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The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells in vitro
© Lechler et al; licensee BioMed Central Ltd. 2011
Received: 7 November 2010
Accepted: 2 April 2011
Published: 2 April 2011
Chondrosarcoma is virtually resistant to chemotherapy and radiation therapy. Survivin, the smallest member of the inhibitor of apoptosis protein family, is a critical factor for tumor progression and resistance to conventional therapeutic approaches in a wide range of malignancies. However, the role of survivin in chondrosarcoma has not been well studied. We examined the importance of survivin gene expression in chondrosarcoma and analysed its influences on proliferation, apoptosis and resistance to chemotherapy in vitro.
Resected chondrosarcoma specimens from which paraffin-embedded tissues could be extracted were available from 12 patients. In vitro experiments were performed in human chondrosarcoma cell lines SW1353 and Hs819.T. Immunohistochemistry, immunoblot, quantitative PCR, RNA interference, gene-overexpression and analyses of cell proliferation and apoptosis were performed.
Expression of survivin protein was detected in all chondrosarcoma specimens analyzed, while undetectable in adult human cartilage. RNA interference targeting survivin resulted in a G2/M-arrest of the cell cycle and led to increased rates of apoptosis in chondrosarcoma cells in vitro. Overexpression of survivin resulted in pronounced resistance to doxorubicin treatment.
These findings indicate that survivin plays a role in the pathogenesis and pronounced chemoresistance of high grade chondrosarcoma. Survivin antagonizing therapeutic strategies may lead to new treatment options in unresectable and metastasized chondrosarcoma.
Chondrosarcomas comprise a heterogeneous group of neoplasms characterized by the production of cartilage matrix by malignant cells [1] and represent the third most common primary malignancy of bone after myeloma and osteosarcoma [2]. Curative treatment of chondrosarcoma is restricted to surgical resection because of pronounced resistance to chemotherapy and radiation therapy [3–5]. The histological grade is directly related to metastatic rate and remains currently the single relevant predictor of patient outcome [6, 7]. After adequate resection, 10-year survival for patients with grade I chondrosarcoma is excellent, whereas only 64% for grade II and 29% for grade III tumors [8]. A large body of evidence has demonstrated that chondrosarcoma's malignant phenotype and resistance to drug therapy is favoured by constitutive activation of antiapoptotic pathways and loss of cell cycle control [9, 10].
Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family is reported to fulfil important roles in cancer initiation, tumor progression and drug/radiation resistance [11]. The molecular structure of survivin reveals one N-terminal baculovirus IAP repeat (BIR) domain and a long C-terminal helix-coiled region. In solution, survivin forms stable homodimers [12, 13]. Extensive alternative splicing and a finely, by transcriptional and post-transcriptional mechanisms, controlled expression regulate survivin [14]. It is a bifunctional protein that acts as a suppressor of cell death and plays a key role in cell division. As a chromosomal passenger protein survivin accumulates to kinetochores at metaphase, localizes to the spindle mid-zone at anaphase and is expressed in mid-bodies at telophase [15, 16]. While survivin is highly expressed in cancer and during embryonal development it is said to be absent in most adult differentiated organs. Thus, survivin appears to be an ideal therapeutic target for cancer treatment with little toxicity to normal tissues [17]. However, little knowledge exists about expression of survivin in chondrosarcoma [18]. Here, we demonstrate, that the antiapoptotic protein survivin is highly expressed in human high grade chondrosarcoma and possibly acting as a major factor for the tumor's pronounced drug resistance.
Unless otherwise stated all chemicals were purchased from Sigma-Aldrich (Taufkirchen, Germany).
The study was approved by the Local Ethics Committee from the University of Regensburg (N° 09-131 and N° 10-101-0170).
Collection of human tissues
Clinicopathological details of tumor specimens
Patient Nr. | Grade | Location | Origin | Size (diameter in cm) | Sex | Age |
1 | I | upper extremity | peripheral | 5 | male | 68 |
2 | II | costae | central | 6 | male | 53 |
3 | II | pelvis | central | 11 | female | 38 |
4 | II | upper extremity | central | 3 | male | 81 |
5 | III | lower extremity | central | 7 | male | 45 |
6 | III | lower extremity | Central | 5 | female | 78 |
7 | III | pelvis | peripheral | 7 | male | 65 |
8 | III | upper extremity | central | 4 | female | 52 |
9 | III | upper extremity | unclassified | 8 | female | 23 |
10 | III | costae | central | 6 | female | 78 |
11 | III | costae | peripheral | 4 | male | 65 |
12 | III | scapula | unclassified | 6 | male | 71 |
Non-arthritic human cartilage of 6 Patients undergoing total knee replacement because of mono- or bicompartmental osteoarthritis was collected. The macroscopically and microscopically healthy chondral layer of the unaffected compartment was harvested and either snap frozen or fixed in 4% paraformaldehyde. The mean donor age was 43 years (34 to 56 years). Written informed consent was obtained from each patient.
Survivin immunohistochemistry
Details of antibodies used
Method | Detected protein | Primary antibody | Concentration (μg/ml) | Secondary antibody | Concentration (μg/ml) |
IHC | Survivin | pAB AF886 (R&D Systems) | 5 | Goat anti-rabbit immunoglobulin/biotinylated (DAKO) | 4 |
IHC | Survivin | mAB clone 32.1 (Novus Biologicals) | 6 | Swine anti-mouse immunoglobulin/biotinylated (DAKO) | 4 |
IHC | Survivin | pAB 500.201 (Novus Biologicals) | 4 | Goat anti-rabbit immunoglobulin/biotinylated (DAKO) | 4 |
IHC | Survivin | mAB clone 60.11 (Novus Biologicals) | 7 | Swine anti-mouse immunoglobulin/biotinylated (DAKO) | 4 |
IF | Survivin | pAB AF886 (R&D Systems) | 2 | Red fluorescent dye-labeled anti-rabbit immunoglobulin (Invitrogen) | 1 |
IF | Survivin | mAB clone 60.11 (Novus Biologicals) | 2 | Red fluorescent dye-labeled anti-mouse immunoglobulin (Invitrogen) | 1 |
IB | Survivin | pAB AF886 (R&D Systems) | 1 | Swine anti-rabbit immunoglobulins/HRP-conjugated (DAKO) | 0,2 |
IB | Survivin | mAB clone 60.11 (Novus Biologicals) | 2 | Swine anti-mouse immunoglobulin/HRP-conjugated (DAKO) | 0,2 |
Cell line and culture conditions
For cell culture studies the human chondrosarcoma cell lines SW1353 (also known as HTB-94) and Hs 819.T (both obtained from American Type Culture Collection) were cultured in Dulbecco's Modified Eagle Medium (PAA, Cölbe, Germany), supplemented with 10% fetal calf serum, penicillin (50 U/ml) and streptomycin (50 μg/ml). Cells were incubated at 37°C at 5% CO2 in humidified air.
Survivin immunofluorescence
Chondrosarcoma cells were grown on glass slides and fixed over 10 minutes in 3.7% Formalin/PBS at room temperature. Next, sections were cooked for 20 minutes in citrate buffer (pH 6.0, 10 mmol/l). The sections were blocked with phosphatase-buffered saline and 5% fat-free dried milk for 30 minutes at room temperature. After incubation overnight with primary antibody at 4°C and thorough washing with tris-buffered saline, tissues were incubated with red fluorescent dye-labelled anti-rabbit immunoglobulin (Invitrogen, Karlsruhe, Germany) at 37°C for 1 hour. Finally, the nuclei were stained with 4,6-diamidino-2-phenylindole (6.5 g/ml; Invitrogen) for 10 minutes, and the stained sections were analysed and photographed with a fluorescence microscope (Zeiss, Jena, Germany).
Protein extraction and immunoblot analysis
Protein extraction of tissues and cells was performed as previously described [20]. In brief, cell pellets and tissues were homogenized into extraction buffer (7 mol/L urea, 10% glycerol, 10 mmol/L Tris-HCl, pH 6.8, 1% sodium dodecyl sulfate, 5 mmol/L dithiothreitol, 0.5 mmol/L phenylmethyl sulfonyl fluoride with 1 mg/L aprotinin, pepstatin, and leupeptin) using a T8 Ultra-Turrax homogenizer (IKA, Staufen, Germany). After quantification, protein samples were run on 14% polyacrylamide gels and transferred to Immobilon P membranes (Millipore, Bedford, MA). Unspecific binding-sides were blocked with PBS and 5% fat-free dried milk for 30 minutes at room temperature. Membranes were probed with either polyclonal antibody AF886 (1:1000, R&D Systems) or monoclonal antibody NB500-238 (clone 60.11, 1:500, Novus Biologicals) and horseradish peroxidase-conjugated secondary antibodies (DAKO). Signals were visualized by chemiluminescence (Pierce, Rockford, IL). Recombinant full-length human survivin served as positive control (R&D Systems).
Survivin knockdown by siRNA
Overexpression of survivin
Expression plasmid encoding wild type survivin was generously provided by R. Stauber [23]. One day before transfection, cells were plated at a density of ~50% and expression plasmids were transfected into chondrosarcoma cells using a commercially available transfection reagent (FuGENE® HD, Roche Applied Science, Mannheim, Germany). Conditions according to the manufacturer's instructions. Transfection of pcDNA3 (Invitrogen) served as a negative control. The medium was removed and replaced with full growth medium 6 hours after transfection. The cells were further incubated at 37°C and 5% CO2 in humidified air. Transfection efficacy was controlled by immunoblot.
Cell Cycle Analysis
Both adherent and detached chondrosarcoma cells were collected by trypsinization and washed with PBS for 5 minutes by centrifugation at 125 × g. Cells were resuspended in a staining solution containing 1.5 μmol/L propidium iodide and 25 μg/ml RNase A and incubated for 30 minutes in 37°C. The samples (10000 cells) were analyzed by fluorescence-activated cell sorting with a FACSCalibur (BD Biosciences, Heidelberg, Germany).
Caspase 3/7 Activity Assay
Apoptosis in chondrosarcoma cells in vitro was studied by measuring the activity of caspases 3 and 7 using a commercial kit (Caspase-Glo; Promega, Mannheim, Germany). Cells were seeded in 6 well dishes at 1.5 × 105 per 3.5 cm well, 24 hours before knockdown was performed. For analysis, 24 hours after knock down cells were incubated for 90 minutes in a luciferase substrate mix. Finally supernatant was removed and cells were homogenized in lysate buffer. Buffer was transferred into a 96-well microplate and luminescence activity was measured in a luminometer (Berthold, Bad Wildbad, Germany). Apoptosis was induced by 24 hours exposure to doxorubicin (5 μM). This concentration resembles the peak plasma level in oncologic patients receiving doxorubicin based treatment regimens [24].
Measurement of cell viability by MTT
The viability of chondrosarcoma cells was measured by methyl thiazolyl tetrazolium (MTT) assay. Cells were plated onto 96-well plates at a density of 5000 cells per well. 6 hours after transfection with specific siRNA or plasmid, the serum-free medium was replaced by complete medium. The transfection was repeated after 48 hours. MTT reagent (5 mg/ml) in 180 μl medium was added at 0, 24, 48, 72 and 96 hours and incubated for 4 hours at 37°C. Next, supernatant was removed and 150 μl dimethyl sulphoxide (DMSO) was added to each well. After the plate was shaken on a rotary platform for 10 min, extinction at wavelength 490 nm was measured.
Measurement of cell proliferation
Cell proliferation of chondrosarcoma cells (SW1353 and Hs819.T) was measured by analyzing BrdU incorporation into newly synthesized DNA using a commercially available ELISA chemiluminescence assay (Roche Molecular Biochemicals). Cells were plated out in 96-well microtiterplates at a density of 5000 cells per well and incubated for 24 hours prior the knock down of survivin was performed. 24 after the transfection of specific siRNA the cells were pulsed for BrdU incorporation over 4 hours. ELISA was performed according to the manufacturer's instructions. Chemiluminescence values (relative light units) were measured by an automated luminometer (Berthold, Bad Wildbad, Germany).
RNA extraction and real-time PCR
At least three replicates for each experimental condition were performed, and the presented results were representative of these replicates. All values are presented as means ± SEM. Student's paired t-test was applied to reveal statistical significances. P values less than 0.05 were considered significant. Statistical analyses were performed using SPSS Software for Windows (version 13.0; SPSS, Inc., Chicago, IL).
Survivin is expressed in human chondrosarcoma
Survivin is expressed in human chondrosarcoma cells in vitro and localizes to heterogenous subcellular compartments
Knock-down of Survivin in chondrosarcoma cells results in reduced rates of proliferation and a failure to exit mitosis
Knockdown of survivin sensitizes chondrosarcoma cells to apoptotic stimuli
Overexpression of survivin protects chondrosarcoma cells against doxorubicin induced apoptosis, but shows no effect on proliferation
Previous studies have shown that survivin, the smallest member of the IAP protein family, has a bifunctional role in cellular division and survival decisions. It is highly expressed at mitosis and is a critical factor for completion of mitotic cell division [15, 16]. Survivin acts as a potent inhibitor of apoptotic and non-apoptotic cell death, and protects cells as a stress response factor against unfavourable environments. From a clinical point of view, the most interesting feature of survivin is the widely accepted concept of an "oncofetal" pattern of expression. While undetectable in most adult differentiated tissues, survivin is ubiquitously expressed during embryonal developement and highly re-expressed in cancer. In malignant tumors, survivin antagonizes programmed cell death, favours tumour-associated neovascularization, promotes cell proliferation and preserves cell viability [11]. Disregarding the yet undefined molecular mechanisms, a large body of evidence has demonstrated that survivin has indeed a strong potential of antagonizing drug and radiation induced apoptosis [25, 26]. In the current study, we report high expression of survivin in human chondrosarcoma. Furthermore, in vitro experiments indicate a potential role in the tumor's pronounced resistance to chemotherapy. Our data shows homogeneous expression of survivin in all analysed human chondrosarcomas (Figure 1A-D), while in adult cartilage no or only low levels of survivin protein were detectable (Figure 1 F). Immunohistochemistry revealed a predominantly cytoplasmic pattern of staining in chondrosarcoma. Immunofluorescence of cultured chondrosarcoma cells confirmed the cytoplasmic subcellular localization of survivin protein (Figure 2), indicating survivin's involvement in extranuclear (i.e. proliferation independent) functions. Of note, recent publications on survivin emphasize the prognostic relevance of subcellular distribution of survivin gene expression. While the prognostic value of nuclear survivin expression in cancer remains unclear, high levels of cytoplasmic survivin protein seem to correlate with resistance to drug/radiation therapy and poor patient outcome [27, 28]. The unfavourable prognosis related to cytoplasmic survivin might be associated with its reported extranuclear function (e.g. counteracting apoptosis), whereas nuclear survivin could rather promote cell proliferation [29]. In this context it is of particular interest that effects of strongly active proapoptotic substances as doxorubicin are significantly reduced by survivin overexpression in SW1353 (Figure 7). Accordingly, downregulation of survivin resulted in increased rates of spontaneous and drug induced apoptosis (Figure 6). It is therefore tempting to speculate that survivin represents a key molecule in maintaining constitutive antiapoptotic activity in chondrosarcoma. In this context, it has been shown, that an upregulation of survivin protein did not increase cell proliferation or changed cell cycle distribution, while suppression of survivin resulted in a failure to exit mitosis, the previously described G2/M-arrest [21].
In summary, we demonstrate that the antiapoptotic protein survivin is highly expressed in human high grade chondrosarcoma. Functional analyses in chondrosarcoma cells in vitro indicate that survivin exerts the classic functions of cell cycle regulation and survival control in human chondrosarcoma. Moreover, our findings indicate that survivin might be a potent promoter of resistance to chemotherapeutic agents in chondrosarcoma. Still, the role of survivin in oncogenesis and the relevance of its predominantly cytoplasmic distribution in human chondrosarcoma remain elusive.
Learning more about survivin's role in chondrosarcoma and evaluating the effects of survivin-antagonizing therapeutic strategies will be an important task for future studies.
inhibitor of apoptosis protein
baculovirus inhibitor of apoptosis repeat
methyl thiazolyl tetrazolium
- siRNA:
small interfering RNA.
We thank Mrs. Luise Rauch and Mrs. Anja Sabo for excellent technical assistance, Dr. S. Capellino for kindly helping with the fluorescence microscope, and Dr. R. Stauber for the gift of the human cDNA for survivin. The study was supported by the Regensburger Forschungsförderung in der Medizin (ReForM).
Authors' Affiliations
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- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/120/prepub
Pre-publication history
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Taco Bell Crime of the Week: Manager Demoted for Stealing Food, Boyfriend Robs Her Taco Bell Branch!
It's one thing to stand up for your woman's honor--but do you really want to stand up for her after she just got demoted from her Taco Bell manager job for stealing food? And do you want to do it by robbing said Taco Bell?
The story comes from a place I'm going to be visiting verrrrrry soon: Crossville (pronounced with one syllable so it sounds "Crosvl"), Tennessee.
Quick note about Crossville: it's so backwards, the local press STILL publishes the home address of people. Tee-hee! Now, on to the story:
The boyfriend of a demoted former manager of the Taco Bell on Peavine Rd. has been arrested and charged with armed robbery and theft in connection with a Saturday morning incident. Police are seeking the girlfriend -- now a former employee -- as an accomplice in the case.
Crossville Police Det. Bill Padgett confirmed yesterday that Robert Jay Gilleand, 24, 112 Avon Rd., was arrested early Sunday morning in connection with the holdup that netted more over $2,500. A portion of the money has been recovered by police.
Follow Stick a Fork In It on Twitter @ocweeklyfood or on Facebook! And don't forget to download our free Best Of App here!
Police say Gilleand is a boyfriend to a former assistant manager who about a month ago was demoted after being accused of stealing food. The woman was employed prior to the robbery Saturday morning but has not shown up to pick up her last check since that incident.
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¶ And Nadab and Abihu, the sons of Aaron, took either of them his censer, and put fire therein, and put incense thereon, and offered strange fire before the LORD, which he commanded them not. |
And there went out fire from the LORD, and devoured them, and they died before the LORD. |
Then Moses said unto Aaron, This is it that the LORD spake, saying, I will be sanctified in them that come nigh me, and before all the people I will be glorified. And Aaron held his peace. |
¶ And Moses called Mishael and Elzaphan, the sons of Uzziel the uncle of Aaron, and said unto them, Come near, carry your brethren from before the sanctuary out of the camp. |
So they went near, and carried them in their coats out of the camp; as Moses had said. |
¶ And Moses said unto Aaron, and unto Eleazar and unto Ithamar, his sons, Uncover not your heads, neither rend your clothes; lest ye die, and lest wrath come upon all the people: but let your brethren, the whole house of Israel, bewail the burning which the LORD hath kindled. |
And ye shall not go out from the door of the tabernacle of the congregation, lest ye die: for the anointing oil of the LORD is upon you. And they did according to the word of Moses. |
¶ And the LORD spake unto Aaron, saying, |
Do not drink wine nor strong drink, thou, nor thy sons with thee, when ye go into the tabernacle of the congregation, lest ye die: it shall be a statute for ever throughout your generations: |
And that ye may put difference between holy and unholy, and between unclean and clean; |
And that ye may teach the children of Israel all the statutes which the LORD hath spoken unto them by the hand of Moses. |
¶ And Moses spake unto Aaron, and unto Eleazar and unto Ithamar, his sons that were left, Take the meat offering that remaineth of the offerings of the LORD made by fire, and eat it without leaven beside the altar: for it is most holy: |
And ye shall eat it in the holy place, because it is thy due, and thy sons' due, of the sacrifices of the LORD made by fire: for so I am commanded. |
And the wave breast and heave shoulder shall ye eat in a clean place; thou, and thy sons, and thy daughters with thee: for they be thy due, and thy sons' due, which are given out of the sacrifices of peace offerings of the children of Israel. |
The heave shoulder and the wave breast shall they bring with the offerings made by fire of the fat, to wave it for a wave offering before the LORD; and it shall be thine, and thy sons' with thee, by a statute for ever; as the LORD hath commanded. |
¶ And Moses diligently sought the goat of the sin offering, and, behold, it was burnt: and he was angry with Eleazar and Ithamar, the sons of Aaron which were left alive, saying, |
Wherefore have ye not eaten the sin offering in the holy place, seeing it is most holy, and God hath given it you to bear the iniquity of the congregation, to make atonement for them before the LORD? |
Behold, the blood of it was not brought in within the holy place: ye should indeed have eaten it in the holy place, as I commanded. |
¶ And Aaron said unto Moses, Behold, this day have they offered their sin offering and their burnt offering before the LORD; and such things have befallen me: and if I had eaten the sin offering to day, should it have been accepted in the sight of the LORD? |
And when Moses heard that, he was content. |
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text:
Blizzard has their Q4 2013 earnings call today, announcing that WoW is up to 7.8 million subscribers. This is up 200k from the Q3 2013 call that listed WoW at 7.6 million subscribers.
But now consider that it's a video game you're looking at the product life cycle of? Many other franchises have to release a new game every year and don't retain the same following that a 10 year old game does.
- - - Updated - - -
35% of it's prime after 10 years? That sounds pretty good considering it was up at what, 12-13million subs at one point? 35% retention of any game even if you only have 100k is pretty damn good, let alone 35% of 12million. And probably on the age part, yes - I turned 20 in December and whilst I was forced to quit at MOP launch due to life commitments I have come back a couple of times and will do so again.
In it's prime? Keep in mind that "in it's prime" isn't the true playerbase, it's lots of "fluff" subs packed onto it.
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Blizzard lose subs - The game is dying
Blizzard gain subs - Multiboxers, It's a fluke, zero credit given.
Man this player-base is so friggin cancerous. I feel like all these SOBs just want WoW to die, yet they continue to play the game and give blizzard money themselves. I think it's rather funny how now that a good thing happens, people just pull baseless claims and accusations out of their ass in a feeble attempt to "prove" the death of WoW.
Q: Blizzard is lying
A: No they're not. Blizzard cannot legally lie about their sub numbers.
Q: It's all multiboxing! fake accounts!
A: So there's 2 accounts for every single player in the game? This is counting the amount of players in the game, not the amount of multiboxers, and i bet if blizzard made stats on that too it'd de-rail your silly theory. Multiboxers have been in the game since vanilla. They've never made a difference then, they wont make one now.
Q: Everybody happy for blizzard is a fanboy
A: Bad thing happens: "WOW IS DYING OMG!" Good thing happens: "IF YOU SUPPORT YOUR GAME COMPANY UR BAD". Logic. Learn it.
Q: It doesn't matter! WoW is still dying!
A: Dont lie to yourself. the game has been "dying" for 10 years now and it still towers over every other MMO. Even this sub gain is alot more than many MMOs could even ask for. The subs always fluctuate between expansions and this sub gain outside of that usual cycle is a good thing, proving against your claims that WoW can't/wont gain anymore subs. I'm anticipating the next sub count showing another rise in subs, but it seems like you people just want the game to die so you can be the first to call it. But that's okay, you're still playing and feeding blizzard money. Thanks for all your help.
My theory with whats happening (as whats always been happening with subs) is that the game is leveling out to it's actual playerbase. Wotlk gave WoW tons of extra subs and it's been deflating over each expansion and leveling out to WoW's true playerbase. The small sub gains prove that in the sense that subs wont just drop to 0, but rather plateau somewhere in the millions as usual. WoW's not dying folks, get over it and be happy for Blizzard or leave and become a doomsayer elsewhere.
Well to be fair, there is an argument that gets used the other way, as well; though it's less an argument and more on how it's reported on their end.
Blizzard lose subs - The game is dying
Blizzard gain subs - Multiboxers, It's a fluke, zero credit given.
Blizz Loses Subs="Mostly from Asia"
Blizz Gains Subs=No Specification on where subs were gained
I'd be curious to hear where the 200k came from mostly-was it 50/50? More West? More East? At the end of the day, numbers are numbers for them, but I do find it a bit odd they're quick to admit that most of the losses are from the East, but not where the gains were from.
At the end of the day, WoW has always gained and lost subs; even back in the older days. It's just as of late it's lost more than it's gained. This time around it's gained a few more, and it actually makes some sense. It's in the tail end of an expac, though not the *end end* of the expac(when subs usually take a dive.) I think they're in the area where people who may have quit before-and for awhile even-where there is enough content now for people to try out at their leisure, without any sorta expectations and such, for them to want to 'give the game a try again.' It's before the end-of-expac dropoff(I'd say that would probably happen more around April-May depending, also I'd say around then due to things like exams and the like), so servers feel fairly busy, and so on. It's actually a pretty good time right now for lapsed players to give the game a go for a month or so; too much later than this and a lot of folks are sicker of the content, may not be running pugs as much, guilds might start going on their end of expac hiatuses, they may be busier due to time of year, and so on. So the small gain, again, doesn't look too far off, but I don't think it's due to some miracle of game design or anything, more just that it's a good time to try the game again.
Hell, I even tried a month not that long ago(otherwise have been out for awhile, since end of 2012.) Was cool, and I'm curious about WoD and plan on trying it, but there wasn't enough to get me to stick for the rest of this expac. (Folks like me would have counted toward that 200k, though, for that example.)
And it's true that WoW isn't dying. But it's also true that nothing lasts forever, and eventually, it's *going* to fizzle out. It'll take years most likely and quite a few of them, but eventually, like anything, it's going to become small. There's a difference between doomcrying and stating the simple fact that eventually, WoW is likely going to get very small, just due to time.
Hmm, trying to find that part of it but I'm not finding anything, but combing through all of the logs is a little trying. Then again, it would still be a win even if they gained in Asia anyway. I remember reading an article that stated something along the lines of 'we have more actual subscribers in the East, but less revenue per subscriber.' So a West gain might be more of a win in terms of profit, but an Eastern gain still at least matters. (I admit, one reason why I tend to make sure they both get recognized is because a lot of WoW's players are in the East, and I sometimes get the impression that they don't get noticed as much. Even with less revenue per subscriber, if 1m subs dropped in the East suddenly, the worldwide subs would go down 1m, and it would still look bad.)
So perhaps losses in the East don't hurt as bad revenue-wise, nor score as much gain-wise if they gain them, but they would still show up the same on the subscriber numbers. (Now, as for how the West's subs are broken up between the US, EU, Oceanic and South America, I'm not sure. I've heard some accounts, though, of some US servers seemingly picking up, while some of my EU friends have said a lot of servers feel dead these days. so I'm wondering what EU numbers are like these days-I can say that when I stopped back on, I had poked around the old server I was on and WOW it felt really dead-and even the populated server I was on saw a drop, so I wonder if the US is who are getting most of these subs? It would perhaps make some sense-the EU's Connected Realms have been moving along a lot slower and I wonder if it caused some to get fed up with it, where the US has been working the connected realms pretty efficiently these days, thus making the game feel more alive and drawing people back.)
EDIT: Hmm, thinking more about Connected Realms...if these gains were mostly in the US, if I were Blizz I'd seriously consider speeding up the EU connections. It might help out quite a bit.
I am not surprised it went up my server has seen an influx of new people since the RAF came out. I have seen tons of people leveling and even the lower MoP LFR's are pretty full and the queue times have been pretty good for even a dps. I actually thought more than 200k, but I am sure it will be short lived depending how long people are will to wait for WoD. Patience is not something many have in this game. it will be interesting to see if we get to May or June without beta out just how many are going to be sticking around.
IMO, an idea they might want to try is to offer guaranteed Beta for pre-ordering WoD. Hell, I'd do it. I mean if the expansion comes with a free month, that'll potentially boost subs nicely(and maybe make some stick, though I'm sure as time goes on others will trickle off.) I don't think another yearly subscription would work too well this time-it's a bit too much, the game is even older, and I think last time, judging by the subs lost in MoP, people may have felt a little burned-but a beta for a WoD pre-order may work.
As for how long these will stick-I reckon that if they can get the beta running and the full game out by the end of June(possible if they've hammered out a lot of internal testing beforehand), they'll not see too much of a negative change-and indeed, gain like they always do with a new expac...but if they end up taking too long with the expansion that will not be good for the subs at all, since summer alone is usually enough to drop them, summer + no new content + another year of the dungeon will *really* bite them in the ass this time, and hard. Much worse than last time. They're doing well for now; they need to keep up the pace, though, and get the expansion out at a decent time or a lot of that goodwill is going to be burned up, and they'll likely gain a lot less than they would have with the new expansion if that happens. While Blizz has made questionable business decisions in the past, I'll say that they're not so daft and they know this time is pretty tight for them and they'll try to get it all to come off smoothly rather than sit on their laurels.
I resigned after Blizzcon... now after having realized that WoD is still 6 months away... I cancelled my sub again.
The game will bleed out during the sommer months... SoO has 10 killable HC bosses and 3 ones you need 200+ tries for... for me as a three times per week semipro raider not achievable.
So the game has nothing to offer for me at the moment unfortunately.
Well maybe they should make a new game. Before you say Titan, what info they did release about it made it sound like a pretty awful game. Facebook integration, extremely casual, hiring people do to in game ads. Then they reset it and took most of the staff off it. Seems they're not looking at the future. Seems their plan is to just stick with an old dying game and pull free to play out of their pocket when it gets bad. I agree, it's an old game. I'd like it to die already and get something new. Either a new MMO or WoW2.
As a former player looking in from the outside, it seems pretty ridiculous to me that players consider a paltry 200k subscriber growth (due most likely to RAF) to be something about getting overly excited over.
PvP in WoW is trash and heading in the wrong direction, and if you don't play a hybrid you forfeit your raid spot. Not the game it was? Absolutely. Not the game people wish it was? Absolutely.
Some anecdotal musings from me: it seems they are still getting an influx of new players, judging from the people I have been grouping with in dungeons. Usually when someone makes a mistake or does something I would consider "dumb" in a dungeon I've made it a habit to ask them if they are a new player, and so far it's been about 50/50 new/old players. It hasn't made my leveling experience very pleasant on my new druid, but I found it interesting nonetheless.


text: The Time This Kid Realized He Was Waving A Turkey LegSam Eifling11/25/13 7:39pmFiled to: FansOklahoma State Cowboyscollege footballnews235EditPromoteShare to KinjaToggle Conversation toolsGo to permalink GIF The waving of the turkey leg — sure, cute, but we've all been there. Having only two hands can feel so limiting, so of course, you're watching Okie State piss-pound Baylor back into the MaybeNextYear.com Bowl, and everyone else starts some kind of en masse arm swing, and what option do you have but to join. Advertisement Where this fan achieves the sublime is in the flickering comprehension that leads him to chomp the bird in rhythm with the wave. Enticement and reward in short order. We should all be so lucky as to have our own, friendly arm be the one taunting us with dinner.[TheLostOgle.com] Advertisement h/t RobertReply23 repliesLeave a reply


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Beginning 2009, the flights operated by Aeroflot and the company's partners are being transferred to Sheremetyevo's new Terminal D located next to Terminal F (Sheremetyevo-2).
To meet the needs of its passengers, Aeroflot is increasing its fleet and has built its own new hub in Moscow. With annual capacity of 12 million passengers, it is designed to serve Aeroflot's flights as well as those of its SkyTeam partners.
The original architectural solution of the Terminal D project has already won the Russian independent award in the sphere of architecture and development «ARX Awards» in the «Best Transport Infrastructure Object» nomination.
Dear Business Class passengers flying on international flights from Terminal D!
For your convenience up to two booths have been allocated in the Arrival and Departure passport control zones each. The zones have signboards and Tensator queue management systems.
The new service will help passengers to significantly decrease time spent in passport control. The new service is user friendly; the airline staff meets Business Class passengers in front of the customs zone, checks their boarding passes and shows them to the specially allocated passport control booths.
The introduction of the new passport control booths is another step towards attaining the main objectives of the company that is providing quality on-ground service comparable with international standards.
For passengers' convenience, it offers 143 check-In counters, including 24 self-check-in kiosks (CUSS-kiosks) and 30 counters for transit passengers and oversized baggage. To speed-up the baggage handling process and improve security, the new terminal will use the Radio Frequency Identification system for baggage recognition, which will reduce the average time of baggage hadling by 90%.
Passengers will be able to use the 6 enhanced-comfort lounges, 5 children's rooms, 25 shops, 18 catering establishments working around the clock, and many other services.
Aeroflot and SkyTeam are assigned 3 business exclusive business halls «Klassika», «Jazz» and «Blues» in the international and domestic departure zones equipped with comfortable rest areas, shower cabins and other conveniences.
Attention passengers of Aeroflot flights departing from Terminal D!
When in Terminal D, double-check that your flight is on the Departures Board. If your flight is not there, please refer to the information desk. If your flight is served by other Sheremetyevo terminal, you will be invited to exit 6 wherefrom you can reach any terminal by shuttle that leaves every 10 minutes.
If by any reason you are late for your flight, your ticket should be changed, so that you can depart by the next flight.
Getting to Terminal D
Terminal D map
New Terminal D has been serving flights since 15 November 2009.
Level 1 — Arrival |
Level 3 — Departure |


text:
67th Golden Globe Awards
January 18, 2010
Same York, January 18, 2010
tom was sitting at the very front! with george lucas, robert de niro, leo dicaprio, martin scorsese and yeah, others but those were the main ones yeah :)
lol at his joke on stanley tucci. cheers! loved the loudness of the applause for tom...i think...
T Johnson, January 23, 2010
RE: Conan's last show
Tom Hanks made an unforgiveable statement SLAMMING Johnny Carson...saying on Conan's (cancelled show for low ratings) that O'Brien will always be the Host of the Tonight Show...Tom Hanks should keep his opion to himself...Johnny Carson will always be the Host of the Tonight Show!!!!


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Saturday saw a somber celebration of Polish pride in Chicago.
The Polish Constitution Day Parade started with a tribute to the country's late president, Lech Kaczynski, and the 95 others killed in a plane crash last month. Polish scouts slowly marched as they carried photos of all 96 victims.
Kaczynski was scheduled to attend this year's parade in Chicago, which marks the 1791 signing of the Polish constitution.
Published at 11:27 AM CDT on May 2, 2010 | Updated at 12:15 PM CDT on May 2, 2010


text:
In Prem Rog, Raj Kapoor raises his voice against caste discrimination and supports widow remarriage. This 1982 treatise on the ghastly caste divide in India and the horrible state of widows is packaged as a sensitive love story between an upper-caste widow and a young man of lowly status. The film has the usual Raj Kapoor approach--a great cast, superb locations, splendid sets and taut script. That a dichotomous character riddles the upper caste in India is shown perfectly by Raj Kapoor here. But what I love the most about this film is how everyone plays his part immaculately and the simply romantic tale turns out to be such a gritty family drama in the end.
Manorama (Padmini Kolhapure) is born with a golden spoon in her mouth. A daughter of a thakur, she is pampered by her family. All her wishes are granted at the swig of her dainty hand. She spends her time throwing simple tantrums and playing with her childhood friend, Radha, the daughter of the village pundit (Om Prakash). Soon arrives Devdhar (Rishi Kapoor), Radha's cousin, from the city, where he is studying to become a doctor. As the funding for his medical education has been done by Bade Raja Thakur (Shammi Kapoor), Manorama's uncle, Devdhar is immensely grateful to him and the thakur family. Manorama, the prankster that she is, tries to trouble Devdhar, but the smart man, turns the tables on her. She is upset but is constantly hovering over him. One instance that shows how pampered Manorama is when Devdhar tricks her to eat the kachoris she has naughtily laced with chilly powder for him. She bites into the kachori and immediately starts crying and saying that this would certainly kill her! Understandably, the director is hinting upon the hardships that she will soon be facing in her life...
Devdhar, the simpleton at heart, falls in love with her. But Manorama, the teenager, is yet to feel the pangs in a mature way. Dev tells her that there comes a day when every heart starts beating for that someone special. But Mano fails to catch the hint. Later, when Radha corners him with the truth that Dev will never be accepted by Rama's family because of the difference in their status, he quietens her saying that he has full faith in his convictions.
But fate has decided otherwise. When Dev goes to the Thakur haveli next day to request for Rama's hand in marriage, he is appalled to see Bade Raja thakur sitting with Raja Virendra Pratap Singh (Raza Murad) and Narendra Pratap Singh (Vijayendra Ghatge), the man who is to marry Rama. Dev gulps down his desires and with a heavy heart readies Rama to meet Narendra (I must say Vijayendra is rather dishy!). Rama admits that quite likes the look of her groom and childishly tells Devdhar that this is the man she has now fallen in love with. But there is one person who senses Dev's discomfiture at the happenings--Rama's mother (Nanda). She somehow puts two and two together and recognises the love for Rama in Dev's eyes. But, she keeps quiet. Rama gets married to Narendra aimidst much pomp and ceremony.
Next day, Rama visits her parents' home, as is the custom in all Hindu households. But soon, a horrific accident happens and Narendra passes away, leaving Rama devastated and a child widow. The world comes crumbling at her feet. Rama's doll's house disintegrates. The girl who was brought up like a fair is now treated like a rag. She eats a frugal meal a day, talks less, never laughs and is a subject of constant scrutiny by her aunt (Sushma Seth). If this was not unfortunate, Rama is cruelly raped by her brother-in-law, Virendra (Raza Murad). And it all comes downhill for her. At this juncture, where life is worth nothing for Rama, comes Devdhar, who brings to her lifeless existence, a gasp of fresh air, a ray of light and hope... But will her autocratic and orthodox aristocratic family let her live a happy life with her new-found love?
Prem Rog, despite the heavy social commentary, is the beautiful love story of Rama and Dev. Rama is the innocent girl, untainted and untarnished. Dev is the rescuer of the damsel in distress. He is brave and sensitive, she is soft and sweet. Rishi and Padmini do make a nice couple. And Radmini's juvenile attitude is a good contrast to Rishi's mature bearings.
While everyone is simply spectacular in the film, I found Padmini Kolhapure remarkable. You can make out that she is barely 20, but the range of emotions she displays is fantastic. Starting with her chirpy behaviour, her childish banter to her sad demeanour and her realisation of Dev's love, Padmini shows that she was to reach greater hieghts. In Padmini, Raj Kapoor found an able protagonist.
What I however like, is how starkly Raj Kapoor, depicts the dichotomy in the world of these aristocrats. At one level these thakurs treat the members of the low caste as mere dirt, whereas, there is Chhote thakur (Kulbhushan Kharbanda) who picks and sleeps with the village women at his own whim. Chamiya (Bindu), the servant, in one rare moment, in a state of undress, points out how these men treat women as commodities. Chhote thakur has made her a subject of his lust and yet in front of the world he projects himself as a man who is true to his honour!
Similarly, while Bade Raja thakur orders a subject to get his widowed daughter get married again to a good samaritan of the village, he cannot accept the fact that his own widowed neice is in love with a commoner. He is more willing to see her elope with her saviour, than standing and blessing the couple in front of everyone.
But, apart from all these depictions, there is one scene that stands out for its starkness. A comment against the blind superstitions rampant in our society, Raj Kapoor presents a flawless picture of the sudden state of Manorama once her husband passes away. The new bride, a child still, is shocked and devastated. But the elderlies do not spare her. They sit and caste aspersions against her saying that she has brought ill luck on her husband's family. They drive home the point that her head needs to be shaved, lest her beautiful long hair attracts other men. The young widow howls and implores everyone so that they have mercy on her. But the fundamentalists are too mercinery. They call the local barber, make the weeping widow sit in front of his sharp razor and...


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In Reply to: RE: Bifrost in Champaign, IL, coming home tomorrow! posted by TubeDriver on March 7, 2012 at 06:48:59:
I've had it on for 3 days straight and it's opening up before my ears! I love this thing, have nothing to compare it to (it's my first DAC) and have been raving about it to anyone who'll listen. It's a new experience, nothing like it before for me. I think I'll keep it!
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- RE: Bifrost in Champaign, IL, coming home tomorrow! - michaelhigh 22:08:29 03/09/12 (0)


text:
Pesticide free lice treatments make their entrance as recommendations from the Canadian Paediatric Society
The Canadian Paediatric Society new guidelines recognize the effectiveness of pesticide free lice treatments.
MONTRÉAL, Sept. 28, 2016 /CNW Telbec/ - Pediapharm welcomes the introduction of pesticide free lice treatments in the Canadian Paediatric Society new guidelines recently updated for the first time in eight years. These new recommendations represent the first step towards the awareness of the adverse effects of neurotoxic substances on children. Such awareness is truly important, especially now as the general public and members of the medical community worry about the risks associated with the use of neurotoxic substances.
''We are very pleased that the Canadian Paediatric Society recognizes the effectiveness of dimeticone-based products, such as NYDA®, to kill lice and eggs while ensuring a safe pediculosis treatment, claims Sylvain Chrétien, former President and Chief Executive at Pediapharm. NYDA® is a dimeticone based product that has a physical mode of action which makes it sought by parents and clinicians".
Dimeticone, unlike all insecticide substances, has been recognized as one of the few products with low risk of irritation and no risk of resistance. The Society "takes into account the growing resistance of lice" to pyrethrin and to permethrine (pesticides) as well as the alarming amount of over diagnosis.
"Through my professional practice I regularly speak with parents who struggle to get rid of head lice using the common pesticide treatments, added Sherry Torkos, pharmacist and author of The Canadian Encyclopedia of Natural Medicine1. Parents are also concerned with the possible risks and side effects. I am happy to see that the Canadian Pediatric Society has included a safe and efficacious non-pesticide treatment option in their guidelines."
Lice as a social issueIt is worth noting that lice infestation is an undesirable transmitted public health issue particularly for school aged children. Unlike body lice, head lice are not a symbol of poor hygiene but an actual social issue since it is spread by direct hair to hair contact. The infested children are generally carrying less than 20 lice that, without treatment, could each live up to three or four weeks.
About NYDA pesticide-free treatmentNYDA® is a head lice treatment solution by Pediapharm, an industry leader in paediatric pharmaceuticals in Canada. It is made from dimeticone 100 cSt, which penetrates the lice's' respiratory system, making it effective against pesticide-resistant lice and safe for children's skin2. Public health authorities recommend limiting the use of pesticides because of the dangers they pose to children's health.
About PediapharmPediapharm is the first and only specialty pharmaceutical corporation in Canada that exclusively distributes and licenses innovative medicines in order to help improve children's health and quality of life.Through its network's ownership of the key stakeholders within the pediatric arena, Pediapharm's key objective is to partner with leading healthcare entities around the world to bring innovative pediatric products to the Canadian market.
Its portfolio of innovative products include NYDA®, a revolutionary treatment against head lice; EpiCeram, a ?non-steroidal cream used to treat eczema; Naproxen suspension, used for pain and inflammation caused by various medical conditions such as juvenile arthritis; and various other registered products.
1 Sherry Torkos (2013), The Canadian Encyclopedia of Natural Medicine (2nd edition), Toronto: Harper Colins Publishers.
2 Heukelbach J, Pilger D, liveira FA, Khakban A, Ariza L, Feldmeier H, A highly efficacious pediculicide based on dimeticone: randomized observer blinded comparative trial. BMC Infectious Diseases, 2008; 8:115.
SOURCE Pediapharm Inc.


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Decimal Degrees: Latitude: 40.2292374 Longitude: -80.657855
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Millionaire edges out Line of Duty
BBC2 drama Line of Duty held its total audience of more than 3m impressively, but was pipped to the post at 9pm by Who Wants To Be A Millionaire?.
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Game Changer? Vimeo Launches a Very Cool Self-Distribution Service for Filmmakers
While YouTube remains king of the cat videos and strippers cracking their skulls open on the dance pole, Vimeo has become a neat platform for artists, musicians and filmmakers thanks to its beautiful displays (especially when it comes to HD) and more discerning taste. The video-sharing website is now taking another step forward with its Vimeo On Demand service — a self-distribution platform for filmmakers with revenue available.
Creatives will be able to upload their original content and sell the work via rental or download. The coolest part about the new service is that they get to keep 90% of their revenue after transaction fees (PayPal and credit card). You must be a PRO member to take advantage of this feature, but the customization options make that alone worth it. Vimeo On Demand films can be viewed on a desktop, a mobile device and connected televisions. Oscar-nominee Don Hertzfeldt kicked off the new Vimeo feature with a screening of It's Such a Beautiful Day, the closing chapter in the filmmaker's animated trilogy about the complexities of a stick figure. You can rent or buy it for $2/$6. Check out this clip explaining the new service, and let us know if you're a filmmaker who can't wait to take advantage of Vimeo On Demand.
In the movie The Resurrection of Gavin Stone, what is the name of the character played by Kirk B.R. Woller
Jack Roth


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I have a vertical menu with submenus that drop down on hover. Is there a way to get the submenu to drop down once the page loads instead of waiting for the hover?
ThemeShaper Forums » Thematic
drop down menu activate on page load?
(4 posts)-
Posted 5 years ago #
anyone? Please and Thank You
Posted 5 years ago # -
well here's the bit of CSS that hides it by default.
.sf-menu ul { position: absolute; top: -999em; width: 10em; }
so if you change the top # it should appear on the screen
Posted 5 years ago # -
Thanks Helga- I'll give that a shot.
Posted 5 years ago #
Topic Closed
This topic has been closed to new replies.


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Escondido California Golf Courses
Featured Golf Course Review:
Eagle Crest Golf Club -- Play this course! | ||
Review by: Anonymous | This is a beautiful golf course that is a must play. A well kept secret in San Diego golf! | |
From Encinitas, CA |
Golf Courses: Additional Golf Course Reviews:
Meadow Lake Golf Club -- great course | ||
Review by: Anonymous | great course for any player. this course has everything! | |
From san diego |
Meadow Lake Golf Club -- Old Style w/ great views... | ||
Review by: morgy | Provided it's a bit out of the way, it is a good course. Worth the drive. | |
From Escondido, Ca |


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After being geographically separated for five months from my wife she flies in to California today from Maryland (aka Stupidlandia).
I might not be posting for a few days as we patronize the fine museums, cultural sites, pristine beaches and excellent dining establishments San Diego has to offer.
Tags: Comic Book Romance
Wednesday, September 05, 2007
Do Not Disturb
Posted by Sleestak at 9/05/2007 02:00:00 AM
13 comments:
Looking back on those old blog entries, I have this question:
Did Batman ever win his election bid for sheriff?
If he didn't, well, there's what wrong with Maryland right there.
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Post Comments (Atom)


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At any rate,welcome to the Best Blog Post Ever This Week! This is a fun, family friendly link party that MMB hosts every Friday. (or Saturday, because sometimes I'm SUPER LATE TO THE PARTY) Link up your family blogs, your craft blogs, your food blogs, your blogging blogs, and whatever else kind of blog you write.
This week has been CRAZY for me. We've had way too many doctor visits, and somehow, June just sneaked up on me. (Hate when that happens!)


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magnitude in Astronomy topic
From Longman Dictionary of Contemporary Englishmagnitudemag‧ni‧tude /ˈmæɡnɪtjuːd $ -tuːd/ ●○○ noun 1 [uncountable]BIG the great size or importance of somethingmagnitude of They didn't seem to appreciate the magnitude of the problem.of such/this/similar etc magnitude We did not think the cuts would be of this magnitude. an increase of this order of magnitude (=size)2 [countable] technical the degree of brightness of a star3 [countable] technical the force of an earthquake
Examples from the Corpus
magnitude• The earthquake registered a magnitude of 6.8, according to early estimates.• It has a B-type spectrum, and is usually just below the fourth magnitude.• Fortunately there is a good comparison star of magnitude 6.6, also in the bowl.• The oil spillage in the Gulf was of such magnitude that its effects will last for decades.• But this is not meant to belittle the magnitude of the adaptive radiations that took place in the Vendian and Cambrian periods.• The budget deficit is no surprise, but the magnitude is.• This increases the magnitude of the vorticity, but because of continuity also reduces the cross-section of the vortex tube.• I cannot emphasize too strongly the magnitude of this problem.• Decisions of this magnitude should not be taken by one person alone.• We've never dealt with a problem of this magnitude before.order of magnitude• With care, about 12 harmonics may be obtained so that about an order of magnitude of frequency range is available.• In the infrared, extinction by dust is an order of magnitude smaller than in the visible portion of the spectrum.• Even with such an unsophisticated method Galileo's estimates turned out to be correct to within an order of magnitude.• We can, however, establish the correct order of magnitude from a number of sources.• These figures serve to indicate a relative order of magnitude.• We do find that, as before, imaging or pattern classification networks are several orders of magnitude simpler to train.• People are normally considered to be risk-averse over amounts of the order of magnitude of their incomes.• If rainfall is variant then the mixture of species increases by two or three orders of magnitude.
Explore Astronomy Topic
- nova
- celestial
- extraterrestrial
- astro-
- eclipse
- solar system
- Big Bang, the
- space capsule
- quadrant
- solar
- orbit
- orbiter
- lunar
- aurora borealis
- Mars
- Pluto
- infinity
- launch
- star
- astronaut
- satellite
- eclipse
- galactic
- Little Bear
- quarter
- phase
- wax
- cosmonaut
- escape velocity
- cosmology
- dead
- space shuttle
- equinox
- quasar
- meteor
- stellar
- meteoric
- corona
- Saturn
- astrophysics


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I have migraines and so take ibuprofen basically every day. I've read that you should avoid taking blood thinners 2 weeks before getting an injection, but I'm wondering how bad it'd be if I didn't wait. I'm considering the laugh lines and possibly later on the tear troughs (restylane or juvederm). Can someone please tell me what would happen if I continued using them? Thanks.
Chronic NSAID User Considering Fillers
Doctor Answers 6
You may bruise alittle more while on your NSAIDs but it is no problem usually. Take arnica and ice the areas really well and you will be fine. Sincerely,
David Hansen,MD
Web reference: http://www.drdavidhansen.com
The "tear trough" of your lower eyelid is the most common location to get a significant bruise following an Injectable Filler treatment. In my hands, this may occur in up to 10% of lower eyelid treatments. This is likely due to inadvertent trauma to a small vein.
I do not routinely discontinue blood thinners in any of my patients that require them for cardiovascular health. I have treated patients on aspirin, Plavix, and Coumadin without significant incident.
There is a correlation between NSAID use and blood thinning, but I think this is not common and is considered an "idiosynchratic reaction". My understanding is that NSAIDs thin the blood in very few individuals. I discontinue their use before major surgery, but not before an Injectable Filler treatment.
I hope this is helpful for you.
Web reference: http://ericmjoseph.com/index.cfm/PageID/4247
You would probably experience some increased bleeding, but I would not discourage you from having the injections if you really are keen on getting them. You may experience a bit more bruising, and your appearance might be impaired for 5-10 days longer, but as long as you schedule your injections with this in mind you should do fine.
I would be very hesistant to inject in the tear troughs, however, as this is a more vascular area than the naso-labial folds. Bruising can persist for a much longer time.
Be sure you go to an experienced injector and make them aware of the medication you are taking. Technique is important in minimizing bruising. The antegrade technique in which the filler is injected in front of the needle will minimize bruising. Slow and meticulous goes a long way.
It is also my feeling that Restylane leads to less brusing than Juvederm, but that is anecdotal and not scientific. I could not find a well done study comparing the two.
You might take bromelain pills before the injections. This is an enzyme derived from the stem of the pineapple and it seems to help with bruising. Similarly, arnica montana, may help afterwards. Some physicians like to use an IPL or a LED device such as GentleWaves to improve post-injection bruising. Auriderm is a cream that can also be used.
You might also like...
If you continued using them you could have mor prominent bruising from the procedure. This could last up to 10 days or more.
Nsaid's will cause more bruising. You may want to stay away from them for at least a week to ten days. If you can not, then expect that you may have more bruising than the norm.
Regarding: "Chronic NSAID User Considering Fillers
I have migraines and so take ibuprofen basically every day. I've read that you should avoid taking blood thinners 2 weeks before getting an injection, but I'm wondering how bad it'd be if I didn't wait. I'm considering the laugh lines and possibly later on the tear troughs (restylane or juvederm). Can someone please tell me what would happen if I continued using them? Thanks"
Instead of bleeding and clotting normally when small blood vessels are injured by the needle, you will bleed much longer, potentially resulting in severe bruising of the areas into which the filler is injected. Such bruising will take 7-10 days to begin clearing thereby changing a lunch time procedure into something which requires a much longer recovery.
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


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I am ready to go QB in first round, we should not have this problem year in and year out. QB is the most important position on the team and we never have the same one start and finish the same season! Last year that happened was 2002!
I just don't understand what happened to our outside LB's... They were the backbone of the defense last season. Ayers and Brown have all but disappeared this year. Am I wrong?
#1: Incompetent coaches #2: Awful scheme #3: No identity #4: No QB Those 4 things will ruin any team and we are lucky enough to have all four!!!
Not wrong at all. You know who the backbone of this defense is? Not that we really have any right now but if i had to pick any. Are DT and CB. Verner and Casey are the only ones playing at a high level. Really impressed with Casey this year, the kid is only 23 and he's dominating the interior of the line. If hes not getting a sack hes constantly getting pressure and collapsing the pocket for the other guys. Now if we only had consistent pass rushing DE to compliment him like we did back in 07-08 with KVB we'd be in good shape. Verner is a ball hawk, always around the ball very rarely gets beats deep. Sound tackler, shows up every game and does his job. Everybody else plays when they want to and it shows. Until everybody starts playing like these two guys are defense is never going to get off the field.
I still believe in this defense. Even the offense looked good most of last night. Its those FCKNING special team plays that keep coming back to haunt us.
I'd like Texas A&M's Mike Evans in the draft. Washington is probably at the end of his career, Brittle will be gone, and that leaves... ? I think Wright, Hunter, and Evans would make a killer WR core. Either him or C.J. Mosley. I give Locker one more year. If he can't get through the season AGAIN, then we should have a decent enough pick to snag a quality QB. If he does get through the season, then I think he can be a franchise QB. I just don't see many good QBs being left after the Faguars, Bucs, Cows, Raiders, and Vikings pick before us. And I'm sure the Browns will trade up to get their future QB as well. The unfortunate reality is that we're not going to lose every game from here on out, so we're not going to be in any position to snag one of the stud QBs. At best I'd say McCarron falls to us, but even though I love me some Alabama football, I don't particularly care to see AJ in a Titans uniform.
I wish i could bud but i cant. We're so inconsistent especially with our run defense its nauseating it really is. Your not going to win any games if you cant stop the run and we cant. 28th against the run says it all. Just look at the pattern after our 3-1 start. Cheifs 108,Seahawks 154,San Fran 138,Rams 127,Indy 133. The Jags had under 60 but MJD gashed us on their opening drive and that was enough to rattle us. It seems like when we really need a stop we cant get off the field its demoralizing to watch as a fan, i can only imagine how the players feel on the field.


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Learn how the inherent thermal resistance of DuPont™ Nomex® makes it ideal for high-temperature automotive applications, including heat shields and other under-the-hood applications.


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A Toledo man convicted of stabbing his wife multiple times was sentenced in Lucas County Common Pleas Court to seven years in prison.
Walter L. Benton, Jr., 30, of 1057 Orchard St. entered a plea Feb. 17 to 14 counts of felonious assault, one for each time he stabbed her in an altercation in September.
Benton was arrested three days after his wife, Jessica, 22, was found Sept. 29 in an apartment in Vistula Manor. She had been stabbed in the face and body. Authorities said the assault was preceded by a domestic dispute.
Judge Gene Zmuda sentenced Benton Wednesday to seven years in prison on each count and ordered them to run concurrently. He noted the victim spoke on Benton's behalf, saying that he needed help and not prison.
The judge dismissed an attempted murder charge as a result of the plea agreement.


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Ocoee Dollar General
This is a photo of what a proposed Dollar General in Ocoee will look like. There are some upgrades to the design in terms of materials being used. It's certainly a step above the Family Dollar's we've seen. Residents near the proposed site of this store are suing the city over concerns about traffic and aesthetics. Can't say I blame them.
Courtesy of city of Ocoee
© 2017, Chicago Tribune


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Investors in the U.S. are very familiar with the Tupperware (NYSE:TUP) parties that family members and friends host (or may have hosted in the past). But what investors may not know is that the firm's investment merits stem from its non-U.S. growth prospects. The company is so well-known in the U.S. that it's sometimes difficult to believe that non-U.S. sales are ~90% of the total. Let's calculate an estimate of Tupperware's intrinsic value, and run shares through the Valuentum Buying Index.
For those that may not be familiar with our boutique research firm, we think a comprehensive analysis of a firm's discounted cash flow valuation, relative valuation versus industry peers, as well as an assessment of technical and momentum indicators is the best way to identify the most attractive stocks at the best time to buy. We think stocks that are cheap (undervalued) and just starting to go up (momentum) are some of the best ones to evaluate for addition to the portfolios. These stocks have both strong valuation and pricing support. This process culminates in what we call our Valuentum Buying Index, which ranks stocks on a scale from 1 to 10, with 10 being the best.
Most stocks that are cheap and just starting to go up are also adored by value, growth, GARP, and momentum investors, all the same and across the board. Though we are purely fundamentally-based investors, we find that the stocks we like (underpriced stocks with strong momentum) are the ones that are soon to be liked by a large variety of money managers. We think this characteristic is partly responsible for the outperformance of our ideas -- as they are soon to experience heavy buying interest. Regardless of a money manager's focus, the Valuentum process covers the bases.
We liken stock selection to a modern-day beauty contest. In order to pick the winner of a beauty contest, one must know the preferences of the judges of a beauty contest. The contestant that is liked by the most judges will win, and in a similar respect, the stock that is liked by the most money managers will win. We may have our own views on which companies we like or which contestant we like, but it doesn't matter much if the money managers or judges disagree. That's why we focus on the DCF -- that's why we focus on relative value -- and that's why we use technical and momentum indicators. We think a comprehensive and systematic analysis applied across a coverage universe is the key to outperformance. We are tuned into what drives stocks higher and lower. Some investors know no other way to invest than the Valuentum process. They call this way of thinking common sense. Let's continue.
Tupperware's Investment Considerations
Investment Highlights
- Tupperware's business quality (an evaluation of our ValueCreation™ and ValueRisk™ ratings) ranks among the best of the firms in our coverage universe. The firm has been generating economic value for shareholders, with relatively stable operating results for the past few years, a combination we view very positively.
- Tupperware sells preparation, storage, and serving solutions for the kitchen/home through the Tupperware brand. Its beauty products are sold through the Armand Dupree, Avroy, and other brands. Emerging markets account for two-thirds of revenue (non-U.S. sales are greater than 90% of total).
- Tupperware has a good combination of strong free cash flow generation and manageable financial leverage. We expect the firm's free cash flow margin to average about 12.5% in coming years. Total debt-to-EBITDA was 1.8 last year, while debt-to-book capitalization stood at 77.2%.
- Tupperware outlines emerging market penetration and the growing middle class in the Asia-Pacific and South America regions as levers for growth. The firm is targeting double-digit EPS growth over the long haul. Though its brand recognition is good in emerging markets, its market penetration is fairly low, revealing a long runway for expansion.
- Performance in its established market business, however, continues to suffer (Germany and Tupperware U.S. and Canada). Tupperware relies on the "party" method of sales, which may have run its course in the U.S. as recruiting initiatives wane.
- At the core of the Valuentum Buying Index, if a company is undervalued both on a discounted cash flow basis and on a relative valuation basis, and is showing improvement in technical and momentum indicators, it scores high on our scale. Tupperware posts a Valuentum Buying Index score of 6, reflecting our "fairly valued" DCF assessment of the firm, its neutral relative valuation versus peers, and bullish technicals. We generally prefer stocks with ratings of a 9 or 10, many of which are included in the Best Ideas portfolio.
Business Quality
Economic Profit Analysis
The best measure of a firm's ability to create value for shareholders is expressed by comparing its return on invested capital with its weighted average cost of capital. The gap or difference between ROIC and WACC is called the firm's economic profit spread. Tupperware's 3-year historical return on invested capital (without goodwill) is 41%, which is above the estimate of its cost of capital of 10.1%. As such, we assign the firm a ValueCreation™ rating of EXCELLENT. In the chart below, we show the probable path of ROIC in the years ahead, based on the estimated volatility of key drivers behind the measure. The solid grey line reflects the most likely outcome, in our opinion, and represents the scenario that results in our fair value estimate.
Cash Flow Analysis
Firms that generate a free cash flow margin (free cash flow divided by total revenue) above 5% are usually considered cash cows. Tupperware's free cash flow margin has averaged about 8.6% during the past 3 years. As such, we think the firm's cash flow generation is relatively STRONG. The free cash flow measure shown above is derived by taking cash flow from operations less capital expenditures, and differs from enterprise free cash flow (FCFF), which we use in deriving our fair value estimate for the company. For more information on the differences between these two measures, please visit our website at Valuentum.com. At Tupperware, cash flow from operations increased about 18% from levels registered two years ago, while capital expenditures fell about 7% over the same time period.
Valuation Analysis
Our discounted cash flow model indicates that Tupperware's shares are worth between $70-$104 each. Tupperware's shares are trading at ~$83 each. The margin of safety around our fair value estimate is driven by the firm's LOW ValueRisk™ rating, which is derived from the historical volatility of key valuation drivers. The estimated fair value of $87 per share represents a price-to-earnings (P/E) ratio of about 16.8 times last year's earnings and an implied EV/EBITDA multiple of about 11.5 times last year's EBITDA. Our model reflects a compound annual revenue growth rate of 3.6% during the next five years, a pace that is lower than the firm's 3-year historical compound annual growth rate of 5.1%. Our model reflects a 5-year projected average operating margin of 17%, which is above Tupperware's trailing 3-year average. Beyond year 5, we assume free cash flow will grow at an annual rate of 2.3% for the next 15 years and 3% in perpetuity. For Tupperware, we use a 10.1% weighted average cost of capital to discount future free cash flows.
We understand the critical importance of assessing firms on a relative value basis, versus both their industry and peers. Many institutional money managers -- those that drive stock prices -- pay attention to a company's price-to-earnings ratio and price-earnings-to-growth ratio in making buy/sell decisions. With this in mind, we have included a forward-looking relative value assessment in our process to further augment our rigorous discounted cash flow process. If a company is undervalued on both a price-to-earnings ratio and a price-earnings-to-growth ratio versus industry peers, we would consider the firm to be attractive from a relative value standpoint. For relative valuation purposes, we compare Tupperware to peers Ball Corp. (NYSE:BLL) and Owens-Illinois (NYSE:OI), among others.
Margin of Safety Analysis
Our discounted cash flow process values each firm on the basis of the present value of all future free cash flows. Although we estimate the firm's fair value at about $87 per share, every company has a range of probable fair values that's created by the uncertainty of key valuation drivers (like future revenue or earnings, for example). After all, if the future was known with certainty, we wouldn't see much volatility in the markets, as stocks would trade precisely at their known fair values. Our ValueRisk™ rating sets the margin of safety or the fair value range we assign to each stock. In the graph below, we show this probable range of fair values for Tupperware. We think the firm is attractive below $70 per share (the green line), but quite expensive above $104 per share (the red line). The prices that fall along the yellow line, which includes our fair value estimate, represent a reasonable valuation for the firm, in our opinion.
Future Path of Fair Value
We estimate Tupperware's fair value at this point in time to be about $87 per share. As time passes, however, companies generate cash flow and pay out cash to shareholders in the form of dividends. The chart below compares the firm's current share price with the path of Tupperware's expected equity value per share over the next three years, assuming our long-term projections prove accurate. The range between the resulting downside fair value and upside fair value in Year 3 represents our best estimate of the value of the firm's shares three years hence. This range of potential outcomes is also subject to change over time, should our views on the firm's future cash flow potential change. The expected fair value of $108 per share in Year 3 represents our existing fair value per share of $87 increased at an annual rate of the firm's cost of equity less its dividend yield. The upside and downside ranges are derived in the same way, but from the upper and lower bounds of our fair value estimate range.
Pro Forma Financial Statements
In the spirit of transparency, we show how the performance of the Valuentum Buying Index has stacked up per underlying score as it relates to firms in the Best Ideas portfolio. Past results are not a guarantee of future performance.
Disclosure: The author has no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it (other than from Seeking Alpha). The author has no business relationship with any company whose stock is mentioned in this article.


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- convert to/from xexpr to sxml
- reading sxml/xexpr from html or xml sources
- managing html and xml enities
(require (planet bzlib/xml))
Xexpr and SXML
Although Xexpr is the default xml representation in PLT Scheme (and the web-server), it lacks the toolkits that SXML enjoys. bzlib/xml helps by providing conversion functions to convert between sxml and xexpr:
;; convert from xexpr to sxml
(xexpr->sxml `(p ((class "default")) "an xexpr instance"))
;; => `(p (@ (class "default")) "an xexpr instance")
; convert from sxml to xexpr
(sxml->xexpr `(p (@ (class "default")) "an xexpr instance"))
;; => `(p ((class "default")) "an xexpr instance")
Converting from xexpr to sxml will allow you to use the facilities such as sxpath, ssax, and sxml-match with xexpr, and converting from sxml to xexpr will allow you to feed sxml into web-server for to generate output based on sxml.Reading and Writing Xexpr/SXML
provides read-xexpr
and read-sxml
to simplify the conversion from html sources to either xexpr or sxml:
;; reading xexpr
(read-xexpr <input-port?>)
;; reading sxml
(read-sxml <input-port?>)
The <input-port?>
can be an http-client-response
structure defined in bzlib/http
, which provides an content-type header that helps aid the determination of whether this is an html or xml document, for example:
(read-sxml (http-get "http://www.google.com/"))
There are corresponding write-sxml
and write-xexpr
;; write-xexpr
(write-xexpr <xexpr?> <output-port?>)
;; write-sxml
(write-sxml <sxml?> <output-port?>)
Managing Entities
As part of converting from xexpr to sxml you'll need to deal with normalizing the xml entities. Since xexpr simply converts entities into symbols and numeric entities into numbers instead of converting them into final strings, bzlib/xml provides a
routine that'll convert the entity into strings for you.
(entity->string <symbol or number entity>)
This is automatically called by xexpr->sxml
, read-xepxr
, and read-sxml
, so you generally do not have to use it explicitly, except to extend the entity mapping.entity->string
converts entities by mapping numeric entities via against the unicode character map, and symbol entities via two separate entity mapping tables, one for predefined HTML entities, and the other is a parameterizable XML entities.The HTML entity table contains a set of pre-defined HTML entities that were mapped to the underlying character numeric code. Generally you should not have to modify this set of entities, but if you need to, you can do so via
(set-html-entities! <list of symbol/integer pairs>)
;; example
(set-html-entities! `((nbsp . 160) (lt . 60) (gt . 62)))
The XML entity table (
) is parameterizable, and it takes a list of symbol and string pairs:
(parameterize ((xml-entities '((lt . "<") (gt . ">"))))
(read-sxml ...))
If you use the same symbol entity in both tables, the xml-entities
takes precedence. Any unknown entity is mapped to the null character.
That's it for now. Enjoy.


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Item #46852-24HR
Your impact spans the continents faster than ever!
Read More About This Item...50%
1 color(s) to choose from!
This item has one color option: Blue
Selected Color(s):
Blue : MulticolorMinimum Quantity | 150 | 250 | 500 | 1000 | |||
Your Price | $1.55 | $1.39 | $1.29 | $1.17 |
For prices, enter the quantity you'd like or click and drag our orange 'i'.
Pat. 7,979,318
Enter the quantity you'd like, or click and drag our orange 'i' to find a quantity and price that's best for you.
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over minimum quantity pricing
Kevin Lyons-Tarr
CEO, with 4imprint
25 years
means you're covered from every angle.
Free samples, free art assistance and lightning-fast service from people who care make ordering easy.
If you find a lower advertised price within 30 days of your purchase, let us know and we'll refund double the difference in price.
We promise the product will meet your expectations and your imprint will be exactly as you approved it, or we'll rerun your order or refund your money - your choice.
If your event is missed because we didn't ship on time, your order is on us.
* Excludes art preparation time, applies only to orders of 1000 items or fewer.
Once you've completed checking out, an option is provided to upload your art file(s).
We gladly accept all file types.
No worries, the confirmation email you'll receive after ordering will have additional instructions. Check out our art tips for more information.
I used this item as a give-away in our annual campus cultural diversity celebration (a street fair type of event), and the students, faculty and staff loved them. Exam week was coming up, so the stress ball was perfect! I think they're getting a lot of use...
May 2007
Heather from Caldwell
Was this review helpful?
Yes No4 / 5 stars
I really like how this stress ball turned out. It is a little bigger than I thought it would be, but that turned out to be a good thing because it allowed for our logo to be more visible on the ball. I couldn't tell from the picture, but the continents are raised and I love it, I think it adds a little something extra. I am very happy with this product.
June 2012
Carly from Houghton
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text:
A chant sung by West Bromwich Albion fans about Ben Foster who plays/ played for Joe Hart.
He dives to his left,
he dives to his right
thats why Ben Foster makes Joe Hart look s**te!
To the tune of: Stevie Bulls a Tatter
Votes: 28
Submitted by: Chloe on Sunday 28 April 2013 at 19:27
Embed this chant in your page/ blog using the html below:


text:
Champion Metered Insecticide 7 ozManufacturer: Chase Products CoUPC: 010228351112Manufacturer Item Number: 4385111Do you manufacture or supply this product? Learn how to get leads and increase your visibility on Anything4Restaurants.com |
Champion Sprayon® Metered Insecticide Spray is a highly concentrated formula that controls flies, mosquitoes, gnats and small flying moths in a 6,000 cubic-foot area. A single can will last for 28 days when sprayed around the clock at 15-minute intervals.
Recommended uses


text: Dictionarysil•i•catePronunciation: (sil'i-kit, -kāt"), [key] —n. 1. Mineral.any of the largest group of mineral compounds, as quartz, beryl, garnet, feldspar, mica, and various kinds of clay, consisting of SiO2 or SiO4 groupings and one or more metallic ions, with some forms containing hydrogen. Silicates constitute well over 90 percent of the rock-forming minerals of the earth's crust. 2. Chem.any salt derived from the silicic acids or from silica. Random House Unabridged Dictionary, Copyright © 1997, by Random House, Inc., on Infoplease.