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(fixes headline. No other changes to text)
PARIS, March 7 (Reuters) - French media giant Vivendi said on Tuesday it would cut the number of its supervisory board members from 14 to 12, effectively increasing the grip of chairman Vincent Bollore on the group.
Independent board members Yseulys Costes, Pascal Cagni and Alexandre de Juniac decided not to renew their four-year term in April, Vivendi said in a statement.
A spokeswoman said two of them would not be replaced. This would cut the number of independent board members from 9 to 6.
Vivendi's employee shareholders, who hold a 3.27 percent stake in the company, elected Sandrine Le Bihan, to be their representative at the supervisory board, replacing one of the board headcounts.
All these decisions depend on formal approval at an annual shareholders' meeting due on April 25
Bollore, who became chairman in 2014, is Vivendi's biggest shareholder with a 20.65 stake according to Reuters data. Two other board members represent Bollore's interests, including his son Yannick, who leads the advertising group Havas.
Reporting by Mathieu Rosemain and Gwenaelle Barzic


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Waxahachie Journal Architecture Chautaqua
Waxahachie's Chautauqua Auditorium - is the sole national survivor of the turn-of-the-century phenomenon - The Traveling Chautauquas. It has been designated a Texas State Historical Building and has been placed on the National Register of Historical Buildings and Sites.
Built in 1902, it seated 2500 culture-hungry Texans from all over the state at Chautauqua activities. They came by covered wagon, surrey, on horseback, and any means at their disposal to hear such American greats as William Jennings Bryan, Will Rogers, and the U. S. Marine Band. For two weeks each July, Waxahachie's Chautauqua Park (now Getzendaner Park) became a "tent city" where entire families came and camped out.
While the original New York Chautauqua was the brainchild of a Methodist Minister, and sponsored by the Methodist Episcopal Church, Waxahachie's Chautauqua Association was organized by the Cumberland Presbyterian Church's Reverend J. C. Smith in 1900.
The typical day then, under the canvas bigtop, included morning religious education, afternoon spiritual and secular education, and evening entertaining lectures. The format soon expanded to accommodate other cultural endeavors and professional entertainment. Chautauqua's growing popularity inspired progressive Waxahachians to make it a permanent institution with its own permanent building. Tent-inspired, this octagonal wooden structure had large wooden windows on all sides. These slid up into the walls to produce an open-air auditorium. 5000 attended the 1902 formal opening: 2500 seated inside, 1500 standing or sitting in window areas, 1000 milling the grounds. Similar Chautauqua auditoriums were constructed throughout the growing Chautauqua Circuit.
Here during Chautauqua season, famous itinerant national "troupers" - men of the cloth, scientists, educators, statesmen, and all types of classical and popular entertainers brought to the "hinterlands" a cross-section sample of the life and experiences of the rest of the nation. The auditorium also became the focal point of local festivities.
The Waxahachie Chautauqua served Texas until 1930 - when radio, talking pictures, and the automobile made culture and entertainment available to everyone in America.
The Waxahachie Chautauqua Auditorium was restored for the National Bicentennial July 4, 1976. It is still in use today as a city auditorium for various functions including several visits each year by the Fort Worth Symphony.
The Chautauqua stands at the edge of Getzendaner Park and provides a look into Waxahachie's past. Still in use, it is home to a number of theatrical events and City celebrations. With its open-air style venue and updated amenities the auditorium is perfect for

subset: commoncrawl


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Ta Baile na gleireach an Tir na nOg mo chara
To contact Tom send email to email@example.com
About Leitrim (Liatroim, meaning "Grey Ridge")
Geographically, the north and south of the county are quite distinct, with wet lowlands to the south and a series of plateaus in the north.
Leitrim today is a sparsely populated region of bogs, hills and lakes, with a lonely beauty all its own. It is difficult to imagine how it must have been in 1841, before the Famine, when it had a population more than five times the present level, the vast majority living in the most abject poverty.


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Epos International, the Japanese financial institution teamed up with Visa and got 100 artists from around the world to come up with beautiful credit card designs. The project launch will last a year until October 2009.
The range of designs was amazing. Beautiful artwork, graffiti, the inevitable anime and some clever and amusing designs can be found amongst the 100. Shown here are 10 Trendhunter favourites. The link to the full gallery on Epos's Design Cards campaign website includes each artist's information and profile.
Unpublished -
100 Designer Credit Cards
More Stats +/-
Design Your Own Credit Card
Diamond Studded Credit Cards
Bejeweled Credit Cards
Credit Card Fashion
Bespoke Earphone Accessories
Epos International and Visa
- By: PearlNov 22, 2008
References: eposcard.co.jp & ifitshipitshere.blogspot
References: eposcard.co.jp & ifitshipitshere.blogspot


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Unwanted competition
Am i the only one that didnt know this? But whilst hard at work in the gym doing my bench pressing i got the feeling i was being watched. A guy bp next to me was eyeing me up:gay: i thought, i was worried! however i soon noticed that when i added weight to my bar he did the same plus an extra 5kg. I spoke to a pt and he explained that most people who train like to compete against each other. Is it me or do i need to change my gym:) Anyone heard of this?
I never pay enough attention in the gym to anyone else that I would notice.
Ive never noticed it before, wondered if you had heard of it..
Why do you give a shit what other people think?
LOL....just concentrate on your own training because not matter what you lift, there IS someone out there who is stronger than you.
So, be humble and worry about yourself.
I would never let it bother me, just find it strange that guys go to a gym to secretly compete with another dude. Could be a British thing.
It's a man thing. Nothing to do with race.
Unless you are west african....because in that case everyone just wants your awesome genetics! :D
Ha, try being a girl that pushes heavy weight in the gym! I train at an all guys gym. I've been there for years, so the guys that have been around forever are cool. The newbies college and high school guys make it a point to come right next to me and go for the heavier weights...or try like hell...
I make it a point not to make eye contact with anyone. I do notice it but who cares...I'm just in there to do my thing and go home.
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Fulton Bearing Protectors
The iBoats Experience
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Protects wheel bearings from the elements during all trailer operations. Automatically maintains the correct internal pressure - cannot damage seals. Chrome-plated steel construction, stainless also available in certain models. Covers sold separately.
This product ships in 1 business day.
Add to Cart and enter your Postal Code to determine the shipping charges.
Most products and orders leave our warehouse in 1 business day. However, select items may take more processing time. Alaska and Hawaii orders please add 1 additional warehouse processing day.
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$18,570 CARFAX Value
No Accident or
Damage Reported
No accident or damage reported to CARFAX
CARFAX 1-Owner
Purchased on 06/12/14 and owned in CT until 06/27/17.
Personal Use
Driven an estimated 12,521 miles/year.
Service History
Last serviced at 37,065 miles in Saint Cloud, FL on 01/16/17 • Maintenance inspection completed • Tires rotated, Oil and filter changed, Fluids checked, Tire repaired


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Kayle Build Guide by bobahebeast
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Thank You!
Your votes and comments encourage our guide authors to continue
creating helpful guides for the League of Legends community.
Kayle Build
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
Hi Boba here. English is not my first language so please give me a break on grammar and spelling. Anyway this is my first guide on Mobiafire. The reason I wanted to make this build because I want other people to know how I build my favorite champ, Kayle. I also wanted to show how effective this way is. I'm not the best player, and I barely play ranked so this is defenitly not a ranked build, therefore it can be countered easily. The sole purpose of using this build is to have fun. So HAVE FUN!
First I chose the magic pen because it is a great buy for Kayle if increases her Damage output on teams with lots of magic resist, plus there aren't very many other marks that apply to Kayle.
Replenishment Seals are a must on ap carrys. or any ap carry that needs mana O.o nuff said
The cool down reduction glyphs help a lot with being able to spam Righteous fury, turning Kayle into a ranged champ.
And the Quittances just add to the effect of the magic pen.
The reason I go 14 0 and 16 is because the defense unless you plan on building Kayle with different items is not gonna make that much of a difference in you tankyiness so I'd rather have the extra damage and utility.
This is the main part of the build and is based around The TIAMATS. I start out with a dorans because of the mana regen along with the health this gives kayle an easier spamming of the righteous fury and gives her that extra health that could be the difference between life and death


text: I use samsung kies to sync my new samsung captivate with my PCs. The sync is seamless and it works perfect. I have noticed one small issue. The song information (like album art etc.) in Kies application on my PC is accurate for all songs. However, after i transfer the songs to captivate the information looks different / inaccurate. I don't understand why this is happening. An example: I have a Pat Benetar song (we belong) having Pat Benetar album art. But, the same album art is applied to Tom Petty and Heatbreakers songs such as Free Fallin' etc. This is kind of hilarious but can anyone tell me why this is happening? When i see the songs within Kies application, the album arts look correct. Can someone help me understand this issue and possibly a solution to fix this. Thanks


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Hi Folks, it's me, your trusty PTFC blogger here on Blogtown. You haven't heard much from me since the last home game, because, well, the Timbers finished the season at the bottom of the table and missed the playoffs for the second time in three years.
It was a season many of us would prefer to forget, but until the Boys in Green take the field next season, we can lick our wounds, kibbutz about how Coach/GM Gavin Wilkinson will be returning (despite royally sucking), and keep our ears to the ground about Timbers and Beavers owner Merritt Paulson's plans to bring Major League Soccer to Portland.
Children, I am the
bringer repeater of good news.
Before yesterday, we knew a few things:
- --Paulson and Company officially outlined their intentions at a press conference on September 3rd, launching Better Beavers Ballpark.com and MLS to Portland.
- --The deadline for submitting the formal application to MLS commissioner Don Garber and his cronies is October 15th,
- --Paulson, through no fault of his own, holds one of the most reviled names in recent political history.
Yesterday, a short press release flashed around the internet.
"Today, on behalf of the greatest soccer fans in America, we submitted our formal application to bring Major League Soccer to Portland. We expect to get a response to our application no later than March of next year. In the meantime, we will continue to work with MLS, city officials and the community to turn this exciting idea into reality for Portland and Oregon." --Merritt Paulson
Yippee! said the Timbers faithful. I wanted more. I'm not naive enough to think that the public would get a look at the official MLS franchise expansion application, but I thought that maybe we'd see what Paulson's company, Shortstop LLC, submitted to the city, or perhaps some sense of what the city thinks of the MLS plans.
Well then, lucky for us--and thanks to some crack reporting from Ryan Frank and Mark Larrabee at the Oregonian--we have a rundown. The article covers a bunch of stuff, including bits about the $700 billion bailout, which is annoying and largely irrelevant.
I thought I might summarize all of this stuff, but I'm no city politics expert. Instead, here are links to three documents that accompanied the article:
- --PDF scan of Paulson's proposal to the city.
- --PDF of The PFM Group's independent evaluation of Paulson's proposal, commissioned by the city.
- --PDF scan of an email from the city's Spectator Facilities Manager, Dave Logsdon, to city stakeholders, reviewing salient points from a meeting with Paulson on August 19th
In those, I point your attention to these facts
I humbly suggest interested parties download these docs and take a look-see. I wish there was a way to turn off comments without proving you'd downloaded the docs, but alas, I don't hold that kind of sway. Let the flame war begin!


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|Property type
|Minimum Stay
|2 - 5 nights
Once you arrive, no need to drive!
Ski to Condo, walk to Gondola and steps to town! Ski Hill Condo is the perfect location for in winter & summer! Located one block from Main Street Breckenridge and we are steps away from the Gondola. The Four O'Clock ski run ends steps away from our property. This one bedroom + loft sleeps up to 8 comfortably! All living room furniture is new this season! A his and her recliner, a new sleeper sofa and love seat makes our home your home! We added a new larger 44" Sony wall mounted LCD TV for your relaxation and pleasure. We have full size bunk beds that sleep 4 were added. New linens and comforters have been added as well. Ski in for lunch and warm up by the fireplace! Ski/In luxury with panoramic views of the mountains and town. The outdoor hot tub is steps from our front door just below and to the right of our unit. The swimming pool is open in the summer only. Enjoy breathtaking views of downtown Breckenridge from every room. Wireless Internet is available to all guests. Parking is located under the Condo and free shuttle pick-up right outside your door, Ski Hill Condo has everything you need to make your next Mountain Vacation one to remember.
This perfectly located mountain condo includes; Vaulted ceilings, panoramic mountain and downtown views, two televisions; (two flat screen), DVD, cable, wireless internet, wood burning fireplace, fully equipped kitchen, community grill, shared laundry facilities, 90% covered parking, (2) outside hot tubs, and (1) pool (summer only).
Once you arrive you will find you won't need to drive!
Keywords: Condominium
If a picture is worth 1000 words, then this picture tells my story. I am a Ski Bum! The best way to enjoy the skiing and mountains is to be a part of them. This is my part. I am a Fire Fighter /Paramedic / Ski Patroller and investor. I have bought and sold many investment properties, but this place is my home. The Mountains are calling! Listen to them. Come join the fun!
Marc Monroe, BS, NREMT-P
Fauquier Virginia Fire Fighter
The Owner purchased this condo in 2009
My wife and I love our home for these reasons.
- Wall to wall panoramic mountain views with Aspen trees as a backdrop.
- Ski In location.
- Proximity (across the street) to the Gondola which is the high speed access to the high altitude powder.
- Walking proximity to the restaurants bars and parties.
- The design and amenities of Ski Hill Condominiums.
Ski Hill is the best place in Breckenridge. All of the competition has something to offer. Breckenridge is a beautiful resort town. Ski Hill Condominiums has the best overall package.
Holler back if you are ready to book our home!
Our home has the unique advantage of the long sided wall which is all windows. It provides a beautiful panoramic view of sunrises, the town and Mt Baldy.
Great location for skiing! Condo was well stocked with toilet paper, spices and lots of other things to get us started. Slept 8 of us without a problem, ski locker available and nice hot tub. I also loved the laundry facility to do a load of towels half way through the week. Very convenient and cozy.
My family enjoyed staying here. It is a very lovely, comfortable place. The location is great. It was very clean, well stocked. It is with in walking distance to several places. I would recommend staying here.
We were unable to stay at this condo for our trip. We arrived at our check in time, 4:00pm, to find the condo dirty and un-cleaned from the previous guests. Dirty towels, linens, food all over the counters and sticky kitchen floors. We understand that the owner lives out of state and gave him a call, he in turn got a hold of his cleaning service to find out that someone had surgery and no one came to clean his home. Now we tried to give him time to fix the problem and he told us 45 minutes someone would be there to clean up the mess, we waited for over an hour, by this time we sat at the dirty condo for almost 3 hours with tired, hungry, and upset children, we decided to leave. We were lucky enough to find lodging nearby but it was not the trip we had planned for. I reserved this home in January, paid for it in full by February, very disappointed. I understand that things like this could happen but somewhere along the line the owner, Marc Monroe, dropped the ball, as well as his cleaning service..... This should not have happened, no one pays money to stay in a dirty place and just accepts it. We did receive a full refund but we would much rather have had the family trip that we had planned the months prior.
I would not recommend this condo to anyone, with the poor suggestions and comments made to us by the owner we left disappointed and disgusted.
We had a terrific time at the Marc's condo. The condo was very comfortable for our family of 4. Easy access to the lifts and to the town. We plan to recommend this place to friends and would definitely stay again.
Colleen and Kevin
The pull out couch needs to be fixed because the springs weren't working and the bathtub drained slowly.. I let the owner know. Other than that, it was accommodating and comfortable.. We were never bothered by noisy tenants in the area.. I loved that all the kitchen staples, condiments and utensils were available that I didn't have to go out and buy anything except for my main meals and snacks..
Would stay again.
The best equipped kitchen that we have seen for a vacation rental (immersion blender, crock pot, plenty of dishes)
Great central location in Breckenridge
Free fire wood
Great value
Be Aware of:
The master bedroom and the loft with two bunk beds are upstairs along with one bathroom that has two doors, one to the bedroom and the other to the loft. The second bathroom is downstairs with the living room and and kitchen. We had two people in the loft and two in the bedroom, the people in the loft used the downstairs bath, meaning a trip up or down the spiral stairs to get from the sleeping area to the bathroom. The loft is between the master bedroom and the stairs, so the people in the master go through the loft to get from the bedroom to the living area.
Other Activities: Shopping, boating, snowboarding, snowmobiling, wildlife viewing, rock climbing, kayaking, hot air ballooning
|Refundable damage deposit
|Property Damage Protection
|Tax Rate
No Pets, No smoking
Cleaning includes all linens & towels.


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Monday's Daily Theme (June 10) was from Kerri Majors, author of This Is Not a Writing Manual: Notes for the Young Writer in the Real World, out July 9 from Writer's Digest. This Is Not a Writing Manual is a memoir with advice about writing and the writing life! You can read more from This Is Not a Writing Manual right now on Figment!
Want your own copy? Enter our sweepstakes to win one of five copies of This Is Not a Writing Manual! Write your response to the theme below, and enter to win here!
Voice and Point of View (POV)
This is one of the most popular and successful prompts I give my creative writing classes It's designed to get you thinking about the differences between, and overlap of, voice and POV. It just might result in some of the fun, spunkiest writing you've done to date!
Choose a famous character with a clear voice (like Philip Roth's Nathan Zuckerman, Virginia Woolf's Mrs. Dalloway, or Stephanie Meyer's Bella), and adopt that voice to write 500-1000 words from the POV of a dog. Yes, a dog-any breed you like!
If it makes it easier, choose a short passage from the novel that stars your chosen character, and pattern your dog's story on that passage. Most important: Have fun with it!
(Special thanks to David Lodge and his novel Thinks… for inspiring this example!)
Not yet receiving Daily Themes in your inbox? Sign up here. And don't forget to tag your work DailyThemes!


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In today's episode of NewsBreak, Carlen Dickerson talks about a suicide bombing in Nigeria, Obama's proposal for "net neutrality" and Rivalry Week at the University of Miami.
NewsBreak is a daily 90 second news update that will provide the University of Miami community with vital information. Each day NewsBreak has a different host that will provide you with the latest in campus news. When the hosts aren't in the field going LIVE at an event, they'll be streaming from the studios of the School of Communication.
Watch this show anytime online.


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sort by best latest
Be satisfied with who you are, and what you are. Don't be afraid to make changes to you life daily, to avoid needing to make huge changes later. Exist in the moment and experience it fully, good and bad. Pursue your dream everyday.
You can help the HubPages community highlight top quality content by ranking this answer up or down.
Some men won't have a crisis Ryan, but those who are destined for one will experience it to a greater or lesser extent anyway. If men become childlike during this period of their natural development, then there's no real harm done. In fact it might even do them the power of good.
It's only when they turn childish (quite different from childlike), and start prancing around like teenagers that things become a bit embarrassing.
Being mindful of the aging process and embracing acceptance is the best mindset to adopt prior to the event, if indeed there is even a crisis looming.
Andy Aitch
You can help the HubPages community highlight top quality content by ranking this answer up or down.


text: Friends today my punto met with minor accident, two motorist banged each other in middle of the road and hit my punto, which left with dent and scratches. Because of unethical driving habits of the motorist my punto got damaged. Attached the photo of the damaged area. Really pain to see the hot hatch with dents . Should I give this to FASS or any other good body shop to repair this in bangalore. Not sure how much this damage will cost, if I go for insurance I will lost my NCB, which needs to be renewed in months time. Sent from my iPad using Tapatalk


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Borough Serviced Office Space
We have a variety of serviced offices available to rent in Borough. Each office space is offered at the best rates and suited to your individual needs and requirements.
We have a variety of serviced offices available to rent in Borough. Each office space is offered at the best rates and suited to your individual needs and requirements.
Located opposite Borough underground and just a 2 minute walk to London Bridge, this 1980's building is great for commuters south of the river. Architects Stiff & Trevillion have created a beautiful work space inside and out. The building offers a mix of individual offices, meeting rooms and shared workspace along with green roof gardens, rainwater harvesting, solar panels, lots of secure bike storage and showers.
This modern 6-storey building has undergone a comprehensive refurbishment to provide air-conditioned office suites with good natural light, ranging in size from 100sqft to 1250sqft. All offices are fully furnished and carpeted, additional equipment is available if required, and the marble reception and entrance has two six-person lifts to all floors. The reception area is modern and staffed by an experienced receptionist, from 9.00am to 5.30pm, who is happy to provide any assistance you may require. Access is available 24-hours a day, 7 days a week with personalised security entry system.
This four-storey building offers modern, high quality, well-appointed office suites. The building has been refurbished and cabled to a high specification. There is a four-person lift to all floors. All offices are fully furnished and carpeted, and additional equipment is available if required. The reception area is modern and staffed by an experienced receptionist, from 9.00am to 5.30pm, who is happy to provide any assistance you may require. Access is available 24 hours a day, 7 days a week with a personalised security entry system. A modern, prestigious 10 person boardroom is available on an hourly/daily rate.
This is a shared workspace for entrepreneurs, start-ups and small businesses. Price includes dedicated desk space with super fast leased line broadband, wifi, use of high spec meeting rooms and full 'big office' services such as printing, copying, scanning, as well as excellent coffee. Great value - Just £114+VAT per week per desk. No hidden costs - An all inclusive price. Flexible - One month minimum stay. No expensive telephone line rental or call charges. VoIP phone handset can be provided to allow you to easily and cost effectively manage your phone services online.
The high-spec studio spaces (many with their own balconies) are home to a wide range of companies, from software agencies, to film production and FinTech start ups. The building also features a co-working space on the ground floor, situated near to an independent café where Square Mile shots are pulled from an original John Gordon-customised Synesso. This centre is ideal for companies looking to locate themselves conveniently between London Bridge and Waterloo, in prestigious surroundings. In terms of somewhere to base your business, the centre has everything you could need; the building has high spec meeting rooms, best in class connected services with a dedicated support team, regular networking and social events, a games room, and is within easy walking distance of Borough Market.
This delightful period 4-storey building near Victoria Station has undergone a comprehensive refurbishment to provide serviced office suites from 150sqft to 650sqft that are offered at affordable prices on flexible terms. There is a four-person lift to all floors, all serviced offices are fully furnished and carpeted, and additional equipment is available if required. The reception area is modern and staffed by an experienced receptionist, from 9.00am to 5.30pm, who is happy to provide any assistance you may require. Access is available 24-hours a day, 7 days a week with personalised security entry system.
This annex building comprises of 15 workstations and offers a convenient location for public transport. Its features include: a gym, bicycle parking and CCTV.
Offers serviced offices and meeting rooms at a prestigious address with easy access to both the West End and the City. The business centre is situated within an impressive Georgian period building located on the London Bridge Quarter district, only a short distance from The Shard. With it's excellent position the area is very well served by both restaurants and transport. Extensively refurbished to provide boutique, fully furnished, spacious offices, benefiting from plenty of natural light. St Thomas Street maintains its heritage, but creates superb unbranded office space fully equipped to modern standards and the latest in IT and Telecoms.
This exciting redevelopment of this business centre has provided brand new studio offices in the heart of Bankside, just 500 metres from Borough station. The striking double height reception area is home to a contemporary on site café, a thriving co-working space and professional meeting room. As a result of a vast rooftop extension, there are new duplex studios available over the fourth and fifth floors. The studios have impressive views across Southwark through the floor to ceiling glazing. All studios feature wooden flooring throughout and flowing natural light. This City fringe location is perfect for entrepreneurs with a fashionable, yet business-orientated attitude looking for a home to grow and develop from. Its central location makes it ideal for meeting clients and provides fantastic transport links to the rest of London.
Less than ten minutes' walk from both Borough and London Bridge, this centre is a beautifully restored period building, now offering a range of studio and office space, all on competitively flexible lease terms. With a huge range of spaces available all situated around a central open air courtyard, the centre is home to a diverse array of start ups and established businesses with strong communities in the consulting, architectural, technology and design industries. The building is also home to a large co-working space, bookable meeting rooms and a bustling events programme; and what's more, the building is currently undergoing a fantastic redevelopment project.
Situated 1.5 miles (2.4 km) east of Charing Cross, Borough forms one of the oldest parts of London and fronts the River Thames to the north. It is now at an advanced stage of regeneration and is the location of the City Hall offices of the Greater London Authority.
The regeneration has given way to residential development, galleries, shops, restaurants, bars and most importantly major office developments, home to many international headquarters of accountancy, legal and other professional services. Serviced offices in Borough are within easy walking distance of the City and the West End. The impressive skyscraper, 'The Shard' is next to London Bridge Station. Borough has become a major business centre with many national and international corporations, professional practices and publishers located in the area.
Borough Market is a well-developed visitor attraction with units that have been converted to form a gastronomic focus for London. Borough High Street runs roughly north to south from London Bridge towards Elephant and Castle.
Tenants with a serviced office in Borough are spoiled for choice when it comes to transport links. Numerous underground tube trains, buses and airports are all close-by, ensuring that you are well connected when it comes to travelling around the city.
London City Airport
London Heathrow Airport
London Gatwick Airport
London Luton Airport
London Stansted Airport
Serviced offices in Borough are currently served by the following bus routes: 21, 35, 40, 133, 343, C10. Night routes: N21 N35, N133 and N343.
Businesses with serviced offices in Borough are served by two underground tube stations that are close by.
Borough tube station is on the Bank branch of the Northern Line between Elephant & Castle and London Bridge stations and is situated in Travelcard Zone 1. The Northern Line takes passengers from Morden in the south, to either Edgware or High Barnet in the north.
Southwark station is a Jubilee Line station, just a few short minutes' walk from Borough station, also in Travelcard Zone 1. The Jubilee Line transports passengers from Stanmore in the North West, through to Stratford in the East, where it connects with National Rail Services.
Below you can see the nearest areas to Borough where you can find serviced offices:


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About This File
The Lord of the End Times has come. His plans brought to fruition, Archaon laughs as the last mortal armies fight a futile battle. Yet hope rests amongst the few remaining mortal lords. Could the End Times be stopped?
Featuring all of the scenarios from the original The End Times: Archaon, this is a must for all fans of the World That Was.
What's New in Version 2.1 See changelog
Updated to Battletome: The End Times 2.0. Biggest new feature is the new campaign at the end of the book. Also some minor corrections and useability updates.


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James Rigney, better known to many as Robert Jordan, bestselling author of The Wheel of Time series, passed away on September 16th after struggling with illness this past year. His cousin Wilson announced the news on Jordan's blog. Responses have been pouring in from his fans, and others in the field have begun to comment such as Patrick Nielsen Hayden and George R. R. Martin.
Our deepest condolences to Jordan's wife, family, and friends.


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Graham Humphreys
Head of Brand
Graham is an award-winning general manager with 20 years' experience in Europe, the USA and Australia. Graham's passion is applying design thinking to make the world better for humans and businesses. His specialty is multi-disciplinary innovation, spanning work on brands, campaigns, products, environments and digital experiences. He has driven more than 500 programs in senior roles including fuseproject, Dare London and Zenith Media. Highlights include global rebrands for Nivea and PayPal, global advertising for Intel, and product innovation for Barclays bank, SodaStream and Samsung.


text: Dne úterý, 27. srpen 2002 21:03 Mario Vukelic napsal(a): > On Tue, 2002-08-27 at 20:26, Ing. Vladimir M. Kerka wrote: > > but my problems with evolution don't end. > > did you try the evolution mailing list? Maybe you have luck there On the end i tried to contact evolution mailing list and one very patient subscriber of this list found solution. It seems to me this problem was quite common, so I will give you short decription of the solution: the problem was in wombat, which needed library libplc4.so (/usr/lib/mozilla-1.0.0/libplc4.so). I added path to the library to /etc/ld.so.conf and run /sbin/ldconfig. After that wombat worked again and evolution started. Today I upgraded 1.0.5 version to 1.0.8 and all seems to be very good, evolution is working and I am very happy. Thank all of you who send me mail to help. I hope that in near future I will be able to help someone, too. Many thanks once more. Aloha Vlada


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Modern robotics and sensors have expanded the ability to collect science data in underwater settings. Oftentimes, the collected data are deposited into files and databases where they sit in their separate and unique formats. Without easy to use visualization tools, it is difficult to understand and interpret the information within these data sets. NORUS, the North America-Norway educational program, has a scientific focus on how climate-induced changes impact the living resources and ecosystems in the Arctic. In order to obtain the necessary science data, the NORUS program utilizes the Slocum Glider, a form of underwater robot. We present a compelling, efficient, and easy to use interactive system for visualizing large sets of science data collected by the Slocum Glider. This goal is obtained through the implementation of various methods taken from scientific visualization, real time rendering, and scattered data interpolation. Methods include visualizations of the surrounding terrain, the ability to map various science data to glyphs, control over color mapping, and scattered data interpolation.
Available at: http://works.bepress.com/zwood/16/


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Lead Generation Advertising
Lead Generation is the exchange of a high quality piece of content for registration information. When you think of lead generation advertising goes hand in hand with it- but does it really? An effective lead gen strategy starts with identifying your buyer persona(s) and then building content that will draw and engage your target audience. The goal is to provide net new names to your marketing database. An efficient lead generation strategy places your buyers ahead of the sale. It effectively establishes the demand for your content, rather than your product.
Here are 3 methods to begin creating a productive lead generation strategy that doesn't require advertising
- Identify Buyer Personas - Before you begin content creation, you must understand your target audience. Setting up interviews with customers to understand their pain points, goals, challenges and most importantly, how your content can benefit them. The key here is to create targeted yet broad content that will draw your potential clients
- Content Alignment- Once you have an understanding of your buyer persona, start aligning your content to stages during the buyer journey. There are 3 generic stages to the buyer journey. The first stage is where buyers are actively seeking solutions rather than a specific brand. At this stage, you provide educational content, which will put you into the tier of a thought leader. In the middle stage, buyers look at your particular solution, just not yet ready to buy. They should receive nurturing and qualifying material. In the final stage, buyers have a higher propensity to purchase your solution and should receive promotional content. All three stages should incorporate distribution across multiple channels
- Hyper Targeted Landing Page - If you properly align your material you will be able to direct a large amount of visitors towards a particular landing page. These landing pages should be created around the specific search phrase and inline with Google's best practices. You want to have a piece of high value content that will garner the visitors attention. Aligning your content provides you with insights to grasp potential buyers at different stages of the buyer journey. The key is to be sure you maximize your content by placing a form-fill in front of the highest value content. This is a win-win situation because you collect contact information and the visitor collects valuable content.
For more lead generation techniques that will help accelerate your pipeline, download our Ebook!
Digital Marketing Acceleration Video


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This fall, AARP Mississippi will conduct a series of Home Fit workshops throughout the state. The workshops will focus on ways to make homes more livable as owners get older. Many people would like to stay in their own homes or communities for as long as possible. The workshop will guide participates in taking a fresh look at their current homes to see if it matches their needs now and if it will continue to meet their needs as they grow older.
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Intellectual property is subject of GET Speaker Series talk
Katherine Card Beckles, Assistant General Counsel of Intellectual Property and Technology Law at JPMorgan Chase will speak on intellectual property in the next installment of the Global Enterprise Technology (GET) Speaker Series.
Beckles will lead a discussion of intellectual property law with a particular focus on patents and their effect on various industries, including financial services. She will also discuss the recent changes implemented by the America Invents Act the most sweeping change to patent legislation since 1952.
The event will be held from 11:50 a.m.-12:50 p.m. on Tuesday, Oct. 18, at the Syracuse University School of Law, room 175.
Website: http://ischool.syr.edu/newsroom/?recid=1203
Contact Person: J.D. Ross
School of Information Studies


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New Delhi: Israel's Ambassador to India expressed disappointment at the release of 2008 Mumbai terror attack mastermind Zakiur Rehman Lakhvi.
"Israel is surprised and disappointed by release of Lakhvi, mastermind of 26-11 Mumbai attacks in which as part of the horrific attack also Israeli nationals and a Jewish Center - the Nariman House - were targeted," tweeted Israel's Ambassador to India Daniel Carmon.
He also termed his release a "setback for the international efforts in the war against terror in which India and Israel are close partners".
"This release is a setback for the international efforts in the war against terror in which India and Israel are close partners," he further said.India on Friday lodged its strong concerns with Pakistan on the release of Lakhvi. French President Francois Hollande also termed his release "deeply shocking".
Read More: 26/11 mastermind Zaki-ur-Rehman Lakhvi walks free; Rajnath terms it unfortunate
Zakiur Rehman Lakhvi was released overnight from Adiala Jail in Rawalpindi without any announcement by the jail authorities or the Jamaat-ud Dawa (JuD), the organisation that Lakhvi was affiliated with, media reported on Friday.
OneIndia News


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Mind you, I'm not doing a complete fast, but I'm limiting my diet for a week to fruit and veggies with some whole grains (not flour). But I have to confess that any type of fasting is hard. So much of my time is spent planning for, buying for and cooking meals, not to mention eating, that I forget I'm fasting several times throughout each day and start to eat something I shouldn't. I also get a little grouchy when I can't please my palate. But I guess this is the reason I'm fasting.
Celebrating is important. There are more celebrations in the Bible than fasts. But fasting is important too. How easy it is to satisfy the flesh! For example, my son has birthday cake and pie (that his friend made and gave him) sitting around in my kitchen. I've almost taken a bite out of one or the other three times while preparing meals in the last 24 hours. And these aren't even something I'd normally eat--at least not a lot--but when I'm fasting my flesh screams, "UNFAIR!"
I feel sorry for my flesh as it squirms and screams, but you see, like a small child, it must be put back in its proper place. If I never discipline my flesh, deprive it, or make it uncomfortable, then it gets out of hand. It starts to believe it's my god and should control all of my decisions. Worst of all, it becomes more and more difficult to please, like most deities of our own making. The most delicious delicacies become mundane. Like a spoiled child, my flesh whines unable to be satisfied.
So this week I'm putting the child down for a nap. The flesh needs this discomfort. And afterward I will relish each and everything I choose to put in my mouth, recognizing the Lord's provision. I and my flesh will have a renewed sense of thanksgiving.
So here's to the New Year, as I dedicate it to my Lord and Savior (and not to my flesh).
Invigorating Salad Concoction:
Good for a refreshing side dish on a normal winter day or a main dish during a fruit & veggie fast.
Nappa cabbage, thinly sliced
Shredded Carrots
Red Pepper, thinly sliced
Bean Sprouts
Lemon Juice
Mix the cabbage and carrots. Top with a few slices of red pepper and bean sprouts. Squeeze some lemon juice over the top.
Even the flesh can't deny it's great taste!


text:
New mods, Pics...
View Single Post
Scooby Newbie
Join Date:
Dec 1999
Dorkland NZ / MTL, Qc, Can
2000 WRX STi 6 wagon
Mellow Yellow
other pics of my car can be found on
my website
these pics are old though, i will get some new ones with my Seedlines and Ver 5 wing next week...
for a list of mods, just click the link for it on my car's page....
and my car is NO rice-a-roni...
i have 7 years experience in racing and the car is tuned for the track as a club-racer, meaning it's also a dayly driver...
before i knew i was moving to New Zealand i was out to build myself something i could not buy at the dealership and that's my favorite car... now the turbo is still going in the car in about 2-3 weeks even thiugh i'm selling it in January. Needless to say i already have plans to buy the real thing when i move there.
and Snoopy, the brakes are amazing, very light compared to the original ones and so damn strong, i never thought i'd use anything made in usa on my car but i have to admit i'm impressed. the stoping power is a little agressive for the N/A car and the race compound pads for the rear are a must to balance it out. one down side is the amount of brake dust produced in a day, anyone wanting to have perfectly clean wheels all the time stay away from these but that's the price you pay for performance.
June 6 i'm leaving for NZ for a month and wiil be shopping for my new car and possibly buying it then also, since my father lives there i can leave it there....
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Mar 19, 1991
|Filing date
|May 17, 1988
|Priority date
|May 17, 1988
|Fee status
|Publication number
|Renee A. Tenzel, David F. Aitcheson
|Original Assignee
|Liposome Technology, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (7), Non-Patent Citations (4), Referenced by (38), Classifications (7), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention relates to a method of preparing uniform-size liposomes, and in particular, uniform-size liposomes having a selected mean diameter less than about 300 nm.
Gregoriadis, G., in Liposomes, vol. III.
Poznansky, M. L., et al, Pharm Revs, 36(4):277 (1984).
Szoka, F., et al, Proc Nat Acad Sci (USA), 75:4194 (1978).
Szoka, F., et al, Ann Rev Biophys Bioeng, 9:467 (1980).
The use of liposomes for drug delivery has been widely proposed. Liposomes have the potential for providing controlled "depot" release of an administered drug over an extended time period, and of reducing the side effects of the drug, by limiting the concentration of free drug in the bloodstream. These advantages of liposome drug delivery apply to a variety of routes of administration, including intravenous, intramuscular, and subcutaneous, application to mucosal tissue, or delivery by inhalation. Where liposomes are administered by intravenous delivery, liposomes provide a further advantage of altering the tissue distribution of the drug. Liposome drug delivery systems have been reviewed (Poznansky, Gregoriadis).
Generally, the optimal liposome size for use in parenteral administration is between about 100 nm and 300 nm. Liposomes in this size range can be sterilized by passage through conventional filters having a particle size discrimination of about 200 nm. This size range of liposomes also favors biodistribution in certain target organs, such as liver, spleen, and bone marrow (Gabizon), and gives more uniform and predictable drug-release rates and stability in the bloodstream. Liposomes whose sizes are less than about 300 nm also show less tendency to agglutinate on storage, and are thus generally safer and less toxic in parenteral use than larger-size liposomes. Uniform-size liposomes in a selected size range less than about 100 nm, are also useful in therapeutic applications. For example, small unilamellar vesicles (SUVs) having sizes between about 30-80 nm are useful in targeting to tumor tissue or to hepatocyte cells, because of their ability to penetrate the endothelial lining of capillaries. SUVs are also advantageous in ophthalmic liposome formulations, because of the greater optical clarity of the smaller liposomes.
A variety of techniques for preparing liposomes have been proposed (Szoka 1983). Typically, these methods yield liposomes which are heterodisperse, and predominantly greater than about 1 micron (1,000 nm) in size. These initial heterodispersed suspensions can be reduced in size and size distribution by a number of known methods. One size-processing method which is suitable for large-scale production is homogenization. Here an initial heterodispersed liposome preparation is pumped under high pressure through a small orifice or reaction tank. The suspension is usually cycled through the reaction tank until a desired average size of liposome particles is achieved. A limitation of this method is that the liposome size distribution is typically quite broad and variable, depending on a number of process variables, such as pressure, number of homogenization cycles, and internal temperature. Also, the processed fluid tends to pick up metal and oil contaminants from the homogenizer pump, and may be further contaminated by residual chemical agents used to sterilize the pump seals.
Sonication, or ultrasonic irradiation, is another method that is used for reducing liposome sizes by shearing, and is especially useful for preparing SUVs. The processing capacity of this method is quite limited, since long-term sonication of relatively small volumes is required. Also, localized heat build-up during sonication can lead to peroxidative damage to the lipids, and sonic probes shed titanium particles which are potentially quite toxic in vivo.
A third general size-processing method known in the prior art is based on liposome extrusion through uniform pore-size polycarbonate membranes (Szoka 1978). This procedure has advantages over homogenization and sonication methods in that several membrane pore sizes are available for producing liposomes in different selected size ranges. In addition, the size distribution of the liposomes can be made quite narrow, particularly by cycling the material through the selected-size filter several times. Nonetheless, the membrane extrusion method has limitations in large-scale processing, including problems of membrane clogging, membrane fragility, and relatively slow throughput
Co-owned U.S. Pat. No. 4,737,323 for "Liposome Extrusion Method" describes a liposome sizing method in which heterogeneous-size liposomes are sized by extrusion through an asymmetric ceramic filter. This method allows greater throughput rates, and avoids problems of clogging since high extrusion pressure and reverse-direction flow can be employed. However, like the membrane extrusion method, the filter-extrusion method requires post-liposome formation sizing. Further, the method may be limited where uniform-size SUVs are desired.
In none of the methods mentioned above, are liposomes with a narrow, symmetrical size distribution produced.
It is a general object of the invention to provide an improved method of preparing uniform size liposomes having an mean diameter less than about 300 nm, without requiring post-liposome formation extrusion or other sizing procedures.
Another object is to provide such a method which can be used to produce uniform-size liposomes having a selected mean diameter between about 30-300 nm.
Still another object of the invention is to provide such a method which can be practiced to achieve relatively high encapsulation rates, and in which loss of non-encapsulated material is avoided.
Still another object of the invention is to provide a novel liposome preparation having a narrow, substantially symmetrical size distribution of liposomes with a selected mean diameter of between about 30-300 mm.
The invention includes, in one aspect, a method of forming a suspension of liposomes having a substantially uniform size distribution. There is first formed a mixture of vesicle-forming lipids in a single-phase solvent system containing a water-miscible lipid solvent and water. The water:solvent ratio of the mixture is raised to a point at which lipid assembly first occurs, as evidenced by the formation of microscopically visible, amorphous lipid structures. The water:solvent ratio of the mixture is then increased, under conditions which maintain the volume of the mixture substantially constant, until uniform-size liposomes are produced.
According to another aspect of the invention, the average liposome size which is produced can vary from about 30-300 nm, according to lipid composition and ionic strength of the mixture during liposome formation. By way of example, SUVs are formed with neutral lipid components, and with lipid components containing 5-10 mole percent negatively charged phospholipid at low ionic strength. Liposomes with average sizes about 250 nm are formed with lipid components containing 5-10 mole percent negatively charged phospholipid at higher ionic strength.
In one preferred embodiment of the method, the water:solvent ratio is raised in a reverse osmosis system in which solvent and water are removed by reverse osmosis, and an aqueous medium is added at a rate which balances solvent/water loss.
In another embodiment, the ratio of water:solvent in the mixture is raised in a solvent evaporation system in which solvent is preferentially evaporated, under pressure and temperature conditions which allow for removal of the solvent, while aqueous medium is introduced at a rate that balances the volume loss by evaporation.
The invention also includes a unique method for producing SUVs without high shear down-sizing of previously formed liposomes.
In another aspect, the invention includes a suspension of liposomes having a mean diameter in a selected size range between about 30-300 nm, and a narrow, substantially symmetrical size distribution.
These and other objects and features of the invention will become more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.
FIG. 1 is a schematic drawing of a reverse osmosis system used in practicing the present invention according to one embodiment;
FIG. 2 is a flow diagram of the steps used in practicing the method of the invention using reverse osmosis;
FIG. 3 is a graph of filtration rate (left ordinate) and calculated ethanol concentration (right ordinate), both plotted as a function of filtration time, in a method designed for preparation of liposomes having an average size of about 250 nm;
FIGS. 4A-4D are reproductions of photomicrographs of a lipid/solvent/water mixture at increasing water:solvent ratios after initial lipid assembly (4A), at an intermediate stage in liposome formation characterized by heterogeneous size globular lipid structures (4B), during formation of discrete lipid bodies (4C), and after final liposome formation (4D), in the method using reverse osmosis to produce liposomes with an average size of about 250 nm;
FIG. 5 is a histogram showing the size distribution of liposomes formed in accordance with the method described with reference to FIG. 4;
FIG. 6 is a graph of filtration rate (left ordinate) and calculated ethanol concentration (right ordinate), both plotted as a function of reverse-osmosis filtration time, in a method using reverse osmosis to prepare SUVs;
FIG. 7 is a histogram showing the size distribution of liposomes formed in accordance with the method described with reference to FIG. 6;
FIG. 8 is a schematic drawing of a solvent evaporation system used in practicing another embodiment of the invention; and
FIG. 9 is a flow diagram of the steps used in practicing the invention using a solvent evaporation system.
The lipid/solvent/water mixture formed in practicing the invention is composed of vesicle-forming lipids, a water-miscible lipid solvent, an aqueous medium, which preferably includes charged solute components. The mixture is brought to a water:solvent ratio at which formation or assembly of amorphous lipid structures first occurs.
The vesicle-forming lipids in the mixture generally include neutral and negatively charged phospholipids, such as phosphatidylcholine (PC) and phosphatidylglycerol (PG). The lipids may also include sterol lipids, such as cholesterol, and/or glycolipids, such phosphatidylinositol, gangliosides, and the like. A variety of lipids having selected acyl chain compositions are commercially available or may be obtained by standard lipid isolation procedures.
One factor in the choice of lipid components in the mixture is the size-effect of charged lipid species. For example, egg PC (with no charged lipid) produces uniform-size liposomes having a mean diameter of about 30-60 nm. By contrast, a lipid composition containing egg PC and 5% egg PG produces a liposome mean diameter which is dependent on ionic strength (Example 1 and 2).
The water-miscible lipid solvent used in the mixture is defined herein as one which can be mixed with an aqueous medium in substantially any proportion without forming a two-phase system. Preferred solvents are small alcohols, such as ethanol, methanol, propanol, and isopropanol, dimethylsulfoxide (all suitable for reverse osmosis), and small dimethoxy and diethoxy compounds, such as dimethoxy methane and dimethoxyethane (also suitable for solvent evaporation).
The solvent may contain additional solvent components, such as chloroform, acetone, or chlorofluorocarbon solvents, which are typically added to increase lipid solubility, and are present at a sufficiently low concentrations that solvent phase separation does not occur. For example, one suitable solvent for preparing liposomes containing phospholipid and cholesterol components contains ethanol as primary solvent component and between about 10%-20% chlorofluorocarbon solvent.
As indicated above, the ionic strength of the mixture during liposome formation may determine liposome mean diameter, when charged lipid components are present. As seen in Examples 1 and 2, a relatively low ionic strength results in liposomes less than about 50 nm, whereas at a tenfold higher ionic strength, a liposome in the 200-300 nm range are produced. The ionic component of the mixture is typically provided by a salt, such as sodium or potassium chloride or phosphate salts, which is preferably added as an aqueous salt or buffer solution to the lipid solvent. Alternatively, the ionic component may include a charged compound which is to be encapsulated or entrapped in liposomes. For forming SUVs with a mean diameter of less than about 50 nm, and with charged lipid components, the ionic strength of the medium during liposome formation is typically less than about 30 mM, and preferably between about 5-20 mM. Alternatively, where neutral lipid components alone are used, the size of the liposomes is relatively independent of ionic strength.
In preparing the lipid/solvent/water mixture, the selected lipids are preferably first dissolved in the lipid solvent. The amount of lipid added is calculated to give a final lipid concentration in the mixture between 10-600 um/ml, and preferably between about 100-300 um/ml, depending on desired final lipid concentration, encapsulation efficiency, and method of solvent removal. One advantage of solvent removal by evaporation is that higher lipid concentrations (above about 300 um/ml may be employed. The lipid solution may also include lipophilic drug components which are to be entrapped in the liposomes. After dissolution of the lipid components, aqueous medium is added to a final water:solvent ratio at which lipid assembly first occurs. The aqueous medium used in forming the final lipid/solvent/water mixture may include salts or other ionic species and water-soluble drug compounds which are to be encapsulated in the liposomes.
The aqueous medium may be added to the lipid/solvent solution by dilution and/or under conditions in which addition of aqueous medium is balanced by removal of solvent, i.e., where the volume of the medium is substantially constant. The procedure described in Examples 1 and 2 is illustrative. Here an initial lipid in ethanol solution is diluted with distilled water to a final water:solvent volume ratio of about 1:9. Additional aqueous medium is then added in a reverse osmosis system (described in Section B below) by addition of a buffer containing the desired salt concentration, under conditions in which the volume of the mixture is maintained substantially constant, i.e., where addition of aqueous medium is balanced by removal of solvent and water.
As the water:solvent volume ratio of the mixture is increased, the mixture typically becomes translucent. With continued replacement of solvent by water (or dilution with water), lipid assembly begins to occur, as evidenced by the appearance of large vesicular structures as well as amorphous lipid bodies (as observed by light microscopy). In the case of ethanol, the solvent ratio at which lipids first form or assemble is typically between about 40%-55%, depending on lipid concentration and percent charged lipid components. Experiments conducted in support of the present invention show that the lipid structure formation occurs at about 56% ethanol for uncharged lipid components, and falls to about 40% ethanol as the percent negatively charged lipid is increased to about 30 mole percent.
In another embodiment, the lipid/solvent/mixture is brought to the desired water:solvent volume ratio by preferential solvent removal under pressure and temperature conditions which allow for removal of the solvent, with addition of aqueous medium to balance solvent loss. An aqueous injection system for producing the mixture is described in Section C. As with the reverse osmosis approach, the lipid solvent may be initially diluted with water or ionic solution, then carried to the desired water:solvent volume ratio under substantially constant-volume conditions.
Other methods of solvent removal, under conditions which preserve a substantially equal lipid-mixture volume, are also possible. For example, the solvent in the mixture can be removed by preferential binding to or inclusion in a solid matrix or substrate, as the total volume of the mixture is maintained by introduction of aqueous medium.
Alternatively, solvent can be removed preferentially from the mixture by contact with an organic solvent which is (a) immiscible with water, (b) miscible with the lipid solvent, and (c) itself a poor solvent for lipid. As an example, a lipid mixture of containing lipid in dimethylsulfoxide (DMSO) and water can be gradually depleted of DMSO by contact with a selected fluorochlorocarbon solvent, having a low solubility for the vesicle-forming lipids in the mixture. Solvent depletion is balanced in such a two-phase system by addition of aqueous medium to maintain the aqueous-phase volume substantially constant.
FIG. 1 shows a reverse osmosis (RO) system 10 designed for solvent exchange in a liposome preparation method. The system includes a holding tank 12 and a vessel 14 which feeds aqueous medium to the tank, at a controlled rate, via a pump 16. In a specific embodiment of the invention, where the volume of the mixture in the tank is maintained at about 1 liter, the pump is operated to supply medium to the tank at between about 5-200 ml/min, preferably 20-80 ml/min, and the pumping rate is preferably controlled to match the rate of removal of liquid from the tank by RO filtration.
A crossflow RO filter 18 is connected to the tank through a high pressure pump 20 which circulates the fluid in the tank in the direction shown. The speed of the pump is adjustable to regulate the rate of fluid flow through the filter. The flow rate is typically set to about 80% of maximum. A valve 24 is adjustable to control the pressure within the filtration device. Typically the filtration pressure is between about 400-600 psi.
Filter 18 is selected on the basis of ability to pass the solvent(s) in the lipid/solvent/water mixture. RO filters designed for passage of a variety of small, water-miscible solvents are commercially available, such as from Millipore Corporation (Bedford, Mass.).
In operation, a given volume of lipid/solvent or lipid/solvent/water mixture is added to the tank. In a preferred embodiment, the water:solvent ratio in the initial mixture is substantially less than that at which lipid assembly first occurs. That is, the RO system is used to raise the water:solvent ratio to the lipid assembly point, as well as during liposome formation following initial lipid assembly, under constant-volume conditions.
The aqueous medium stored in vessel 14 preferably contains larger molecular weight solute molecules to be encapsulated in the liposomes, and salt or other ionic species added to control liposome size. If the compound to be encapsulated is contained in the first portion of aqueous medium, the total volume of the first portion of aqueous medium preferably should be no greater than that required to bring the mixture in the tank to the point of lipid assembly. In the method illustrated in Examples 1 and 2, where the first aqueous volume contains the ionic species in the mixture, but not drug solute molecules, the first aqueous medium and the initial mixture in the tank both have the same 1 liter volume. Four additional volumes of distilled water are added subsequently, to remove all but residual amounts of the solvent from the liposome preparation.
FIG. 2 is a flow diagram of the processing steps in the RO method. The reverse osmosis step in the diagram involves circulating the tank mixture under pressure across an RO membrane, with addition of aqueous medium from vessel 14 to balance solvent/water RO filtrate loss. As the water:solvent ratio in the tank is raised, the mixture will reach that water:solvent ratio at which lipid assembly first occurs, i.e., the lipid/solvent/water mixture described in Section A will be formed. With continued solvent exchange, the mixture passes through the stage where smaller lipid aggregates are observed, followed by a final reformation producing uniform-size liposomes having the desired mean diameter. After final liposome formation, the solvent is conveniently removed by continued RO, with addition of several volumes of distilled water.
FIG. 3 shows the course of solvent exchange in the liposome-preparation method described in Example 1. Retentate fractions were collected every minute. Flow rate was determined during the course of the method. The filtrate rate, expressed in g/min (left ordinate) is shown in open circles in the figure. Between tubes 6 and 15 (tubes numbered consecutively by time of collection), the appearance of the mixture changed from clear to translucent, but with no indication of liposome formation. The flow rate curve shows a sharp drop at about 16-17 minutes, indicating initial formation of lipid structures, and tubes 16 and 17 showed large lipid aggregates (FIG. 4A). From sample 16 to sample 19, flow rate was substantially constant, as the large lipid structures showed a gradual reduction in size (FIG. 4B). At tube 24, the lipid structures included a mixture of smaller and medium-size vesicles (4C), and by tube 30, the lipid structures had the appearance of the final uniform-size liposomes seen at the end of the solvent exchange (FIG. 4D).
The dotted line in FIG. 3 shows the ethanol concentration of the collected fractions, calculated on the basis of theoretical dilution in a constant-volume RO system (left ordinate). The first liter of aqueous volume added was supplied as a 158 mM (0.9 M) NaCl solution. At sample 16, when lipid assembly first appeared, about 600 ml of the aqueous medium had been added to the tank, producing a salt concentration of about 95 mM, and an ethanol concentration of about 50%. After the entire 1 liter volume was added (sample 31) an additional 4 liters of distilled water were added, producing a final ethanol concentration of less than 1%. FIG. 5 shows the size distribution of the liposomes formed in the Example 1 method. The size range is from about 110-340 nm and the average size, about 258 nm. As seen, the size distribution of the vesicles is substantially symmetrical about the mean particle size, in contrast to the size distribution of liposomes prepared by liposome sizing methods which involve shear forces on pre-formed liposomes.
As indicated above, one aspect of the invention is the ability to control average liposome size, by varying the proportion of charged lipid components and/or ionic strength. The effect of ionic strength can be seen from the RO method described in Example 2. This example is identical to the one in Example 1, except that the ionic strength of the first wash solution is only one-tenth as great, i.e., about 15 mM. FIG. 6 shows the change in flow rate (left ordinate) and calculated ethanol concentration (right ordinate). Flow rate was measured by change in filtrate weight over time. The curves are similar to those shown in FIG. 3. The histogram of liposome sizes, seen in FIG. 7, shows a narrow, substantially symmetrical distribution of sizes between about 30-50 nm, with an average size of about 33 nm.
The lipid mixtures in Examples 1 and 2 both contained 95% egg PC and 5% egg PG, with buffers of varying ionic strengths. The RO method has also been applied to uncharged lipid compositions, e.g., 100% egg PC. The liposomes formed were uniformly sized SUVs, with sizes between about 30-50 nm. Little effect of ionic strength was observed with uncharged lipids.
FIG. 8 shows a solvent evaporation system 50 designed for solvent exchange according to another embodiment of the invention. The system includes a tank 52 where liposome formation occurs, and a vessel 54 which feeds the aqueous medium to the tank, at a controlled rate, through a pump or valve 56. The pump or valve is adjusted to supply medium to the tank at a rate which balances loss of solvent from the tank.
The reduced pressure in the tank, typically below 1 atm, is produced by vacuum pump 58 which is connected to the tank through a valve 60 used to control pressure. The vacuum preferentially removes solvent in the solvent/water mixture, and this solvent is recovered in a condenser 62. The solvent can also be removed by raising the solution temperature.
As in the RO system, the preferred mixture in the initial stage of operation is a lipid/solvent/water system having a relatively low water:solvent ratio, e.g., 1:10 or less. Thus, the approach to the initial lipid assembly point, as well as the stage between first lipid assembly and uniform-size liposome formation, occurs under substantially constant-volume conditions. The aqueous medium supplied in the method are substantially equivalent to those which would be selected for the RO system. The method yields substantially uniform-size liposomes with a beam diameter value less than about 300 nm.
FIG. 9 is a flow diagram of the preferred processing steps in the solvent evaporation method. The scheme parallels that used in the RO system. In particular, solvent replacement by evaporation is used to bring the initial mixture to the point of initial lipid assembly, and to raise the water:solvent ratio until uniform-size liposomes form, both under constant volume conditions. Final solvent removal after liposome formation is also performed in the same system.
The uniform-size liposomes may be readily sterilized by passage through a sterilizing membrane having a particle discrimination size of about 200 nm, such as conventional 220 nm depth or membrane filter.
Where liposomes are formulated to contain an entrapped drug, for use in parenteral drug administration, it is often desirable to further process the sized liposomes to remove free drug, i.e., drug present in the bulk aqueous phase of the suspension. Several methods are available for removing free drug from a liposome suspension. The sized liposome suspension can be concentrated by ultrafiltration, then resuspending the concentrated liposomes in a drug-free replacement medium. Alternatively, gel filtration can be used to separate larger liposome particles from solute (free drug) molecules. Ion-exchange chromatography may provide an efficient method of free drug removal, in instances where a suitable drug-binding resin can be identified. One preferred method of free drug removal is by diafiltration, using a conventional hollow fiber or stacked filter device, which preferably has a molecular weight cutoff of between about 10,000-100,000 daltons.
Sized liposome suspensions prepared according to the invention are useful in liposome therapeutic compositions in which controlled sizes less than about 300 nm are desired. One important class of compositions includes drug-containing liposomes for parenteral drug administration. As noted above, liposomal drug-delivery systems have been developed and tested with a wide range of water-soluble and lipid-soluble drugs. Liposomes having a 100 to 300 nm size range are generally preferred to larger-size liposomes, as indicated above, because of ease of sterilization, improved biodistribution, and less tendency to aggregate on storage.
SUVs formed in accordance with the invention are useful in therapeutic applications which involve tumor targeting or infiltration into hepatic cell liver sites. An advantage of SUVs in ophthalmic liposome applications is greater optical clarity. SUVs are also used for producing larger, high-encapsulation liposomes by freeze-thaw methods.
From the above, it can be appreciated that the present invention offers a number of advantages over prior art liposome-sizing methods. The constant-volume processing method is unique in its ability to produce uniform-size liposomes, without the requirement for extrusion or other additional liposome sizing steps. This feature is due at least in part to the substantially constant solvent/water volume during solvent exchange, which maintains a uniform lipid environment at all stages of liposome formation, and avoids localized lipid dilution effects. This contrasts with earlier-proposed methods in which the water:solvent ratio in a lipid/solvent/water mixture is raised by dilution with water, e.g., as disclosed in EP Patent Application 0,158,441 for "Liposome-Forming Composition", where formation of relatively heterogeneous-size liposomes is observed. The present method also provides for immediate solvent removal, thus lessening encapsulation loss. In addition, the liposomes formed have a significantly more symmetrical size distribution about the mean particle size than has been observed for liposome sizes by prior art methods.
In two preferred processing systems, solvent exchange is carried out under conditions where solvent molecules only are exchanged, and solute molecules, including ionic species, are retained in the mixture. Inherent in these two systems is a uniform-environment solute concentration during liposome formation, since localized solute dilution effects are avoided. Solute retention also minimizes problems associated with solvent recovery and loss of non-encapsulated water-soluble drugs. Since the solute compound is neither lost nor diluted during liposome formation, higher encapsulation efficiencies are possible.
The ability to selectively vary the average size of liposomes, according to lipid composition and/or ionic strength, is another useful feature of the invention. One selected size range, between about 100-300 nm, is advantageous for a variety of parenteral uses, as discussed.
Finally, the invention provides a unique method for forming SUVs, having selected sizes between about 30-80 nm, without shearing-energy input, such as by prolonged sonication or homogenization. Problems of sample contamination, scale-up, oxidative degradation, and extended processing time associated with sonication and homogenization are avoided or minimized. Preliminary studies conducted in support of the invention also indicate that SUVs formed by the present method may have greater size stability on long-term storage than SUVs formed by mechanical shearing.
The following examples illustrate both use and results achievable with the method of the invention, but are in no way intended to limit the scope of the invention.
Egg phosphatidylcholine (egg PC) was obtained from Lipoid KG, Federal Republic of Germany and egg phosphatidylglycerol (egg PG) was obtained from Avanti Lipids (Birmingham, Ala.). Reverse osmosis membranes, #SK2P473E5, were obtained from Millipore Corp (Bedford, Mass.). A Prolab reverse osmosis (RO) filtration apparatus was obtained from Millipore, Model #MSDPROLAB.
Egg PC (38 g) and egg PC (2 g) were dissolved in 473 ml 100% ethanol in a 1 liter flask. After addition of 100 ml distilled water, with stirring, the lipid/ethanol/water mixture was brought to 1 liter with ethanol. The resulting mixture was approximately 50 umole/ml lipid in 90% ethanol.
The mixture was placed in the processing tank of a Prolab filtration apparatus for RO filtration. The RO filter was flushed with an approximately 90% ethanol solution prior to use. The system was run at 80% crossflow with 500 psi backpressure.
NaCl (9 g) was dissolved in 1 liter of distilled water, and this solution was used as the first aqueous medium, for replacement of ethanol and water lost by RO filtration. Subsequent medium additions were with 4 liters of distilled water. Samples from the process tank were collected every minute. Volume replacement with the five volumes of aqueous medium was complete after about 110 minutes, and the filtration rate varied from about 30 to 60 ml/min during the five-volume replacement. The final concentration of ethanol in the filtered mixture was less than 1%.
The filtrate weight was measured to determine flow rate during the filtration period. FIG. 4 (left ordinate) is a plot of flow rate vs. time (solid circles). The percentage of ethanol in the filtrate (right ordinate) shown in dotted lines in the graph was calculated from theoretical value. At an ethanol concentration corresponding to about 50% ethanol, a sharp decrease in flow rate occurred. This flow gradually increases as the ethanol in the mixture is replaced by water.
To examine the relationship between the formation of lipid structures in the mixture, and the sudden reduction in flow rate observed, samples were taken from the processing tank every minute. Those spanning this portion of the curve were examined by light microscopy. The samples were consecutively numbered by their collection time. Those examined were identified as 6, 12, 15, 16, 17, 18, 19, 20, 24, 30, and 36, where sample 16 corresponds to the peak in filtrate rate. The appearance of samples 16 (FIG. 4A), 19 (FIG. 4B), 24 (FIG. 4C), and 30 (FIG. 4D) are discussed above. No change in liposome appearance was observed after sample 30.
The size distribution of the final liposomes was examined with a dynamic light scattering instrument with Nicomp and Brookhaven correlators. FIG. 5 shows a histogram of liposome sizes. The particles have a mean diameter of 258.5 nm, with a standard deviation of 88.9 and a chi square value of 7.1. No evidence of size change in the liposomes was observed during storage.
A lipid/solvent/water mixture containing 95% egg PC, 5% egg PG in 90% ethanol was prepared as in Example 1. The ethanol in the mixture was replaced by RO filtration, as above, except that the initial 1 liter aqueous medium was 0.09% NaCl, rather than 0.9% as used in Example 1. The initial 1 liter aqueous volume was followed by 4 liters of distilled water. One-minute samples of the process solution were taken. Filtrate weight was continuously monitored and used to determine filtrate rate.
FIG. 6 (left ordinate) is a plot of filtrate rate vs. time (solid circles) in the RO procedure, where the calculated percent ethanol is also shown here in dashed line. As above, the RO filtrate rate peaks at about tube 16 or 17, corresponding to about 50% ethanol, declines sharply, then slowly increases as progressively more of the ethanol in the mixture is replaced.
The size distribution of the final liposomes was examined as above, and FIG. 7 shows a histogram of liposome sizes. The particles have a mean diameter of 33 nm, with a standard deviation of 7.1 nm and a chi square value of 6.8.
Although the invention has been described with respect to particular embodiments and uses, it will be appreciated that various changes and modifications may be made without departing from the invention.
|Cited Patent
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|Papahadjopoulos Demetrios P
|Method of encapsulating biologically active materials in lipid vesicles
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Owner name: LIPOSOME TECHNOLOGY, INC., 410 SOUTH STATE STREET,
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Owner name: LIPOSOME TECHNOLOGY, INC., A CORP. OF DE,DELAWARE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TENZEL, RENEE A.;AITCHESON, DAVID F.;REEL/FRAME:004900/0332
Effective date: 19880517
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|Sep 8, 1998
|Fee payment
Year of fee payment: 8
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Year of fee payment: 12


text:
Operating Procedure For Cement Mill
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text:
Shane Co.
Round Amethyst, Round Garnet, and Round Smoky Quartz Necklace (24")
Description & Specifications
This stunning and unique necklace is crafted of quality sterling silver, measures 24 inches long with an additional two inch chain, and displays square link accents complete with three amazing gemstone types. The gemstones alternate in design and include four round purple amethysts (approx. 4.48 carats TW), three round red garnets (approx. 4.89 carats TW), and three round smoky quartz (approx. 3.40 carats TW). The total gem weight is approximately 12.77 carats.
Item Number: 41072031
Item Number: 41072031
- *Total Carat Weight12 3/4 ct. t.g.w.
- *Clasp TypeSpring
- *Metal FinishPolished
- Metal TypeSterling Silver
- Adjustable ChainYes
- Stone TypeGemstone
- Stone ShapeRound
- Semi Precious StonesAmethyst


text:
I can't stop thinking about Aleppo.
Whilst things are happening there that I can't even read about or hear about without feeling sick….I'm in the camps in Greece, meeting men, women and children who, when I ask them where they're from, they look down at the floor, and quietly tell me,
What do I even say in response to that?
I'm so sorry that this is happening to your city?
I'm so sorry for the loss of your home, and so many of the people you love.
I'm so sorry that you were forced to leave to save your life.
I'm so sorry that you now live in a tent in an abandoned battery chicken factory.
I'm so sorry that although you're out of Aleppo, you're still stuck in a nightmare.
I'm so sorry that so many stood by and watched.
But I don't say that…because before I can, they look up at me and smile.
They invite me into their tents for tea.
They make me falafel in front of their makeshift homes.
They play music.
They dance.
They sing.
Despite the pain…they laugh.
I'm so grateful to be here meeting such incredible people and I'm so determined to learn from this ultimate resilience and strength.
We're here installing wifi, sustainably connecting thousands of people with their loved ones this Christmas…wherever in the world they may be. Hopefully not still in Aleppo.
Please please please if you can, donate even the tiniest amount to our efforts here:


text:
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