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Author Affiliations
- Jie Yu Ye1,
- Godfrey Chi Fung Chan1,
- Liang Qiao2,
- Qizhou Lian3,
- Fan Yi Meng4,
- Xue Qun Luo5,
- Levon M. Khachigian6,
- Ming Ma1,
- Ruixia Deng1,
- Jian Liang Chen1,
- Beng H. Chong6 and
- Mo Yang1,4,5⇓
- 1 Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China
- 2 Storr Liver Unit, Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Westmead, NSW, Australia
- 3 Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China
- 4 Department of Hematology, Nanfang Hospital, Southern Medical University, Guang Zhou, PR China
- 5 Department of Pediatric, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China and
- 6 Centre for Vascular Research, University of New South Wales, Sydney, Australia
- Correspondence: Mo Yang, Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. E-mail: yangm1091{at}yahoo.com.hk or Godfrey Chi Fung Chan, MD, Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong; Phone: international +852.28554091. Fax: international +852.28554089. E-mail: gcfchan{at}hkucc.hku.hk
Background Platelet-derived growth factor is involved in the regulation of hematopoiesis. Imatinib mesylate, a platelet-derived growth factor receptor inhibitor, induces thrombocytopenia in a significant proportion of patients with chronic myeloid leukemia. Although our previous studies showed that platelet-derived growth factor enhances megakaryocytopoiesis in vitro, the in vivo effect of platelet-derived growth factor in a model of radiation-induced thrombocytopenia has not been reported.
Design and Methods In this study, we investigated the effect of platelet-derived growth factor on hematopoietic stem/progenitor cells and platelet production using an irradiated-mouse model. We also explored the potential molecular mechanisms of platelet-derived growth factor on thrombopoiesis in M-07e cells.
Results Platelet-derived growth factor, like thrombopoietin, significantly promoted the recovery of platelets and the formation of bone marrow colony-forming unit-megakaryocyte in irradiated mice. Histology confirmed the protective effect of platelet-derived growth factor, as shown by an increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, platelet-derived growth factor had a similar anti-apoptotic effect as thrombopoietin on megakaryocytes. We also demonstrated that platelet-derived growth factor activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression.
Conclusions Our findings show that platelet-derived growth factor enhances platelet recovery in mice with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via platelet-derived growth factor receptors with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockage of platelet-derived growth factor receptors may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.
Platelet-derived growth factor (PDGF) is a 28–30 kDa protein originally found in and purified from the α-granules of platelets.1 The PDGF family comprises four different genes that form at least five different dimers,2 including PDGF-AA, AB, BB, CC and DD, which exert their biological functions through binding to PDGF receptors (PDGFR)-α and β.2,3 Only PDGF-BB interacts with both PDGFR-α and -β with high affinity.2–4 PDGF was originally recognized as a serum-derived growth factor in a variety of cell types.1,4 Genetic studies have shown that both PDGF-B and PDGFR-β knockout embryos develop thrombocytopenia and other lethal defects during development.5,6 PDGF also stimulates the proliferation of megakaryocytes, erythrocytes, leukocytes, and their progenitors,7–11 presumably through the multiple endogenous growth factors released from mesenchymal stem/stromal cells.8,10,12 More importantly, we have identified both PDGFR-α and β on human megakaryocytes and platelets.13,14 We have postulated that PDGF may directly enhance megakaryocytopoiesis via its receptors.9,10,13
Clinical data also suggest a potential connection between PDGF/PDGFR and thrombopoiesis. Imatinib mesylate (Gleevec or STI-571) has been used to treat patients with chronic myeloid leukemia (CML).15 However, a significant number of CML patients treated with imatinib mesylate have developed thrombocytopenia.16 The rate of imatinib mesylate-induced thrombocytopenia was found to increase from 24% in those with low-grade CML to 60%-72% in those with blast crisis. This imatinib mesylate-induced thrombocytopenia is associated with decreased megakaryocytic progenitors.16 In line with these clinical findings, recent in vitro studies have shed light on the possible mechanism of imatinib mesylate.17 As a tyrosine kinase inhibitor, imatinib mesylate has been found to be a potent inhibitor of both PDGFR-α and -β and their respective signaling pathways.18–20 These data point to a significant role of PDGF receptors in imatinib mesylate-induced thrombocytopenia. Moreover, imatinib mesylate also has anti-proliferation and anti-differentiation effects on human mesenchymal stem/stromal cells,21 which play an important role in supporting thrombopoiesis.
We previously found that PDGF enhances the proliferation of megakaryocytic progenitor cells and up-regulates the expression of transcription factors NF-E2, GATA-1 and c-Fos in megakaryocytes.10,13,22 However, the in vivo effect of PDGF in thrombocytopenic animals has not been reported. In this study, we investigated the in vivo effect of PDGF on hematopoietic stem/progenitor cells, and its effect on platelet recovery in radiation-treated mice. We particularly focused on the anti-apoptotic effect on megakaryocytes, and the PI3-k/Akt pathway, which has previously been shown to be involved in PDGF-dependent anti-apoptosis and proliferation in a wide variety of cell types.23,24
Design and Methods
Radiation-induced thrombocytopenia in mice and peripheral blood cell counts
Male Balb/c mice (7 or 8 weeks old) were obtained from Charles River (Yokohama, Japan) and given free access to food and water. Ethical permission for the studies was granted by the Animal Research Welfare Committee of the University of Hong Kong. The murine model of myelosuppression with thrombocytopenia was established by irradiating mice with 4-Gy irradiation.25 Animals were divided into three groups: a PDGF treatment group, a thrombopoietin (TPO) treatment group, and a saline control group. Mice were injected intraperitoneally with PDGF-BB (1 μg/kg/day) (PeproTech, NJ, USA), or TPO (1 μg/kg/day) (PeproTech, NJ, USA) or saline. The injections were performed on a daily basis starting from the day of irradiation. Peripheral blood platelets, red blood cells (RBC) and white blood cells (WBC) were counted in blood samples collected on days 0, 7, 14 and 21. Mice were sacrificed on day 21 and their bone marrow samples were harvested for colony-forming unit (CFU) assays and histological analysis.
Murine colony-forming unit-megakaryocyte assay
Bone marrow cells (2×105) were collected from the three groups of mice, after the animals had been sacrificed on day 21, and cultured in Petri dishes (35 mm, Lux) using the plasma clot culture method.10,26 The system contains 1% deionized bovine serum albumin (Sigma, MO, USA), 0.34 mg CaCl2, 10% citrated bovine plasma (Sigma), and Iscove's modified Dulbecco's medium (IMDM) with TPO (50 ng/mL) in a total volume of 1 mL. Dishes were incubated at 37°C in a fully humidified atmosphere with 5% CO2 for 7 days. After 7 days of incubation, the acetylcholine esterase staining method was used for identification of colony- forming unit-megakaryocyte (CFU-MK). A CFU-MK was defined as a cluster of three or more acetylcholine esterase-positive cells counted under an inverted microscope.
Murine bone marrow colony-forming unit-fibroblast assay
Mouse bone marrow cells (2×106 cells) from different groups were seeded in 2 mL of IMDM with 10% fetal calf serum using 35 mm Petri dishes in triplicate and maintained in a fully humidified incubator at 37°C with 5% CO2 for 9 days.8,26 Adherent cells were stained with Giemsa. The number of colony-forming unit-fibroblast (CFU-F) colonies was counted under an inverted microscope. An aggregate containing 20 or more fibroblasts was defined as a CFU-F.26
Other murine bone marrow colony-forming unit assays
To analyze the effect of PDGF and TPO on hematologic stem/progenitor cells, the CFU-mix assay was performed.26 Mouse bone marrow cells (2×105 cells) from different groups were plated into 35 mm culture dishes in duplicate in 1% of methylcellulose (Sigma) supplemented with 30% of fetal calf serum, 1% of bovine serum albumin, 0.1 mM of β-mercaptoethanol (Sigma), 10 ng/mL of interleukin-3 (PeproTech, Rocky Hill, NJ, USA), 50 ng/mL of stem cell factor (PeproTech), 3 U/mL of erythropoietin (Calig, Zug, Switzerland), and 10 ng/mL granulocyte-macrophage colony-stimulating factor (GM-CSF; Sandoz, Basel, Switzerland). The dishes were incubated at 37°C with 5% CO2 in a humidified atmosphere. Colony-forming unit - granulocyte-macrophage (CFU-GM), burst-forming unit/colony-forming unit - erythroid (BFU/CFU-E), and colony-forming unit - mixed (CFU-GEMM) were scored after 7 days.26
Bone marrow histology
Bone marrow samples from three groups of animals were collected on day 21, after the mice had been sacrificed. Tha samples were frozen in cryo-molds and cut into 5-μm sections. The slides were stained using the Wright-Giemsa staining method. Twenty-five high-power (400×) fields from each bone marrow sample were randomly selected and photographs were taken for analysis. The number of erythroid, granulocytes and megakaryocytes and their morphological changes were examined.25
Annexin V, caspase-3, and mitochondrial membrane potential analysis of M-07e cells by flow cytometry
The megakaryoblastic cell line M-07e (American Type Culture Collection, Manassas, USA) was maintained in IMDM supplemented with GM-CSF (20 ng/mL) and 10% fetal calf serum.26 To investigate the anti-apoptotic effect of PDGF, cells were resuspended in cytokine and serum-depleted IMDM medium. PDGF (50 ng/mL) or TPO (50 ng/mL) was added to the culture for 72 h. Cells were then collected for flow cytometry analysis. The population of apoptotic cells was measured by three complementary methods: annexinV-FITC/PI, active caspase-3-PE, and JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide) (BD Biosciences, San Diego).26,27 Ten thousand events were acquired for each sample and analyzed by flow cytometry using the Lysis II software (FACScan; BD Pharmingen).
Phospho-Akt analysis of M-07e cells by flow cytometry
M-07e cells were maintained in IMDM supplemented with GM-CSF (20 ng/mL) and 10% fetal bovine serum as described previously.26 Apoptosis was induced by serum and cytokine depletion. Cells were pretreated with wortmannin (100 nM) (Sigma) and imatinib mesylate (1 μM) (Novartis, MO, USA) for 30 min and 60 min, respectively, and then incubated with PDGF-BB (100–200 ng/mL) for 30 min. Cells from different treatment groups were collected and stained with anti-phospho-Akt (p-Akt)/PE antibody (BD Biosciences, San Jose, USA) (http://www.bdbiosciences.com/external_files/pm/doc/tds/cell_bio/live/web_enabled/558275.pdf) for flow cytometry analysis. Ten thousand events were acquired for each sample and the population of p-Akt positive cells was analyzed using flow cytometry.
Western blotting
M-07e cells were maintained in IMDM supplemented with GM-CSF (20 ng/mL) and 10% fetal bovine serum. Subconfluent cells were starved and pre-incubated with wortmannin for 30 min and imatinib mesylate for 60 min, and then stimulated with PDGF-BB for 30 mins. Cells were washed with ice-cold phosphate-buffered saline and lysed. Protein concentrations were determined by the Bradford protein assay. Proteins were then loaded on sodium dodecyl sulfate polyacrylamide gels and separated by electrophoresis. The gels were transferred to nitrocellulose membrane and blocked with 5% bovine serum albumin in Tris-buffered saline solution containing 0.1% Tween-20.28 Primary antibodies, phospho-Akt or Akt (Cell Signaling, MA, USA) were incubated overnight at 4°C. After washing, the membrane was incubated with secondary antibody, goat anti-rabbit antibody (Santa Cruz, CA, USA). Total Akt and phospho-Akt were visualized by ECL detection systems.
Colony-forming unit-megakaryocyte assay for imatinib mesylate study
Bone marrow cells (2×105) from Balb/c mice were cultured in the system as described before, with PDGF-BB (50 ng/mL) and/or imatinib mesylate (1 μM) and stained with acetylcholine esterase after 7 days of incubation. A CFU-MK was defined as a cluster of three or more acetylcholine esterase-positive cells.26
Statistical analysis
Data from different treatment groups were compared using Student's paired t test and are expressed as mean ± SEM. A P value of less than 0.05 was considered statistically significant. Three different symbols are used to denote P values: * means P less than 0.05, # means P less than 0.01, and + means P less than 0.001.
In vivo effects of platelet-derived growth factor on peripheral blood cell counts in thrombocytopenic models
On day 0, the basal numbers of peripheral blood platelets in experimental mice were around 580×109/L, and decreased after irradiation. The platelet counts of the irradiated mice reached a nadir (200×109/L) on day 7, but recovered gradually. There was no difference in platelet counts among the three groups at day 0 or day 7. Recovery was better in the PDGF-treated group than in the saline control group, and the PDGF-treated animals had significantly higher platelet counts at day 21 (344±18.37×109/L versus 264±19.65×109/L, n=5, P<0.05). Both PDGF and TPO had similar potency in accelerating platelet recovery in this thrombocytopenic model (Figure 1A). These results showed that PDGF, like TPO, had radioprotective effect on platelets.
The peripheral WBC and RBC counts also decreased following irradiation, with the nadir at day 7, and started increasing thereafter. No significant differences were found on day 0 or day 7 among different treatment groups. Compared to saline, administered to the control group, PDGF caused a significant increase in the number of RBC on day 21 (9.74±0.24×1012/L versus 8.40±0.32×1012/L, n=5, P<0.05), while TPO treatment produced better recovery after day 14 (Figure 1B). Although no statistically significant difference was observed in WBC recovery between the PDGF group and the saline control group, a trend suggestive of an increased recovery rate was evident for the PDGF group (Figure 1C). On the other hand, a significant difference was observed between the TPO group and the saline group. Our results demonstrated that PDGF has positive effects on RBC and WBC recovery, although the effect of PDGF is weaker than that of TPO.
Effects of platelet-derived growth factor on murine bone marrow colony-forming unit formation and bone marrow histology
Consistent with peripheral blood cell counts, there was a significant increase in CFU formation in the PDGF group compared to that in the saline group (Figure 2A). CFU-MK were cultured using the plasma clot method. PDGF, similar to TPO, significantly promoted CFU-MK formation (17.25±0.92 versus 11.50±1.50, n=8, P<0.05). CFU, including BFU-E, CFU-GM, and CFU-GEMM, formation assays were performed using the methylcellulose method. PDGF promoted the formation of BFU-E (35±5.97 versus 8.4±1.93, n=4, P<0.05) and CFU-GEMM (17.25±1.11 versus 8.8±0.73, n=4, P<0.01), but not that of CFU-GM, suggesting that PDGF enhanced hematopoietic recovery, except for the granulocytic lineage (Figure 2A). CFU-F were detected using a fibroblastic colony-forming assay. More CFU-F were found in PDGF-treated mice than in TPO-treated mice (Figure 2A), indicating that PDGF protected bone marrow stromal cells better than TPO did (21.13±1.53 versus 9.3±0.67, n=8, P<0.0001). The above data suggest that PDGF has a similar effect as TPO on CFU-MK, CFU-GEMM and BFU-E formation, further confirming the radioprotection of PDGF in hematopoiesis. PDGF had more significant and convincing effects on the megakaryocytic and erythrocytic lineages.
Bone marrow histology, assessed on day 21, revealed impaired hematopoiesis in irradiated control mice, as evidenced by decreased numbers of total cells. The numbers of necrotic and apoptotic cells were also higher than in normal mice that had not been irradiated. However, radioprotective effects were observed in both the PDGF-and TPO-treated groups as hematopoiesis was maintained, especially in the megakaryocytic lineage. Bone marrow was hyperplasic in the PDGF-treated mice. Significantly more megakaryocytes and their progenitors were found in PDGF-treated mice than in control mice. In addition, there was a significant reduction of apoptotic cells in the PDGF-treated samples (Figure 2B). In the TPO-treated mice, the recovery of megakaryocytes and their progenitor cells was better than the recovery of the granulocytic lineage and erythroid cells. Overall, there were more hematopoietic cells in the TPO-treated mice than in the PDGF-treated mice. These data suggest that PDGF significantly enhanced the recovery of the megakaryocytic lineage as well as hematopoietic stem and progenitor cells, although the effect was slightly weaker than that of TPO.
Effects of platelet-derived growth factor on in vitro megakaryocytopoiesis. Platelet-derived growth factor exerted anti-apoptotic effects on the Mo7e cell line
Apoptosis assays were performed to elucidate whether the radioprotective potential of PDGF on megakaryocytopoiesis may be a result of reducing apoptosis of megakaryocytes and their progenitors. Nutrition-depleted M-07e cells were treated or not with recombinant PDGF-BB or TPO. As shown in Figure 3, there was a marked increase in the proportions of early apoptotic cells [annexin V positive, propidium iodide (PI)-negative, R2], late apoptotic and necrotic cells (annexin V-positive, PI-positive, R1) and total apoptotic cells (annexin V positive, R1+R2) in nutrient-depleted cells compared to in the normal samples that had not undergone nutritional depletion. PDGF significantly reduced the proportions of early apoptotic cells (n=8, P<0.001) and total apoptotic cells (P<0.01) (Figure 3A). These data suggest that PDGF has an anti-apoptotic effect on megakaryocytes, and that its effect is similar to that of TPO.
Caspase-3 is an effector protein of the caspase family, which plays an essential role in apoptosis. Levels of active caspase-3 in serum and cytokine-depleted controls were significantly higher than those in normal samples that had not undergone serum and cytokine depletion (n=5, P<0.01), suggesting that apoptosis was induced. Addition of PDGF suppressed active caspase-3 expression (P<0.01) (Figure 3B). Similar results were also obtained in the TPO group, suggesting a decrease of apoptosis in PDGF- and TPO-treated cells. The data again showed an anti-apoptotic effect of PDGF on megakaryocytes, possibly through down-regulation of caspase-3 activity.
JC-1 can be rapidly taken up into mitochondria by the polarized mitochondrial membrane potential (Δψ) to form JC-1 aggregates in living cells. Depolarization of Δψ indicates altered mitochondrial function which could be used as a marker of apoptosis. JC-1 fluorescence in these apoptotic cells does not accumulate in mitochondria and remains as monomers (R2). There is a subset of transitional cells containing both monomers and aggregates (R1). Our data suggest that the proportion of cells containing JC-1 monomers (R2) increased significantly in serum- and cytokine-depleted cells compared with in normal samples that had not undergone nutritional depletion (n=7, P<0.001), indicating a drop in Δψ and an increase in the proportion of apoptotic cells. Treatment with PDGF reduced the population of apoptotic cells (P=0.01) (Figure 3C) considerably. The total population of apoptotic cells (R1+R2) in each group exhibited a similar fluctuation (Figure 3C), suggesting the anti-apoptotic effect of PDGF may be mediated by the intrinsic mitochondrial pathway.
Effects of platelet-derived growth factor may be mediated via platelet-derived growth factor receptor and PI3-k/Akt signal pathway
PI3-k/Akt is a well-characterized pathway that plays an important role in both anti-apoptosis and proliferation processes. To determine whether PI3-k/Akt is involved in PDGF-induced megakaryocytopoiesis, nutrition-depleted M-07e cells were incubated with PDGF alone or in combination with wortmannin (an inhibitor of PI3-k). Cells were then stained with anti-p-Akt/PE antibody. PDGF increased the expression of p-Akt (n=9, P<0.05) (Figure 4A), indicating Akt activation. The addition of wortmannin to PDGF cultures reduced the expression level of p-Akt (P<0.05). This PDGF-induced Akt phosphorylation was also confirmed by the western blot. Reduced p-Akt expression was found in the presence of wortmannin (Figure 4B). Wortmannin alone did not change the pattern of p-Akt expression in the two experiments. This observation indicates that Akt activation was abrogated by the PI3-k inhibitor.
In a further investigation for an upstream executor that triggers the PI3-k/Akt signal cascade, nutrition-depleted M-07e cells were treated with PDGF alone or PDGF plus imatinib mesylate. As shown in Figure 5, PDGF alone increased the production of p-Akt, determined by either flow cytometry (Figure 5A) (n=4, P<0.05) or western blot, while the addition of imatinib mesylate compromised the effects of PDGF (Figure 5B). Imatinib mesylate alone did not affect the expression of p-Akt. This indicates that PDGF triggered the PI3-k/Akt pathway via PDGFR, and that imatinib mesylate was able to block this effect. These results suggest that PDGFR are essential for activating the PI3-k/Akt pathway involved in the PDGF-conducted anti-apoptotic process in megakaryocytes. In summary, the megakaryocytopoietic effect of PDGF is likely to be mediated via its receptor with sub-sequent activation of PI3-k/Akt pathway. Blockage of PDGFR by imatinib mesylate was capable of inhibiting the downstream phosphorylation of Akt.
Effects of imatinib mesylate on platelet-derived growth factor-induced colony-forming unit-megakaryocyte formation
A CFU-MK assay of mice that had not undergone irradiation treatment was performed to determine whether PDGF was able to directly promote megakaryopoiesis and whether it would be affected by imatinib mesylate. PDGF considerably stimulated the size of acetylcholine esterase-positive megakaryocytic colonies (Figure 6A, upper right) as well as the number of CFU-MK compared with untreated control (n=6, P<0.005) (Figure 6B). Imatinib mesylate treatment reduced both the size (Figure 6A, lower right) and number of the colonies. This finding indicates that PDGF is capable of inducing megakaryocyte proliferation, suggesting an additional mechanism for PDGF-mediated radioprotection.
Here we report that PDGF effectively enhances in vivo platelet recovery in a murine model of radiation-induced thrombocytopenia. We further demonstrated that this protective effect is likely to be mediated via PDGF receptors with subsequent activation of the PI3-k/Akt pathway, which inhibits apoptosis in megakaryocytes.
In our previous studies, we found that megakaryocytes and platelets express both PDGFR α and β.13 PDGFR-β is also expressed in early hematopoietic/endothelial precursors.29 Activation of the various PDGFR triggers multiple cellular activities including cell growth, actin reorganization and migration.30–32 In this study, we showed that PDGF exerts an anti-apoptotic effect via an interaction with its receptors. Stimulation of PDGFR induces dimerization and stabilization which leads to auto-phosphorylation and hence provides the docking sites for different signaling molecules, including PI3-k. PI3-k then activates a subset of down-stream signaling executors, including serine kinases, such as Akt,33 by phosphorylation (Figure 7). It is well known that the PI3-k/Akt pathway transmits a cell survival signal in a large spectrum of cell types, and activation of this signaling confers resistance to apoptosis. However, the anti-apoptotic role of PI3-k in hematopoietic cells has been rarely reported. By using imatinib mesylate, a tyrosine kinase inhibitor, and wortmannin, a PI3-kinase inhibitor, we confirmed an involvement of PDGFR and activation of the downstream PI3-k/Akt pathway in PDGF-initiated megakaryocytopoiesis.
Phosphorylation of Akt prevents cytochrome c, a major component of the mitochondrial respiratory chain, from leaking out of mitochondria.34 Mitochondria play an essential role in the intrinsic apoptotic pathway through mobilization of cytochrome c and subsequent activation of caspase-9 and caspase-3, leading to apoptosis.35 On the other hand, blocking the release of cytochrome c from mitochondria inactivates caspase-3 and prevents cell apoptosis. Akt phosphorylation also directly inhibits caspase-3 activation (Figure 7).36 Our flow cytometry data showed that PDGF reduced the collapse of Δψ and attenuated the expression of active caspse-3, indicating that PDGF prevented megakaryocytic apoptosis through preventing the leakage of mitochondria membrane and reducing active caspase-3 expression (Figure 7).
The PDGF-initiated anti-apoptosis presented here at least partially elucidates the radioprotective effect of this growth factor. However, the mechanism may not be exclusive. Our previous studies and data shown in Figure 6 suggest a direct stimulatory role of PDGF on megakaryopoiesis and hematopoiesis. PDGFR are also found to be crucial in these biological processes.9,10 The administration of a PDGFR blocker may, therefore, impair the factor's stimulatory and anti-apoptotic effects. Imatinib mesylate is a tyrosine kinase inhibitor, and recent studies suggested that it can potently block both PDGFR- α18 and -β20 by inhibiting PDGFR tyrosine kinase activity in fibroblasts and various tumor cells. There are reports on CML patients15,16 and on patients with non-hematologic malignancies, such as gastrointestinal stromal tumors37 and glioma,38 who had had varying degrees of thrombocytopenia after treatment with imatinib mesylate. However, the underlying mechanism of the imatinib mesylate-associated thrombocytopenia has not been revealed. In vivo and in vitro evidence suggests that imatinib mesylate may directly inhibit normal hematopoiesis.39,40 In our present study, we found that inhibition of PDGFR by imatinib mesylate inactivates PI3-k/Akt signaling and PDGF-induced anti-apoptosis in megakaryocytes. This suggests that blockade of PDGFR by imatinib mesylate may reduce megakaryocytopoiesis leading to thrombocytopenia, highlighting a crucial role for PDGF receptors in megakaryocytopoiesis. Since PDGFR appear to participate in the pathogenesis of many human malignancies, it is not surprising that newer anti-tyrosine kinase inhibitors other than imatinib mesylate, such as sunitinib41 and nilotinib42, which also inhibit PDGFR kinase activity and their downstream signal molecules, could induce thrombocytopenia.
Essential thrombocythemia is a chronic disease characterized by thrombocytosis. Increased plasma levels of PDGF were found in patients with this disease.43 Increased PDGF expression was also observed in coronary artery smooth muscle cells from a patient with Kawasaki disease,44 a vasculitis associated with thrombocytosis. Serum isolated from patients with Kawasaki disease may also induce PDGF-B expression in vascular endothelial cells.45 Moreover, PDGF has been associated with idiopathic myelofibrosis,46 a chronic myeloproliferative disorder. This growing clinical evidence suggests that platelet overproduction in these patients is accompanied by increased PDGF expression or release. Hence, these disorders may be a consequence of PDGF-driven pathological thrombopoiesis, again suggesting a positive regulatory effect of PDGF in hematopoiesis, particularly in platelet production
we gratefully acknowledge the technical support of Mr. Shing Chan. We also acknowledge the following colleagues: Mr. Sau Wan Cheng, Mr. Ching Po Lau and Mr. N.H. Pong, from The Chinese University of Hong Kong for technical assistance in the animal study.
Funding: this work was supported in part by Seed Funding for Basic Research, The University of Hong Kong.
Authorship and Disclosures
The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.
Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.
- Received December 8, 2009.
- Revision received June 7, 2010.
- Accepted June 8, 2010.
- Copyright© Ferrata Storti Foundation


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I hope you all had a great Thanksgiving if you live in the USA. If not I hope you had a wonderful day as well. As the weather gets colder the thought of warm beverages is more and more inviting. Which brings me to my project for the challenge from the Paper Players. I'm using the Hug In A Mug Stamp set along with Coffee Café and Coffee Cups framelits.
I did my best to create a clean an simple card. Believe it or not this is pretty clean for me 🙂 .
Stamps: Hug In A Mug, Coffee Café Paper: Cherry Cobbler, Be Merry DSP, White, Dazzling Diamonds Glimmer Paper Ink: Cherry Cobbler Accessories: Layering Ovals, Stitched Shapes Framelits, Coffee Cups Framelits, Seasonal Layers Thinlits, Large Letters Framelits, Rhinestones, Stampin' Dimensionals
Here is the challenge that inspired my card:
If you need any stamping supplies I'd be happy to be your demonstrator. Just click on any of the items below or the Shop Now button and you'll go directly to my online store. If you have any questions or comments I'd love to hear from you.
Thank you for stopping by today,
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subset: commoncrawl


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How to Safely Bring a New Dog Home & Introduce Them to Your Kids
Get your camera ready for all the cute cuddle moments that are coming your way.
Is your family welcoming a new four-legged pup soon? Bringing home a dog is a very exciting time. However, there is a ton of preparation that needs to be done before the canine arrives. Outside of puppy proofing your home, getting them a bed, food, and toys, you need to teach your kids how to play with and approach the new dog.
While dogs are known as man's best friend, it is not uncommon for them to bite humans, especially small children that handle them poorly. According to 2018 dog bite statistics, 55.6 percent of all dog bite fatalities occur in kids less than 10-years-old. Dog bite injuries are also the fifth most frequent cause of emergency room visits for children.
Teaching your kids how to properly handle a puppy is not an easy feat. You will have to continuously remind them how to hold the dog, where they can pet the dog, and much more. These lessons will help facilitate a solid foundation, inspire a good friendship between your children and the canine, and most importantly, keep your child safe.
Here is what you should do before bringing your new pupper home.
How to Handle the Dog
Prior to bringing the dog home, you should teach your kids where they are allowed to pet them. Many young children think that the most effective way to get a dog's attention is to tap them, grab them, or pick them up. However, these quick and abrupt movements can often spook a dog and cause them to bite the person doing it to them.
To prevent dog attacks, tell your children to slowly approach the dog when they want to play or pet it. They should never sneak up on them from behind, shake them, or poke them. Warn the kids not to touch the pup if they are sleeping.
Educate your kids on the safe spots to pet or touch a dog. Dogs typically like to be touched on the side of their face, under their chin, and on their backs. This might not be true for all dogs, so observe your new pet and see if they have certain quirks and dislikes. Remind your kids that they should never pull on a dog's tail or legs, even if the canine is calm.
You should also teach your kids to read a dog's body language. If a dog is standing with a stiff stance, has their ears up, and are glaring at something, it most likely means that they are feeling aggressive. Alternatively, if they are shrunken down and trying to hide, it could mean that they are feeling anxious and nervous. Both of these poses could signify a bite or lurch. Watch your dog to learn their signs and prevent attacks.
The Introduction
First impressions are everything. If your child has a bad first meeting with the new family dog, they might be scared and be unwilling to trust the dog. This is also true for the puppy. Prior to bringing the dog into the house, familiarize them with the smell of your kids. You can do this by giving them a piece of clothing that your kids recently wore. Doing this will hopefully prevent them from jumping on your kids or barking at them when they meet.
When you finally let them into the house, keep them on a leash. Hold them tightly and close to your body so that you can keep them under your control. Allow them to slowly walk around and learn their surroundings. They will want to smell every nook and cranny of the dwelling, if possible. When your kids come, let the canine smell your kids and instruct them to stand very still. If the pup does something that you dislike or displays negative behavior, tug on the leash and say, "no" or "stop."
While the dog is still adjusting to the house and your family, keep them on a leash. This isn't meant to punish the dog, but allow it to have the time that it needs to learn their new environment. This will also, hopefully, keep your house in one piece. Stay patient with your new pet and stay patient as you get to know each other.


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Breakfast Porridges at the Jamaican Dutchy Cart
You may know The Jamaican Dutchy's cart on 51st Street and Seventh Avenue for its eye-catching flags, flat-screen TV, or tongue-searing jerk chicken. But as the New York Times tipped us off last week, this vendor does a mean breakfast trade.
While I wasn't quite up for ackee and saltfish at 7 a.m., the Dutchy's breakfast porridges sounded like the perfect thing to warm up a chilly Midtown morning. There's something different in the vat each day, and on Thursday it was hominy corn porridge—a traditional Jamaican dish, left to simmer long and low until the ample kernels soften and the whole porridge thickens.
For $4, I got an enormous steaming cup, sixteen whole ounces of piping hot porridge that even I, a hot-breakfast addict, couldn't finish. While nothing fancy to look at, it was creamy and sweet, with notes of cinnamon and nutmeg and vanilla, cradling large, squishy hunks of hominy. Tasty and hearty, it was the kind of morning meal that leaves you warmed from within and ready for the day. Especially after a beaming smile from the Jamaican man within.
Here's the daily schedule: Monday is cornmeal porridge, Tuesday is banana oatmeal, Wednesday is plantain, Thursday is the hominy corn discussed above, and Friday is peanut porridge. I just might see you there.
The Jamaican Dutchy 51st Street at Seventh Avenue, New York NY 10019 (map)
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The Montessori Academy of Chicago provides for a nurturing, authentic Montessori education and parent community, enriching the lives of Chicago's modern families and students. Our school is an extension of the home. Our parents have peace of mind. Our students are responsible and self-assured global citizens, prepared to lead in today's world. To kick off the admissions process, we encourage you to come visit us. To RSVP for a Coffee Chat, schedule a tour, or request additional information, please complete our inquiry form.
Admissions Process
You can apply to the Academy at any time, but we encourage you to attend an Admissions Coffee Chat prior to doing so. When we receive your application, along with a $150 application fee, a member of our Admissions Department will contact you with information about availability depending on your child's age and requested enrollment date. Once enrollment is confirmed, our Admission Department will work with you directly to introduce you to your child's new
teachers. Families enrolling in our Nursery Program should expect a teacher to conduct a home visit prior to your child's start date. Families enrolling in Primary, Elementary, or Middle School should plan for your child to visit her new class room prior to her start date. Elementary or Middle School applicants may be asked to visit prior to an enrollment offer. The Academy offers need-based financial aid, with applications processed by FAST aid system. Once your application is completed via the portal, our admissions team will receive an automatic notification and reach out to you.
Download an Application
You may submit an application at any time:
Send any questions or completed applications to: firstname.lastname@example.com Applications can also be dropped off in person between our operating hours of 7:00 a.m. and 6:30 p.m.
Coffee Chats
Admissions Coffee Chats offer prospective families the opportunity to speak directly with Academy staff, tour our state-of-the-art facilities, and observe our students in action. You will hear an informal presentation and Q&A about our school, our curriculum, and the Montessori approach–along with other components of our program that make the Academy unique. You will also be able to ask about specific information regarding the admissions process and availability.
If you're unable to attend one of our Coffee Chats, you may schedule a one-on-one tour by completing our Inquiry Form.
Coffee Chats are scheduled every other Tuesday from 9 – 10:30 a.m. and are for adults only. See upcoming dates below.
There are no Coffee Chats scheduled at this time.


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Today is the first day of our holiday – the mission day… our first flight of the trip! To be honest, it was a nightmare. I used to LOVE travelling and flying. But flying with a baby is NOT fun. Especially not flying four hours with a very active toddler.
But we survived and FINALLY made it to our lovely serviced apartment in central downtown Sydney just in time to flop on the bed and order some DELICIOUS burgers from room service, while bubba enjoyed munching on the hot chips.
It's a holiday… but not as I used to know it!


text: Guest r.schmidt Report post Posted March 3, 2006 Hey Guys, Figured I'd post this up even though it isn't finished. The idea behind it was to give the old XK a modern facelift and then place it into a setting that I thought suited it. I am thinking about adding a person descending down the stairs toward the car, and then I still need to fix some minor things like the perspective of the split windshields and the back wheel, and screw around with a couple other things like contrast, etc. I'd love to hear ideas about how to improve it, or maybe just what you think about it. I used sketchbook to draw the car and layot the backgorund, then brought it into painter for the painting, then cleaned it up in photoshop. All in all it took probably 7-8 hours stop and go, wasn't really rushing it, just doing it for fun. Share this post Link to post Share on other sites


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Apparently still a favorite of police departments. Accosted by word processors, and the ease of sending emails. Wounded by the fillable PDF.
Desktop Computer
Preferred by the government, cash-flush companies, and extreme gamers. Also used by those with work-life balance, who leave the computer in the home office.
Laptop Computer
Digital natives adapt seamlessly to smartphones, leaving heavier Windows-operating machines to suit-and-tie professionals. Where's the USB port on the Apple iPad? There is none. Low-cost Netbooks fill gaps which smartphones are ill-adept, such as word processing.
Vinyl Record Players
They're coming back, right? You can get your favorite alt-rock hits on new vinyl.
They have a bad rap for being associated with bad news, whether in 1928 (1) or in WWII. But they could also be used for good news as well.
It was more convenient to use a telex or fax machine than walking to the telegram office. Long-distance phone calls and later email displaced the messenger boy.
Reliable, lower cost international phone service and the
internet banished the typewriter-resembling device from land. Still
reigns with pilots and mariners in the air and at sea.
Fax Machine
Dogbert from the Dilbert cartoon may have hated the fax machine, but I. Technophobes in some state legislatures have not allowed signed emails to hold the same legal status as faxed documents. For this reason, lawyers and doctors err on the side of conservative caution and continue to use fax. From my point of view it is a convenient way of sending medium-sized documents, as an alternative to priority mail. Fax machines work on the basis of dial-and-send. To email a document, you must fire up the computer, scan each page, create an email and attach the scanned files. Beware: smartphones, with snap-and-send features, are eliminating this advantage.
Forget putting dimes in the copy machine. The all-in-one machine meant that a family could get a full-color printer, a copier, scanner and fax machine for the price of one machine.
As far as old technologies go, sending a letter is really easy. Stamp and envelope and go to a blue mailbox- or raise the flag on your own mailbox. And for those dreaded bills, you can save a stamp and pay online. It also helps the business save on data entry staff.
Regular correspondence is cheaper and faster by email, unless it's the US Navy. From boot camp letters to family photos sent to sailors on ships, snail mail is slow but ultimately reliable.
Telephone Operators
Direct dialing of long distance calls began in the 1950's. Local calls in big cities were automated even earlier. Large businesses and institutions kept telephone operators until relay electronics and computers became widespread, allowing extension lines to be dialed directly. If you are feeling nostalgic, call a friend in his or her hotel room. You will likely be connected through the front desk.
Dial Up Internet
According to Time Magazine, about 3% of internet users in the US still use a dial up service. In the 1990's, dial-up was slow but awe-inspiring. Today, it's fairly slow, and the modern age has adapted to DSL and other high-speed services. You can't watch videos, but you can check basic email. Better than nothing.
Landlines and DSL
The younger generation wants their smartphones, and want it now. This increasing traffic has proven a challenge to wireless data providers on 3G and LTE networks. A sober approach would be to increase use of wired internet through seamless WiFi connections in public spaces; providers must adapt to the reality that "millenials" are choosing to forgo wired services like landlines and DSL internet.
Overnight Letters
Fred Smith thought that the Dilbert-era 1990's fax machine (and later, email) would kill his Federal Express business. Instead, the need for overnight parcels kept increasing. Overnight mail is my preferred method of transmitting large documents from overseas, since some fax machines reject international lines.
Camera Film
It used to come in rolls of 24 exposures. You paid for the roll of film and you paid for the development at a photo lab. You made three trips to get a photo: one to buy the film, one to drop off the completed roll of film, and one to pick up the developed pictures. For this reason, places like convenience stores and groceries were 'in' on the photo business. Polaroid was a bit different; my family never had one but the photos would be ready after a few minutes.
CD Players and Walkmans
"Want to buy a Tower Records?" asks Sean Parker, the founder of Napster. Still used by my family's 2006 Volvo and durable home stereo. With a near-ban on USB sticks, Uncle Sam is propping up the decades-old CD-ROM industry. CDs were replaced by the MP3 player for music, notably the iPod and Zune, which were supplanted by smartphones. Files went to USB sticks and cloud services.
Floppy Disks, Cassette Tapes and VHS
Navy ships commissioned in the early 1990s used state-of-the art computer technology, including floppy disks that saved engine performance data. Comparison with today's readings would guide maintenance planners as the ships enter mid-life.
For tapes and VHS, remember to be kind and rewind.
Punch Cards
Unlike most of today's electronics, the machines were pretty durable, and some served into the computer age. I have come across these cards in the back of library books.
Carbon Copies
Today, making a copy of a saved document is as easy as Control+P.
Carbon copies are still used on handwritten forms like sales receipts of small businesses.
Handheld tablets and the ubiquity of credit card use meant that manual imprint machines gave way to point-of-sale receipt printers.
Rooms filled with Filing Cabinets
I like to keep paper records for the day we are hit by solar flares. Many people go full electronic, and for many businesses, retaining paper records means paying for storage space in the tunnels of Iron Mountain. You can sympathize with the secretary who was replaced by Control+F on the keyboard, with which you can find a long-lost e-file in a few seconds.
Flip Phones
Once a technological breakthrough. Today, they are relegated to 'late adapters' and business that hand out no-fun dumbphones to employees.
Creative destruction at its finest. Mobile internet became more widely available and ended need for proprietary services; but more importantly, seemed to fall behind learning curve.
(1) http://www.telegraph-office.com/pages/telegram.html
Thursday, August 17, 2017
The Old Technology Review
Posted by Atticus Sawatzki at 11:23 PM No comments:
Labels: History, Technology
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Businesses today are in competition with each other on reaching to the customers first. For this reason, the pressure on the supply chains and warehouses is very much. If you need to make your business successful and your clients happy and satisfied, you must choose the warehouse space carefully. When looking for the best warehouse Singapore, you can check whether the place is insured or not; will it be able to handle, packing and crating, labeling, dispatching, inspection, dispatching and reporting; the layout of the warehouse and its capacity; facilities offered.
Place your trust in SDR Logistics for all the services mentioned as we have been in the business for a long time.


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Doctors have a host of medicines to control pain ranging from over the counter medicines like paracetamol right up to very strong opiates like morphine.
Baby-Arabia will now look at the most common drugs used in labor for pain relief…
This is a mixture of oxygen and nitrous oxide gas. Gas and air won't remove all the pain, but it can help reduce it and make it more bearable. Many women like it because it's easy to use and they control it themselves.
You breathe in the gas and air through a mask or mouthpiece, which you hold yourself. The gas takes about 15-20 seconds to work, so you breathe it in just as a contraction begins. It works best if you take slow, deep breaths.
This is an injection of the drug pethidine into your thigh or buttock to relieve pain. It can also help you to relax. Sometimes, less commonly, a drug called diamorphine is used.
It takes about 20 minutes to work after the injection. The effects last between two and four hours, so wouldn't be recommended if you're getting close to the pushing (second) stage of labor.
There are some side effects to be aware of:


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I started a new journal today.
My purse journal had been filled with notes from a seminar, drawings by the Magpie and myself and scraps of notes, price comparisons and phone numbers. There wasn't a blank scrap left. So, today, I wrote the first lines in a brand new coiled book, capable of surviving life in my purse, work back and the occassional toddler doodle.
I can only lust after moleskins from afar; I'm far too scared to cough up the price knowing the torture it will have to endure.
Here is the first entry:
Tues, 29 Jul 2009.
The label on my Starbucks sandwich ways "USE BY 29JL09".
And so I shall start my new journal in the sweltering summer heat, over an iced Americano and nearly expired baguette.
Smells okay.
I have not been blogging nearly as much – who has the time? – and until the day I have a netbook and the where-with-all to carry it with me everyone, I won't. With five blogs and four journals and facebook and twitter, it's amazing anything ever gets updated.
And now I am registered for a course in the fall. I am also registered for a reiki level 2 class. I am, however, the only person registered in each, at the moment, so we'll see if either one goes ahead.
And, all of this, of course, is secondary to the Little Girl. Sometimes even the husband and animals too… 🙂
But the Little Girl is 3 going on 30 and has very strong opinions that are all subject to change at a moment's notice. She has to try everything for herself. She has a tonne of friends and no known enemies. She loves the aquarium, the art museum, skytrain and the beach. She desperately wants a bicycle and to go on a helicopter ride. She likes chocolate bars and Smarties, but only wants vanilla ice cream.
I could go on for another few pages – the danger of starting a journal entry – but it's tiem to go back to work.
So many blank pages. So little time.


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Metlox -Vernon Kilns Pottery "Aztec" Creamer
$8.00Or Best Offer
Quantity available: 1
Metlox-Vernon Kilns Pottery "Aztec" Creamer. This Creamer is 6 3/4" Long and Holds 7 Oz. This is a Very Hard Pattern to Locate. The Replacement value of this Creamer is $17.00. Ref-V#24
Prairie Peddler
Brighton, Illinois
Dealer accepts: PayPal, Money Order
Shipping: $10.00


text: Feel Good Watercolor Painting Posted by dcastr on May 15, 2019 Posted in: Drawing On The Ritz, Paintings. Tagged: DCastr, feel good, Happiness, happy face, praise, smile, Water color, Water color painting. Leave a comment "FEEL GOOD" Watercolor painting I did today. New paper. 6X9 inches. bought two sets 30 pages each. If I can complete half a book I'll title the collection and print it.


text: Sinkest 39 Posted October 10, 2018 9 minutes ago, Gauge said: Said by a low level player. Trust me, once you get high enough level with crap gear, it doens't matter if you can buy scrolls or soul soulshots. The number 1 problem affecting this game is the adena and drop rate. This affects ALL players equally. There is no economy without this. I understand they want to monetize the game somehow, and I'm ok with that, but if you are VIP4, you should not be playing a gimped version of the game. VIP4 should be normal drop rates. I really don't care if they sell soulshots on the L2Store. Nothing matters without an in game economy. No talking, arguing or anything matters without that. You are wrong. If nobody can afford soulshots in game and someone buys them on the store then they are directly buying power. Two exact same characters fight and only one has soul shots the one that has them will win hands down. Yes the number one problem is the adena drop rate and that is directly what makes buying soul shots in the store P2W. If everyone could afford them in game then it wouldn't be an issue. Also, if a person .buys soul shots from the store then that lets them save adena to spend on gear meanwhile the other person wouldn't be able to. Share this post Link to post Share on other sites


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Please Note: This article is written for users of the following Microsoft Word versions: 2007, 2010, and 2013. If you are using an earlier version (Word 2003 or earlier), this tip may not work for you. For a version of this tip written specifically for earlier versions of Word, click here: Adjusting Column Width from the Keyboard.
by Allen Wyatt
(last updated August 22, 2018)
Many people who are familiar with WordPerfect later find the need to learn how to use Word. Sometimes the transition is not entirely smooth, in large part because tasks aren't accomplished the same way in Word as they are in WordPerfect.
A case in point is adjusting the width of table columns by using the keyboard. WordPerfect, which has always been a "keyboard oriented" program, makes the adjustments easy: just press > or < to widen or narrow the column. Word, on the other hand, has always been more mouse oriented and has no equivalent keyboard command for this task.
There are workarounds; for instance, you can use the keyboard to type Alt+A, R, U, and then press Tab a couple of times to get to the column width field. The problem with this, of course, is that it is not anywhere near easy (or intuitive).
If you don't mind using the mouse, you can hold down the Alt key as you drag a column border. The Ruler changes to show the precise width of your columns as you move the border. Very cool, but still a pain for those who would rather just use the keyboard. (It is also not terribly helpful for those who may not have very good mouse resolution or who cannot move the mouse very small distances.)
Perhaps the best solution is to make your own emulation of the WordPerfect capability. The following macro can do just that:
Sub StretchColumn() Dim iCol As Integer Dim sCurrent As Single If Selection.Information(wdWithInTable) Then If Selection.Columns.Count = 1 Then iCol = Selection.Cells(1).ColumnIndex sCurrent = Selection.Tables(1).Columns(iCol).Width Selection.Tables(1).Columns(iCol).SetWidth _ ColumnWidth:=sCurrent + 1, RulerStyle:=wdAdjustNone Else MsgBox ("More than one column selected") End If Else MsgBox ("Insertion point not within a table") End If End Sub
If you assign this macro to a shortcut key (as described in other issues of WordTips), then you can increase the width of the current table column by one point (1/72 of an inch) each time you press the shortcut key. You can make a simple change to the macro to create a version that decreases the column width, as well:
Sub ShrinkColumn() Dim iCol As Integer Dim sCurrent As Single Dim sNext As Single If Selection.Information(wdWithInTable) Then If Selection.Columns.Count = 1 Then iCol = Selection.Cells(1).ColumnIndex sCurrent = Selection.Tables(1).Columns(iCol).Width sNext = sCurrent - 1 If sNext < 1 Then sNext = 1 Selection.Tables(1).Columns(iCol).SetWidth _ ColumnWidth:=sNext, RulerStyle:=wdAdjustNone Else MsgBox ("More than one column selected") End If Else MsgBox ("Insertion point not within a table") End If End Sub
WordTips is your source for cost-effective Microsoft Word training. (Microsoft Word is the most popular word processing software in the world.) This tip (13369) applies to Microsoft Word 2007, 2010, and 2013. You can find a version of this tip for the older menu interface of Word here: Adjusting Column Width from the Keyboard.
Comprehensive VBA Guide Visual Basic for Applications (VBA) is the language used for writing macros in all Office programs. This complete guide shows both professionals and novices how to master VBA in order to customize the entire Office suite for their needs. Check out Mastering VBA for Office 2010 today!
Like to use the mouse to help you with your document editing? You can move table rows and column with the mouse by using ...Discover More
If you make structural changes to your table by adding new columns here and there, you could easily end up with a table ...Discover More
Word's new Insert Column and Insert Row tools can be a timesaver when adding table rows and columns. They can be a ...Discover More
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2018-08-22 13:13:02
Check this out, Mike:
2018-08-22 12:55:57
Your tips are awesome. They clarify questions before they are asked.
One issue that annoys me a lot is having files I created become read-only when it wasn't requested.
Would love to read an answer to that annoyance.
Thanks for everything.
Got a version of Word that uses the ribbon interface (Word 2007 or later)? This site is for you! If you use an earlier version of Word, visit our WordTips site focusing on the menu interface.
FREE SERVICE: Get tips like this every week in WordTips, a free productivity newsletter. Enter your address and click "Subscribe."
(Your e-mail address is not shared with anyone, ever.)


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Ubisoft has announced that The Division closed beta will start on the 28th of January on Xbox One, and on the 29th of January on PS4 and PC. The closed beta will run on all three platforms until the 31st of January
In order to get access to the beta, players will need to pre-order the game. There's also the option to register your interest on The Division's website, however, only a few will be selected. Meanwhile, Ubisoft has yet to reveal the amount of content that will be featured in the beta.
Tom Clancy's The Division releases worldwide on the 8th of March.


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Where we can go in Verona
Ciao my friends. I will spend 10 days in Verona for Marmomacc exhibition next month. Could you show me 1. Some good small hotels with price 50..100EUR 2. Where we should go for drink or dancing in the evening, after exhibition. 3. I may spend some more day after exhibition in Italy for holiday, where I should go and visit? Especially some places closed to Verona? Thank you.
Country: Italy
Close to Verona you may visit the Garda lake. In particular the peninsula of Sirmione (thermal baths and roman ruins) and the "GardaLand" amusement park.
never tought to have some climbing or hiking experience on Garda Lake?
visti my web site or my profile. Bye stefano
visti my web site or my profile. Bye stefano
for hotels there are many you can have s look at tripadvisor for cities there around do not miss venice and padova
More Information
Get travel answers from locals in Italy


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showing 1-1 of 1 breaks
A snapshot from the early Earth
The physical and chemical evolution of planets relies on certain volatile elements, such as Hydrogen (H), Carbon (C), and Nitrogen (N). For instance, on Earth volatile elements influence magma chemistry, volcanism and the evolution of our atmosphere and climate. Perhaps most important, the presence of... click to read more
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Search found 1 match
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- Tue Feb 17, 2015 1:30 pm
- Forum: Help Forum
- Topic: installPackage() path name
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installPackage() path name
I'm trying to use installPackage() on an xml file off of my drive. When I do that using the xml file's path, the package is installing using the entire path as the package's name instead of just the package name. I've seen a workaround for this before, but I'm having a lot of trouble retracing it. D...
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Tag Archives: Dental Digital X-ray
Dental Digital X-ray Market Size Incredible Possibilities and Growth Analysis
The ****** Dental Digital X-ray market factors such as technological advancements, rapidly growing geriatric population, ability of digital systems to reduce diagnosis time and provide improved image quality, growing adoption of cone-beam computed tomography (CBCT), increase in dental disorders, and the growing demand for cosmetic dentistry are propelling the market of dental digital X-ray during the forecast period.
On the basis of type, the market is segmented into extraoral X-ray systems and hybrid X-ray systems. The extraoral X-ray systems segment accounted for the largest market share in 2015. This segment is further categorized into panoramic/cephalometric X-ray systems and cone-beam computed tomography (CBCT) systems.


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An AIDS Quilt Songbook: Sing for Hope album available November 18
Isabel Leonard joins a roster of acclaimed colleagues, including Joyce DiDonato, Melody Moore, Anthony Dean Griffey, Nicole Cabell, and Sean Panikkar, on An AIDS Quilt Songbook: Sing for Hope, a new album with all profits benefiting amFar, the foundation for AIDS research. Ms. Leonard and others lend their voices to this effort, performing songs from some of America's preeminent and emerging composers. Acclaimed cellist Yo-Yo Ma and clarinetist Anthony McGill are also featured on the recording, with actors Sharon Stone and Ansel Elgort providing spoken word. This landmark album will be available via Amazon on November 18 – pre-order your copy today!


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Booking Forms for the 2019 / 2020 School Year
Guidance to Parents
The Brownlee After School Club is organised and run by Brownlee
The After School Provision at Brownlee operates Monday to Friday during term time from 2.00 – 6.00pm with two intake times at 2.00pm and 3.00pm. At 3pm children from P4-7 have a choice of taking part in the activities organised by the After School Club or in the normal extra-curricular activities organised by the school.
Some extra-curricular activities which are organised through outside agencies require a nominal fee to be paid for each child taking part. Children from the After School Club who wish to attend these activities will not be charged this fee.
Activities offered by the After School Club include;
- Use of the computer suite
- Outdoor games
- Structured Play
- Drawing and painting
- Craft activities
- Games and puzzles
- Friendships
- Healthy snacks
- Homework club
A Healthy snack is available to children at 4.00pm and is included in the fees of the After School Club.
The Homework Club is available to children availing of the whole session (2/3-6pm) and usually runs from 4:00-5:00pm
The whole day session – 2.00/3.00pm – 6.00pm = £12.00 per day
We also offer a £4.00 per hour rate
There is a minimum charge of £1.00 per child during the first 15 minutes after the agreed collection time has elapsed. After the first fifteen minutes, we will have to charge the full hourly rate as normal.
At the beginning of each month parents are given a sheet showing the days that the After School Club will be open. Parents should complete this indicating the days and times they wish their child to attend, and enclose the appropriate payment.
Unfortunately, we cannot refund money if a child is collected early as the staff are still contracted and paid up until the end of the club at 6.00pm. We have found from experience that calculating refunds and exchanging early and late collections only serves to cause unnecessary paper work and confusion.
Tax Credits
Our After School provision is approved and Tax Credits for childcare can be claimed back using the Education Authority as the named childcare provider.
The After School Club is organised through Brownlee Primary School and therefore is covered under the insurance held by the Education Authority.
Contact Information
Parents should give the leaders all relevant contact and medical information relating to their child. It is important that the club is kept informed of any allergies or medical conditions that may have an impact on the activities that a child can be involved in.
Homework Club
Homework will be supervised each day by After School staff. Although this homework has been supervised, it is still the parents' responsibility to ensure that it has been completed correctly and signed.
Health and Safety
All activities undertaken in the After School Club have been given a risk assessment and will be totally safe for your child to be involved in. All procedures will be in accordance with the school's Health and Safety Policy.
Child Protection
The After School Club will be organised in line with the school's Child Protection and Pastoral Care policies as well as the 2017/04 Child Protection document published by the Department of Education. All staff have been vetted and police checked prior to taking up employment at the school and are aware of Child Protection issues.
Staff however will not be left alone in a one to one situation with any child during the After-School club.
Children who attend the After School Club are expected to behave as they would at any other time of the school day. Children should be polite and courteous to all members of staff and respectful to each other. Procedures and sanctions for discipline in the After School Club are in line with those contained in the Brownlee Primary School Discipline Policy.
The Brownlee After School Club does not receive additional funding from any outside source. Any profit made once wages and resources are paid for is transferred into school funds.
Parent Interviews
During parent interviews, when pupils normally leave school at 2.00pm, the After School Club will take care of those children who booked in to attend the club from 3pm. There will be no additional charge for this. Others may book between 2.00-3.00pm at a cost of £4.00.
Early Closing
School normally closes at 12.30pm prior to the Christmas, Easter and Summer holidays. There is no After School provision on these early closing days.
Full copies of school policies for Discipline and Child Protection are available to be viewed on the school website at;


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Ron Viejo de Caldas Gran Reserve
Aged Rum
Ron Viejo de Caldas // Colombia
The Ron Viejo de Caldas line of rums originates in Colombia and is produced by the state-owned Industria Licorera de Caldas. This particular expression is aged for a minimum of eight years in oak casks at high altitude. There are conflicting reports of it being either virgin oak casks or ex-bourbon. The packaging is spartan, but the pricing is fair for what it is.
age8 year
Aged RumRum that is aged, but no specific type or size barrel required. No set time required for length of aging, but will often carry an age statement (which should be taken with a grain of salt). Often thought of as "sipping rums".
Cask Typeoak
Tasting Notes
"The color is surprisingly dark for an eight year rum. The nose brings to mind vanilla and oak, reminiscent of bourbon. The initial taste includes a bit of peppermint and menthol, which fades quickly. From there the flavors become subtle, with a very dry finish with no indication of added sugar. Although not particularly complex or an everyday sipper by any stretch, it's a good match for cocktails calling for a light, dry rum in the Nicaraguan or Cuban style. You might be tempted to dismiss it as a bottom shelf rum, but if given a chance, you'll find it has more than a passing similarity to Cuban rums of the same age."


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With charming illustrations from Salvatore Rubbino, this delightful non-fiction picture book tells the story of a rescue dog. Sophie is a boisterous and lovable Jack Russell, brought home from a rescue centre. The book follows her delightful adventures: join Sophie and her new family as she learns how to respond how to orders such as "sit" and "stay", is taken for walks in the park where she encounters other dogs and accidentally wins a dog show! The smaller caption text gives readers information about feeding and grooming your dog, different dog breeds, communication and training, and how dogs respond to human voices. The back matter includes a helpful index and bibliography.
Categories: Non-Fiction
For readers aged: 5+
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Copyright © 2008 Walker Books Ltd. Designed by Magic Lantern Productions Ltd. Built by Virtusales Ltd.
Walker Books Ltd., 87 Vauxhall Walk, London SE11 5HJ. Registered in England under Company No. 1378601


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BLM's James Harvey and David Thompson have provided an update on Vnuk in the latest edition of Airmic News.
Discussing the need for clarity from the European Commission on how to deal with the ramifications from the European Court of Justice on the Vnuk decision, James and David look at the changes that the decision has brought about, the impact of Vnuk on recent court decisions and the recently launched consultation.
They also tackle the question that many are asking which is are UK insurance costs on the rise as a result?
To read the full article please click here.
<< Back
Disclaimer: This document does not present a complete or comprehensive statement of the law, nor does it constitute legal advice. It is intended only to highlight issues that may be of interest to customers of BLM. Specialist legal advice should always be sought in any particular case.
For more information about any of our news releases, please contact:
Natalie King
+44 20 7638 2811
+44 20 7920 0361
Email Natalie
Semi Da-Cocodia
+44 161 236 2002
+44 161 838 6840
Email Semi
Jo Murray
+44 20 7638 2811
+44 20 7865 4849
Email Jo
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Monthly Archives: December 2014
Simeon held to a promise
That he would see God's Son;
That he would not die but live
To hold the Holy One.
Simeon watched for Him each day,
In prayerful meditation,
Until in his arms there lay
The Savior of nations.
Anna watched and waited too;
She served God day and night,
Till she saw Messiah who
Would set the world right.
When we watch and pray, we know
We will see Jesus too;
He opens our hearts to show
Himself to me and you.
Seek the Lord who makes you whole
And you will surely see
Him the Lover of your soul,
King through Eternity.
The flower started as a seed,
Hidden in a secret place
That cradled and nurtured it
Providing a growing place.
The seed had everything needed
To germinate, sprout and grow
Into the lovely flower
That would be admired so.
The rain and sun brought nourishment;
That helped to make the plant strong;
Fresh air boosted the fragrance;
The roots grew deeper and long.
Then at last the flower blossomed
With petals so soft and fair
Standing in glorious splendor,
Its beauty beyond compare.
Then the blossom turned back to seed;
It faded, withered and died;
But the seeds will live and grow,
Becoming the flower's pride.
And so it goes every season:
Reminders of life and death;
Starting in secret places;
Emerging to light and breath.
All things in nature around us
Tell about Heaven above,
Pointing to God's provision;
Expressing His endless love.
A new description of hope came to me this morning: Confident expectancy.
With that in mind, here is a poem:
Because God is good;
Because He loves us so;
We have every confidence;
We truly know
Every perfect gift
is presented to us by Him,
Until our expectancy grows brighter,
Never becoming dim.
Trusting in God's love;
Walking in His great light;
We receive His providence;
All that is right
As His dear children;
We are treasured and blessed each day;
Until we see His glory
And reflect Jesus in every way.
oh God is our Hope;
His faithfulness is true;
We respond with gratitude
In all we do.
Expressions of joy
Are like streams that flow from our souls;
Bubbling up in our delight,
Songs of praise and hope that ever grows.
Even Elizabeth your relative is going to have a child in her old age, and she who was said to be barren is in her sixth month. Luke 1:36
Gabriel told Miriam (Mary) this when he announced that she would be Messiah's mother.
Elizabeth, whose name means, "Oath of my God," had not been able to conceive children; yet here she was, beyond normal child bearing years, six months pregnant.
I love pondering this for a couple of reasons:
*Even after we are way past giving up, God is still at work. He brings things into our lives at exactly the right time; age, physical ability and any other factor we could name simply doesn't stop Him.
I have heard numerous people say that God is blessing and anointing the younger generation. That's good. The deal is, He is still blessing and anointing people of all ages, from 100+ to infancy. He isn't ageist; we are. It doesn't matter what stage of life you're in, you can still conceive and do the things that are on your heart.
*God always keeps His word. 2 Corinthians 1:20 says, "All of God's promises are 'yes' and we add the 'amen' to the glory of God."
He said He would send a messenger to prepare the way for the Savior and He did; He said He would send Messiah to save us and He did.
What has He promised you? He is doing and He will do it.
In the very next verse, Gabriel says,
"Nothing is impossible with God."
Perhaps a better translation of that is,
For no word from God will be void of power."
Then Mary answers, "Let it be according to your word."
So here's a question: When did Mary conceive?
Faith is the seed that grows to fruition when God empowers it.
Oh most beloved;
My heart's dearest treasure;
Delight of my life;
My greatest pleasure;
I did everything
Because I love you so.
I came from Heaven so glorious
As a humble child;
Died and rose victorious;
After walking with you for a while.
I ascended into glory
Holy Spirit came to you;
Now it's you who tell My story
In all you say and do.
Oh My precious ones
So priceless to Me;
My daughters and sons;
You will always be
The joy of My heart,
Because I love you so.
God's goodness is reflected everywhere;
In all that He has created.
In wonders great and subtle;
Sometimes boldly stated.
God's goodness is expressed in many ways;
In beautiful music and word;
In panoramic splendors;
In things felt, seen and heard.
God's goodness is always reality;
Even when we don't seem to know
That He holds us in His arms,
Never letting us go.
God's goodness is an expression of Him;
Not merely a thing He might do;
Not based on whim or notion,
But constant, real and true.
EXPECTATION vs EXPECTANCY
"Expectation leads to fear; expectancy leads to hope." Danny Silk
My pastor has been meditating on this and has shared it with me a couple of times.
So, let's take a gander at it:
"Expectation leads to fear…"
It can, if we are thinking that a situation is going to be painful, confrontational or difficult in some other way. It could be a job interview or the office Christmas party. For me, it's gatherings where I can't really move freely or join in fully.
I think expectations can also lead to disappointment, when they are not met. This also leads to anger and offense. I am betting that a lot of people leave Church because they were looking for things they didn't find.
Here's a question: When are expectations healthy and good; when are they hurtful and unwise?
The implication in Danny Silk's comment is that expectations are always undesirable; that we should lay them all down.
I'm not so sure about that.
They do reflect hopes and standards; they help us to set goals and boundaries. Sometimes, expectations call us to re-examine our ideals and desires.
Perhaps the more biblical approach is to submit them to Holy Spirit and let Him help us sort the treasures.
"…Expectancy leads to hope."
This part of Mr. Silk's quote intrigues me. His point is, when we know that God is good and that He has good things for us, we can simply rest and anticipate with eagerness.
Now the same gathering has no fear or disappointment, because God is in charge of the outcome.
I'm not able to go to the place of expectancy without expectation just yet. I do think that both have their places.
Holy Spirit, we ask for discernment and wisdom. Let our desires and expectations match Yours; reveal any wants that need to be laid down. Most of all, teach us to trust in Your goodness. Amen.
Sitting with Jesus in heavenly places
Gives the world a very different look:
Instead of troubles being over me;
Their tucked under my foot.
And when I speak to Jesus, I know
He hears my every word,
Sitting here with my Savior,
My Redeemer, Healer and Lord.
Worshipping Jesus in glory and honor,
Brings great pleasure and joy to my heart.
Inner awareness and love seem to grow;
New songs just seem to start.
When I'm held in Everlasting Arms,
I feel His loving touch;
Devotion to Him explodes
With joy, I love Jesus so much!
Sunlight reflected in water;
Stars and moon above;
Fragrance of trees and flowers;
So many reminders of God's great love!
Warm embraces and loving words;
Fit like an old glove;
Giving such encouragement;
So many reminders of God's great love.
Jesus is born in Bethlehem;
Gentle as a dove;
Died and rose to set us free;
So many reminders of God's great love!
Look around and count all the ways
You find examples of
His ever faithful presence;
So many reminders of God's great love!
God sent the star to announce His son's arrival,
Which Rested over Bethlehem, large and bright;
Lowly birth yet accompanied by miracles,
God came to save us that fateful night.
This heavenly wonder declared promise fulfilled,
Accompanied by angels worshipping God;
His lovely world would now be delivered and healed;
Israel and all the Earth abroad.
A beacon sent to proclaim salvation to all,
Through Jesus Christ, God's only begotten Son;
Who lived among us, died and rose, defeating Hell;
God who saves, Jesus the only One.


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text: Someone in Team Vinyl must've realized that going beyond the band's circle was necessary for freshness, so Fogshack Music Vol. 1 relies on the tried and mostly true method of remixers remixing. Local production duo the Rondo Brothers (perpetrators of last year's Hawaiian hip-hop experiment No Time Left on Earth) blow up eight new Vinyl tracks here and the result is the band's best recorded work. Clean and concise but still raw and funky as hell, these tracks ride the Rondos' whiplash drum programming and exaggerated electronic thump but still swell with the horn-heavy, percussion-driven foundation Vinyl was built on. Veteran P-Funk keyboardist Bernie Worrell, sitting in throughout, adds incontrovertible soul to up-jumping opener "Give and Go" and renders the old Parliament nugget "Moonshine Heather" as genuine as can be. "Imperial Majesty," a syncopated cut 'n' paste burner, proves how sexy you can get with just a rim shot and a slinky trumpet line. Vinyl is still a slave to the groove, but Fogshack is a much-needed update thanks to the new guys cracking the whip. Jonathan Zwickel


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This item is available on the Militant Islam Monitor website, at http://www.militantislammonitor.org/article/id/1953
May 29, 2006
|Bush Tells West Point Graduates Terror War Is in Early Stages
May 27 (Bloomberg) -- President George W. Bush, marking the fourth anniversary of his doctrine of preemptive military force, said the war against terrorism is in its early stages and will rival the Cold War in its length and difficulty.
"The war began on my watch, but it's going to end on your watch," Bush said in a commencement address today to 861 graduating cadets at the U.S. Military Academy at West Point, New York. "One day the world will celebrate your achievements," he said, acknowledging "setbacks and challenges" in Iraq, Afghanistan and elsewhere.
Bush alluded to Iran and Syria as governments that aren't adopting democratic principles. "The message has spread from Damascus to Tehran that the future belongs to freedom, and we will not rest until the promise of liberty reaches every people and every nation," he said.
Bush compared the spread of communism during the Cold War to the more recent rise of Islamic radicalism, recalling the pressure Democratic President Harry Truman was under sending troops around the world in a "struggle between tyranny and freedom."
"Like America in Truman's day, we are laying the foundation for victory," Bush said. Terrorists armed with weapons of mass destruction post a threat "as great as the Soviet Union."
Today's West Point graduates were the first to enter the elite Army school after the Sept. 11, 2001, terrorist attacks. Speaking at the academy in June 2002, Bush said the Cold War policy of deterrence "means nothing against shadowy terrorist networks" and America must "be ready for preemptive action when necessary to defend our liberty and to defend our lives." Ten months later the U.S. invaded Iraq and toppled its then-leader Saddam Hussein.
No Second Thoughts
Bush and other administration officials have said they had no second thoughts about the results of the preemption policy, even though no chemical, biological or nuclear weapons were found in Iraq after dictator Hussein was deposed.
Bush defended his policy in his weekly radio address today, saying that the formation of Iraq's new, democratic government is a milestone in the fight against terrorism. "We can expect the terrorists to continue bombing and killing, but something fundamental has changed," Bush said. "The terrorists are now fighting a free and constitutional government."
The number of U.S. military personnel killed in Iraq since Bush announced May 1, 2003, an end to major combat operations totaled 2,316 as of May 25, according to Pentagon figures. In and around Afghanistan, U.S. combat deaths totaled 235.
Limited Success
"The fundamental principles underlying the Bush administration's stated approach to Iraq were sound," said Michael Levi, a fellow at the Council on Foreign Relations in New York. "The execution was not."
Outside Iraq, Bush's policy has had limited success in the Middle East, experts said.
Libya agreed in December 2003 to end programs to make nuclear and chemical weapons and permitted inspectors, leading the U.S. to lift economic sanctions. While Syria bowed to United Nations demands in September 2004 to withdraw its forces from Lebanon, the government in Damascus continues to support Hezbollah, the Lebanese militia the U.S. considers a terrorist group. Egypt, which receives about $2 billion in U.S. aid per year, drew U.S. criticism when it jailed opposition leaders earlier this month.
"In terms of the successes, it did raise the issue that there is a problem about how the U.S. and other major countries deal with terrorists who might have access to weapons of mass destruction," said Esther Brimmer, a professor at Johns Hopkins University in Washington.
The number of countries that promote free societies rose to 89 in 2005 from 86 in the year before Bush took office, while the number that restrict freedoms fell to 45 last year from 48 in 2000, according to a survey by Freedom House, a nonprofit group in Washington that gets three-quarters of its funding from the U.S. government.
"If by preemption we mean going after terrorists in Afghanistan and worldwide, we need to do so and have done so effectively," said Ashton Carter, a Harvard University professor who was an assistant secretary of Defense in the Clinton administration. "But President Bush meant preempting rogue governments, and there the record is dismal."
Bush's refusal to rule out military force hasn't deterred countries the U.S. calls sponsors of terrorism or developers of nuclear weapons from defying the international community's efforts get them to stop.
North Korea, Iran
North Korea has refused to return to the six-nation talks on its nuclear program until the U.S. removes economic sanctions imposed last year. Talks in Beijing in November ended without an agreement after negotiators in September called for a nuclear-free Korean peninsula.
Iranian President Mahmoud Ahmadinejad on May 25 insisted his country has the right to develop atomic energy, saying any aggressor who tries to thwart the nuclear program will be faced with a "historic slap."
In March, the Bush administration updated its national security strategy, maintaining the preemption doctrine and saying in a 49-page foreign policy paper that Iran and its nuclear ambitions are the biggest future challenges to the U.S. "We will continue to take all necessary measures to protect our national and economic security against the adverse consequences of their bad conduct," the administration said of the Iranian government.
Bush's preemption policy had the unintended consequence of generating "sympathy" for countries such as North Korea, said Michael O'Hanlon, a defense policy analyst at the Brookings Institution in Washington.
"Articulating this concept made the world even more nervous about the Iraq war because everyone wanted to know, `who's next?"' O'Hanlon said. "But by a sitting president, already seen as too prone to unilateralism and the use of force, I think it has clearly been a failure in terms of serving our nation's interests."
To contact the reporter on this story: Brendan Murray at West Point at [email protected]Last Updated: May 27, 2006 10:49 EDT
This item is available on the Militant Islam Monitor website, at http://www.militantislammonitor.org/article/id/1953


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So, it is recommended that you prepare your own toxin-free bath bomb and protect yourself from these harmful substances. Here is how you can prepare a moisturizing and healing natural bath bomb:
- 1 cup of baking soda
- 1/2 cup of citric acid
- 1/2 cup of Epsom or magnesium salts
- 2 tablespoons of coconut oil
- Essential oils
- You can leave it white, or use some natural foods to color it. For instance, you use beet juice which will give it a nice pink color.
- Muffin dome or tin molds
The procedure is very simple. Combine the dry and wet ingredients separately and then slowly add the wet mixture to the dry mixture. Stir constantly. Note: The citric acid may create a lot of foam.
Finally, add the essential oils and food coloring ingredients.
There are a number of essential oils you can choose, including:
- Jasmine, which is a highly sensual essential oil
- Lemongrass, due to its candy scent
- Lavender, as it is extremely relaxing
- Lavender and orange for sweet relaxation
- Orange and lemon, in order to get a nourishing, inspiring and fresh bath
Also, you can make a combination of essential oils. Add 5-10 drops of the essential oil to your bath bomb.
Then, use a little bit of oil to oil the muffin tins or dome molds. Pour the prepared mixture in them. Do not fill the molds to the top since the citric acid expands. Next, allow the mixture to dry at room temperature in order to harden. Once they are hard enough, remove them from the tins or molds and you can enjoy your relaxing bath.
Optionally, you can cover it with glitter and keep it in a jar. This natural bath bomb has a number of health benefits and has amazing calming effects and incredibly pleasant scent.
Epsom and magnesium salts are extremely beneficial for your health, baking soda has alkalizing properties, while the essential oils will calm your body, relieve stress, and the coconut oil has powerful moisturizing effects.


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Blog Archives
I might actually start freaking out here …
The last few days have been pretty exciting around here in book land. 🙂 Well, exciting in that teeny-tiny fish in the big huge ocean that is Kindle books on Amazon kind of way.
As you know from my previous post, I had been experimenting with using my free promotional days on Amazon, and it was going pretty well. Really well, actually. In the end, Dusk Gate: Seeds of Discovery made it all the way to being the #72 best-selling free book on Amazon.
The promotion expired at midnight last night, Pacific time, and my fun little book is now back among the ranks of paid Kindle books on Amazon. And I'm still having trouble staying in my chair today, because …
Well, let me start with a comparison. Last week, before the free promotion, Seeds of Discovery had been consistently ranking somewhere above #200,000 in the paid rankings on Amazon all of this month. And before today, the highest it's ever hit has been somewhere in the high #20,000.
Today? Well … right this minute, it is number 2,270 overall.
It is also #41 in Contemporary Fantasy.
And #84 in Children's Science Fiction and Fantasy … yes … 83 books below The Hunger Games.
We're celebrating here tonight. It's a small celebration, sure, but big for me! 🙂
And a huge, enormous, monumental, earth-shattering, THANK YOU to all of you who have supported me, and read the blog, and taken a chance on picking up the book. The success is really yours.
Daily Writing Progress, Week Five: Monday
Sheesh, maybe I should change it to weekly writing progress. 🙂 When the block hits, it hits hard! 🙂 I should at least be blogging, though.
We have been having a great time around here … lots of fun preschool activities, scented pumpkins, real pumpkins, and play-doh! And the leaves have been
falling in earnest. We live right next to this lovely, tree-covered hill and there are thousands of delightful yellow leaves everywhere. Enough to rake up great, heaping piles, and jump into them, rolling, laughing and screeching.
It has certainly been fun. 🙂 No, that isn't actually a picture of our hill. I will post one soon, though.
So, I am finally at 30k, two weeks late. I think I may have finally broken through the issue I was having, so we'll see where it goes. 🙂 And my goal for the week? Hit 40k!
What fun fall things are you doing? Now that it's Monday again, what are your goals for the week? How can we support each other in meeting them?
Daily Writing Progress, Week Four: Monday
Okay, so last week was an utter disaster in terms of word count. 🙂 I don't know why. Maybe it was stress, probably distraction had something to do with it… and I think a big part of it was "incubation." I had all these ideas of where the story was going to go… I've had it mapped out for a long time, but they needed time. Time to sit, to "incubate" before they were ready to hatch. At least that's the story I'm telling myself. 😉
Anyway, I spent the weekend in discussions and outlining sessions with my dear friend, and writing partner, Krysta Hunt, and I'm hoping I'll be able to get back on track this week. Any magic sparkling writing dust blowing my way would be much appreciated. I am really going to try for 10k this week.
How was your week last week? Did you meet any goals? Anything exciting happen?
What are your goals for this week? Anyone else need magic dust?
Book Two current word count: 25,979
Total word count from Week Three: 4,146
Book Release Party
Today was the "official" Book Release Party for Seeds of Discovery: Dusk Gate Chronicles Book One, and I have to say, I have the best family, friends, and readers in the world, and I feel truly blessed. Thank you so, so much to the wonderful people who came to celebrate with me over the book (and my housewarming and Little Goose's (excessively belated) Fourth Birthday). Words cannot express how much I love and appreciate you.
So, it's 9:43 P.M., and needless to say, I haven't gotten any writing done today. I do hope to snag a few more words between now and when Little Goose either gets tired of playing with her new fairy costume, puzzle, and Color Wonder Markers, or when she starts throwing up from the 1,000 grams of sugar she ingested today.
Writing Progress – Week Two: Saturday
How many words did I write yesterday? 576 – Yeah, so a little distracted with party preparations, and then we spent the evening building a Playmobil school with my sweet nephew, Monty, and my dad, who makes an awesome "Papa."
How many words have I written this week? 5,617 – Eh. 😉
Book Two progress so far: 19,350 – Yup, still have not hit the 20k mark.
How are you doing with your goals this week?


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12th May 2017 Nebojsa Tower
Heavy transport going around the city, by the rivers, through the valuable land. It will end soon, next year maybe. It happens during the night now. Hearing the noise, I had to imagine all the wars that happened around here. And yes there were so many. I wonder if the noise was louder. Looking at the city fortress behind the train, or at least what is left of it, one doubt appeared. Considering that constant train noise can be even compared to the war noise, I was wondering if the city was noticing the difference. I was wondering, if all the wars ruined that much, were these trains actually saving the city in past decades? Maybe they were an unintentional preservation tool. After they get retired the investors will take their place. They treat preservation differently.
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Creative Composting
WILD Weekend Series
Have you wanted to compost but aren't sure how to start? Come to this WILD Weekend to start simple composting at your own home. Composting turns waste into soil enhancers, saves space in landfills, and helps reduce pollution runoff from reaching the ocean. You will learn the basics of composting at home and create simple bins to take home to put your composting knowledge into practice. We will also be designing a special composting inspired dessert that you will create and eat while you learn!
Saturday, July 13
11:30 am – 12:30 pm
2:00 pm – 3:00 pm
$12.50 per adult
$9.50 per child
$2.50 per Ocean Institute Member (enter member ID upon checkout)
*Ticket includes admission to Ocean Institute for the day
Minors must be accompanied by an adult at all times.


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Steve King slammed Macclesfield's 'unacceptable' performance after they failed to see off bottom club Nuneaton.
Lacklustre Macc had the better of a scrappy affair but after failing to capitalise on the precious few openings they created, they were thankful for a good save from Lance Cronin as Nuneaton broke late on.
"It's two points dropped, I'm very disappointed," said the manager (pictured right) after their goalless draw. "I just feel that performance is not acceptable. That was a game that we should have won but too many players had an off-day.
"There were too many average performances and you can't win any football match like that.
" I'm not being disrespectful to Nuneaton because they've come here and given everything but they had the worst away record in the division and conceded the most goals away from home, so that for me is a definite three-pointer and it's two points dropped. We're only two points off the top six but this was a game where we could have got into the top six and settle in there nicely going into the Christmas period.
"That was the carrot for us so to not win was bitterly disappointing."
Macc were less than sparkling against the strugglers, who had worked hard all week on their defending after a 6-1 drubbing at the hands of Wrexham the week before.
But King wasn't surprised that opposite Kevin Wilkin had his troops well-drilled in defence, albeit with little attacking threat posed.
"Games against teams at the bottom are always battles and you've got to win those battles to earn the right to play," continued King.
"They battled hard, they fought hard and they had a game plan. When we played them last time they'd been beaten 6-1 in the previous game and I know Kevin well and I knew he was going to have them tighter and it proved that way.
"If we'd taken those chances we'd have been out of sight but it is what it is, we have to regroup for Tuesday and we're feeling disappointed because we'd drawn at Forest Green and beaten Hyde and if we'd won today we'd have been in the top six, exactly where we want to be, in and around it."