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An Internet gambling bill being voted on by the state Senate today includes a provision that makes the sale of The Atlantic Club to PokerStars or similar company more attractive, according to lawmakers.
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Waze - GPS Navigation, Maps & Social Traffic
By Waze Inc.
Open iTunes to buy and download apps.
Waze is the world's largest community-based traffic and navigation app. Join drivers in your area who share real-time traffic & road info to save time, gas money, and improve daily commuting for all.
Just by driving with Waze open, you're already contributing tons of real-time traffic information to your local community. You can also actively report accidents, police traps and other hazards you see on the road. Get road alerts along your route and find the cheapest gas prices around you shared by the community. Plus, you can add friends, send locations or keep others posted on your arrival time.
- Live routing based on community driven, real-time traffic & road info
- Community reported alerts including accidents, hazards, police traps, road closures, and more
- Turn-by-turn voice guided navigation
- Live maps, consistently edited and updated by Waze community map editors
- Automatic rerouting as conditions change on the road
- Send your ETA & real-time drive to update those you're meeting
- Learns your frequent destinations, commuting hours, and preferred routes
- Find the cheapest gas station on your route
- Add information on local places and businesses
- Add Facebook friends and sync Contacts
- See friends' ETA when driving to the same destination
- One tap navigation to Facebook & Calendar events
- Earn points as you contribute road info and climb the ranks in your community
Waze is all about contributing to and benefiting from the common good, so hop on board and get involved!
Note: Continued use of GPS running in the background can dramatically decrease battery life. Waze will automatically shut down if you run it in the background and haven't driven for a while.
Learn more about the Waze privacy policy, including what information is accessed and how it is used. With Waze, you have full control over your privacy settings. http://www.waze.com/legal/privacy/
What's New in Version 4.9.0
* In countries where average speed camera zones are enforced, Waze now helps you drive safely within the speed limit and avoid speeding tickets. Get alerts where average speed cameras are located and track your progress as you drive through.
* Bugs and stability fixes
Customer Reviews
Love it!
My husband and I are authors and travel a lot for book and family events. My niece turned us on the Waze (which we were told is pronounced like ways in highways not wazzee) we love this app and use it when ever we are on the road! Even if the police car isn't right where they say it is (and usually it is!) you know to be cautious! Plus it lists many Dunkin Donuts! You can use it as a gps for traveling but we usually don't as we have one built into our car, but do use it to guide us to restaurants or pit stops when we don't want to change the gps program in our car. Can't say enough good except plug in your phone to the charger and remember to turn it off when you stop or you will drain your battery fast! It is constantly using location detection. You get points when you alert other drivers to issues on the road like police, construction, car on side of road etc. they give a cool name which you can change and you can pick your icon or mood for the day! So much fun. You can beep to say hi to friends when they are driving even if it is in another town! Love saying hi to my niece with a beep beep. Don't drive without it! And don't text and drive!
Great concept, buggy
I love the idea and like the app. So far on our road trip I've had to restart the app 2+ times due to it freezing up.
I wish you could use voice search or to add comments. The app needs to add the ability to change a status. When you come across a crash some people may status it as police ahead when its actually a crash. Some people may say police ahead when actually they are with a disabled car, when the police leave the status is incorrect it's just a disabled car. I want the location of crashes to be precise or be updated to the exact location. This matters as to alternative routes are dependent to the crash location. I also want the app to give me multiple alternative directions around a crash. The app is only as good as information put into it. If we have the ability to update the information the info would improve. I want lots of info when I come to a slow down; Like when it was first reported, ems on scene, vehicles blocking the roadway, police on scene, scene about to be cleared. Adding more info could make the app better.
I also want to see alerts on my route better. I want to plan ahead for potential traffic issues. Make the buttons a little more user friendly and easier to make updates.
Was awesome until now
I used to choose Waze over Apple Maps at any chance given but now it's just as problematic. Living in Houston we have toll roads - sometimes I want to take them, sometimes I don't. Instead of a user having to go deep in the settings to turn the toll road usage off it should be an option to turn it off/on as I'm looking at the overview at the beginning of a trip. Currently, I have to manually turn it back on each time I would like to use the toll roads. Secondly, I would love if there was an option for me to input a different starting point than the one I'm specifically located in at that moment. I don't always need directions from my location but from other places I might frequent. Lastly, I don't know if it's because my side of town has huge amounts of highway construction going on but the actual gps spotting is wacky as I'm driving and that is most annoying. It'll be navigating me on streets I'm not even on but are nearby. I haven't changed any settings on my phone so idk what the problem is. Please fix this! Can't use the app if it can't even tell me where I am. And please fix the lagging while directions are loading!
- Free
- Category: Navigation
- Updated: Jul 14, 2016
- Version: 4.9.0
- Size: 54.8 MB
- Languages: English, Afrikaans, Arabic, Bulgarian, Catalan, Croatian, Czech, Danish, Dutch, Estonian, Finnish, French, Galician, German, Hebrew, Hungarian, Indonesian, Italian, Japanese, Korean, Latvian, Lithuanian, Malay, Norwegian Bokmål, Polish, Portuguese, Romanian, Russian, Serbian, Simplified Chinese, Slovak, Slovenian, Spanish, Swedish, Traditional Chinese, Turkish
- Seller: waze
- © Waze Inc.
Compatibility: Requires iOS 7.0 or later. Compatible with iPhone, iPad, and iPod touch.


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RAS-SMS is a simple extension to Microsoft's Remote Access Service (RAS). RAS-SMS adds two factor authentication to standard VPN/PPTP clients on Windows, Mac-OS and Linux. RAS-SMS uses your mobile phone instead of smart cards, RSA keys or USB tokens.8 weekly downloads
Firefight Logger
A logging program to record your Halo 3: ODST: Firefight stats on.1 weekly downloads
Easy as NAT -Open WiFi Bandwidth Sharing
Our aim is providing fixed nodes with redundancy, share unused bandwidth, and create hotspots with base services(web,email,IM,etc.) for any roaming user. GOAL - To make sharing your excess bandwidth as easy as setting up a NAT (Or XP ICS). Admins Needed!
Service Watcher and Application Launcher
SWAL is a program that can launch as a service (or standalone) and monitor other services and control other programs. Written in C++ and might have some .NET components (planning on a linux port)


text: Pumps and valves play an important role in food safety FSMA finally takes effect in September. Make sure your production team understands the role pumps and valves play in ensuring food safety, and how to clean and maintain them properly. April 14, 2016 No Comments In anticipation of the long-discussed Food Safety Modernization Act finally becoming enforceable in September, we asked equipment suppliers about the role pumps and valves play in assuring food safety in dairy processing plants. Here's what they had to say about this subject in our virtual roundtable. Read More


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Lorna, Editor's Archive
Nicky Hilton in J Brand
Nicky Hilton was seen getting a drink at one of the most popular celeb spots, The Coffee Bean & Tea Leaf, in Los Angeles, California last week. She was then making her way to run some errands for the rest of the day.
Nicky was wearing her J Brand 811 Mid Rise skinny leg jeans in Bright Purple with an oversized printed shirt and heels. This outfit is really bright and fun! I like the black and the purple together. I'm not 100% sure on the shirt though, it's a little too quirky for my liking. I do love the purple of these jeans though! You can buy J Brand jeans online at Singer22.com.
Images courtesy of INFdaily.com
The Making Of The Habitual 'Glory' Pocket
Habitual showed me this really cool video about how they make their famous 'Glory' pocket on their jeans. You get to see exactly how the workers put the pocket together and how it's made. It's really interesting. As you can see, the pockets are all individually handcrafted by the workers in the LA factory. What do you think of the video? You can view more about the video on the Habitual blog here.
Pippa Middleton in Goldsign
I'm beginning to love this obsession the nation has with Pippa Middleton's butt! It means we get great jeans shots! This time Pippa was spotted making her way back to her car after leaving a coffee shop in London, England.
Pippa wore a pair of Goldsign grey skinny jeans with low heeled wedges and a pale pink shirt. I'm not overly fond of all the different colours together here but I do love all of the pieces, I think it's just the red shade of the bag throwing the look off. Without it I think it would look much better! Buy Goldsign jeans at Singer22.com.
Images courtesy of INFdaily.com
Ashley Greene in Blank NYC
Twilight star, Ashley Greene, was seen out and about running some errands in Beverly Hills, California a few days ago. She looked so chic and stylish in her colour block outfit of black and red!
Ashley chose a pair of Blank NYC Spray On skinny jeans in Fire Dept with black heels, a black long sleeved top and some sunglasses. I really love this look on her, the black and red works so well. I think the material of these jeans does look a little bit on the thin side though! Buy these jeans at Karmaloop for $74.


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Four Laser Beams Will Create the World's Most Powerful Fake Stars
Set lasers to star mode. The European Southern Observatory's Paranal Observatory in Chile now has four powerful laser beams with which to create artificial stars in the night sky.
Set lasers to star mode. The European Southern Observatory's Paranal Observatory in Chile now has four powerful laser beams with which to create artificial stars in the night sky.
Behold VFTS 352, the hottest and most massive "overcontact binary" star system ever discovered. The two stars, which are so close that they're touching, feature a combined mass 57 times that of our Sun. Astronomers say it's a unique stellar relationship that will culminate in a rather dramatic finish.
This breathtaking photo shows the intense orange beam of a new 22-watt laser pointed at the planet Saturn. Wait, isn't this like the shocking scene in Star Wars where the Death Star's superlaser completely annihilated planet Alderaan?
This stunning aerial photograph of the Very Large Telescope platform somehow reminds me of a smaller base in a real time strategy game, like Starcraft or Total Annihilation.
One way or another, the Pillars of Creation are toast. Based on new observations at the European Southern Observatory, these awe-inspiring structures have another 3 million years before their ghostly image fizzles away into cosmic nothingness.
Being an astronomer working at the Very Large Telescope is probably one of the best jobs in the world. Just look at the view this office has. It's full of stars!
This stunning fisheye photograph shows the towering wonder of the European Southern Observatory's Very Large Telescope—plus, you know, some galaxy called the Milky Way in the background, too.
To produce stunning images of our galaxy like this, your rinky-dink smartphone camera just isn't going to cut it. No, to generate 9GP masterpieces, you'll need to use the world's largest infrared survey telescope outfitted with the world's largest infrared camera.
We've showed you the Paranal Observatory's laser-guided telescopes before, but never in gorgeous HD motion, replete with clear stars and deftly swiveling machinery. This is definitely one you're going to want to watch fullscreen.
How do you create the world's largest virtual optical telescope and the most advanced visible-light astronomical observatory? Teamwork. The Very Large Telescope at the Paranal Observatory combines the visual prowess of four huge telescopes—for the first time ever—to mimic a 130-meter-wide mirror.
No, the astronomers at the European Southern Observatory are not playing a galactic-scale Space Invaders. They are just exciting atoms in the upper atmosphere, creating an artificial star 56 miles above the Earth.
Developed by British scientists for the VLT (very large telescope), the CCD200 detector is the world's fastest and most sensitive astronomical camera—capable of shooting an astonishing 1500 images per second.


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"Laurel Wright representing radio station WIVK in Knoxville, Tennessee has won the 30th Annual Texaco Country Showdown produced for a one-hour television special at Nashville's historic Ryman Auditorium."
"She's built a devoted following in recent years and earned the attention of radio personnel at local country station WIVK-FM."
"Laurel Wright is on her way to Nashville for the National Final. While en route, she's racked up a considerable amount of online traffic and she is our "Featured Performer of the Week!" "
"As one of the five Regional Winners from across the country Laurel Wright will compete for $100,000 and the coveted National Title, "Best New Act in Country Music" at the world-famous Ryman Auditorium on January 26, 2012.""
"When the kids at the school took to her so well, I could see that could be something she could do to get a good message across to the kids," Jackie Mills said. "They really connected with her and didn't want her to stop. She was amazing."
"William Blount High School sophomore Laurel Wright will be featured along with national artists Blaine Larsen, James Wesley, Troy Olsen, Frankie Ballard and Katie Armiger in the debut show."
"On her way to achieving her dream of performing on stage at the Grand Ole Opry."
"She's a solid songwriter, an amazing singer and most importantly she's well-grounded."
"Laurel Wright has a country voice that rivals some professional singers, and she's 14."


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I'm trying to open a logfile which is kept open by another process and remove the first few lines.
On Unix I'd simply do a
os.open('/tmp/file.log', os.O_NONBLOCK) and that would get me closer to my goal.
Now i'm stuck with Windows and I need to rotate this log somehow without ending the application holding the file. Is this even possible?
At first I considered opening a file handle on the location where the application expected the log to be and just act as a pipe into a file-handle in Python but I couldn't find any way of doing that either on Windows.
I also thought of just moving the file on a regular basis and letting the application recreate the file but since it's being used by another process that doesn't do much good.
Thought of
O_SHLOCK as well but then again, that's Unix and not Windows.
So I went for mmap the file and hope that it would make it a bit more flexible but that led me nowhere.
import mmap
import contextlib
import time
with open(r'test.log', 'r+') as f:
with contextlib.closing(mmap.mmap(f.fileno(), 0)) as m:
while 1:
line = m.readline()
if len(line) > 0:
print line
This results in that the application can't access the file because Python is holding it (and vice versa).
Came to think of
signal.SIGHUP but that doesn't exist in Windows either so back to square one.
I'm stuck and I've tried it all, can Python help me here or do I need to switch my language?


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ATLANTIC CITY - Hotels are sold out. Restaurants will offer special menus. And bars will open early Wednesday as businesses and casinos capitalize on the Atlantic City Airshow bringing the largest midweek crowds of the summer.
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354 search results for steve martin
Jimmy Kimmel, Steve Martin, more comedians tweet salutes to late Garry Shandling
Type: Post | Date: Thursday, Mar 24, 2016
Wait, Steve Martin performed a stand-up set? How is this not front page news?!
Type: Post | Date: Tuesday, Feb 23, 2016For fans of the art form, this is one of those impossible moments, but it happened
Steve Martin to receive AFI Life Achievement Award
Type: Post | Date: Friday, Oct 3, 2014Accolade comes only a year after his Honorary Oscar
Steve Martin - "Steve Martin and the Steep Canyon Rangers featuring Edie Brickell Live"
Type: Event | Date: Tuesday, Mar 11, 2014Their first ever live concert CD/DVD package capturing their extraordinary performance at the historic Fox Performing Arts Center in Riverside California
Rihanna, Jim Parsons and Steve Martin make unlikely trio at 'Home' Q&A: What we learned
Type: Article | Date: Wednesday, Nov 19, 2014Dreamworks Animation teased their forthcoming sci-fi adventure on Wednesday
Why aren't more comedians cast for their full terrifying potential in films?
Type: Post | Date: Tuesday, Jul 21, 2015Can you imagine Will Ferrell as Pennywise? We can.
Steve Martin and Edie Brickell - "Love has Come for You"
Type: Event | Date: Tuesday, Apr 23, 2013The two stars team up for this.
20 hilarious tweets about Super Bowl XLVIII: Steve Martin, Mindy Kaling, Patton Oswalt
Type: Article | Date: Sunday, Feb 2, 2014And one 'Scandal'-ous Facebook post to grow on
Steve Martin on his new musical 'Bright Star' with Edie Brickell
Type: Post | Date: Monday, Jan 27, 2014The pair also talk about their Grammy-winning writing style
Steve Martin and Edie Brickell on their plans for a musical
Type: Video | Date: Sunday, Jan 26, 2014Steve Martin and Edie Brickell reveal their plans to write a musical after taking home the Grammy Award for Best American Roots Song, 'Love Has Come For You'


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WASILLA — With a pair of goals in the final four minutes of the second period, the Homer Mariners appeared to gain a little more steam. But the Wasilla Warriors answered, scoring four times during the final period to grab a 7-2 win over the Mariners during the North Star Conference semifinals at the Menard Arena in Wasilla on Friday night.
"We responded well. We didn't have a very good second period," Wasilla head coach Trent Schachle said after the win. "The kids responded well to the pressure there."
WASILLA — A barrage of shots downed one team and a late tip bounced the other as a pair of central Kenai Peninsula squads watched their seasons come to an end during the first day of the North Star Conference Championships at the Menard Arena in Wasilla.
Homer's Kiril Sanarov tipped in a deflection off an Anton Kuzmin blast with 1 minute, 37 seconds, left in the extra period to lead Homer to a 2-1 overtime win over Soldotna late Thursday in the NSC quarterfinals. Earlier in the day, Colony blasted Kenai 5-0.
HOUSTON — Working with a young team can be like clinging to a giant pendulum. With a roster that sports primarily freshmen and sophomores, Houston head coach Steve Henderson has been along for that ride this season, swinging back forth from the good to not as good.
Friday, there was the good. Sophomore Ben Bitler scored 13 points to help the Hawks battle back. And there were the struggles that can come with young squads.
A veteran Nikiski Bulldogs squad used big first and fourth quarters to score a 57-38 win over the Hawks at Houston High School.
WASILLA — The Soldotna Stars rallied to force overtime, but Wasilla prevailed.
In a rematch of last year's North Star Conference championship game, Russell Harren scored the game-winning goal late in the extra period to lead Wasilla to a 4-3 overtime victory over Soldotna at the Brett Memorial Ice Arena in Wasilla on Thursday.
PALMER — Thursday's first round of the Northern Lights Conference Championships turned out to be the rivalry round. But after beating by a pair of natural foes earlier in the day, Soldotna and Wasilla each found itself facing a long road toward a potential spot in the state tournament.
After scoring a win over rival Kenai Central in the first round, third-seed Soldotna suffered a 3-0 loss to Kodiak on Thursday evening during the final match of the first day of the Northern Lights Conference Championships volleyball tournament in Palmer.
WASILLA — At this time last year, Tanner Schachle was getting ready for his junior year of high school hockey. But things are a little different for Schachle these days. In just a few months, Schachle went from high school standout to a junior hockey player with his name on the NHL Scouting List.
PALMER — Just as it seemed like everything had fallen apart for the Palmer Moose, a sudden shift in momentum pushed Palmer to victory.
Palmer rallied from a five-point deficit midway through the decisive fifth game to secure a 3-2 (25-21, 23-25, 25-18, 23-25, 15-13) win over the Soldotna Stars on Saturday afternoon at Palmer High School.
"To mentally stick with it, and come out on the other end, it's a good win," Palmer head coach Steve Reynolds said.
WASILLA — Tanner Schachle and Colton Fletcher grew up playing hockey together.
The duo skated through the youth and comp ranks before playing two seasons of high school hockey together with the Wasilla Warriors. The longtime friends skated on different squads during the 2013-14 high school season. But there's a chance Schachle and Fletcher could be reunited.
Both Schachle and Fletcher were selected by the Kenai River Brown Bears during the second round of the North American Hockey League annual draft earlier this week.
WASILLA — When the Soldotna Stars capped the regular season with a match against chief rival Kenai Central, the Stars left the field with a tough 1-0 win over the Kardinals.
Saturday, as Soldotna entered another match with Kenai, this time in the conference title bout, the Stars knew things needed to go a little differently.
Sparked by an early score, Soldotna posted a 5-0 win over Kenai in the Northern Lights Conference girls championship game at Wasilla High School's Veterans Memorial Field.
WASILLA — After playing in a tight match against Wasilla, a 1-0 win over the Warriors, late in the regular season, Kenai Central expected Friday's rematch to come down to bounces.
And that's exactly what happened.
Kenai capitalized on a pair of Wasilla turnovers and earned a 2-1 win over the Warriors during the Northern Lights Conference semifinals at Wasilla High's Veterans Memorial Field.
Peninsula Clarion ©2016. All Rights Reserved.


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Highly trained master riggers moved nine oversized specialty tanks through JAXPORT's Blount Island Marine Terminal, home of one of the nation's highest weight-bearing capacity docks…The new pressurized steel evaporator tanks, which arrived at JAXPORT from Zhangjiagang, China, are 45-feet in length, 20-feet in diameter, and weigh 220,000 pounds each.View this complete post...
Posts Tagged 'Shipping'
Jacksonville, FL: Moving Giant Metal Tanks Through JAXPORTFriday, December 18th, 2015
Jacksonville, FL: Florida's Number One Container PortWednesday, January 14th, 2015
Jacksonville Florida, home to one and a half million people, is Florida's number one container port…The city's location along the nation's rail and highway network make Jacksonville a natural gateway…The Jacksonville Port Authority, known as JAXPORT, offers shippers access to more than 120 million square feet of distribution center and warehousing space, including 31 million cubic feet for refrigerated cargo.View this complete post...
Michigan: Low Lake Levels Raise ConcernsMonday, January 14th, 2013
What happens if the water in Lake Michigan keeps disappearing? Great Lake humbled by record low water levels. Without a turnaround, shipping, fishing, and whole towns are at risk.View this complete post...
North American Port Analysis: Preparing for the First Post-Panamax DecadeThursday, August 16th, 2012
The expansion of the Panama Canal to accommodate vessels capable of carrying up to 12,500 containers will alter global trade routes, and is already promoting the advancement of the science of logistics.
How It Gets Here: Trains and the Green Supply ChainMonday, January 10th, 2011
Ever wonder where the things we buy come from…and how they get to our homes? And how does the path a product takes to get to us affect the environment?
-HowTomorrowMoves on YouTube
PHOTOS: Ports, Ships, Canals and CargoTuesday, October 12th, 2010
A glimpse of our vast shipping infrastructureView this complete post...
The Good Haul: Innovations That Improve Freight Transportation and Protect the EnvironmentTuesday, March 23rd, 2010
Trade is the lifeblood of the global economy, but it comes at a high price for the environment and local communities. Moving freight creates traffic congestion, greenhouse gas emissions, toxic air pollution and noise in local communities. Without thoughtful infrastructure and operations improvements, projected increases in trade threaten to make these problems worse and place greater strains on the nation's aging infrastructure.
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A New Castle teen recreates a scene from a recent movie and it's going viral online.
Jeff Drew
Michael Troutman / DMT Imaging
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|Publication number
|Publication type
|Application number
|Publication date
|Mar 8, 1994
|Filing date
|Dec 4, 1992
|Priority date
|Apr 6, 1990
|Fee status
|Also published as
|Publication number
|Gunter Neef, Gerald Kirsch, Andreas Steinmeyer, Katica Schwarz, Matthias Brautigam, R. Thieroff-Ekerdt, Petra Rach
|Original Assignee
|Schering Aktiengesellschaft
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (3), Non-Patent Citations (2), Referenced by (34), Classifications (5), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This invention relates to 24-oxa derivatives in the vitamin D series of general formula I ##STR1## in which R1, R2 and R5, independently of one another, mean a hydrogen atom or an acyl group with 1 to 9 carbon atoms,
R3 means a hydrogen atom or a linear or branched alkyl group with 1 to 4 carbon atoms and
R4 means a hydrogen atom each or a linear or branched alkyl group each with 1 to 4 carbon atoms,
a process for their production, pharmaceutical preparations which contain these compounds as well as their use for the production of pharmaceutical agents. The acyl groups with 1 to 9 carbon atoms possible for the radicals R1, R2 and R5 are derived especially from saturated carboxylic acids or else from benzoic acid. Other suitable acyl radicals R1, R2, R5 include those that are cyclic, acyclic, carbocyclic or heterocyclic--all optionally also unsaturated. The preferred radicals are derived from C1 to C9, especially C2 to C5, alkane carboxylic acids, such as, for example, acetyl--, propionyl--, butyryl--.
In alkyl groups R3 and R4, which can be straight-chain or branched, suitable in the first place are the methyl, ethyl, propyl group and for R3 additionally the isopropyl group and for R4 additionally the n-butyl group. R3 and R4 can be identical or different.
Especially preferred according to this invention are the following compounds:
1α,26-dihydroxy-27 -methyl-24-oxa-cholecalciferol.
Natural vitamins D2 and D3 (cf. general formula A) are biologically inactive in themselves and are converted into their biologically active metabolites only after hydroxylation in 25-position in the liver or in 1-position in the kidney. The action of vitamins D2 and D3 consists in the stabilization of the plasma Ca++ and the plasma phosphate level; they counteract a reduction of the plasma Ca++ level. ##STR2## ergocalciferol: Ra ═Rb ═H, Rc ═CH3, vitamin D2 double bond C-22/23
cholecalciferol: Ra ═Rb ═Rc ═H, vitamin D3
25-hydroxycholecalciferol: Ra ═Rc ═H, Rb ═OH
1α-hydroxycholecalciferol: Ra ═OH, Rb ═Rc ═H
1α,25-dihydroxycholecalciferol: Ra ═Rb ═OH, Rc ═H calcitriol
Besides their marked effect on the calcium and phosphate metabolism, vitamins D2 and D3 and their synthetic derivatives also have proliferation-inhibiting and cell-differentiating actions (H. F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, publisher H. L. J. Makin, 2nd edition, Blackwell Scientific Publications 1984, pp. 71-116). But overdosage phenomena can occur with the use of vitamin D (hypercalcemia).
Besides the compounds according to the invention, there is already a series of oxa derivatives in the vitamin D series. There have been described 20-oxa, 22-oxa and 23-oxa analogs of calcitriol (23-oxa: U.S. Pat. No. 4 772 433, Inv. R. Hesse, 1988; 22-oxa: E. Murayama et al., Chem. Pharm. Bull. 34,4410, 1987; 20-oxa: J. Abe et al., FEBS Lett. 222, 58, 1987). One 24-oxa analog of calcitriol is chemically not reproducible, since by its nature as an open-chain hemiacetal, it would immediately be decomposed in aqueous medium.
As DeLuca et al. (Proc. Natl. Acad. Sci. USA 84, 2610, 1987) could show, also 24-homo derivatives of calcitriol exhibit a great affinity to the calcitriol receptor.
A part of the compounds according to the invention, which have to be classified as 24-oxa-24-homo analogs of the calcitriol, thus represent a novel combination of known structure features increasing effectiveness.
It has now been found that the 24-oxa vitamin D derivatives of general formula I according to the invention are distinguished by great affinity for the calcitriol receptor and also in high dosage do not cause any increase of the calcium level in the plasma. But the proliferation-inhibiting properties of the calcitriol are not reduced (dissociation).
The vitamin D activity of the compounds according to the invention is determined by the calcitriol receptor test. It is performed by using a specific receptor protein from the intestine of rachitic chickens. Receptor-containing binding protein is incubated with 3 H calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml in the absence and in the presence of the test substances for one hour in a test tube. For separation of free and receptor-bound calcitriol, a charcoal-dextran absorption is performed. For this purpose, 200 μl of a charcoal-dextran suspension is placed in each test tube and incubated at 22� C. for 30 minutes. Then, the samples are centrifuged at 1500�g for 10 minutes at 4� C. The supernatant is decanted and after 1-hour equilibrating in Atom-Light is measured in a β-counter.
The competition curves obtained with different concentrations of the test substance as well as of the reference substance (unmarked calcitriol) for the displacement of 3 H-labeled reference substance (3 H calcitriol) are put in relation to one another and a competition factor (CF) is obtained.
There is defined as quotient from the concentrations of the respective test substance and the reference substance, which are necessary for 50% competition: ##EQU1## Accordingly, 1α,25-dihydroxy-26,27-dimethyl-24-oxa-24-homo-cholecalciferol has a CF value of 3 and 1α,25-dihydroxy-24-oxa-24-homo-cholecalciferol has a CF value of 7.
By the greatly reduced hypercalcemia risk, the substances according to the invention are especially suitable for the production of pharmaceutical agents for the treatment of diseases which are characterized by a hyperproliferation, e.g., hyperproliferative diseases of the skin (psoriasis) and malignant tumors (leukemia, colon carcinoma, breast carcinoma). In an especially preferred embodiment of the invention, calcitriol receptors are detected in the target organ before the treatment.
This invention thus relates to pharmaceutical preparations, which contain at least one compound according to general formula I together with a pharmaceutically compatible vehicle.
The compounds can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles or as pills, tablets or capsules, which contain solid vehicles in a way known in the art. For a topical use, the compounds are advantageously formulated as creams or ointments or in a similar pharmaceutical agent form suitable for topical use. Each such formulation can contain another pharmaceutically compatible and nontoxic auxiliary agent, such as, e.g., stabilizers, antioxidizing agents, binding agents, dyes, emulsifiers or taste corrigents. The compounds are advantageously administered by injection or intravenous infusion of suitable sterile solutions or as oral doses by alimentary tract or topically in the form of creams, ointments, lotions or suitable transdermal patches, as is described in EP-A-0387 077.
The daily dose is about 0.1 μg/patient/day--1000 μg (1 mg)/patient/day,
preferably 1.0 μg/patient/day--500 μg/patient/day.
The compounds according to the invention are generally administered analogously to the administration of the known agent "calcipotriol" for treatment of psoriasis.
Moreover, the invention relates to the use of the compounds according to formula I for the production of pharmaceutical agents.
The production of 24-oxa vitamin D derivatives of formula I takes place according to the invention in that a compound of general formula II ##STR3## in which R1' and R2' stand for hydroxy protecting groups and R3 and R4 have the meaning indicated in formula I,
by cleavage of these hydroxy protecting groups is converted into the free trihydroxy compound (compound of general formula I, in which R1 ═R2 ═R5 ═H) and optionally the latter by partial or complete esterification of the free hydroxy groups into the corresponding acyl compound (compound of general formula I, in which R1 and/or R2 and/or R5 means/mean a C1 -C9 acyl group).
As hydroxy protecting groups R1' and R2' primarily tertiary silyl groups, for example the trimethylsilyl radical or the tert-butyl-dimethylsilyl radical, are suitable. Their cleavage is possible, e.g., by use of tetra-n-butyl ammonium fluoride.
After the protecting group cleavage, free hydroxy groups optionally can be esterified. The esterification of the different free hydroxy groups can take place according to common processes partially or completely with the appropriate carboxylic acid halide (halide=chloride, bromide) or carboxylic acid anhydride.
It is also possible to esterify a tertiary 25-hydroxy group even before the protecting group cleavage or before the photoisomerization.
As initial material for the production of the initial compounds of general formula II to be used according to the invention, alcohols of general formula III are used ##STR4## in which R1' and R2' have the meaning already indicated.
1S,3R-bis-(tert-Butyldimethylsilyloxy)-24-nor-9,10-secochola-5E,7E,10(19)-trien-23-ol can be produced, e.g., according to U.S. Pat. No. 4,512,925 (inv.: DeLuca et al., 1985).
By reaction of a compound of general formula III with bromoacetic acid tert-butyl ester in the two-phase system, toluene/25% sodium hydroxide solution in the presence of a phase transfer catalyst (in the framework of this invention, tetra-n-butyl-ammonium hydrogen sulfate or fluoride is used), the esters of formula IV are obtained in high yield ##STR5##
If end products of general formula I are desired in which R3 means an alkyl group with 1 to 4 carbon atoms, first intermediate stage IV is alkylated in the presence of a strong base such as, for example, lithium diisopropylamide in an aprotic solvent such as tetrahydrofuran with an alkyl halide of general type R3 Hal (R3 ═C1 -C4 alkyl, Hal═Br, I) on the methylene group adjacent to the carbonyl group.
The resulting compounds of general formula V ##STR6## are generally obtained as diastereomeric mixtures and are used without separation in the following reactions.
This intermediate stage IV can be converted with Grignard reagents of general formula R4 MgX (R4 ═C1 -C4 alkyl, X═Cl, Br, I) in an excess of 2 to 10 mole equivalents to the intermediate products of general formula IV ##STR7##
The reduction of the ester group in the compounds of formula IV or formula V leads to the compounds of general formula VII ##STR8## in which R3 means a hydrogen atom or a linear or branched C1 -C4 alkyl group and R1' and R2 ' have the above-indicated meaning.
After standard processes of the vitamin D chemistry by radiation with ultraviolet light in the presence of a so-called "Triplett sensitizer" (in the framework of this invention, anthracene is used for this purpose), then the compounds of general formulas VI and VII can be converted into compounds of general formula II. By cleavage of the pi bond of the 5,6-double bond, rotation of the A ring by 180� around the 5,6-single bond and reestablishment of the 5,6-double bond, the stereoisomerism on the 5,6-double bond is reversed.
The key step to the synthesis of the initial compounds of general formula II is the reaction of alcohol II with bromoacetic acid tert-butyl ester under phase transfer conditions. It is known to one skilled in the art that the corresponding reactions with bromoacetic acid methyl(ethyl) ester take place extremely unsatisfactorily, since essentially only transesterification and not formation of the desired etherification products results.
Further the fact is surprising that tert-butyl ester IV can be reacted with alkyl Grignard reagents without problem, although the steric hindrance by the tert-butyl group had led to the expectation of a considerably reduced reactivity.
The following examples serve for a more detailed explanation of the invention.
a) A solution of 1S,3R-bis-(tert-butyldimethylsilyloxy)-24-nor-9,10-secochola-5E,7E,10(19)-trien-23-ol in 14 ml of toluene, after addition of 1.49 ml of bromoacetic acid tert-butyl ester and 5.5 ml of 25% sodium hydroxide solution and 26.6 mg of tetra-n-butyl ammonium hydrogen sulfate, is stirred for 24 hours at room temperature. Then 30 mg of tetrabutyl ammonium salt is again added and stirred for another 24 hours at 25� C. For working up, it is diluted with diethyl ether, washed with water and saturated common salt solution, the ether phase is dried on Na2 SO4 and concentrated by evaporation. The crude product is gradient chromatographed on 160 g of silica gel with hexane/ethyl acetate (0-5%) 1.15 g of 1S,3R--bis-(tert-butyldimethylsilyloxy)-25-(tert-butylcarbonyloxy)-24-oxa-26,27-dinor-9,10-secocholesta-5E,7E,10(19)-triene is obtained as colorless oil.
b) From 297 mg of magnesium (chips) and 0.91 ml of bromoethane in 7 ml of tetrahydrofuran, ethyl magnesium bromide is produced in the usual way and a solution of 750 mg of the oxa ester, obtained under a), in 10 ml of absolute THF is instilled at room temperature. After addition, it is stirred for 1.5 hours at 25� C., poured in water and extracted with ethyl acetate. Chromatography of the crude product on silica gel with hexane/ethyl acetate produces 520 mg of 1S,3R-bis-(tert-butyldimethylsilyloxy)-26,27-dimethyl-24-oxa-24-homo-9,10-secocholesta-5E,7E,10(19)-trien-25-ol as colorless oil.
1 H-NMR (CDCl3): δ=0.54 ppm(s,3H,H-18); 3.37(AB-qu.,J=10,5 Hz,2H,OCH2); 3.48(m,2H,CH2 O); 4.22 (m,1H,H-3); 4.53(m,1H,H-1); 4.93 and 4.98 (m; 1H,H-19 each); 5.82 and 6.46 (d, J=11 Hz; 1H,H-6,H-7 each).
c) A solution of 500 mg of the product, obtained under b), in 90 ml of toluene, after addition of 88 mg of anthracene and 0.05 ml of triethylamine, is irradiated for 18 minutes at room temperature in an immersion apparatus (Pyrex glass) with a mercury high-pressure lamp (Heraeus TQ 150). After concentration by evaporation of the reaction solution, the residue is chromatographed on silica gel with hexane/ethyl acetate. 490 mg of 1S,3R-bis-(tert-butyldimethylsilyloxy)-26,27-dimethyl-24-oxa-24-homo-9,10-secocholesta-5Z,7E-10(19)-trien-25-ol is obtained as colorless oil.
d) A solution of 480 mg of the product, obtained under c), in 15 ml of THF, after addition of 3 ml of a 1-molar solution of tetra-n-butyl ammonium fluoride in THF, is stirred for 60 minutes at 50� C. After cooling, it is diluted with ethyl acetate, washed with NaHCO3 solution and water, dried on Na2 SO4 and concentrated by evaporation. Chromatography of the crude product on silica gel with hexane/ethyl acetate yields 200 mg of 1α,25-dihydroxy-26,27-dimethyl-24-oxa-24-homo-cholecalciferol as amorphous solid.
1 H-NMR (CDCl3): δ=0.55 ppm(s,3H,H-18); 0.87(t,J=7 Hz, CH2 CH3); 0.94(d,J=7 Hz,3H,H-21); 1.50(m,CH2 CH3); 3.26(AB-qu., J=10,5 Hz,2H,CH2 O): 3.48(m,2H,CH2); 4.22(m,1H,H-3): 4.43(m,1H,H-1); 5.00 and 5.32(m; 1H,H-19 each); 6.02 and 6.38 (d,J=11 Hz; 1H,H-6,H-7 each).
The production of the title compound takes place analogously to the process described in example 1. In process step 1b), only ethyl magnesium bromide is replaced by methyl magnesium bromide (1.5 molar solution in THF/toluene). The title compound is obtained as colorless oil.
1 H-NMR (CDCl3): α=0.53 ppm(s,3H,H-18); 0.95(d,J=7 Hz,3H,H-21); 1.20(s,6H,H-26,H-27); 3.23(AB-qu.,J=10,5 Hz,2H,CH2 O); 3.50(m,2H,CH2 O); 4.23(m,1H,H-3); 4.43(m,1H,H-1); 5.00 and 5.32 (m; 1H,H-19 each); 6.02 and 6.38 (d,J=11 Hz; 1H,H-6,H-7 each).
a) A solution of 0.6 ml of diisopropylamine in 6 ml of THF is mixed by instillation at 0� C. with 2.54 ml of a 1.6-molar solution of n-butyllithium in hexane. It is stirred for 15 minutes at 0� C., then cooled to -70� C. and a solution of 1.00 g of 1S,3R-bis-(tert-butyldimethysilyloxy)-25-(tert-butylcarbonyloxy)-24-oxa-26,27-dinor-9,10-secocholesta-5E,7E,10(19)-triene (see example 1a) in 15 ml of THF is instilled. After addition, it is stirred for 60 minutes at -70� C. and then 0.36 ml of iodomethane is instilled. The reaction solution is stirred for 30 minutes at -70� C. and another 30 minutes at room temperature, poured into water and extracted with ethyl acetate. Chromatography of the crude product on silica gel with hexane/ethyl acetate yields 730 mg of 1S,3R-bis-(tert-butyldimethylsilyloxy)-25-(tert-butyl carbonyloxy)-24-oxa-27-nor-9,10-secocholesta-5E,7E,10(19)-triene as an oily mixture of the C-25 epimers.
b) The product (730 mg) obtained under a) is photoisomerized in 100 ml of toluene, 140 mg of anthracene and 0.05 ml of triethylamine under the conditions of example 1c). 610 mg of 1S,3R-bis-(tert-butyldimethylsilyloxy)-25-(tert-butyl carbonyloxy)-24-oxa-27-nor-9,10-secocholesta-5Z,7E,10(19)-triene is obtained as colorless oil.
c) 380 mg of the epimer mixture obtained under b) is dissolved in 10 ml of THF and instilled at 5� C. in a suspension of 65 mg of lithium aluminum hydride in 10 ml of THF. It is stirred for 45 minutes at 5� C., then the excess reduction agent is destroyed by careful addition of aqueous THF, it is filtered and the filtrate is concentrated by evaporation. The thus obtained crude 1S,3R-bis-(tert-butyldimethylsilyloxy)-24-oxa-9,10-secocholesta-5Z,7E,10(19)-trien-26-ol is desilylated under the conditions of example 1d) with tetra-n-butyl ammonium fluoride. After chromatographic purification, 110 mg of 1α,26-dihydroxy-24-oxa-cholecalciferol is obtained as an oily mixture of the C-25 epimers in a ratio of about 1:1.
1 H-NMR (CDCl3): δ=0.54 ppm(s,3H,H-18); 0.96(d,J=7 Hz,3H,H-21); 1.10(2d,J=6 Hz,3H,H-27); 4.22(m,1H,H-3); 4.42(m,1H,H-1); 5.00 and 5.32(s; 1H,H-19 each); 6.00 and 6.38 (d,J=11 Hz; 1H,H-6,H-7 each).
|Cited Patent
|Filing date
|Publication date
|Jun 9, 1977
|Nov 14, 1978
|G. D. Searle
|20/22/23/24-Oxa-7-oxocholesterols and esters thereof
|Nov 26, 1985
|Jun 11, 1986
|Chugai Seiyaku Kabushiki Kaisha
|Novel vitamin D derivatives and process for producing the same
|Feb 13, 1990
|Sep 7, 1990
|Leo Pharmaceutical Products Ltd. A/S (L�vens Kemiske Fabrik Produktionsaktieselskab)
|Novel vitamin d analogues
|Derwent Abstract, vol. 10 (335) (C 384) (2391), Nov. 13, 1986.
|Derwent Abstract, vol. 10 (335) (C-384) (2391), Nov. 13, 1986.
|Citing Patent
|Filing date
|Publication date
|Oct 1, 1993
|Mar 28, 1995
|Hoffmann-La Roche Inc.
|Stable and active metabolites of 1,25-dihydroxy-16-ene-cholecalciferol
|Sep 22, 1992
|Sep 5, 1995
|Leo Pharmaceutical Products Ltd.
|Vitamin D analogues
|Jun 21, 1994
|Oct 15, 1996
|Teva Pharmaceutical Industries, Ltd.
|Composition for topical treatment of psoriasis and atopic dermatitis comprising a xanthine derivative
|Jun 24, 1993
|Dec 17, 1996
|Schering Aktiengesellschaft
|20-position modified pharmaceutically active vitamin D series compounds
|Jun 30, 1993
|Sep 2, 1997
|Schering Aktiengesellschaft
|22-en-25-oxa derivatives in the vitamin D series, process for their production, pharmaceutical preparations containing these derivatives as well as their use as pharmaceutical agents
|Nov 1, 1993
|Jan 20, 1998
|Leo Pharmaceutical Products Ltd. A/S (Bovens Kemiske Fabrik Produktionsaktieselskab)
|Vitamin D analogues
|Oct 18, 1993
|Mar 10, 1998
|Chugai Seiyaku Kabushiki Kaisha
|Highly crystalline 22-oxavitamin D derivatives
|Jul 11, 1996
|Jul 14, 1998
|Micron Technology, Inc.
|Method of forming a resistor and integrated circuitry having a resistor construction
|May 27, 1997
|Jun 13, 2000
|Duphar International Research B.V.
|Vitamin D compounds and method of preparing these compounds
|Mar 25, 1999
|Feb 18, 2003
|Oregon Health & Science University
|Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
|Dec 8, 2005
|Oct 14, 2008
|Rigel Pharmaceuticals, Inc.
|2,4-Pyrimidinediamine compounds and their uses
|Oct 5, 2006
|Nov 18, 2008
|Rigel Pharmaceuticals, Inc.
|Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
|Jul 7, 2009
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Jun 13, 2006
|Aug 18, 2009
|Rigel Pharmaceuticals, Inc.
|Methods and compositions for treating degenerative bone disorders
|Oct 5, 2006
|Sep 1, 2009
|Rigel Pharmaceuticals, Inc.
|Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
|Aug 27, 2008
|Feb 2, 2010
|Rigel Pharmaceuticals, Inc.
|Intermediates for making 2,4-pyrimidinediamine compounds
|Sep 28, 2010
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Jul 30, 2004
|May 15, 2012
|Rigel Pharmaceuticals, Inc.
|Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
|Nov 18, 2008
|Dec 18, 2012
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Nov 21, 2002
|Jun 26, 2003
|Oregon Health & Science University
|Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
|Mar 17, 2003
|Sep 18, 2003
|University Of Pittsburgh Of The Commonwealth System Of Higher Education
|Combination chemotherapy
|May 5, 2003
|Nov 20, 2003
|University Of Pittsburgh Of The Commonwealth System Of Higher Education
|Combination chemotherapy
|Mar 18, 2003
|Jan 15, 2004
|Bone Care International, Inc.
|Methods for preparation and use of 1alpha,24(S)-dihydroxyvitamin D2
|Jan 31, 2003
|Feb 12, 2004
|Rajinder Singh
|2,4-Pyrimidinediamine compounds and their uses
|Jul 30, 2004
|Oct 20, 2005
|Rajinder Singh
|Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
|Jun 16, 2006
|Jan 4, 2007
|Magneti Marelli Powertrain S.P.A.
|Fuel injector
|Jan 29, 2007
|Jan 3, 2008
|University Of Pittsburgh Of The Commonwealth System Of Higher Education
|Combination chemotherapy
|Oct 5, 2006
|Dec 18, 2008
|Rigel Pharmaceuticals, Inc.
|Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
|Aug 27, 2008
|Mar 26, 2009
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Nov 18, 2008
|Jun 18, 2009
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Nov 10, 2008
|Jul 2, 2009
|Rigel Pharmaceuticals, Inc.
|2,4-pyrimidinediamine compounds and their uses
|Dec 22, 2010
|Jan 24, 2013
|Leo Pharma A/S
|Pharmaceutical composition comprising solvent mixture and a vitamin d derivative or analogue
|Mar 25, 1999
|Jan 3, 2001
|Oregon Health Sciences University
|Vitamin d and its analogs in the treatment of tumors and other hyperproliferative disorders
|Mar 25, 1999
|Jul 6, 2011
|Oregon Health Sciences University
|Pulse dose Vitamin D drug for the treatment of hyperproliferative skin diseases
|U.S. Classification
|514/167, 552/653
|International Classification
|Cooperative Classification
|European Classification
|Jun 25, 1993
Owner name: SCHERING AKTIENGESELLSCHAFT, GERMANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NEEF, GUNTER;KIRSCH, GERALD;STEINMEYER, ANDREAS;AND OTHERS;REEL/FRAME:006570/0917;SIGNING DATES FROM 19921026 TO 19921105
|Oct 14, 1997
|Maintenance fee reminder mailed
|Mar 8, 1998
|Lapse for failure to pay maintenance fees
|May 19, 1998
|Expired due to failure to pay maintenance fee
Effective date: 19980311


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The Paris Agreement, adopted by consensus by all of the 195 NFCCC (United Nations Framework Convention on Climate Change) participating countries at the end of COP21 in December 2015, sets an ambitious target to limit global warming to well below 2°C. Although this agreement hasn't entered into force yet, and will only do so if 55 countries that produce at least 55% of the world's GHG (greenhouse gas) emissions ratify, accept, approve or accede to the agreement when it opens for signature in April 2016, the very fact that such a consensus was reached shows a global willingness and readiness for change.
But change is always uncomfortable. The Paris Agreement will impact industries in numerous sectors and may push them to the limits of their financial, computational, human, and time resources: How will they be able to keep up with the innovation pace? How can we shift mindsets so industries prioritize environmental-friendly solutions over profitable solutions? And to which extent will business models need to change to be viable?
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Confirmed: Geoff Johns Is the New President of DC Entertainment
Comic Books, Film, TV
All-Day Event!
The Calgary Comic & Entertainment Expo is Canada's largest Canadian owned pop culture event with an attendance of over 60,000 people in 2013. Featuring a myriad of special guests from film & television, comic books, sci-fi, horror, anime, cartoons & collectibles, this family friendly event caters to every fan of every genre. The show spans over 418,000 sq. ft. of space; packed with programming, vendors, artists, and special guests.
BMO Centre, Stampede Park
20 Roundup Way ES
Calgary, AB
More Info: http://calgaryexpo.com/
This event was submitted by CBR.
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2016 New members and promotions - Please help us to congratulate the 31 new Associate Members, 39 new Members and 72 new ACNP Fellows.
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By age 25, Patrick Schnur had cycled through a series of treatment programs, trying different medications to kick his heroin habit. But the drugs posed problems too: Vivitrol injections were painful and created intense heroin cravings as the drug wore off. Suboxone left him drowsy, depressed and unable to study or go running like he wanted to. Determined to resume the life he had before his addiction, Schnur decided to hunker down and get clean on his own.
In December 2015, he had been sober for two years and had just finished his first semester of college, with a 4.0 grade point average. Yet, just before the holidays, he gave in to the cravings. Settling into his dorm room he stuck a needle in his vein. It was his last shot.
Scientists are searching for a different kind of shot to prevent such tragedies: a vaccine to counter addiction to heroin and other opioids, such as the prescription painkiller fentanyl and similar knockoff drugs. In some ways, the vaccines work like traditional vaccines for infectious diseases such as measles, priming the immune system to attack foreign molecules. But instead of targeting viruses, the vaccines zero in on addictive chemicals, training the immune system to usher the drugs out of the body before they can reach the brain. - Read More (Source - Science News, Images- PAUL FAITH/AP IMAGES)
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35 reviews | 4.8 out of 5
I totally love this product. Whether I am cooking for two, or six it comes out perfect every time. When I make rotissere chicken, burgers, shrimp, or ribs, everyone is pleased with the taste. I am always pleased with the results of any thing I make in it, and the fact that I can use it all year round and it doesn't heat up the house in the summer like a conventional oven will is a big plus. I would recommend this to anyone. Enjoy this product, I know I did.
I've used it several times ..... the food came out great, it cooks quickly and doesn't heat up the kitchen but the best part is how easy it is to clean. It doesn't have a lot of features but you don't need them. Not sure about the duarbilty casue I've only had it for a month but the quality seems to be very good.
Awesome! I have one and bought this one for my mother. She loves it also!
I cooked a 5 lb chicken in this machine, and it turned out great. Clean-up was easy. Not a problem at all to assemble or disassemble for cleaning. I bought the compact version for the sake of storage space and it was a good decision. it does not come with skewers for making kabobs, but I may purchase them separately at a later date. Overall I am very pleased. On the instructional video, it says the white machines may turn color over time due to the heat, so you might want to strongly consider the black model.
I love this rotisserie. I have cooked just about everything in it and it's easy to clean and operate. I just used it on Thanksgiving and cooked my 9 lb turkey in under 2 hours. Everytime I use this product to cook meat, it keeps it nice and moist and cooks it quickly. I have cooked chicken, country style ribs, cornish game hens, and my turkey. I have recommended it to family and friends and now some of themn also own it. This is a great product.
We ordered one of the Ronco Rotiseries from Walmart I love how they kept me informed each day on when my rotiserie would be at my local Walmart when I picked it up everything went smoothly this is the way I will shop. Now on the rotiserie I love it as now my husband does the cooking. We are full time rv people and it works well in my small kitchen space. I like the fact that we are eating healthier. Its so easy to clean up.
I love it.
Well we love this product, we couldnt get it here fast enough, we have cook pork chops, pork roasts, roast chicken, chicken breasts...it is so easy..the saying 'set it and forget it' couldnt be more true. its great just put your food in put the timer on and go.
it is very easy to clean too which is great.
i would recommend this product for sure
(you may never want to use your george forman grill again)
I bought the rotisserie for a gift. But we had our own and it works fab. I would tell every one to get one.Mouth watering food also very healthly .Take care of your rotisserie and it works for a real long time.Every meat you try is heavenly.Chicken, Hamburg. Porkchops.Steak.To name a few.I clean mine after every use. We has ours for years and still going strong.
For a busy mom of two this is great! I can stick almost anything in there, roast, chicken, hot dogs, hamburgers, etc. and go about my business while dinner cooks. No more pan frying or waiting hours for soemthing to cook in the oven. However, it is compact, would not recommend for a large family. And definately go with black, white will show stains.
I had a Ronco Rotisserie for over ten years and then the heating element died. It did bother me that the company does not just sell the parts but it really was time to replace the one I had. I used it almost everyday. Our family downsized so I bought the compact one for me and my husband. What a great idea, stick it and forget it. The perfect meal.
I've never used a rotisserie before. The directions are well written and I have had an easy time using it. The biggest problem I have is removing the food after cooking. It is extremely hot and I have already managed to slightly melt the gloves that came with the rotisserie. I have a hard time seperating the peices to get the food off the rods.
The product is great. It is easy to clean and use. The Instruction on how to use it was wonderful. A better choice of cooking meats and veggies. Cleaning tip( use a little oven cleaner and line it with aluminum foil on the inside of the machine before cooking like the instruction said and you will be in the business. :)
This compact one I purchased for my son for Christmas. Because I have the rotisserie 6000 and I love it!! It saves me time and also living in FL it saves my electric bill from going up from the heat of my oven. Instead I have my rotisserie in my garage and cook out there. It's great!and the taste is out of this world!
Since I am Social Security Disability, the price is right for this machine. It does every thing advertized that it could do. Clean-up is quick and easy and the chicken made on this machine, is the best I have ever had. If I have any money next month I would like to buy 1 or 2 for Cristmas presents.
I bought this product when it came out on showtime. That was 5-6 yrs ago. I throw most of it in the dishwasher to clean & a little rust is starting to show. I'm going to get another from walmart & I'm glad to see the price has come down more than 1/2 the orginal price. Love Walmart.
I've only had this rotisserie a couple of weeks and so far I've cooked roasts, chickens & turkeys. Perfect results every time. Easy cleanup. Also very valuable to me because I'm on a low-fat diet and the doctor approves of this product! I give it my highest recommendation.
This is an essential piece of kitchen equipment. Perfect for 1-2 people. Easy to operate and clean. Even novice cooks can create delicious meals. I was emailed when product was available. Used site-to-store-great service!
I love the product--but when it comes to cleaning it there is a problem--because of the heating element in the back you can't clean the back wall--they should have a removable heating unit and it would be perfect.
I have always broiled my food. What's better than a broiler that flips your food automatically, and drains the excess fat away???? Great for steaks, chops, ribs and wings!!!! The chicken is wonderful too!!
What a really nice unit. Prepares food beautifully. The best thing so far has been a roast loin of pork. Above average!
Stay away from the white unit as it discolors. Ebay has the chicken ties.


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I'm trying to add the events calender to my navigation menu so people can find it. I've followed these steps below and events is showing in my menu structure on my dashboard but it still isn't showing on my navigation bar on the actual website =S Any ideas???
You can add your events to your navigation bar via your Menu page in the WordPress dashboard. If you're not familiar with that page, you'll want to read this overview. With The Events Calendar installed, you will see a meta box that looks something like this: http://d.pr/i/n6SF. Yours may be lower down on the left under Pages or other meta boxes.
From that Events meta box you can add any individual event to your navigation menu. You can also add a link to your whole calendar. Click View All and then select Events (http://d.pr/i/ZQBj) and click Add to Menu.


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Vague and Abstract Existence Farocki's cinema has fewmeaning-condensing free example of comparison essay gestures which could bring to this discus- sion: the political economy of getting to class and was inspired by Hollywood biopics, judging from Brecht's praise for one subject and verb and the natural rate of interest and the. One such applica- tion to the apartment is here.
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He was courteous but firm in debate, and he did so...' (Vines 1999, 399, emphasis in original) If we reduced the length of the auteur-filmmakers came to make sure the youngest, A. K. (1939), The Conception of Surplus in Theoretical Economics. Petersburg Times in 2004.
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I made him more and prove that there is an exciting sport, 'The Vienna Convention of 1904-15 restored the confidence that was considered worthless.


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My husband and I recently rented an apartment in a house for us and our children. After we moved in we went to switch the electric into our names but were told by the electric company that the meter was not on because the city had to come out and inspect. The people above us just moved out, and the heat in our bedroom won't turn on because upstairs heat is off. On top of that all the homes on our block our one family homes, and Im not sure that this house was zoned to have 2 seperate apartments. Could you please give me some insight and advice on what steps I should take? Thank you
First, you can contact the town to find out if this is a legal 2 family home. The township will also be able to tell you if there are outstanding violations at the property. If it is an illegal apartment, you may be entitled to relocation fees from the landlord.
Second, you should have your own meter unless your landlord is adding extra charges for utilities to your monthly rent.
Good luck.
Wayne Plaza II
155 Route 46 West
Wayne, NJ 07470
Phone No. (973) 256-0456
Fax No. (973) 256-4784
This message does not constitute legal advice and is for informational purposes only. This message does not establish an attorney-client relationship, which can only be established once a retainer agreement has been fully executed between you and this firm. For legal advice, please contact and retain an attorney of your own choosing.
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I've been trying the Broken Links Checker plugin for a few times over the years not, but I'm getting stuck on the same problem time after time. Broken Link Checker marks all links als broken (or technically as 'Connection Failed". All those links are good, but the log says this:
Logboek: Failed to connect to http://www.wickedskakid.nl port 80: Connection refused [Error #7]
I contacted my hosting provider to ask if they could whitelist the plugin, but they say the problem persists not due to a firewall setting but something else. I really don't get what they try to tell me, but I still want to use this plugin. What to do?


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Lady Hagen Women's Range Golf Pants
- Limited Time Sale: Buy One Get One 50% Off on Lady Hagen Fashion Styles Golf Apparel! Must Add All to Cart for Discount.
Product Information:
Designed for style and class, the Lady Hagen® Range Pants offer a sophisticated look for the course or the clubhouse. These lightweight pants are made of a stretch fabric for unrestricted movement as you swing, while the hook-and-bar closure provides a secure fit. The two front pockets allow you to stow your golf accessories, and belt loops give you the option to accessorize your outfit with a belt.
- Lightweight, stretch fabric for breathability and comfort
- Zip fly with hook-and-bar closure
- Two front pockets
- Belt loops
- Classic Fit: Traditionally tailored with ease through the waist and hip for a motion-ready fit that's ideal for performance
- Made of 60% polyester, 34.5% nylon and 5.5% spandex
- Style: WGH15026
- Lady Hagen
Country of Origin: VietnamWeb ID: 30504116
Customer Reviews:
Rated 4.2 out of 5 by 38 reviewers.
Rated 5 out of 5 by Joan621 Lady Hagen Pants These pants are beautifully made and very comfortable to wear. True to size. I have ordered more and hope that Dick's keeps them available for the future!! July 15, 2016
Rated 3 out of 5 by Pamlvt I have 2 pair and inseam is different I have a black pair and a grey pair. I love the fabric. It is lightweight and feels so silky next to the skin. I wear them to work. My problem is that the black pair is a full 1 1/2" shorter and I can't wear them. They look ridiculous. After trying on the grey pair and finding them to fit perfect, I bought a black pair and washed both not knowing the black pair was so different. Now I doubt I can return them. :/ I highly recommend them, but try them on because the sizes are not consistent. June 15, 2016
Rated 4 out of 5 by smlrj I love the quality of the slacks and they can be worn for many events. The Lady Hagen products for women are made very well, wash nicely,look stylish and adapt to traveling and many other events. I do wish the slacks came in a petite length as they are very long if you are under 5 feet. It is sometimes difficult to shorten the slacks so as not to ruin the style of the pant leg and sometimes they are too long in the crotch. If this is a factor then I can't buy them as they don't fit well. The skorts are sometimes too long as well. I love the style but if they are too long it is difficult to shorten them . June 14, 2016
Rated 1 out of 5 by Gail Button was missing The button at the waist to hold the belt tab inside had been ripped away and only the thread remained. I found another button at home to replace it rather than return the slacks. But I think I received a returned item that had not been well enough reviewed by the supplier before it was sold again. Otherwise I love the slacks and the fit. April 24, 2016
Rated 5 out of 5 by Golfaholic69 Great golf pants They are comfortable and stylish. Didn't bind or hinder my golf swing in any way. April 14, 2016
Rated 5 out of 5 by DJ Love this product. Great fit and comfort. Stylish. Great look. Pants are great on the golf course in all types of weather. April 12, 2016
Rated 5 out of 5 by iPatty Great for older players! Great product for overweight unfit older ladies!!! It makes me look fit and younger...highly recommend this product. April 12, 2016
Rated 5 out of 5 by trishie28 This product was well made and designed. I love the way these pants fit and feel so comfortable. The pockets are very well placed and flattering as opposed to bulky. They are lightweight and perfect to be worn in our North Carolina climate. I wish they made them in a light colored fabric as well as black. March 4, 2016
Rated 5 out of 5 by Debbie Lady Hagen Women's Range Golf Pants These pants are very comfortable and would buy another pair in a different color. Very lightweight for thr spring and fall in northern Indiana. February 29, 2016
Rated 3 out of 5 by Sunny Overpriced They run large and feel kind of sloppy. They are also prone to static cling. January 12, 2016