in any organ and the blood from DW-treated or FTY720-treated SCID mice retained the characteristics of TEM cells, including the MLN, indicating that FTY720 did not affect the TEM-to-TCM conversion in this model.
Colitogenic CD4+ TEM cells express receptors for S1P.
Because it has been reported FTY720-phosphate acts via S1P receptors (5), we finally evaluated the expression pattern of S1P receptors in sorted normal splenic CD4+, CD4+CD45RBhigh, and colitic LP CD4+ TEM cells using quantitative PCR analysis. As depicted in Fig. 10, colitogenic LP TEM cells contained mRNA encoding S1P1, S1P2, and S1P4 receptors, albeit to a lesser extent compared with naïve CD4+CD45RBhigh T cells, with only a minimal representation of S1P3 and S1P5 receptors.
In the present study, we demonstrated that FTY720 suppressed the development of colitis induced by the adoptive transfer of colitogenic LP TEM cells into SCID mice under the condition without the impact of naïve T cell migration. In addition, we also found that FTY720 ameliorates the development of colitis induced by the adoptive transfer of naïve CD4+CD45RBhigh T cells into SCID mice, in which all processes responsible for the development of colitis, such as the initiation of naïve T cells by antigen-bearing dendritic cells and the elicitation to effector or TEM cells in secondary lymphoid organs, are involved. Because we demonstrated that colitogenic LP TEM cells as well as normal splenic CD4+CD45RBhigh T cells expressed several S1P receptors that are targets for FTY720-phosphate, the present study provides the suggestion that FTY720 can directly control memory CD4+ T cell-mediated immune diseases in addition to the impact of naïve T cells.
Because it has been largely thought that the effect of FTY720 treatment on autoimmune diseases in the previous preventive protocols is owing to the sequestration of naïve T cells rather than pathogenic memory T cells, it was unclear whether FTY720 directly affects the migration property of memory T cells in autoimmune established stages. To overcome this issue, we conducted the adoptive transfer of only colitogenic LP CD4+ TEM cells into SCID mice in the present study. As there were no naïve T cells in this transfer system because almost all isolated LP CD4+ T cells from colitic mice had a characteristic of CD44highCD62L−CD45RBlow TEM cells, we could directly evaluate the effect of FTY720 on colitogenic LP CD4+ TEM cells. Surprisingly, we found that FTY720 suppressed the development of colitogenic memory TEM cell-mediated colitis, indicating that FTY720 affects the migration of colitogenic LP CD4+ TEM cells. Consistent with this, we demonstrated that colitogenic LP TEM cells as well as normal splenic CD4+CD45RBhigh T cells expressed several S1P receptors (S1P1, S1P2, and S1P4). However, we found that the numbers of CD4+ T cells in the MLN were also significantly decreased in FTY720-treated mice transferred with colitogenic LP TEM cells compared with DW-treated mice. Although the result might indicate that FTY720 could not sequester colitogenic CD4+ TEM cells in FTY720-treated mice, it is more likely that colitogenic CD4+ TEM cells in PBS-treated mice had a greater chance to repeat the migration into the MLN and the egress from the MLN to sites of inflammation and could expand their number, which exceeded the original transferred cell number (3 × 105 cells). However, it is possible that the finding that there were decreased numbers of CD4+ T cells in the various compartments may be a result of the lack of the colitis in FTY720-treated mice and not necessarily a direct effect of FTY720 on egress or sequestration, because we could not detect any differences of cell numbers in the MLN between TEM cell-transferred DW-treated mice and FTY720-treated mice. Nonetheless, we found that FTY720 caused a significant loss of CD4+ TEM cells from the blood (lymphopenia) and spleen, reducing numbers by ∼100- to 1,000-fold compared with DW-treated mice, indicating that FTY720 induced a smaller chance to recirculate into the MLN repeatedly, followed by no development of colitis. Further studies will be needed to address this issue using another short-term in vivo transfer system.
The present study would provide another impact in terms of a characteristic of memory T cell trafficking for the maintenance of autoimmune diseases. Although some investigators have suggested that LP T cells do not migrate out of the gut (12), our results indicated that LP CD4+ TEM cells are needed to constitutively recirculate into the MLN and are restimulated by antigen-bearing dendritic cells in the MLN to maintain colitogenic CD4+ TEM cells for sustaining chronic colitis. An earlier study (32) has demonstrated that the thoracic duct lymph (TDL), which empties into the blood, contains many lymphocytes. In a landmark experiment, Gowans and Knight (7) transferred radiolabeled thoracic duct lymphocytes intravenously into naïve syngeneic recipients and detected donor memory lymphocytes in their TDL again, providing the first formal demonstration that memory lymphocytes recirculate continuously between blood and lymph. Consistent with this notion, we also found that LP CD4+ T cells obtained from FTY720-treated SCID mice transferred with colitogenic CD4+ TEM cells in FTY720-treated mice produced less amounts of Th1 cytokines compared with DW-treated SCID mice, indicating that the recirculation and restimulation of Th1 cells in lymph nodes, in this case, the MLN, are essential for the maintenance of Th1-mediated autoimmune disorders.
In nohuman primates treated with FTY720 for over 100 days, however, ∼10% of peripheral blood CD4+ T cells were refractory to depletion by FTY720 (23). It is likely that these cells represent long-lived TEM cells. Because TEM cells lack the lymph node homing receptors CCR7 and CD62L (28) and express high levels of inflammatory chemokine receptors (28), and they therefore could preferentially reside in nonlymphoid tissues (16) in contrast to naïve and TCM cells. Thus it is possible that TEM cells might not be trapped by FTY720 treatment in the lymph node but be controlled by the unidentified mechanism of action of FTY720 in our model. Conversely, Henning and colleagues (9) recently reported that FTY720 rescues the homing defect in both CCR7−/− mice and plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on high endothelial cells (9), suggesting that FTY720 enables TEM cells to sequester into lymph nodes in a CCR7/CD62L-independent mechanism for lymphocyte homing through endothelial venules, which is strongly augmented in the presence of FTY720. Further studies will be needed to address this issue.
The ultimate goal of any treatment for autoimmune diseases, including IBDs, is antigen-specific suppression of pathology. Autoaggressive antigen-specific lymphocytes need to be eliminated or controlled to prevent tissue damage and halt the progression of clinical disease. Although it is so far poorly understood regarding the self-antigens and commensal bacteria flora responsible for the pathogenesis of IBDs, colitogenic memory T cells rather than naïve T cells should be the targets for the treatment of IBDs, even if the primary, initiating self-antigens/commensal bacteria flora are unknown and inflammation is progressive (19, 25). Although Mizushima and colleagues (18) recently demonstrated that FTY720 treatment of established colitis in IL-10−/− mice ameliorated colitis, it was still unclear whether FTY720 affected the migration of naïve T cells or colitogenic memory T cells. In light of this, the present SCID colitis model induced by the adoptive transfer of colitogenic CD4+ TEM cells is a useful model, because we can assess a character of memory T cells without the impact of naïve T cells. Because we demonstrated that FTY720 could control and suppress colitogenic CD4+ TEM cell-mediated colitis, FTY720 might be beneficial for the treatment of ongoing or established IBDs as well as their prevention.
In conclusion, we demonstrated here that FTY720 was useful to suppress memory T cell-mediated chronic colitis without the impact of naïve T cell activation using memory CD4+ TEM cell adoptive transfer experiments. Although we have to pass many critical checkpoints, this study indicates that FTY720 offers a hope for the treatment of human IBDs.
This work was supported in part by Grants-In-Aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research, and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labor and Welfare; the Japan Medical Association; the Foundation for the Advancement of International Science; Terumo Life Science Foundation; Ohyama Health Foundation; Yakult Bio-Science Foundation; and Research Fund of Mitsukoshi Health and Welfare Foundation.
The authors express special thanks to Novartis Pharmaceuticals (Basel, Switzerland) for kindly providing FTY720.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 the American Physiological Society


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In his opening remarks at Missouri's press conference announcing it had accepted a bid to the 2005 Independence Bowl, head coach Gary Pinkel talked about what a good experience the Tigers had in Shreveport after the 2003 season. But this time around, the Tiger players are aiming to change one thing.
"We definitely want to win," said senior captain Calvin Washington. "That's gonna be one of our things that's gonna drive us is to get a win out of this. We haven't won. We got to a bowl, didn't win it, but we've got a chance now to get one."
The Tigers lost the 2003 game to Arkansas 27-14 to finish 7-5 on the season. But, according to the seniors, there is a difference between that team and this one.
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"I think we're a little bit more mature about it," said quarterback Brad Smith. "I think there was a lot of excitement about it, not going in a while, but I think a lot of the seniors have been there and just want to go out with a win. More of our focus is on that."
"It's definitely more important to win this one," said offensive guard Tony Palmer. "(Last time) was definitely a great experience for us and we played up against a great team. Leaving there with a loss, it left a sour taste, I think, in everybody's mouth. We definitely want to come out with a W."
The Tigers think they have something to prove in Shreveport.
"It's good to play in front of an audience," said Jason Simpson. "We've played on TV two or three times this year, sucked every time. We're definitely going to try to do a lot better this time."
The Tigers went through their first bowl practice on Saturday morning, though they have been conditioning since the end of the regular season a little more than two weeks ago.
"We have to kind of balance this out a little bit between recruiting," Pinkel said. "Our coaches came back in town and we had a practice (Saturday) morning. It was a good practice. We hadn't practiced for a while...It went very, very well, a lot of enthusiasm, a lot of excitement."
The Tigers will release a practice schedule, including which sessions will be open to the media, in the next couple of days. Pinkel also said he hoped to have Sean Coffey back for the bowl game. The senior wideout injured his shoulder returning a punt against Baylor and did not play against Kansas State. Marcus Woods did not practice on Saturday due to a severe groin pull suffered in the K-State game.
PowerMizzou.com will attend all open practices leading up to the bowl game and will have continuous coverage of the Tigers leading up to the December 30th kickoff.

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Earlier this month, Smith & Nephew recalled the optional metal liner used with their R3 Acetaburlar hip replacement system, which can make it a metal-on-metal design. A number of different metal-on-metal hip replacement systems sold by several manufacturers have been linked to problems, and the Smith & Nephew indicates that the R3 metal hip liner has a revision rate that is higher than acceptable.
The hip replacement lawyers at Saiontz & Kirk, P.A. are reviewing potential claims for individuals who have experienced complications after receiving a recalled Smith & Nephew hip, or any other metal-on-metal hip replacement, including systems sold by DePuy, Wright Medical, Biomet and other manufacturers.
Metal-on-metal hip replacements have been found to release microscopic shavings of metal into the body as the metal parts rub against each other. This can damage soft tissue, cause inflammatory reactions, lead to bone loss or a loosening of the implant.
The Smith & Nephew hip recall was issued on June 1, for a metal liner that may be used with the R3 hip replacement system. Since the product was introduced in 2007, and launched globally in 2009, approximately 7,700 of the recalled metal hip liners have been implanted, with most used in total hip replacements.
Smith & Nephew Hip Lawyers Reviewing Lawsuits Nationwide
Symptoms of problems from a Smith & Nephew metal-on-metal hip replacement may include:
- Hip or Groin Pain
- Difficulty Walking or Standing
- Inflammation or Swelling
- Loosening or Failure of the Implant
- Development of Tumors
- Revision Surgery to Replace the Artificial Hip
Although many consumers were told that metal-on-metal hip replacements would be more durable and last longer, individuals often require revision surgery within a few years after experiencing problems.
The lawyers at Saiontz & Kirk, P.A. are reviewing potential claims for individuals throughout the United States who may be entitled to financial compensation through a Smith & Nephew hip replacement lawsuit. As a result of the defective and dangerous design, individuals may face an increased risk of catastrophic failure for their implant.
To discuss a case for yourself, a friend or family member, request a free consultation and claim evaluation.


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wikiHow to Do the Piggy Blimp Glitch on Zelda: Wind Waker
The Piggy Blimp glitch is a glitch that allows you to make a pig on Outset Island float in the air much like a blimp. Want a flying pig? Read on.
1Go to the Forest Haven and get a bottle of forest water.
2Venture to Outset Island and take the big pig down to the walkway bridge that gaps the east side of the island to the west. Go to the middle gap in the bridge and stand on any part made of wood.
3Wait until the forest water expires, still holding the pig on your hands.
4When it expires, a message box will pop up telling you the water has expired and meanwhile, the pig will slowly float away from you. It will keep floating farther away until you close the message box then he will be back in your hands.
5Have a laugh or two!
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- You can only do this when you are able to pick up very heavy items with the strength bracelets and can freely go to Outset Island without the King of Red Lions yelling at you.
- This works on all versions.
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Thread: [system tables] Index list
04-10-02, 09:31 #1Junior Member
- Join Date
- Mar 2002
- Posts
- 3
Unanswered: [system tables] Index list
I need to write a sp_helpIndex kind in SQL.
I still miss the name of the column the index is refering to !
SELECT i.name, s.name, i.status
FROM mybasename.dbo.sysindexes i,
mybasename.dbo.syssegments s,
mybasename.dbo.sysobjects o "
WHERE i.indid!=0 AND
i.segment=s.segment AND
i.id=o.id AND o.name=mytabename
It lists the indexes with their segment and status for a given table.
How can i introduce the column of the table ???
04-17-02, 16:10 #2Registered User
- Join Date
- Mar 2001
- Location
- Lexington, KY
- Posts
- 606
You need to tie the id from sysindexes (or sysobjects) into the id from syscolumns. syscolumns will have a row for each column in the index for a specfic ID.Thanks,
04-18-02, 04:14 #3Junior Member
- Join Date
- Mar 2002
- Posts
- 3
In fact the only way I found to link an Index with the columns concerned is the function : index_col(object name, index id, nd of the index) (as there is no link in the system tables diagram to answer my need).
I did this way. I works very well.
Thanks for your answer.


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Yair Emanuel Silk Matzah Cover Set with Blue PatchesProduct ID: MZC-EY-12991
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A beautiful addition to your family and friends' Seder table, this incredible matzah cover set is a great gift.


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Jewish Women Writers in Victorian England
Jewish Medical Association with the Institute of Jewish Studies, UCL
Thursday, 24 April 2014 from 18:00 to 20:00 (BST)
Who's Going
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Sara Haughty
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Luke Picard
London, United Kingdom
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Rick Vespucio
Florence, Italy
Florence, Italy
Event Details
Lecture by Nadia Valman.
Nadia Valman studied English at the Universities of Cambridge and Leeds and worked operating the autocue for BBC News before completing her doctorate at Queen Mary. Her research focused on literature and the campaign for Jewish civil rights in Britain in the nineteenth century. This topic led her to discover a number of unknown Victorian Jewish and Christian women writers, and to her first monograph on the figure of the Jewess in nineteenth-century literature. She taught at the University of Southampton for 10 years before returning to Queen Mary in 2007.
Do you have questions about Jewish Women Writers in Victorian England? Contact Jewish Medical Association with the Institute of Jewish Studies, UCL
When & Where
University College London
Gower St
United Kingdom
Thursday, 24 April 2014 from 18:00 to 20:00 (BST)
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Located on Telegraph Avenue near 66th Street in North Oakland, close to the Berkeley border, is the unique hair salon and vintage boutique Down At Lulu's -- which is owned and run by the fun, music-minded duo of Tina Lucchesi and Seth Bogart, two good friends who both happen to love music, fashion, hairdressing, and retro rock culture. They also clearly love what they do at Down At Lulu's which, while only a little over a year old, has won a Best of the Bay award and gained a strong clientele. The store, which is located roughly midway between the White Horse pub and the Smokehouse burger joint, has a festive storefront window with the large glittery words GABBA GABBA HEY -- a nod to one of their mutual favorite bands, the Ramones. Inside are records (not a whole lot, but carefully selected ones), cool clothing, and of course, the hair styling stations. I recently stopped by the store and caught up with Tina (Seth was away on tour with his band), who talked about Down At Lulu's, and about her and Seth's interests and passions -- especially music.
AMOEBLOG: How would you describe Down At Lulu's to someone who has never seen it?
TINA: Hmmm !!! A John Waters, Beyond the Valley of the Dolls, Rock N Roll High School, the Madonna Inn, Rock N Roll Burrito!
AMOEBLOG: How exactly did Down At Lulu's come into being?
TINA: Seth and I have been pals and are interested in the same sort of everything: rock'n'roll, hairdressing, the sixties and the seventies, and the eightes -- fashion from those eras, as well as hamburgers, Mexican food, the Ramones, girl-groups, boys, boys, boys and men! We had the same vision I think, so we decided 'Hey, let's do this!" We are both totally thrift-store maniacs but the hairdressing is our money-maker. So we thought, why not combine the two and make it an all round good times and fun? Work must be fun -- why not make it that way if you can?
AMOEBLOG: And why did you choose that song title as the name?
TINA: Well, we both love bubblegum music and we love the Ohio
AMOEBLOG: And do many of your customers know the origin of the name or do you have to answer questions about it constantly?
TINA: Hmmmm. Yeah, most of them ask why the name, but the coolsterz know.
AMOEBLOG: How important is music to you guys? I heard that you are both in bands.
TINA: Rock N roll is everything to us for sure. 100%. I'd drop everything if I couldn't have rock in it for sure. Seth is in Gravy Train. And also when they play, which isn't too often, he is a member of the bands Baby Jail and Panty Raid. Plus, he's working on his solo project, which will be out soon. And I'm in the bands Top Ten and the Bobbyteens and I'm working on all sorts of side band stuff. Me and Seth have a band together called Dinky BIts And The Lil Guys. It's a funny band about food, fashion, thrift shopping and sex.
AMOEBLOG: At your recent one-year anniversary party at the store did you have live music?
TINA: We had Russell Quan DJ and our friends' vaudevile act The Party Breakers.
AMOEBLOG: How do the two main sections of Down At Lulu's complement or play off one another?
TINA: The hair is the main part of the shop I think. The clothes are just fun. We love clothes and vintage fashion so much. And I think it works well together: it's your one stop to get the total look.
AMOEBLOG: I'm sure you've also noticed the surge in art related store fronts on Telegraph, mainly further down in the Oakland direction, but nonetheless, they are also fellow small independent businesses like yours. Would you agree that there is an East Bay art renaissance of sorts and that Down At Lulu's fits into it in a way?
TINA: Yeah, but we are not artsie craftsie. And although I'm not personally into that stuff, I do support all of the small businesses who are [around], definitely.
AMOEBLOG: What are the future plans for Down At Lulu's?
TINA: Hmmm, Probably to add more stylists in the future. We just hired a new lady named Mitra and she's an awesome hairdresser, so we are so stoked to have her. We needed to hire someone cuz we were turning people away. Also in the future we plan to have more art shows. Our next one is scheduled for September 7th. We also plan to do more fashion shows. Fun!!
Down At Lulu's is located at 6603 Telegraph, near 66th Street in North Oakland, and is open Tuesday through Sunday Noon-7PM. For hair appointments call (510) 601-0964.


text:
Legal Question in Civil Litigation in Pennsylvania
If someone gives you a washer & dryer& says the washer needs a timer & you take them&fix the washer can they say they are taking them back. I just broke up with her niece & she is moving out. Now her aunt wants them back . We lived together & had themfor 2yrs. I offered my girl 100 for the dryer & she said no her aunt wants them back. Ipaid to fix the washer so I feel it should be mine. I feel the dryer is ours so we should come to an agreement
Asked on 4/22/13, 10:03 pm
1 Answer from Attorneys
Greg Artim Morrow & Artim, P.C.
If they were truly given to you without strings, then they are yours. That is common sense. A break-up does not negate a gift, unless the aunt said so at the time that she made the gift. She cannot rescind a gift after the fact.
Answered on 4/23/13, 4:31 am


text:
UPI 2.0 Could Be Great for Consumers, but Bad for Many Fintech Companies
While we believe we saw a prototype design in an old chassis (it was identical to the currently selling Nexus 10), the performance difference in popular benchmarks was night and day. The final design of the part (Google currently does not have final versions of the chassis) should address the shortcomings of the original design, even though we were told that the company was satisfied with the original design. They did agree that the design lacked a bit of "wow factor", but that will probably wait for the third generation.
For the latest tech news and reviews, follow Gadgets 360 on Twitter, Facebook, and subscribe to our YouTube channel.


text:
Sixteen people, including known associates to overseas terrorists, face charges in connection with a cigarette smuggling ring that flooded New York with more than a million carts of untaxed cigarettes and netted more than $55 million in illegal cigarette sales, prosecutors and federal officials said.
The 244-count indictment charges the suspects with enterprise corruption, money laundering and related tax crimes. Prosecutors say investigators seized more than 65,000 forged cigarette tax stamps and nearly 20,000 cartons of untaxed cigarettes during the year-long investigation.
The cigarettes were allegedly bought in bulk in Virginia and illegally resold in New York.
Authorities recovered three handguns and more than $1 million in cash while executing search warrants in the suspects' homes and at storage facilities in four states.
Officials are investigating whether some of the profits may have been funneled to Hamas supporters in the Middle East. Some of the suspects arrested in the scheme are known associates to terrorists, officials said. They were known to the NYPD and it appears they were being monitored by the intelligence division when the fraud was unraveled, authorities said.
"By cheating New Yorkers out of tens of millions of dollars in tax revenue, this dangerous criminal ring was able to generate astounding profits that we are still continuing to trace," Attorney General Schneiderman said. "Not only did this organized crime ring hurt law abiding mom-and-pop shops and other businesses in New York by putting those who do pay taxes at a competitive disadvantage, there is a very real concern about the possibility of violence related to this type of enterprise."
Prosecutors said profits from similar schemes have been used to help fund terrorist organizations in the past.
-Shimon Prokupecz contributed to this report


text:
Thread will only show slip. Scrtsqrl had this idea:
Glad everything was ok apart from the FPV cam and I hope that it comes around too. Try setting it on a really warm heating pad overnight to see if the warmth drives out any leftover moisture.
Honestly, I "felt" like your plane was going to stall. Maybe it's because I knew how the ending was going to be in advance, but just something about the bobbly way she was flying told me you were skating a fine line. I guess I'm also a bit used to the apparent airspeed as seen through the goggles, because it seemed like a very slow approach to me. Between the two, I felt a bit on edge watching it. Gosh, I don't suppose that could be in part from experiencing similar things, could it?
Rick NR417
Great idea going electric with the Ajax - look forward to the photos and report.
Please excuse the off topic post, ladles and jellyspoons...!
thanks. I have washed and carefully brused the cam with destilled water and left it overnight in the oven a bowl of rice, but I can see a little corrosion has formed on some of the IC pins. It's still drying in the sun today, so I'll give another shot.
The plane is a lightweight twin motor conversion (680g AUW FPV), which does have a very low stall speed, but appearantly, I still managed to blow it.
Watching the video afterwards, I can see to distinct mistakes; First one is that I line up with the surface of the water, not the lawn behind beach, which is 2-3' above it . That forces me to try to ascend when the plane is almost out of speed and actually triggers the stall. Second Mistake is that I cut power too much on the final - in two steps even...
Sorry Guys - No more off topic from me.
Well, here I come with bad news again...
I had repaired my EZ after the last big crash, which did a LOT of damage, and I also reconfigured the plane to be more like it was in the "good old days". Back then, I was doing easy cruising on 4 - 5 amps, running 6+ mile round trips on a 3000mAH pack and loving it. I had my 808HD keycam on the right wingtop, and the FPV cam in its little pillbottle panning turret, and life was good. Flying was more about where to go and what to see than worrying about if the plane would come home or not. I logged a lot of uneventful flights and I felt really accomplished. Then I got GoPro crazy, had some bad crashes, and did probably irreparable harm to the wings by coating them in a liquid plastic film, which did distort the wingshape somewhat. I thought she'd be fine, but today proved a bad feeling I was getting after the last time and the crash that resulted.
Anyway, I went to the usual place where I do quadcopter flights and plane testing, and right away I knew I was in a lot of trouble. It was windy, but nothing I haven't flown in before, and ROG takeoff was actually pretty easy. I was thinking I was back in the good times until I noticed how wild she seemed in the air. This was purely FPV, thank God, because had I been flying LOS I would surely have lost her almost right away just like last time. Any time I did a turn, she'd wobble shakily into it, and on the slower speed right hand turns she'd want to snap and roll. I had enough time to really think about what she was doing this time, and my bad feeling seemed pretty well proven - distortion of the airfoil shape made her unbalanced and eager to tipstall to the right.
As I was struggling to keep her fairly close, keep her from tipstalling, and avoid going too high, too low, and too close to obstacles, I got the ultimate nervousness booster - the local rent-a-cop paid me a visit on his golf cart. I knew it was coming because lol on a return pass I saw him cruising along the parking lots toward my car, haha. Gotta love the recon advantage of FPV. Anyway, between the crazy flight characteristics and having security guy next to my car asking me if I work there, my hands were shaking like mad.
I explained to him, while flying over 1000' out in crazy zigzags mind you, what I was doing and I even showed him the live feed on my laptop monitor. The hilarious thing was, he was like "no big deal" about it. He actually said, "Oh ok then... Well you just take your time. I was just wondering who you were." Hahahaha omg I couldn't help but chuckle as he pulled away... like hey whatever, like this sort of thing is a daily affair there or something.
And then, what just HAD to happen, finally did happen. After having survived some near misses with trees, buildings, and powerlines, she did the inevitable on final approach. And that's the awful thing about it - I KNEW I was going to be taking her home in pieces again. In retrospect, I should have gunned the motor to keep her moving fast, and came in hot and low... but I was too high up and I just really wanted to get her on the ground so I could rest.
I could see my car, the big grass strip, and security guy's little golf cart parked just to the side of my landing path. I JUST cleared him, and down she went, heavy tipstall to the right and SMACK. This time, the electronics all did spectacularly well (except for the 3S 3000 Zippy Flightmax, which was crushed badly) and I haven't found any damages to the flight or FPV systems. The plane however was again badly damaged - broken tail, broken wing, and crushed nose and canopy foam bigtime.
So... I'm retiring my baby because she's simply beyond my trust now. I don't really have the confidence in my skills to rework the wingshapes and I don't want to put my expensive electronics at risk for more testing on a squirrely plane again. Also, I mean geez... all the fractures throughout the body must look like a plane-shaped spiderweb by now from all the many disasters she's seen. She's been my best girl since January of 2011 and taught me to not only fly proper LOS, but also FPV.
And that brings me to the hard decision... I have a big car payment that will be on my back for a few years, and Christmas is coming up and I want to be able to get myself back in the air without a big expense... If I want to stay in the hobby then I have to cut expenses all I can. So I'm going to get myself a Bixler 2 to cut expenses down on a new plane. Just the kit version of the EasyStar 2 is $110, where the Bix 2 kit is just $42 before insanely high shipping and still only $70 something after. That's a $40 difference that I can be putting into a couple new battery packs and whatever minimal parts expenses I'll need in order to finish the build. Going the EasyStar 2 route would have me easily at $150 by the time I'm done. I *could* be persuaded to do another EasyStar 1 but man it's like Multiplex rounded them all up and exterminated them. That's horribly unfair because the EasyStar 1 kit was only $74 before shipping if I recall right, competitively priced against the Bix 2 and probably a lot more durable than the Bix 2.
So that's where I'm at. If I go with this decision it means I'll be just here for the conversation... wouldn't feel right at all posting Bix vids here.
*grumble grumble* :-(
Rick NR417
One note - I'm also considering building an EasyStar 1 from replacement parts on eBay. It depends on how high the total cost goes.
Looks like Phil's Hobby Shop on eBay would be the best bet... I can get the tail assy, wings, and fuse for something just about $69 before shipping.
Rick NR417
I just built/rebuilt my old EasyStar 1 using ta kit off eBay - just the fuse and wings etc- and cut ailerons into the wings. I did this after flying an EasyStar II for a while and missing the original, which somehow seems to fly better for me. I like that the original is a little bit wider so it's easier to pack bigger batteries in and other electronics. I haven't dumped my EasyStar II, it's still fully functional and on standby, but I prefer my number one.
I've also have a Bixler, which is great but not as good as the EasyStar. Doesn't feel as tough and doesn't carry stuff with the same ease. I can practically chuck stuff on the EasyStar willy nilly and it doesn't seem to care, but the Bixler is finely balanced and just won't fly right if everything's not perfectly placed, and it doesn't cope as well in high/low winds. Haven't tried the Bixler 2 though.
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We're planning a trip of 5 to Disney world this year, 3 of us have Deluxe pass to disneyland. Will upgrading to premier passes save us money? Does this give us discounts to hotel and more?
Upgrading to Premier Passport
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Upgrading to Premier Passport
Re: Upgrading to Premier Passport
Originally posted by Johana95 View PostWe're planning a trip of 5 to Disney world this year, 3 of us have Deluxe pass to disneyland. Will upgrading to premier passes save us money? Does this give us discounts to hotel and more?
You can get AP rates at Disney hotels, but it's not something that's well advertised. Generally, you need to call and ask for AP rates about 3-4 months in advance of your trip. If they tell you the AP rates haven't been released yet, keep calling every few days until you find out they've been released. This could save you a bit.
You'll also get a 20% merchandise at all Disney owned retail locations on property, and a 10% discount at a few (very limited) dining locations. Having an AP also makes you eligible for Tables In Wonderland, which costs $75 for a one year membership for an AP holder, but gets you a 20% discount at all Disney-owned table service restaurants, some non-Disney-owned table service restaurants, and all quick service restaurants at DAK and the value resorts - only one person in your party needs Tables In Wonderland for all of you to get the benefit (as long as you're paying on one check).
More on the benefits here. All in all there's a fair amount of math to determine whether or not it'll be worth it for you, but hopefully that helps you get started.Last edited by PSUMark; 06-15-2012, 10:41 PM.I knew if this business was ever to get anywhere, if this business was ever to grow, it could never do it by having to answer to someone unsympathetic to its possibilities, by having to answer to someone with only one thought or interest, namely profits. For my idea of how to make profits has differed greatly from those who generally control businesses such as ours. I have blind faith in the policy that quality, tempered with good judgment and showmanship, will win against all odds.
-Walt Disney
- Apr 2008
- 454
Re: Upgrading to Premier Passport
I go there annually and I think it is worth it. If anything just upgrade one atleast to get the discounts then buy tickets for the rest of the family. I went during off season and saved $1650 on the hotel aloneIm here for fun and info not be a bully! Carsland here I come:yea:
Re: Upgrading to Premier Passport
Originally posted by Johana95 View PostWe're planning a trip of 5 to Disney world this year, 3 of us have Deluxe pass to disneyland. Will upgrading to premier passes save us money? Does this give us discounts to hotel and more?
We are booked for a November trip, and the Magic-Your-Way tickets would have been about $100 more than it cost us to upgrade the passes. So right there is some savings.
Total up how much it would cost to upgrade your 3 Deluxe passes to the Premiere passes, then compare them to the cost of park tickets with all your bells and whistles added in (park-hopper, water parks, etc). If the park tickets are more, then go for it! You can upgrade directly at the Disneyland ticket booths. And then enjoy Disneyland/DCA as well, because the Premiere passes act as Premium passes for all parks!
We found out last time in 2010 that Disneyland pass discounts apply at WDW, and the same is true for the Premiere pass. Plus the discount information found in the link PSUMark provided.
I hadn't heard about AP rates for hotel rooms, I should look into that closer to our trip!I'm making a note here: HUGE SUCCESS.
New MiceChatter
- Jan 2011
- 24
Re: Upgrading to Premier Passport
PRIOR to hotel discounts, the sweet spot for a family of 4 seems to be 7 days (with park hopper and water park options). Less than that it seems that you are better off not upgrading).
Some of this also depends upon how you are handling parking at DL. That might push the break even point to 6 days. Plus there is a big upside (it seems) to being able to enjoy the DLR parks on Saturdays rather than Sundays.
- Jan 2012
- 1511
Re: Upgrading to Premier Passport
I don't have much else to add, but also consider how the pass will work its way into your plans for Disneyland. With the Premier, you can go on weekends and will have free parking on both coasts.
Re: Upgrading to Premier Passport
I upgraded my Premium Pass in June. I renewed the Premium in May before the price increase and wanted to upgrade it after the price increase. Disneyland wanted to charge me $400. I upgraded it in Florida instead and they charged me only $200ish + tax.
The Florida and California computer systems are not compatible (Or at least they were not then per Guest Relations) and they had no way of knowing that I purchased it before the price increase.
My friend tried to do the same thing but he did not have his pass with him as his renewal pass got lost in the mail. Disneyland told him it would not be a problem just give FL his confirmation #, but Disneyworld would not upgrade him as they stated that they could not look up his pass as their computer systems were not compatible with Disneyland's and they needed the old pass for accounting reasons as well, so they made him buy a ticket (9 Days) which was more than the upgrade would have cost. For me it was great though especially as I used it for Disney Quest as well.
The free parking was great as well as my freind rented a car and we stayed off property.
Re: Upgrading to Premier Passport
I currently have a premium pass purchased before the price increase. If I wanted to upgrade to the premier do I have to pay the difference between what I paid and the current price or just the current difference?Follow me on Instagram: @disneylovingnurse :ap:
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if this link doesn't work,you should go to my skydrive and search for it.
skydrive link is given upper right side or (Click Here) .
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Here's a beautiful riff on traditional Moss Cones. Designer Diane Flowers wrapped the tops in silver paper to create Elegant Moss Topiary Cones. To keep it easy, she used a silver adhesive paper, found in the scrapbooking aisle. Diane decorated her DIY Moss Cones with beads and sequins for extra "wow." I think you could display these Elegant Moss Topiary Cones all winter long – there's no need to take them down with the Christmas decorations. Ya gotta love that!
I've used the moss sheets before, and they're easier to use than loose moss. And a little less messy, too. One other tip – you can change the silver foil paper to another color – you'll see several options in the scrapbook aisle.
To make Elegant Moss Topiary Cones, you'll need:
(Note: The materials listed will make two)
- STYROFOAM™ brand foam:
- Two, 18"x 5" cones
- Two, 8"x 4" x 2" blocks
- Moss cloth sheets, two packs
- Adhesive backed paper in silver, two 8-1/2"x 11" sheets
- Sequins, ¾":
- 30 green
- 70 silver
- Beads, 3/8":
- 30 iridescent green
- 70 iridescent clear
- Head pins, six stems with green and opal beads*
- Containers, two 5"
- Wood skewers, six, 6" lengths
- Low-temp glue gun
- Tools needed: Scissors; ruler; straight pins; serrated knife and old candle or bar of soap
*Note: Beaded head pins are often found in the floral aisle. If you can't find them, DIY your own using head pins from the jewelry aisle and extra beads.
To make Elegant Moss Topiary Cones:
1. Roll each of the glittered paper sheets into cone shapes, adjusting them so they fit snuggly and evenly on the top 6" of each cone. Trim paper, remove the adhesive backing and carefully wrap the sheets around the tops of the cones.
2. Wrap the bottom 12" sections of each of the cones with the moss sheets. Use scissors to trim the moss as needed to avoid excessive overlap and use floral pins to secure the moss sheets to the cones.
3. Insert a blocks of STYROFOAM Brand Foam into each of the containers. Wax the serrated knife with an old candle or bar of soap, and trim the tops of the foam blocks so they're even with the tops of the containers. Cut scraps into smaller pieces and use to fill the containers. Be sure the containers are packed tight.
4. Insert three wooden skewers halfway into the top of each container and secure with hot glue.
5. Carefully position the cones on top of the skewers in each container, making sure they are centered. Apply glue to the tops of the skewers and push the cones down onto the skewers until they rest securely on top of the containers.
6. Use straight pins to secure the silver sequins to the moss half and the green sequins to the silver portion. Adjust as needed so the sequins are evenly spaced around the cones.
7. Glue (or pin) the green beads to the green sequins, and clear beads to the silver sequins.
8. Twist together three of the beaded head pins, and insert into the top of a topiary. Repeat with remaining head pins for the second topiary. Or, if making your own, thread beads onto head pins, twist to secure the beads, and then insert into the top of the trees.
How would you change up this Moss Topiary? Or, would you make it just like this?
And speaking of topiaries, don't forget about our Deco Mesh Christmas Topiary giveaway!
Happy crafting.


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About Me
eat my wieght in pickles and peaches..... and travel the world!
The whole self explanatory blurp has always been one of my awkward downfalls.... But in a nutshell I'm a fun, very social, happy and laid back young traveller. I love meeting new people and experiencing new things.
Why I'm on Couchsurfing
at the moment im surfing but i am really looking forward to hosting when i end up settling in a city
I've been surfing around europe on and off for 4 months now! I can't wait till i get an apartment of my own soon so I can start hosting:)
I'm a music journalist and I also have worked in PR and events back home. At the moment I'm lucky enough to be traveling and broadening my tastes and knowledge of all things, something I'm really passionate about.
- performing arts
- cooking
- traveling
- music
- surfing
- journalism
Music, Movies, and Books
Movies: Drive, Darjeeling limited, Igby goes down, There will be Blood, Annie Hall, Let the right one in, The Beginners, Into the Wild
Music: Gonjasufi, Flying Lotus, The Hives, Death Grips, Deerhunter, The Monks, Grauzone, Grimes, The Horrors, The Velvet Underground, Deerhoof, Captain Beefheart, SBTRKT, Outkast, Purity Ring, France Gal, Cloud nothings, Wild nothing, dirty beaches, ect
One Amazing Thing I've Done
1. Seeing one of my favourite artists Gonjasufi play at The Village underground in London, which is a performance i would have never got to see at home and it was absolutely incredible.
2. Visiting Cappadoccia in Turkey it was like i had been transported to a set of star wars. It truly was unlike anything i have ever seen.
Teach, Learn, Share
I would love to share my music taste and experience I can't play anything yet but I'm looking to learn keyboard in the next few months:) I also can teach you to cooking some of my favourite dishes there isn't much to it but it'll be fun nonetheless:)
I want to meet all kinds of people from all over the world so I can broaden my understandings and appreciation for all things that are foreign from me!!
Countries I've Visited
Croatia, Hungary, Italy, Spain, Turkey, United Kingdom
Countries I've Lived In
Australia, Germany


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The Electoral College and Federalism
I was recently asked to participate in a workshop on federalism, and my first reaction was: "Is there anything new that I can say? Hasn't that topic been beaten to death?" Necessity worked its magic though, and I got to thinking about how the Constitution protects states.
At the Founding, the most important structural protection for federalism was a Senate comprised of appointees by state legislatures. Not far behind were the doctrine of enumerated powers and the Tenth Amendment. All of those safeguards were diminished by subsequent constitutional developments. In some instances the Senate does protect states or a given state, and there are a few cases that strike down an Act of Congress for violating federalism, but these occasions are few and far between.
So what does protect states nowadays? The answer is the Electoral College and the presidential nominating process. Take Ohio. It gets showered with attention by presidents and officials of both parties. Why? Because it is a swing state. That is now worth a lot more than having a powerful member of Congress. If the Electoral College were abolished and the winner determined by the national popular vote, no single state would get disproportionate attention. The same would be true for a given state if it went from a winner-take-all system to a proportional or congressional district method of allocating electors.
The question of which states are swing states is a product of demographics that are beyond their control. Iowa and New Hampshire's role in the presidential nominating process, however, is the product of a choice. The Iowa caucus does more to protect Iowa as a state than anything else. (Ethanol subsidies are a good example.) Ditto for any state that get itself early in the calendar (such as Florida).
There are many other interesting federalism issues raised by the presidential selection system. More on that next week.


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Cabin Fever: Patient Zero will begin shooting in the Dominican Republic next month and we have an update on who has been cast in the film.
We previously reported that Sean Astin (The Lord of the Rings) and Brando Eaton (Dexter) were starring in the movie and they are now joined by Lydia Hearst, Jillian Murray, Ryan Donowho, and Mitch Ryan.
Kaare Andrews will direct the film and this will be the first of two upcoming Cabin Fever sequels, with the next movie being titled Cabin Fever: Outbreak. In Cabin Fever: Patient Zero, a "bachelor party cruise in the Caribbean unexpectedly runs ashore on a medical-research island". Somehow a deadly virus is unleashed and, as you can probably guess, things won't turn out well for most of the survivors.
The script was written by Jake Wade Wall (The Hitcher remake) with Cabin Fever producer Evan Astrowsky producing once again, along with his company Hypotenuse Pictures and Indomina Group.


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Andheri tower blaze: Hoax call about trapped girl delayed rescue operations
After the control room received the first emergency call around 9.45 am about the fire at Lotus Business Park, the incident soon diverted all the city's emergency services to Andheri.
Also read: A fire NOC can be obtained for Rs 25 lakh, reveal senior fire officials
However, fire officials claim that the fire could have been brought under control much sooner had they not received a hoax call.
According to officials, they received a call from the control room, as they were about the reach the building, informing them that a girl was stuck in an elevator on the thirteenth floor. After receiving the false information, fire officials got busy trying to find the girl and sent a team to look for her inside the building. But, when they reached the thirteenth floor and managed to open the elevator doors, they did not find anyone inside.
Wild-goose chase: Fire officials claim that the call about the girl stuck in the elevator wasted a lot of their time, which could have been used for dousing the fire. Pic/Suresh KK
Officials said that after reaching the spot around 10 am, their first priority was to save the girl. This process of looking for her wasted precious time, which could have been better used for the dousing operation. One fireman died in the fire and several people were injured.
The firemen later found out that the girl they were looking for was already downstairs and out of danger.
Also read: One fireman killed, 20 injured in Andheri corporate tower blaze
"We received a hoax call about a girl stuck in the elevator, which wasted a lot of our time. We have informed the police and asked them to investigate the source of the call," said Deputy Chief Fire Officer, S H Nesarikar.
9.45 am: The time at which the control room received the first emergency call about the fire at Lotus Business Park


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At a meeting with his fertility-clinic partners and staff earlier this year, Dr. Carl Laskin was shocked to hear the latest figure.
Frozen in tanks of liquid nitrogen, he was told, the Lifequest office in downtown Toronto is holding 1,000 embryos belonging to in-vitro fertilization (IVF) patients who have essentially disappeared.
Across the country, in fact, fertility practices are storing thousands of such abandoned or "orphaned" embryos, while grappling with a moral and legal quandary: what to do with so many germs of potential human life when their owners are nowhere to be found.
Some are destroyed but most held indefinitely, partly out of a fear the patients will some day emerge from the woodwork, suddenly wanting to make another child.
Meanwhile, a bioethicist proposed a contentious solution at a conference last month — donate the stranded embryos to science rather than let them go to waste. Many clinics are unwilling to take that or any definitive action.
"The issue is, you are dreading that phone call from the couple that says, 'We've been out of the country and we've decided we want to use the embryos.… And [when told the material is no more] they say: 'You threw them out? How could you?', " said Dr. Laskin. "It is a very difficult area. As clinic directors, we talk about it frequently."
In fact, a University of Saskatchewan-based fertility scientist, Roger Pierson, said he knows of an ongoing case where the clinic donated a supposedly abandoned embryo to research, only to have the patient resurface — and be appalled at what had happened. The couple's lawyer is now involved.
Glenna Owen, a Vancouver woman whose two children, aged three and five, were born through IVF, said she is almost ready to allow her six surplus embryos in storage be destroyed, but admitted she feels a strong tie to them.
"It's kind of akin to your parents selling your childhood home: You don't want to live there yourself, but it is sad to see it go," she said. "As humans, we just form these attachments."
Part of the problem for the clinics is that, like so many aspects of the burgeoning field of fertility medicine, governments offer little guidance on the issue. A 2010 Supreme Court ruling left the area split between federal and provincial jurisdiction, but neither Ottawa nor most provinces have passed regulations on what to do with abandoned embryos.
"It is anywhere from disappointing to disgusting that we don't have an ethical framework," said Dr. Art Leader, another fertility physician. "Neither level of government really wants to touch this with a 10-foot pole."
The embryos used in IVF are created by fertilizing eggs with sperm in a laboratory. The result is barely recognizable as human material — a collection of as few as six cells that cannot even be seen with the naked eye. But for some infertile couples, single women and same-sex partners, they are the only route to having a baby.
Those that are not needed are cryo-preserved, giving the patient the option trying to conceive again later, with clinics charging storage fees of up to about $300 a year.
Sometimes, the fees stop coming in and clinics lose contact with the patient, despite considerable efforts to find them. The search can include sending letters and making phone calls, contacting the family physician and even reaching out to relatives, said Dr. Laskin.
Until several years ago, consent forms did not even address what would happen if patients no longer wanted surplus embryos — or abandoned them. More recently, forms have given patients the option of having them destroyed, donated to other couples or used in research.
'If it was me, I wouldn't be able to do that. It's worse than abortion'
Yet even when the consent document allows clinics to dispose of an orphaned embryo, many remain loath to act.
"What we spend all our time doing is creating embryos for people to help them have babies," said Simon Phillips, laboratory director at Montreal's Ovo Clinic. "It would be pretty difficult to have to allow them to perish."
A minority of clinics are more determined. Dr. Leader's Ottawa Fertility Centre, for instance, routinely destroys abandoned embryos, and has yet to receive any complaints.
Still, it is an emotional issue for the owners of those tiny collections of cells. Often the choice they made on lengthy consent forms in the tumultuous days leading up to IVF treatment changes when they are contacted much later, said Dr. Janet Takefman, director of psychology at Montreal's MUHC Reproductive Centre.
Those who managed to have a baby from their treatment, for instance, can turn against the idea of left-over embryos going to research, she said. "They have this live child, and they can't imagine experimenting on them."
Another option is for embryos to be "adopted" to patients unable to create their own, but fertility specialists say it is crucial to involve the parents of the embryo in that process.
Unwanted embryos are now used in stem-cell experiments and other research, when the patients are reachable and directly consent to it. But there is nothing legally or morally preventing clinics from doing the same with embryos that have been "willfully" abandoned, especially if the alternative is to destroy them, argues Ryan Tonkens, a former research fellow with Dalhousie University's Novel Tech Ethics unit.
For stem-cell research specifically, using abandoned embryos without direct consent may be inappropriate, as the life is in essence extended through the resulting stem-cell line, he said. But there is other science, such as developing more effective fertility treatments, that could benefit greatly from all those orphaned embryos, Mr. Tonkens said in a presentation to a Canadian Bioethics Society conference in June.
"Insofar as we expressly discard these abandoned embryos, we are wasting a valuable scientific and clinical resource," he said in an interview.
Most fertility professionals say they would balk at donating an embryo for research unless the patient could be contacted for permission, or there was at least legislation allowing it.
'It is anywhere from disappointing to disgusting that we don't have an ethical framework'
Gloria Poirier, acting director of the Infertility Awareness Association of Canada, said she believes the choice should be in patients' hands, but would personally be uncomfortable to see an abandoned embryo go to science.
"If it was me, I wouldn't be able to do that," she said. "It's worse than abortion."
The space requirements and cost of maintaining cryogenic equipment to store abandoned embryos is not a massive logistical or financial burden on clinics yet, but that will change, they say. IVF continues to build in popularity, and with it comes more and more embryos, noted Mr. Tonkens.
"It's a significant problem and it's a growing one … and we really don't have anything in place to deal with it."
National Post


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IRVING, Texas – With a T-3 finish at the HP Byron Nelson Championship, Charles Howell III earned the 24th top-three result of his career.
Two wins, 14 seconds, eight thirds.
Let's put this into a little context, though: On 22 different occasions, only one or two other players posted a better score for the week than Howell.
In a whirlwind close to Sunday's final round, he finished bogey-eagle-birdie-bogey to shoot a 3-under 67 and tie for third behind only Brendon Todd and Mike Weir.
"When you find yourself not in the mix, you kind of wonder if you'll ever get back there again," he said. "This is a hard game. These players are so good it's a challenge. So I've learned to appreciate the times I'm up there and try to take advantage of them. And in the hard times you just keep working and keep believing and try and find yourself there again."


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The east ridge of point...
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The east ridge of point 11,062 during an April 2005 attempt of Hilgard via Papoose Creek. This point is more easily accessed by the ridge on the west
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It is just a Puzzle! This is really going about nothing!
Isn't it bad enough that the stores rush the seasons??????????????
True, it won't be long now, the way time goes these days...
Well, to be honest I really had enough of Christmas so I thougt Easter is almost there....
First thoughts:-?????
wondered how long easter would take to arrive, curiosity satisfied
You are sad for making this jigsaw ,and I am sad for doing it


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Advanced WorkHorse PHANTOM Grenade 1" Nozzle - Phantom Sewer Nozzles - Advanced Infrastructure Technologies
Product Code: LHD-21.16
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Advanced WorkHorse PHANTOM Grenade 1" Nozzle
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It may come as a surprise to some but 2013 marks the 113th (!) anniversary of the New York Auto Show. From March 29 until April 7, the Jacob Javits Center at New York City will host the third major international auto show of the year on U.S. soil, in four levels and nearly 900,000 sq ft.
Even though it comes right after Geneva, the NY show isn't short on premieres – though, admittedly, the most important of them are targeted to the North American market.
General Motors, for example, will reveal no less than five new models, among them the all-new Cadillac CTS and the revamped 2014 Chevrolet Camaro.
If Geneva was the hypercar show, then New York is certainly the SUV one, with Toyota, Acura, Land Rover and Infiniti launching the Highlander, MDX, Range Rover Sport and QX60 respectively. Oh, and of course, Chrysler's brand new, controversially styled 2014 Jeep Cherokee will also make its world debut in NYC.
Last, but not least, the Hyundai group will unveil the new Equus sedan and the revised Kia Optima Hybrid and VW its new Golf in normal and GTI versions.
As always, the list that follows will be updated constantly so keep an eye on this page for any new info.
By Andrew Tsaousis


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Byrd Middle School is located in the Eastern San Fernando Valley section of Los Angeles and is a "Green" campus; having modern solar panels and energy efficient heating and cooling technologies.
Our school has top-notch teachers, administrators, and staff. Students who Byrd Middle School can be assured to receiving and excellent education and preparation for high school and beyond.
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Serious Reporting. Serious Business.
Linking directly to your accounting data is the key to automating your cashflow forecasts.
For Managing Your Business
Getting an accurate snap shot of where the business is going is important. Easy to understand reports and graphs enables informed decision-making.
Picture At A Glance
Sometimes, pictures can tell the story better than numbers. Summarised reports will give you an instant idea of key areas that need tweaking Enough information to make solid decisions and take action. Reports like the "Where Did Our Money Go" eliminate the complications spreadsheets cause and allow you to understand where the money has gone.
Project The Cashflow
Trading whilst solvent is a great responsibility and needs constant watch. Clear monthly cashflow reports and charts will guide you.
For Your Bank
Applying for that business loan is no longer just a simple process. Banks want 3-way forecasts and historical data to mitigate their risks.
Impress The Bank Manager
Easily create Profit & Loss and Balance Sheet budgets using shortcuts and wizards. Then just select the cashflow settings and you are ready to print out some visual reports that will make you look like a pro.
For Tracking Branches & Cost Centres
If you are trying to track the performance of various branches, departments or franchises, linking to the jobs or tracking categories in your accounting system is easy with Calxa.
Comparing Actuals Vs Budgets
Typing actuals into spreadsheets, updating new accounts, adding the latest jobs, classes or categories all adds up to days of work each month. Calxa links directly to your MYOB, QuickBooks or Xero automating this task and simply automates hours of tedious work.
KPI Reporting
Benchmark the performance of each department and run off a bar chart or simply add some Key Performance Indicators to your management reports.
For Planning Growth
Scenario planning is important in preparing for growth. Setting best and worst case budgets are important in forecasting the cash.
Scenario Planning
Easily prepare best case and worst case scenarios by setting up multiple budgets in no time. Create budgets for up to 10 years in advance to help with business restructuring, diversification or succession planning.
Cashflow Forecasting
Once your budgets are done, simply click on the forecast reports and track how the cash will flow. It's a great tool to help you plan ahead for the cash pain points.


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Preview Clip for House and Cuddy Hook-up Scene in Episode "Under My Skin"
TV Tonight: House
For the second year in a row, House seems to have really kicked it up a notch at the end of its season. Last year, the fantastic plotline was the death of Amber and the way it disrupted the bromance of House and Wilson. This year's killer story once again involves Amber — but now, she's back as some kind of apparition, haunting House and giving voice to some of his meanest and most devious thoughts.
It's in that environment that we get tonight's episode, "Under My Skin." It contains some pretty big developments for House personally and for his relationship with Cuddy. Lisa Edelstein recently chatted with reporters about the episode, and while the details are fairly spoilery, I'll be happy to spill and share some video of the episode when you
Word is this is the episode when House and Cuddy finally do the deed. Could it just be a hallucination brought on by House's pills (or lack thereof)? "There's a chance for anything, isn't there?" Edelstein said.
But while she wouldn't say what the latest twist in House and Cuddy's relationship might mean going forward, she was happy to talk about the scene itself. "I wouldn't complain," she said wryly. "We did probably about five takes — we didn't really do it for that long. . . . I have a great friendship with Hugh, and he's super sexy, so who could complain about kissing him?"
These moments with House and Cuddy aren't necessarily just a fleeting moment of passion — but nor does Edelstein expect that Cuddy and House will be the love story of the century: "I don't think it'll necessarily ever be a satisfying relationship in terms of both of them settling in and saying, 'This is what we're doing,' she said. 'She has a complicated relationship with men, it seems. She likes the screwed-up ones."
And if they do get together, it won't exactly rock the PPH world, she said. "I think that the rest of the staff is pretty much waiting fo them to get together. I dont' think it's a secret," she said. "It's not like he doesn't talk about it! He's constantly talking about her body. . . . It might as well be schoolyard banter with him chasing her and pulling her braids."
Curious to see how everything goes down tonight? Here's one clip to whet your appetite:
Photo courtesy of Fox


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- - Model is 177cm/ 5'10" and is wearing a size XSmall
In luxurious fine-knit silk, Alexander McQueen's ocelot-print cardigan is the picture of laid-back glamour. Pair yours with a muted color palette to keep the animal motif in focus - a leather skirt and black ankle boots will finish a fierce look.
Shown here with: Adam top, Eddie Borgo bracelet, Philippe Audibert bracelets, Aurélie Bidermann cuff, Roberto Cavalli cuff, Preen Line skirt, Wolford tights, Lanvin boots, Marc Jacobs clutch.
- - Brown and black ocelot-print semi-sheer fine-knit silk
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Belts for clothing; Jackets; Shoes; Tops; Women's clothing, namely, shirts, dresses, skirts, blouses
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Mindset has a powerful influence on your success or failure when it comes to money. Your daily thoughts determine your reality. What do you daily thoughts about money consist of? Are you constantly worrying about bills or your fleeting paycheck?
Your negative thoughts will attract negative outcomes - that is the law of attraction hard at work. This book helps you generate positive thoughts and feelings about money so that you are able to attract positive outcomes. The right thoughts about money are the first steps in achieving your financial goals.
These positive affirmations are designed to attract financial freedom and wealth. They are worded in ways to get you to accept that you are already wealthy - you only need to find your wealth. Set to calming music, this positive affirmations guide sets the stage for some very powerful thoughts about your financial success.
©2012 Zhanna Hamilton (P)2012 Zhanna Hamilton
"Gets you in the right mood for business"
Every entrepreneur and business person should have this audiobook in their motivational toolbox. It gets you into the right mood to do business, think big and have a positive attitude.
"amazing energy surrounding this audiobook"
Whenever I listen to this audiobook, I immediately feel like a money magnet and am always in a better mood. This has a very positive effect on my psyche. I think everyone worries about money and how to pay their bills on a regular basis. Anxiety about money can drain your energy, but this audiobook infuses me with the right frame of mind. Definitely something I will listen to multiple times.
"These are very strong money affirmations"
I enjoyed the affirmations, the music and the message behind this audiobook.
Ever since I was a child, I had known I was meant to be successful at something. My family wasn't rich - and my options weren't overflowing due to money. As I grew older, I realized my family had a bad attitude towards money. Their mentality was that we "never had enough", that the world had too much scarcity and that there wasn't enough to go around. Even before discovering the law of attraction, I somehow felt these conclusions were wrong. When I listened to this audiobook, that intuition came back to me. There is abundance in this world and you can have as much money as you are willing to work for. I have since then monitored my own thoughts about money and success. This book has helped me confirm what I've known all along - that it all started with your thoughts. Thanks for the great audio!
"Amazing Money Affirmations Audiobook"
I have listened to Rewire Your Brain: 300 Affirmations for Positive Thinking. I'd say they are tied, but serve different purposes. This affirmations audiobook focuses on prosperity, wealth, success, abundance and happiness. The latter focuses on positive thinking, well-being, health, success and seeing the world through a positive and healthy lens.
By the middle of the audiobook, I felt motivated to work on my freelancing business and focus more on wealth building projects. Sometimes, it takes a while for me to get motivated and amped about get more work done. However, after listening to this audiobook, I naturally felt self-motivated and inspired. It served its purpose and I will continue to listen to it whenever I need the motivation to do my best and focus on building my wealth.
Success is right around the corner - and that is exactly how this audiobook makes you feel.
"I enjoy it, every time I hear it !"
With a smooth and nice voice, affirmations in a lovely music background, cheers up my spirit! Short and effective ! I just love it !
"Helps keep me possitive!"
it helps keep me possitive, I listen to it while im at work and it lifts my sprit thru the day.
"Pleasant Voice"
Great affirmations in a pleasant voice with relaxing background music.
I wish I could only listen to track 2, but can't figure out how to make my tablet only play that track. I like to listen to it as I fall asleep, but when it gets to track 3 it always wakes me up!
"Very Meditative"
I loved the meditative delivery of the book. The background soundtrack was great for the message of the book. The soothing voice delivery was also great. I will be using this before bed to fall asleep to.
There really isn't a story, but it is a guided meditation.
The soothing voice and background soundtrack. I think the main point of the book is to be a guided meditation, and you cannot get that from a hard copy book, only an audio book.
There isn't really a movie that could be made of this audio book just due to the nature of it.
Great audio book that includes positive reinforcement meditation for the acquisition of money. I would not listen to this on a long drive, but for bedtime, plane ride, or just a relaxing moment after work, it is a great track to put on. It's only a touch over 30 minutes, so it is a great length for a quick pick me up.
"A True Jewel in the Law of Attraction Topic"
I would 100% recommend this to anyone who needs to get into the right mind from for making money and becoming more prosperous. It really all does start with your mind.
The narrator's voice is a confident and relaxed one. Every time an affirmation was read, I felt more excited about becoming more prosperous. There is something magical that happens when you realize you hold the power to change your career or business for the better.
This audiobook reminds you that you can thrive at anything - you just need to remember that you can. You are capable, and if you are willing - you can make as much as you want to make. It is all up to you!
"Perfect for a daily or weekly medotation"
This is a very calming way for focusing my attention on money. I will use her affirmations every day and use this full recording once a week for a full half hour meditation.
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It's the latest show of support for hit and run survivor--17 year old Christian Carrillo.
This time, a benefit was held by a group of nine year olds. The baseball team's head coach, Robert Martinez said,it shows the kids everyone has to work as a team, for this little boy to get healthy. It's all team work." He says the kids saw what happened to Christian and wanted to help. They held a bake sale outside of Shoe Carnival on SPID. They hope the money raised will help Christian's family with medical bills and any other costs his family might encounter. It was just yesterday when his family released video of the young man to show the progress he is making.