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Staff Writer
SAN DIEGO -- The Chargers not long ago had a promotion called"Paint the Q Blue," the intent being to fill Qualcomm Stadium withfans wearing the team's dominant color.
Raiders fans pulled a major graffiti act Saturday afternoon,turning those very stands decidedly black.
For years, they have been well represented when their team comes to town to play the Chargers, but perhaps never to the degree they were Saturday. The Chargers estimated they had sold about 25,000 tickets to Raiders fans, yet clearly more than half of the crowd of 67,349 were partial to an Oakland side that prevailed 13-6.
"It's crazy," said defensive end Marcellus Wiley, playing his first year with the Chargers. "I bought 130 tickets, and I still didn't hear that many Chargers fans. They came down from L.A. I'm from L.A., so I know how much support and enthusiasm they have for the Raiders even though they moved (to Oakland)."
It was the third-largest home crowd in Chargers' history. But it provided little home-field advantage for the hosts. The Raiders, meantime, thrived on the boisterous backing they received almost 500 miles from home.
"It was great," said Raiders linebacker William Thomas, who had two interceptions. "It seems like we have our own stadium here."
Jerry Rice has played here before with the 49ers, but this was his first visit with the Raiders. The future Hall of Famer said he has never seen anything like this before.
"The guys told me it was going to be weird because a majority of the fans in the stadium would be Raiders fans," said Rice, who scored the game's only touchdown. "There were a lot of Raiders diehards out there."
Security update
More than 1,100 police and security personnel worked the game. Preliminary reports are the audience was well behaved, as far as Chargers-Raiders crowds go.
Two years ago, there were so many fights and arrests that the Chargers have had to resort to calling press conferences to announce security measures for Raiders games. At last year's Raiders game, a fan was stabbed.
"We're very pleased because the number of incidents was greatly reduced over the past couple of years," said Gus Kontopuls, co-owner of Elite, a security company contracted to work Chargers home games. "Last year wasn't that bad either except for the stabbing."
Kontopuls said his staff made a larger number of "contacts," which contributed to the decrease in "incidents." He described a contact as intervention at the first sign of trouble. Several people were turned away at the gate, he said, for carrying prohibited items or being intoxicated.
"And a lot of people left voluntarily," Kontopuls said. "When they saw us patting people down in front of them, they turned around and left."
One fan wearing a Raiders jersey was John Souza of Vista. He recently moved here from Oakland.
"The real Raiders fans aren't bad guys," he said. "The ones up in Oakland don't act like a lot of the ones down here who are from L.A. But it was pretty tame out there."
Further review
Several players pleaded with Chargers coach Mike Riley to challenge the call when officials ruled Curtis Conway didn't get both feet in bounds on a diving catch in the third quarter that would have netted about 40 yards. Riley elected not to risk losing a timeout. But the Chargers nevertheless had to spend a timeout before taking their next snap because the play clock was set to expire.
Injury update
The Chargers' depleted secondary took another hit on the game's opening drive when Davis Sanchez, starting at left cornerback for the injured Tay Cody, suffered an injury to his lower back and missed the rest of the game.
Quick hits
A member of the chain crew apparently suffered a heart attack.The game was delayed for about 15 minutes just before halftimewhile medical personnel tended to Carl Robbins, near the Chargers'bench. He was taken to Kaiser Hospital. Robbins is an El Cajonresident. … The Chargers' Marcellus Wiley had two sacks toestablish a new career high with 12 for the season. He also tookover the AFC lead from the New York Jets' John Abraham (11). … TheRaiders' Tim Brown lost a fumble on a punt return one week afterrunning one back for a touchdown. Brown took over punt returnduties last week after the Raiders cut David Dunn. … The Chargerswere held without a touchdown for the first time this season andhave now gone six quarters without reaching the end zone. … Theloss clinched the Chargers' sixth straight losing season since thefiring of head coach Bobby Ross, who didn't have a single losingseason in five years here. … Tyrone Wheatley did not play for theRaiders. Oakland coach Jon Gruden said the running back is healthyand called it a "coach's decision."


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Written on: 20/06/2005 by babrahams (130 reviews written)
Good Points
A good cosy typically Lancashire pub with beams, fireplaces and an excellent restaurant attached.
Bad Points
General Comments
The Roebuck in Strinesdale, Saddleworth is just a lovely place to go, whether you just want a drink or a full sit down meal. The atmosphere is cosy and the menu is extensive. You can go for a snack or go into the restaurant and have a full four courses. The food is typically English but with some variation, with plenty of specials to choose from. Prices are good, and portions are big, so you will not go hungry. Just a nice place to go to. Oh and the views are stunning!
As rated by our community of reviewers
" Great Food. Excellent location. Terrible staff. " Read More
" Excellent " Read More
" Fantastic Value! " Read More
" Very dissapointing " Read More
" Excellent service and lovely food " Read More

subset: commoncrawl


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Touch of Spice is a welcoming and inviting restaurant in Worthing, providing a delicious and enjoyable dining experience to locals and visitors alike.
The restaurant serves top quality Indian and Bangladeshi cuisine and the restaurant menu includes a host of classic favourites cooked using authentic recipes and techniques.
As well as all the favourites, the chef lists a great range of specials to choose from, including the mild Butter Chicken, cooked off the bone with coconut and butter in a creamy sauce. A favourite for those looking for something hot is the Lamb Jalfrezi, cooked with freshly ground spices in a thick sauce, garnished with strips of ginger and fresh coriander.


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EU watchdog placed at the heart of credit rating agency supervision
The latest amendments to the rules regulating credit rating agencies (CRAs) were approved by Parliament on Wednesday. These changes were needed to effectively entrust ESMA with the direct supervision of the agencies. MEPs, with Member State support, empowered ESMA, rather than the Commission, to impose fines on CRAs.
European Securities and Markets Authority (ESMA) to directly supervise agencies by July 2011
ESMA empowered to make dawn raids, impose fines, and ensure agencies evaluate the accuracy of their past ratings
All credit rating agencies to be checked by July 2014
The amendments were approved with 611 votes in favour, 15 against and 26 abstentions.
Fining power
The Commission's initial proposal argued that the Commission itself was best placed to impose fines, upon a recommendation from ESMA. However, the final text agreed in negotiations and approved by Parliament gives this role to ESMA. A range of fines, reflecting the type of infringement, the size of the CRA, and possible aggravating or attenuating conditions, is laid down in the rules. ESMA will be able to impose fines of up to 20% of a CRA's turnover for the previous year.
Stronger investigative powers
The new rules will allow ESMA to conduct "dawn raids" (unannounced checks), at the premises of a CRA. At Parliament's insistence, ESMA is also specifically responsible for ensuring that CRAs comply with their "back testing" obligation, a task that involves comparing performance predictions for a rated financial instrument with its actual performance. Finally, ESMA is given a mandate to carry out checks on all CRAs by 2014.
Competition, transparency and dependence issues
Parliament had initially pushed to facilitate access to information for CRAs wishing to produce unsolicited ratings on the grounds that this would increase competition, allow for more transparency and give investors more information on which to base their decisions. This idea was dropped because Member States were reluctant to accept it, but the text still asks the Commission to table legislative proposals to this end. This is set to become a key issue on which Parliament is expected to focus on when further changes to this regulation are hammered out in the latter part of 2011.
Next steps
The Council will now need to officially approve the text adopted today. Parliament's Economic Affairs Committee has meanwhile begun working on the next financial supervision reform, and is to set out its priorities in a paper likely to be approved in February.


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Song of the Day #567
Song of the Day: I'm in the Mood for Love, music by Jimmy McHugh, lyrics by Dorothy Fields, is a classic of the standard songbook. Originally from the 1935 film, "Every Night at Eight" (okay, okay, another film song for good measure!), it has been recorded by so many vocalists, including Barbra Streisand, Jamiroquai, and Rod Stewart. And it has also been recorded in different forms... as we'll see tomorrow.


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Answers to Your Most Frequently Asked Questions
Cosmetic Surgery FAQ Long Island
Nearly 8.5 million Americans underwent cosmetic procedures to improve their appearance last year. If you are one of the many individuals considering a cosmetic change, you probably share similar questions as those I recently received from my readers:
Q: Dear Dr. Greenberg: My teen-age daughter is extremely self-conscious about her nose. At what age can she consider a nose job? — Stacey, Woodbury
A: Dear Stacey: Wait until your daughter is about 16 years old. A nose job (rhinoplasty) performed on teenagers and young adults is often very beneficial to their social development and self confidence. However, a rhinoplasty procedure is generally avoided in children younger than 16, as there are major growth centers in the nose that affect the growth of the face.
Q: Dear Dr. Greenberg: I am a 34 year old mother of four children who can't lose her large thighs no matter how hard I exercise. I have heard of a new technique called power-assisted liposuction. Would that work for me? How long do I have to take off from both the gym and work? — Mary, Garden City.
A: Dear Mary: Liposuction is one of the most common and safest cosmetic surgical procedures. Several types of liposuction now exist which provide outstanding results. Power assisted liposuction is one of the newest techniques. I use power-assisted liposuction for those areas which are typically more difficult, or when I need to remove larger amounts of fat. The down time after liposuction is only a few days, and you can return to the gym in about three weeks.
Q: Dear Dr. Greenberg: I am 48 years old. Can you tell me know what the best methods are for getting rid of the lines in my face and forehead without getting a face lift? — Leslie, East Islip.
A: Dear Leslie: Many non-invasive methods are now available which help both the fine lines and the deeper wrinkles of the face. Botox, a very well accepted treatment, is FDA approved and has a proven multi-year track record as safe and effective. It works well to eliminate the forehead and crow's feet wrinkles. Collagen or fat transfers work well for the deeper laugh lines. IPL Photo Rejuvenation is another advanced technique that combats the effects of aging in a soft, gentle way. By stimulating collagen production, it softens the appearance of aging skin. Fine lines, wrinkle, pigmentations and the redness associated with rosacea are dramatically reduced. I also encourage good skin care regimens and light facial peels to eliminate the signs of aging. Most of the treatments I've described are quick procedures that can be performed during a lunch hour.
Q: Dear Dr. Greenberg: I am 21 years old and I have always had very small breasts. What types of breast implants are available and how safe are they? — Janet, Old Brookville.
A: Dear Janet: Breast augmentation is more common than ever and is an extremely popular procedure. The implants that are used in most patients are filled with saline (salt water) and are perfectly safe. There are several types of saline implants which are now available that allow us to obtain the absolute most natural results possible. I believe that the specific implant shape and type should be individualized to the patient's body and size.
Q: Dear Dr. Greenberg: I have 3 children and I am 48 years old. My abdomen has extra skin and fat. What is the best way to get back my old tummy? — Margaret, Dix Hills
A: Dear Margaret: A full tummy tuck (abdominoplasty) or a mini tummy tuck is probably what is needed to remove both the extra skin and fat. This procedure also tightens the abdominal wall muscles to restore your former, more youthful stomach. Results are immediate: the abdomen is actually flat as soon as this procedure is performed. I often combine some liposuction along with the tummy tuck to get even better overall results.
Get in Touch
(516) 364-4200
Greenberg Cosmetic Surgery Manhattan Office
45 E 72nd St, Ste 1-C
New York, NY 10021(212) 319-4999
Woodbury Office
160 Crossways Park Dr
Woodbury, NY 11797(516) 364-4200
Southampton Office
365 County Rd 39A, Ste 7
Southampton, NY 11968(631) 287-4999
Boca Raton Office
1599 NW 9th Avenue
Boca Raton, FL 33486(561) 208-1080
45 E 72nd St, Ste 1-C
New York, NY 10021(212) 319-4999
Woodbury Office
160 Crossways Park Dr
Woodbury, NY 11797(516) 364-4200
Southampton Office
365 County Rd 39A, Ste 7
Southampton, NY 11968(631) 287-4999
Boca Raton Office
1599 NW 9th Avenue
Boca Raton, FL 33486(561) 208-1080


text: Paper – Copyright and Innovation: The Untold Storyby Sabrina I. Pacifici on Jul 14, 2012 Copyright and Innovation: The Untold Story by Michael A. Carrier via SSRN "Copyright has an innovation problem. Judicial decisions, private enforcement, and public dialogue ignore innovation and overemphasize the harms of copyright infringement. Just to pick one example, piracy, theft, and rogue websites were the focus of debate in connection with the PROTECT IP Act (PIPA) and Stop Online Piracy Act (SOPA). But such a debate ignores the effect of copyright law and enforcement on innovation. Even though innovation is the most important factor in economic growth, it is difficult to observe, especially in comparison to copyright infringement. This article addresses this problem. It presents the results of a groundbreaking study of 31 CEOs, company founders, and vice-presidents from technology companies, the recording industry, and venture capital firms. Based on in-depth interviews, the article offers original insights on the relationship between copyright law and innovation. It also analyzes the behavior of the record labels when confronted with the digital music revolution. And it traces innovators and investors reactions to the district courts injunction in the case involving peer-to-peer (p2p) service Napster." Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to share on Google+ (Opens in new window)


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Since she left her native Mexico 16 years ago, sometime Cinemactress Linda Christian, 33, has mastered most of the trick-or-treat rules of the international set. She racked up a lushly alimonied divorce from Tyrone Power, was the rumored reason for the divorce of British Actor Edmund Purdom. She collected some controversial jewelry from Milwaukee Playboy Robert Schlesinger, kissed the Marquis Alfonso de Portago goodbye before he raced his Ferrari off to death in last year's Mille Miglia in Italy. Linda learned a lot, but last week she proved she was still no match for Brazil's brand of sportive millionaires,...
BRAZIL: Gentlemen Jokesters
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Masters to distribute $9M in prize money
AUGUSTA, Ga. (AP) -- The Masters will distribute a record $9 million in prize money.
The tournament announced the disbursement Sunday, a few hours before the final round ended at Augusta National.
The winner will get $1.62 million, up from $1.44 million in 2013. Second place will pay $972,000, up from $864,000 a year ago.
The Masters doled out $8.102 million in 2013. Ten years ago, the total payout was a little more than $6.28 million.
- Mark Long, https://twitter.com/APMarkLong
LOW AMATEUR: Oliver Goss is the first Australian to finish as the low amateur at the Masters.
Goss, who turned 20 on Saturday, will be awarded with the Silver Cup. The low amateur must make the 36-hole cut to be eligible for the award, which began in 1952.
''I can't believe it,'' Goss said after a 3-over 75 that left him plus 10 for the tournament. ''To be the first (Australian) is really quite unbelievable. ... I've just got to step back now and have a look at the entire week and just learn as much as I can from the whole week.''
Goss plans to play the U.S. Open as an amateur in June and then decide whether to turn pro.
- Mark Long
LEGALLY BLONDE: Caroline Wozniacki is back to blonde.
The Danish tennis star, who is engaged to golfer Roy McIlroy, showed up for the final round of the Masters on Sunday with her hair dyed to its typical blonde color.
Surely by coincidence, McIlory's game improved, too. The two-time major winner shot a 3-under 69 - his best score in four rounds at Augusta National.
The 15th-ranked singles player in the world, Wozniacki spent the earlier part of the week with her hair dyed bright pink. Her colorful locks were all the talk during the Par 3 tournament Wednesday, when McIlroy said he wanted her hair to ''match the azaleas.''
Oddly enough, McIlroy spent some time in the azaleas looking for his ball during the first three rounds.
- Mark Long
MIZE'S MOMENT: Larry Mize, the 1987 Masters champion, was the first one off the tee Sunday, and just like Rory McIlroy a day earlier, he played with amateur marker Jeff Knox.
The 55-year-old Mize shot a 7-over 79 for the second straight day and finished at 16 over for the tournament. It wasn't the final score Mize was looking for after playing the first two rounds at 2 over.
''It wasn't the weekend I wanted,'' said Mize, who was playing the weekend at the Masters for the first time since 2009. ''I just struggled. As good as I putted the first two days, especially Friday, that's as bad as I've putted on the weekend. ... tough weekend.''
Knox beat McIlroy by one stroke, prompting McIlroy to say, ''He obviously knows this place.''
And though Mize struggled, he used some of the time during the round to talk about Augusta National with Knox, who owns the course record for members with a 61.
''I gave him some comments on the golf course that I heard,'' Mize said. ''I thought it might be good for him. I don't know how involved he is, but he is involved.''
- Mark Long
Masters Watch follows golf's first major of the year and all the activities surrounding the big event in Augusta, Ga., as seen by journalists from The Associated Press. It will be updated throughout the day.


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Brian Elliott Finley wrote:
I'm having various problems with the debian archive (http://http.us.debian.org/debian)Joey, Here's an update for my mirror: Old Site Name: mirror.mcs.anl.gov Updated entry: ---------------------------------------------- Site: mirror.anl.gov Aliases: n/a Type: leaf Archive-ftp: /pub/debian/Archive-architecture: alpha amd64 arm hppa i386 ia64 m68k mips mipsel powerpc s390 sparcArchive-http: /debian/ Mirrors-from: ftp.debian.org Maintainer: Brian Elliott Finley <email@example.com>, firstname.lastname@example.com Country: US United States Location: Chicago, Illinois Sponsor: Argonne National Laboratory http://www.anl.gov/ Comment: This is a complete mirror, connected by Gigabit. Cheers, -Brian Thus spake Joey Hess (email@example.com):A quick look at what Mirrors.masterlist says about mirrors carrying amd64 finds a lot of probably wrong information:* 154 mirrors listed as mirroring !amd64, but having all other arches. This is probably wrong for most of them ... it's definitly wrong for the couple Ispot-checked. * 69 mirrors listed as mirroring only amd64 and one or two other arches. Probably correct for most of them. * 65 mirrors listed as mirroring some list of archirectures that does not include amd64. Such as mirroring only i386. Probably right for many and wrong for many others. Would someone like to go through and fix all this in Mirrors.masterlist? Bonus points if you fix the archive lists to be accurate for all other arches too. Super bonus points if you don't do it by hand like I did, last time I did it. :-) (In case you're not familier with Mirrors.masterlist, it is here:http://cvs.debian.org/webwml/english/mirror/Mirrors.masterlist?rev=1.636&root=webwml&view=logAnd it controls what mirrors users are shown for their arch in d-i, amoung other things.) -- see shy jo
For example, chalcogenide:/etc/apt# apt-get update Get: 1 http://http.us.debian.org testing Release.gpg [189B] Hit http://http.us.debian.org testing Release Get: 2 http://security.debian.org testing/updates Release.gpg [189B] Get: 3 http://http.us.debian.org testing/main Packages [5180kB] Hit http://security.debian.org testing/updates Release Get: 4 http://http.us.debian.org testing/contrib Packages/DiffIndex [10.7kB] Get: 5 http://http.us.debian.org testing/non-free Packages [52.7kB] Ign http://security.debian.org testing/updates/main Packages/DiffIndex Ign http://security.debian.org testing/updates/contrib Packages/DiffIndex Ign http://security.debian.org testing/updates/non-free Packages/DiffIndex Get: 6 http://security.debian.org testing/updates/main Packages [3431B] Get: 7 http://security.debian.org testing/updates/contrib Packages [20B] Get: 8 http://security.debian.org testing/updates/non-free Packages [20B] Fetched 14.2kB in 2s (6226B/s)Failed to fetch http://http.us.debian.org/debian/dists/testing/main/binary-amd64/Packages.gz MD5Sum mismatch Failed to fetch http://http.us.debian.org/debian/dists/testing/non-free/binary-amd64/Packages.gz MD5Sum mismatch
Reading package lists... DoneW: Couldn't stat source package list http://http.us.debian.org testing/main Packages (/var/lib/apt/lists/http.us.debian.org_debian_dists_testing_main_binary-amd64_Packages) - stat (2 No such file or directory) W: Couldn't stat source package list http://http.us.debian.org testing/non-free Packages (/var/lib/apt/lists/http.us.debian.org_debian_dists_testing_non-free_binary-amd64_Packages) - stat (2 No such file or directory)
W: You may want to run apt-get update to correct these problemsE: Some index files failed to download, they have been ignored, or old ones used instead.
The MD5Sum mismatch is intermittent. Yesterday, after the update, apt simply couldn't find the packages that an upgrade required. Today, I switched to the full mirror at anl. The results were clean but seemed incomplete. I'm running testing (amd64) so I would expect more than two packages to be updated on any given day, yet the only packages that needed upgrade were tasksel and tasksel-data.
So I have three questions: 1. Is the amd64 repository at http.us.debian completely screwed up? 2. If it is, what is the plan to unscrew it?3. Is the anl-site actually a complete mirror? If so, why does and upgrade there give so few packages in testing?
Art Edwards


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Numbers 11:26
26Two of the elders, Eldad and Medad, did not go out to the Tent. Their names were on the list of elders ˻(leaders)˼, but they stayed in camp. But the Spirit also came on them, and they began prophesying in camp.
English Version for the Deaf brought to you by World Bible Translation Center.


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Kobe Bryant, in his 18th and final appearance in the NBA All-Star Game, was the subject of a pre-game tribute including two videos in Toronto on Sunday.
With the NBA calling his career brilliant, there was first a video that showed clips of some of Bryant's best moments — starting with his draft-night selection, an array of dunks, a famous lob to Shaquille O'Neal in a playoff win over Portland, some game-winning shots, his defensive intensity and even some images of his Olympic play.
And yes, there was mention of his 81-point game against Toronto, probably to the dismay of the home crowd.
After the first video, Magic Johnson took the microphone to laud Bryant even further and eventually introduce a second tape of Bryant's moments, with the retiring Los Angeles Lakers great narrating parts of it and other All-Stars offering him words of thanks.
Bryant then addressed the crowd, as they chanted his name at a deafening level. Bryant said he's "been extremely fortunate to play the game I love and be in the NBA for more than half my life."
He ended his remarks by saying, "Thank you so much — and now I've got to go get loose."
Bryant checked out of the game with just over a minute remaining, leaving to a standing ovation, hugs from players, and more chanting of his name.
The West easily defeated the East by a whopping score of 196-173.
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Ohio University Libraries will host a conversation with local author Katherine Ziff, as part of the Authors @ Alden series on Tuesday, April 16 at 7 p.m. Ziff will discuss her research and her book, Asylum on the Hill: History of a Healing Landscape. Much of Ziff's extensive research on the Athens Lunatic Asylum was done through the asylum archives at the Robert E. and Jean R. Mahn Center for Archives and Special Collections at Alden Library.
Katherine Ziff is a scholar of psychiatric history and asylums. Asylum on the Hill, published in 2012, is considered one of the most detailed accounts on the history as well as the revolutionary practices in psychiatry and patient care that took place at the Athens Lunatic Asylum.
"Stories of patients and their families, politicians, caregivers, and community illustrate how a village in the coalfields of the Hocking River Valley responded to a national impulse to provide compassionate care based on a curative landscape, exposure to the arts, outdoor exercise, useful occupation, and personal attention from a physician," wrote by Samuel T. Gladding in the forward for Asylum on the Hill.
Ohio University Libraries Curator of Manuscripts Doug McCabe, will be an active participant in the conversation. McCabe is familiar with the asylum archives through his work at the Mahn Center. McCabe will also be presenting a display of rarely seen artifacts from the Athens Asylum.
All community members are encouraged to attend this event which will take place from 7-8 p.m. at the 1951 Lounge located across from the circulation desk on the 4th floor of Alden Library. A live webcast of the event will be available from Authors @ Alden page.


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The second "Hobbit" movie, "The Desolation of Smaug," dominates DVD and Blu-ray releases this week.
"The Hobbit: The Desolation of Smaug" (Warner/Blu-ray, 2013, PG-13, two discs, $35.99; Blu-ray, DVD, digital versions; featurettes, music video). Stretching J.R.R. Tolkien's "Hobbit" novel to three very long movies has never seemed like a good idea but I must confess that this second episode feels much more vital than the first, and it moves at a better clip. And although the dragon Smaug isn't encountered until the end, he is one formidable villain (voiced perfectly by Benedict Cumberbatch).
Martin Freeman is still great as the redoubtable Bilbo Baggins, accompanying Gandalf (Ian McKellen) and 13 dwarves to reclaim their mountain, and among the dangers they encounter along the way is a particularly creepy clan of giant spiders.
If "Part 3" manages to capture as much magic as "Part 2," I'll stop complaining about the story's interminable length. (Also on DVD, $28.98; 3D/Blu-ray, $44.95; Limited Collector's Edition 3D/Blu-ray, $105.43)
"Snake & Mongoose" (Anchor Bay, 2013, PG-13, $19.98, featurette). This true story of drag racers Don "The Snake" Prudhomme and Tom "The Mongoose" McEwen, who helped legitimize their sport in the 1970s, was overshadowed last year by the big-budget Ron Howard film "Rush," which was about Formula One rivals during the same era. That film is better than this one, but "Snake & Mongoose" has a scrappy, independent vibe that proves to be an advantage, and it's certainly more family friendly. Actual drag-racing footage helps but you don't need to be a fan of the sport to enjoy this one. (Also on Blu-ray, $24.99)
"The Nut Job" (Universal/Blu-ray, 2014, PG, two discs, $34.98; Blu-ray, DVD, digital versions; deleted scenes, featurettes, storyboards, two short cartoons with characters from the film). Canadian animated feature about a squirrel stealing nuts from a store when he stumbles onto a bank heist. It's an OK cartoon for kids. Voice talent includes Will Arnett, Brendan Fraser, Jeff Dunham, Liam Neeson, Maya Rudolph and Katherine Heigl. (Also on DVD, $29.98, and 3D/Blu-ray combo, $49.98)
"Lizzie Borden Took an Ax" (Sony, 2014, not rated, $22.99). Competent Lifetime cable movie of the notorious true story of the Sunday School teacher charged with the ax murder of her father and stepmother in 1892, her lawyer claiming a woman could not commit such a crime. Christina Ricci is good as the title character and Clea Du Vall shines as her older sister, but the film is undermined by a very odd choice, an anachronistic rock-music soundtrack.
"Grudge Match" (Warner/Blu-ray, 2013, PG-13, two discs, $35.99; Blu-ray, DVD, digital versions; deleted/alternate scenes, featurettes). This tale of two aging, adversarial boxers (Sylvester Stallone, Robert De Niro) reunited in their dotage for one last match is a comedy with one funny idea and way too many vulgar gags, which likely chased away the obvious older theatrical audience. The great Alan Arkin is here, too, but he's reduced to foul-mouthed one-liners. Everyone deserves better, including the audience. Also on DVD, $28.98)
"Cavemen" (Well Go/Blu-ray, 2014; R for sex, nudity, language; $29.98). Attractive cast in a by-the-numbers sex comedy about a playboy (Skylar Astin) and his pals living in a downtown Los Angeles loft together. He's tired of one-night stands, cries on the shoulder of his best friend (Camilla Belle) and can't see that she's the one for him. (Also on DVD, $24.98)Comment on this story
"Paranormal Activity: The Marked Ones" (Paramount/Blu-ray, 2013; R for language, violence, sex, nudity, drugs; two discs, $39.99; Blu-ray, DVD, digital versions; R-rated and unrated versions; featurette). Ever notice that when sequels reach the fourth or fifth go-round, they drop the number in favor of a subtitle? Yeah, this is No. 5 in the found-footage horror film franchise, this time with a Latino twist as a high school grad tries to clear his friend of the murder of a local "witch." You can take it from there. (Also on DVD, $29.98)
"Sheriff of Contention" (Lionsgate, 2014, PG-13, $26.98, trailers). Cheapjack independent thriller has an amateurish look as it tries to blend the Western and horror genres in the tale of a serial killer stalking women alone in an Old West town.
Chris Hicks is the author of "Has Hollywood Lost Its Mind? A Parent's Guide to Movie Ratings." Website: www.hicksflicks.com
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|Publication number
|Publication type
|Application number
|Publication date
|29 Aug 2006
|Filing date
|30 Jul 2003
|Priority date
|22 Jul 1994
|Fee status
|Also published as
|Publication number
|Steven L. Bennett, Kevin Connolly, Elliott Gruskin, Ying Jiang
|Original Assignee
|United States Surgical Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (105), Non-Patent Citations (3), Referenced by (5), Classifications (33), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of application Ser. No. 09/934,639 filed Aug. 22, 2001, now abandoned, which is a continuation of U.S. application Ser. No. 09/282,724 filed Mar. 31, 1999, now U.S. Pat. No. 6,339,130, which is a continuation of application Ser. No. 08/733,683, filed on Oct. 17, 1996, now abandoned, which is a continuation-in-part of application Ser. No. 08/477,098, filed on Jun. 7, 1995, now U.S. Pat. No. 5,578,622, which is a continuation-in-part of application Ser. No. 08/278,898, filed on Jul. 22, 1994, now abandoned. The entire disclosure of application Ser. No. 08/477,098, now issued as U.S. Pat. No. 5,578,662 as well as Ser. No. 08/278,898 filed Jul. 22, 1994, now abandoned, are herein incorporated by reference.
1. Technical Field
This disclosure relates generally to bioabsorbable polymer compositions. Specifically, this disclosure relates to highly branched or star polymers derived from monomers known to form absorbable polymers. The bioabsorbable polymer compositions are particularly useful in the manufacture of absorbable surgical devices such as sutures, staples clips, anastomosis rings, bone plates and screws, matrices for the sustained and/or controlled release of pharmaceutically active ingredients, etc., fabricated at least in part therefrom.
2. Background of Related Art
Polymers and copolymers of, and surgical devices made from, lactide and/or glycolide and/or related compounds are well-known. See, e.g., U.S. Pat. Nos. 2,668,162, 2,683,136, 2,703,316, 2,758,987, 3,225,766, 3,268,486, 3,268,487, 3,297,033, 3,422,181, 3,442,871, 3,463,158, 3,468,853, 3,531,561, 3,565,869, 3,597,449, 3,620,218, 3,626,948, 3,636,956, 3,736,646, 3,739,773, 3,772,420, 3,773,919, 3,781,349, 3,784,585, 3,792,010, 3,797,499, 3,839,297, 3,846,382, 3,867,190, 3,875,937, 3,878,284, 3,896,802, 3,902,497, 3,937,223, 3,982,543, 4,033,938, 4,045,418, 4,057,537, 4,060,089, 4,137,921, 4,157,437, 4,243,775, 4,246,904, 4,273,920, 4,275,813, 4,279,249, 4,300,565, and 4,744,365, U.K. Pat. or Appln. Nos. 779,291, 1,332,505, 1,414,600, and 2,102,827, D. K. Gilding et al., "Biodegradable polymers for use in surgery-polyglycolic/poly (lactic acid) homo- and copolymers: 1," Polymer, Volume 20, pages 1459–1464 (1979), and D. F. Williams (ed.), Biocompatibility of Clinical Implant Materials, Volume II, chapter 9: "Biodegradable Polymers" (1981). All of the foregoing documents are hereby incorporated by reference.
In addition, other patents disclose surgical devices prepared from copolymers of lactide or glycolide and other monomers including caprolactone or trimethylene carbonate have been prepared. For example, U.S. Pat. No. 4,605,730 and U.S. Pat. No. 4,700,704 disclose copolymers of epsilon-caprolactone and glycolide useful in making surgical articles and particularly surgical sutures having low Young's modulus. In addition, U.S. Pat. No. 4,624,256 relates to the utilization of high molecular weight caprolactone polymers as coatings for surgical sutures, while U.S. Pat. No. 4,429,080 discloses surgical articles manufactured from triblock copolymers prepared from copolymerizing glycolide with trimethylene carbonate.
Polymers, copolymers and surgical devices made from ε-caprolactone and/or related compounds have also been described in U.S. Pat. Nos. 3,169,945, 3,912,692, 3,942,532, 4,605,730, 4,624,256, 4,643,734, 4,700,704, 4,788,979, 4,791,929, 4,994,074, 5,076,807, 5,080,665, 5,085,629 and 5,100,433.
Polymers derived in-whole or in part from dioxanone are known. Homopolymers of p-dioxanone are described, e.g., in U.S. Pat. Nos. 3,063,967; 3,063,968; 3,391,126; 3,645,941; 4,052,988; 4,440,789; and, 4,591,630. Copolymers containing units derived from p-dioxanone and one or more other monomers that are copolymerizable therewith are described, e.g., in U.S. Pat. Nos. 4,243,775; 4,300,565; 4,559,945; 4,591,630; 4,643,191; 4,549,921; 4,653,497; 4,791,929; 4,838,267; 5,007,923; 5,047,048; 4,076,807; 5,080,665; and 5,100,433 and European Patent Application Nos. 501,844 and 460,428. Most of the known dioxanone-derived homopolymers and copolymers are indicated to be useful for the fabrication of medical and surgical devices such as those previously mentioned.
The properties of the bioabsorbable polymers may differ considerably depending on the nature and amounts of the comonomers, if any, employed and/or the polymerization procedures used in preparing the polymers. Aforementioned U.S. Pat. No. 4,838,267 discloses block copolymers derived from p-dioxanone and glycolide that exhibit a high order of initial strength and compliance but lose their strength rapidly after implantation in the body. Sutures made from the copolymers are said to be particularly useful in surgical procedures, such as plastic surgery or repair of facial wounds, where it is desirable for the suture to lose its strength rapidly.
The general formula of the novel polymers described herein is:
CH2OR1—(CHOR2)—(CHOR3)—(CHOR4) . . . (CHORn)—CH2ORn+1
wherein: n equals 1 to 13, preferably 2 to 8 and most preferably 2 to 6;
R1, R2 . . . Rn+1 are the same or different and selected from the group of a hydrogen atom or (Z)m wherein Z comprises repeating units selected from the group consisting of:
wherein p is 3 to 8 and each R′ may be the same or different and are individually selected from the group consisting of hydrogen and alkyl having from 1 to 5 carbon atoms, such that at least three of said R1, R2 . . . Rn+1 groups are other than hydrogen;
m is sufficient such that the star polymer has an inherent viscosity in HFPI at 25� C. between about 0.01 and about 0.5 dl/gm, preferably from about 0.15 to about 0.3 dl/gm, and most preferably from about 0.15 to about 0.2 dl/gm; and
the m's for each (Z) group may be the same or different.
The polymers are initiated with a polyhydric alcohol. Preferred initiators are mannitol, pentaerythritol and threitol.
In a particularly useful embodiment, a bioabsorbable polymer of the foregoing general formula is provided wherein (Z) consists essentially of repeating units of the formula:
and the polymer has an inherent viscosity between about 0.05 and 0.5 dl/gram in HFIP at 25� C.
The polymers described herein are useful in the production of surgical devices. In particularly useful embodiments the polymers are used in coatings on surgical devices, such as, for example fibers used to produce sutures, meshes, woven structures, etc.
The polymers may be endcapped with an isocyanate. The isocyanate capped polymer may be cross-linked in the presence of water and/or a catalyst, such as tertiary amine catalyst. The cross-linked star polymers are useful for example as bone adhesives or bone fillers. Optionally, the polymer may be mixed with a filler such as hydroxyapatite, tricalcium phosphate, bioglass or other bioceramic prior to cross-linking to produce a bone putty or a bone-growth-inducing substance to be packed into or used in conjunction with a bone fusion implant.
Alternatively, after endcapping with an isocyanate, a charge may be chemically induced on the polymer, such as, for example by reacting a fraction of the available isocyanate groups with diethylene ethanolamine (DEAE) and then cross-linking at least a portion of the balance of the remaining available isocyanate groups to form a water-insoluble, degradable, charged particle. These charged compositions are useful for example as an agent to enhance soft tissue wound healing.
The general formula of the basic polymer in accordance with this disclosure is:
CH2OR1—(CHOR2)—(CHOR3)—(CHOR4) . . . (CHORn)—CH2ORn+1
wherein: n equals 1 to 13, preferably 2 to 8 and most preferably 2 to 6;
R1, R2 . . . Rn+1 are the same or different and selected from the group of a hydrogen atom or (Z)m wherein Z comprises repeating units selected from the group consisting of:
wherein p is 3 to 8 and each R′ may be the same or different and are individually selected from the group consisting of hydrogen and alkyl having from 1 to 5 carbon atoms, such that at least three of said R1, R2 . . . Rn+1 groups are other than hydrogen;
m is sufficient such that the star polymer has an inherent viscosity in HFIP at 25� C. between about 0.01 and about 0.5 dl/gm, preferably from about 0.15 to about 0.3 dl/gm; and most preferably from about 0.15 to about 0.2 dl/gm, and
the m's for each Z group may be the same or different.
The viscosity of the polymer, which is reflective of a number of factors including molecular weight, can be chosen to provide easier processing for different applications. Thus, for example, where the polymers are to be used for coatings or to form a bone wax, viscosities in the range of 0.15 to 0.2 dl/gm (coinciding to a molecular weight in the range of about 15,000 to about 25,000 are particularly useful. When using the polymers as a bone substitute, viscosities in the range of less than about 0.1 dl/gm (corresponding to a molecular weight of 500 to 2,000) are particularly useful.
The purified monomer(s) used to form the Z groups are preferably dried and then polymerized at temperatures ranging from about 20� C. to about 130� C., preferably above 75� C., in the presence of an organometallic catalyst such as stannous octoate, stannous chloride, diethyl zinc or zirconium acetylacetonate. The polymerization time may range from 1 to 100 hours or longer depending on the other polymerization parameters but generally polymerization times of about 12 to about 48 hours are employed. In addition, a polyhydric alcohol initiator is employed to provide a highly branched or star structure. Any polyhydric alcohol may be employed, with mannitol (C6H8(OH)6), pentaerythritol (C(CH2OH)4) threitol (C4H6(OH)4) being preferred. Generally, the amount of initiator used will range from about 0.01 to about 30 percent by weight based on the weight of the monomer. The amount of initiator employed will depend on the final properties desired in the polymer and the ultimate end use of the polymer. Thus, when preparing polymers for use as a coating, the initiator will be present in the reaction mixture in an amount from about 0.5 to about 5.0 weight percent based on the weight of the monomer. When preparing polymers for use as a bone substitute, the initiator will be present in an amount from about 15 to about 25 weight percent based on the weight of the monomer.
The polymeric chains (Z groups) may be formed using any monomer known to form a bioabsorbable polymer, however, preferably monomers of the type know as soft segments forming polymers constitute the predominant component (i.e., constitute more than 50 mole percent) of the polymeric chains. Thus, for example, the polymeric chains may be formed predominantly from ε-caprolactone, alkylene carbonates such as trimethylene carbonate; substituted alkylene carbonates such as dimethyl trimethylene carbonate (DMTMC); and/or p-dioxanone. When the polymers of this invention are used without isocyanate endcapping (as described more fully hereinafter), homo- or copolymers of DMTMC and homopolymer of p-dioxanone are preferred.
Particularly useful polymers are those wherein the Z groups consist essentially of repeating units derived from monomer having the formula:
The monomer can be prepared using known techniques such as, for example, those processes described in U.S. Pat. Nos. 2,900,345; 3,119,840; 4,070,315 and 2,142,033, the disclosures of which are incorporated by reference. A preferred method of preparing the monomer is by dehydrogenating diethylene glycol in the presence of a copper/chromium catalyst.
The monomer should be purified, preferably to at least about 98 percent purity. The monomer may be purified using any known technique such as multiple distillations and/or recrystallizations. A preferred purification process is recrystallization from ethyl acetate as described in U.S. Pat. No. 5,391,768 the disclosure of which is incorporated herein by reference.
Polydioxanone star polymers can be made by reacting p-dioxanone monomer with mannitol initiator in the presence of stannous octoate catalyst. The reaction is allowed to continue until a polydioxanne chain is bound to three or more hydroxy groups per molecule of mannitol. The resulting polydioxanone star polymer can be represented by the following formula:
where the value of x, y and z for the polydioxanone chains may be the same or different so long as the product has an inherent viscosity between about 0.01 deciliters per gram and about 0.5 deciliters per gram in hexafluoroisopropanol (HFIP) at 25� C.
Polymers of p-dioxanone are not soluble in common organic solvents. An advantage of the polymer described herein is that it is soluble in methylene chloride. Thus it is easily used as a coating.
The polymerization parameters are controlled to provide a polymer having an inherent viscosity between about 0.01 and 0.5 dl/gram in HFIP at 25� C. It is within the purview of those skilled in the art to determine the appropriate polymerization parameters to provide polymers having the desired inherent viscosity in view of the disclosure herein.
The polymers described herein can be used as an absorbable coating for surgical devices formed from using any known technique, such as, for example, extrusion, molding and/or solvent casting. The polymers can be used alone, blended with other absorbable compositions, or in combination with non-absorbable components. A wide variety of surgical articles can be coated with the polymers. These include but are not limited to clips and other fasteners, staples, sutures, pins, screws, prosthetic device, wound dressings, drug delivery devices, anastomosis rings, and other implantable devices. Fibers coated with the present polymers can be knitted or woven with other fibers, either absorbable or nonabsorbable to form meshes or fabrics.
The star polymers described herein may advantageously be endcapped with isocyanate groups.
Isocyanate endcapping can be achieved by reacting the polymer with a diisocyanate. Suitable diisocyanates include hexamethylene diisocyanate, diisocyanatolysine ethyl ester and butane diisocyanate with diisocyanatolysine ethyl ester being preferred. Diisocyanates which may lead to harmful by-products upon hydrolysis of the polymer, such as, for example, certain aromatic diisocyanates, should not be employed where the composition is intended for use within a mammalian body. While endcapping with diisocyanate is preferred, it is also contemplated that other agents having at least two reactive sites can be employed for endcapping and for facilitating cross-linking. Suitable other endcapping agents include, for example diketene acetals such as bis-vinyl-2,4,8,10-tetraoxyspiroundecane.
The conditions under which the polymer is reacted with the diisocyanate may vary widely depending on the specific polymer being end capped, the specific diisocyanate being employed, and the desired degree of end capping to be achieved. Normally, the polymer is heated to a temperature sufficient to form viscous liquid (e.g., to temperatures of about 75� C. for p-dioxanone homopolymers) and added dropwise to a solution of the diisocyanate at room temperature with stirring. The amount of diisocyanate employed can range from about 2 to about 8 moles of diisocyanate per mole of polymer. Suitable reaction times and temperatures range from about 15 minutes to 72 hours or more at temperatures ranging from about 0� C. to 250� C.
Once endcapped with isocyanate, the polymers may advantageously be cross-linked. Cross-linking is normally performed by exposing the endcapped polymer to water in the presence of a catalyst, such as a tertiary amine catalyst.
The exact reaction conditions for achieving cross-linking will vary depending on a number of factors such as the composition of the polymer, the degree of endcapping, the specific isocyanate used to end cap and the desired degree of cross-linking. Normally, the cross-linking reaction is conducted at temperatures ranging from 20� C. to about 40� C. for five minutes to about 72 hours or more. The amount of water employed will normally range from about 0.05 moles to 1 moles per mole of polymer. While water is a preferred reactant to effect cross-linking it should be understood that other compounds could also be employed either together with or instead of water. Such compounds include diethylene glycol, polyethylene glycol and diamines, such as, for example, diethylamino propanediol. Suitable catalysts for use in the cross-linking reaction include 1,4 diazobicyclo [2.2.2] octane, triethylamine, and diethylaminoethanol.
The amount of catalyst employed can range from about 0.5 grams to about 50 grams per kilogram of polymer being cross-linked.
When the composition is intended for implantation it is possible to effectuate cross-linking in situ using the water naturally present in a mammalian body or with added water.
The isocyanate endcapped polymers can also be cross-linked by the application of heat alone, or by exposing the polymer to diamine vapor. These cross-linking techniques are particularly useful when the polymers are to be used as a filament coating.
In an alternative embodiment, the isocyanate endcapped polymers described herein are admixed with a filler prior to cross-linking. While any known filler may be used, hydroxyapatite, tricalcium phosphate, bioglass or other bioceramics are the preferred fillers. Normally, from about 10 grams to about 400 grams of filler are mixed with 100 grams of polymer. Cross-linking of the polymer/filler mixture can be carried out using any of the above-described methods. The filled, cross-linked polymers are useful, for example, as a molding composition. As another example, the filled endcapped polymer (with or without crosslinking) can be packed into a bone fusion implant (e.g., fusion cage, plug, hip joint prosthesis, etc.) as a bone-growth-inducing substance. The use of such packed implants are disclosed, for example, in U.S. Pat. No. 5,026,373 the disclosure of which is incorporated herein by this reference. The filled polymers are stable for several months when kept dry. These dry mixtures will cross-link upon exposure to water without dispersing in water.
In another embodiment, an isocyanate endcapped star polymer is chemically altered to provide a desired charge on the polymer. The presence of charged groups on the polymer can enhance wound healing in either hard or soft tissue. To impart a positive charge, the endcapped polymer may be reacted with a positive charge inducing reactant. One suitable positive charge inducing reactant is diethylethanolamine which results in the presence of diethylaminoethyl (DEAE) groups on the polymer. To impart a negative charge, the endcapped polymer may be reacted with a negative charge inducing reactant. One such reactant is carboxymethanol which results in the presence of carboxymethyl (CM) groups on the polymer.
The conditions at which the charge inducing reactant is reacted with the isocyanate endcapped polymer will vary depending on the specific polymer, the degree of endcapping, the nature of the isocyanate used for endcapping and the number of charges to be provided on the polymer. Normally, from about 0.1 to about 0.5 moles of charge inducing reactant are employed per mole of isocyanate groups. The polymer is normally dissolved in a solvent and added dropwise to a solution of the charge inducing reactant. Stirring and heating to temperatures up to about 40� C. can facilitate the reaction.
It is also contemplated that the isocyanate endcapped polymer can be mixed with a material known to carry a charge to provide a charged composition which enhances wound healing. Such materials include polysaccharides modified to include charge inducing substituents such as, for example, carboxymethyl or diethylaminoethyl groups. The weight ratio of modified polysaccharide to polymer should be in the range of about 1 to about 20%, preferably about 5 to about 10%. DEAE-Sephadex is a particularly useful material to be mixed with the bioabsorbable polymers described herein.
In another embodiment, isocyanate endcapped star polymer and filler are first mixed together as disclosed hereinabove and thereafter charge inducing reactant is added to the mixture in the same manner as disclosed hereinabove. It has been found that these mixtures of isocyanate endcapped star polymer, filler and charge inducing reactant are stable for several months and more when stored under dry conditions.
It should be understood that for polymers of the embodiments having an induced charge and/or endcapped with a lysine isocyanate, any bioabsorbable polymer may be employed. Preferred bioabsorbable polymers according to this embodiment are those having the general formula:
CH2OR1—(CHOR2)—(CHOR3) . . . (CHORn)—CH2ORn+1
at least three of said R1, R2 . . . Rn+1 groups being other than hydrogen;
at least one of said Z groups being endcapped with an isocyanate; and
at least a portion of said endcapped Z groups having diethylamino ethyl group thereon.
Other suitable bioabsorbable polymers which may be endcapped with isocyanate include polyalkylene oxides containing a major amount, i.e., greater than 50 weight percent, of alkylene oxide units such as ethylene oxide units, propylene oxide units and combinations thereof and a minor amount, i.e., less than 50 weight percent, preferably less than about 20 weight percent, more preferably less than about 5 weight percent, units derived from a bioabsorbable monomer such as glycolide, lactide, glycolic acid, lactic acid, p-dioxanone, trimethylene carbonate, trimethylene dimethylene carbonate, dioxepanone, alkylene oxalates, epsilon-caprolactone, combinations of the foregoing, and the like. The polyalkylene oxides can be linear or branched random, block or graft copolymers. The polyalkylene oxides employed herein will generally be of low molecular weight, e.g., the polymer will possess a molecular weight of less than about 6,000.
It has also been discovered that novel polymers in accordance with this disclosure can serve as a substrate for is cell growth. Specifically, star polymers endcapped with lysine diisocyanate and cross-linked, with or without an induced charge, can be used as a cell growth substrate.
When being used for cell growth, the polymers described herein can also be mixed with collagen, gelatin or other growth proliferating/enhancing materials.
In yet another embodiment, the isocyanate capped star polymer is reacted with an alkylene oxide polymer. In this manner, hydrophilic pendent chains are formed from at least a portion of the isocyanate groups on the polymer. Preferably, at least a portion of the isocyanate groups remain available for cross-linking. Suitable polyalkylene oxides include polyethylene oxide, polypropylene oxide and block copolymers of polyethylene oxide and polypropylene oxide. The alkylene oxide side chains reduce cell adherence while maintaining the biodegradability of the polymer.
It is further contemplated that one or more medico-surgically useful substances, e.g., those which accelerate or beneficially modify the healing process when particles are applied to a surgical repair site, can be incorporated into surgical devices made from the materials described herein. So, for example, the surgical device can carry a therapeutic agent which will be deposited at the repair site. The therapeutic agent can be chosen for its antimicrobial properties, capability for promoting repair or reconstruction and/or new tissue growth. Antimicrobial agents such as broad spectrum antibiotic (gentamicin sulfate, erythromycin or VX glycopeptides) which are slowly released into the tissue can be applied in this manner to aid in combating clinical and sub-clinical infections in a tissue repair site. To promote repair and/or tissue growth, one or several growth promoting factors can be introduced into the sutures, e.g., fibroblast growth factor bone morphogenetic protein, epidermal growth factor, platelet derived growth factor, macrophage derived growth factor, alveolar derived growth factor, monocyte derived growth factor, magainin, and so forth. Some therapeutic indications are: glycerol and tissue or kidney plasminogen activator to cause thrombosis, superoxide dimutase to scavenge tissue damaging free radicals, tumor necrosis factor for cancer therapy or colony stimulating factor and interferon, interleukin-2 or other lymphokine to enhance the immune system. It is also contemplated that the medico-surgically useful substance may enhance blood coagulation. Thrombin is one such substance.
It is further contemplated that the isocyanate capped polyalkylene oxide polymer described above can be combined with therapeutic agents, preferably charged oxidized beads, e.g., cross-linked dextran, which are commonly employed to promote wound healing. The above mixture of hydrophilic isocyanate capped polyalkylene oxide and therapeutic agent can be reacted with any of the aboveidentified isocyanate capped star polymers prior to introduction to the wound site to form a polymer network that entraps the therapeutic agent. Upon placement of the polyalkylene oxide/isocyanate capped star polymer network in the wound, the liquid present at the wound site causes the polymer network to swell; thereby allowing delivery of the therapeutic agent through either diffusion or degradation of the polymer network.
The following non-limiting Examples illustrate the preparation of polymers in accordance with the present disclosure.
100.0 grams of purified p-dioxanone (99.5% purity) is placed in a polymerization tube. Then 0.02% (w/w) Sn(Oct)2, i.e., weight of Sn(Oct)2 to weight of polydioxanone, in diethyl ether is added to the tube and dried for two hours under vacuum at 25� C. In addition, the following amounts of the indicated initiator is added to the vessel:
Example No. Initiator Amount 1 Mannitol 1.0 gram 2 Mannitol 2.0 grams 3 Threitol 2.0 grams
Polymerization is conducted at 100� C. for 24 hours. The resulting polymer is heated to 75� C. at reduced pressure (0.5 mmHg) to remove any residual monomer or other volatile impurities. The polymers produced have the following inherent viscosities in HFIP at 25� C.:
Example No.
Inherent Viscosity
75 grams of p-dioxanone (99.5%=purity) is placed in a polymerization tube. Then, 0.015% (w/w) Sn(Oct)2, i.e., weight of Sn(Oct)2 to weight of polydioxanone, in diethyl ether is added to the tube and dried for two hours under vacuum at 25� C. In addition, the following amounts of the indicated initiator is added to the vessel:
Example No. Initiator Amount 4 Mannitol 1.0 gram 5 Mannitol 0.5 grams 6 Threitol 1.5 grams 7 Threitol 0.75 grams
Polymerization is conducted for 24 hours at 100� C. The resulting polymers are particularly useful for coatings on braided absorbable sutures.
A star copolymer of p-dioxanone and glycolide is prepared as follows: 458.3 grams of previously dried p-dioxanone, 41.7 grams of previously dried glycolide, 147.5 grams of mannitol, and 0.106 grams of stannous octoate catalyst are reacted in a N2 atmosphere under anhydrous conditions in a one liter 3 neck flask equipped with a mechanical stirrer.
The flask is heated overnight at 98� C. with stirring at 60 rpm. The mixing rate is increased to 100 rpm after about 12 hours of reaction. After 20 hours, the temperature is reduced to 90� C. The stirring rate is further increased to 200 rpm after a total of 22 hours of reaction time. After a total reaction time of about 39 hours, the material is extruded at 94��4� C. The flask is placed under vacuum for 6 hours and the polymer is post-treated by heating at 75� C. for about 63 hours. A total weight of 599.5 grams of polymer is recovered.
The product of Example 8 is useful as a bone substitute. The low viscosity absorbable polymer can be worked by hand and applied directly to a bone defect to achieve hemostasis.
The following non-limiting Examples illustrate the endcapping of polymers in accordance with this invention:
Preparation of Star Copolymer
A star copolymer of p-dioxanone and glycolide is prepared as follows: 458.3 grams of previously dried p-dioxanone, 41.7 grams of previously dried glycolide, 83.5 grams of pentaerythritol, and 0.106 grams of stannous octoate catalyst are reacted in a N2 atmosphere under anhydrous conditions in a one liter 3 neck flask equipped with a mechanical stirrer. Polymerization is conducted at 90� C. with stirring for a total reaction time of about 69 hours. The copolymer is then extruded and heated at 75� C. for 48 hours to remove vaporizable impurities.
Preparation of Lysine Diisocyanate Compound
A five 1 round bottom flask equipped with a mechanical stirrer, condenser and thermometer is dried by heating to >100� C. under nitrogen purge. After cooling the reactor is charged with 500.0 g lysine ethyl ester dihydrochloride (I) and 4000 ml 1,1,1,3,3,3-hexamethyl disilazane (II). The slurry is heated to 117� C. for 24 hours, cold and filtered through Celite to remove the silazane hydrochloride salt. After filtration excess disilazane (II) is removed under vacuum at room temperature leaving a clear light pink liquid (III). This product is purified by distillation at <50 mT. 325 ml of a light yellow liquid is obtained between 120 and 130� C. (Yield: 295 g, 48%)
A five-liter round bottom flask equipped with a mechanical stirrer, 1 liter addition funnel and thermometer is dried by heating to >100� C. under nitrogen purge. After cooling the reactor is charged with 2500 ml anhydrous ether, 245 ml triethyl amine and 317 ml of the previously obtained reaction product (III). In a separate dry flask 189 g of triphosgene is combined with 1250 ml of ether and stirred under nitrogen until a clear solution is obtained. This solution is transferred to the addition funnel and added dropwise to the solution in the flask at −20� C. After the addition is complete the reaction is allowed to warm to room temperature and stirred for 40 hrs. At the end of this time the solution is filtered to remove the TEA hydrochloride salt and placed on the rotovap to reduce the volume. A simple distillation at <200 mT results in a purified product received between 107 and 110� C. The clear, colorless liquid weights 125 g, (60% yield). The total yield is 29%.
The reaction sequence can be schematically represented as follows:
Preparation of Lysine Isocyanate Endcapped Polymer
A 500 ml round bottom flask is dried by heating under a nitrogen purge. 57.6 grams of the lysine diisocyanate prepared as described above and 28.6 grams of the star dioxanone/glycolide copolymer are added to the flask. The reactants are heated to and maintained at 60� C. for six hours. 82 grams of lysine isocyanate endcapped polymer are obtained.
A star copolymer of dioxanone and caprolactone is prepared by reacting 250 grams of p-dioxanone with 250 grams ε-caprolactone and 36 grams of mannitol in the presence of a stannous actuate catalyst at 135� C. for 72 hours. The resulting polymer is then heated at 75� C. overnight. 25 grams of the polymer is dissolved in 125 ml of methylene chloride. Hexamethylene diisocyanate (25 ml) is mixed with 50 ml of methylene chloride. The polymer solution is added dropwise to the hexamethylene diisocyanate solution with stirring. The reaction mixture is maintained at the boil with continuous stirring overnight (about 24 hours). The resulting endcapped polymer is the precipitated in hexane and recovered by decanting the solvent. Excess solvent is removed by evaporation.
A homopolymer of DMTMC is prepared by placing 500 grams DMTMC in a reactor with 14 grams of pentaerythritol initiator and 0.01 grams of stannous octoate catalyst. Polymerization is allowed to occur at 150� C. for 24 hours. The resulting polymer is heated at 90� C. and >0.5 mmHg for 48 hours to remove residual monomer and other volatile impurities.
45 grams of the DMTMC polymer is dissolved in 50 ml methylene chloride and is added dropwise to 100 grams hexamethylene diisocyanate. The mixture is stirred at room temperature for 48 hours. The resulting endcapped DMTMC polymer is washed twice with hexane and dried.
The following Example illustrates the use of the cross-linked polymers as a coating for sutures.
Five grams of the endcapped polymer of Example 1 are dissolved in 100 ml of methylene chloride. The polymer solution is applied to an absorbable mdnofilament suture. The coated suture is heated to simultaneously drive off solvent and effectuate cross-linking of the polymer coating. The monofilament coated in this manner exhibits greater in vivo strength retention compared to uncoated monofilaments of the same size and composition.
The following Examples show filled cross-linked polymers useful as a bone-putty.
Ten grams of the isocyanate endcapped polymer of Example 9 is mixed with 5 grams of hydroxyapatite. Once a substantially homogenous mixture is attained, the polymer is cross-linked by the addition of 0.5 ml of water, 1 ml of DEAE and 0.5 ml stannous octoate. As the reaction proceeds, CO2 is released, forming a moldable foam which has a puttylike consistency and can be molded by hand into a desired shape or easily packed into a bone defect.
10 grams of isocyanate endcapped star copolymer of Example 9 is mixed with 5.0 grams of hydroxyapatite until a substantially homogeneous mixture is obtained in the form of a white paste. Various formulations of bone putty are produced by adding water, stannous octoate, and diethylethanolamine to 1.0 gram of the hydroxyapatite/endcapped star copolymer paste. These formulations are presented in the following table:
of Ex. 9
in Volume
1.0 gram
1 drop
2 drops
2 drops
1.0 gram
1 drop
2 drops
3 drops
1.0 gram
1 drop
3 drops
3 drops
1.0 gram
1 drop
3 drops
2 drops
1.0 gram
1 drop
4 drops
7 drops
Each formulation hardens to provide structural support to aid in hard tissue healing. The bone putty of Examples 16–18 becomes hard to the touch in 10 minutes or less.
A modified bone putty is prepared as follows: 6.1 grams of calcium phosphate tribasic are mixed with 3.2 grams of hydroxyapatite. 15 grams of endcapped star copolymer of Example 10 are added to the calcium phosphate tribasic/hydroxyapatite mixture.
1.0 gram of the endcapped star copolymer/calcium phosphate tribasic/hydroxyapatite composition is placed into a scintillation vial. Two drops of a 2:1 diethylethanolamine/H2O mixture and 2 drops of Sn(Oct)2 catalyst solution are added to the vial. The resulting composition is placed into a tibia-bone defect, where it foams with the release of CO2, absorbs blood and hardens to provide structural support to the bone.
The following Examples show the use of the present polymer as a substrate for cell growth.
The endcapped polymer of Example 9 is mixed with various amounts of DEAE solution as set forth in the following Table:
Concentration DEAE
The polymers are coated onto one half of a 5 cm tissue culture plate and allowed to cure for two days. Mouse fibroblasts (L929) are trypsinized and seeded onto the plates. The cells are grown in minimal essential media with 10% fetal calf serum. The medium was changed after 1,4 and 7 days. Cell growth was observed on both the uncoated and coated half of the tissue culture plate, indicating that the present polymers are a suitable substrate for cell growth.
The following Example shows the preparation of a polymer of another embodiment.
10 grams of the lysine isocyanate capped polymer of Example 9 are placed into a reaction vessel with 9 grams of poly(ethylene oxide monomethylether) (Mol. Wt. 350) and 0.0038 grams stannous octoate. The reactants are stirred at ambient temperature for 4 hours. The resulting polymer is recovered as a viscous liquid which can be applied directly to a wound site.
20.6 g of diisocyanatolysine ethyl ester was placed in a clean, dry 100 mL round bottomed flask equipped with stirrer and N2 flow. The material was allowed to dry. A 95:5 weight percent polyethyleneoxide-glycolide copolymer (1000 molecular weight) was placed under vacuum for about 1 hour. The polymer was then added dropwise to the diisocyanatolysine ether ester via syringe to provide an isocyanate-endcapped material.
The lysine-diisocyanate endcapped star dioxanone/glycolide copolymer obtained in EXAMPLE 9 is applied to tissue as an adhesive. The material is placed between tissue to be joined and is of sufficiently low viscosity to enter small crevices and interstices present in the tissue. Water present in the tissue causes the endcapped polymer to cross-link in situ and cure to a solid. In this matter, the cured encapped polymer provides a mechanical interlocking function which effectively maintains the tissue in the desired, joined configuration.
A bone substitute material is prepared by mixing 0.55 grams of the encapped star copolymer obtained in EXAMPLE 9 with 1.65 grams of fine grained b-TCP. Both the copolymer and TCP were previously dried at 145� C. for 2 hours under vacuum prior to mixing. Then, 38.5 ml of DEAE is added to the mixture. The resulting material is packaged in a substantially dry state within a foil or other water-impermeable package. In this state, the product is stable for several months. When needed, the package is opened and the product is packed into bone. Upon contact with water naturally present or added, CO2 gas is generated so that when the material hardens a rigid, porous material is then provided, giving structural support to aid in hard tissue healing. Over time, the biodegradable polymer is replaced with new bone tissue growing into the porous bone substitute.
The material of EXAMPLE 27 is further mixed with excess lysine-diisocyanate (110 ml) which increases the amount of CO2 generated upon implantation thus increasing the number of pores in the resulting bone substitue. In this manner, the porosity of the bone substitute can be adjusted as desired.
It will be understood that various modifications may be made to the embodiments disclosed herein. For example, the compositions in accordance with this disclosure can be blended with other biocompatible, bioabsorbable or non-bioabsorbable materials. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Those skilled in art will envision other modifications within the scope and spirit of the claims appended hereto.
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|Citing Patent
|Filing date
|Publication date
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|25 Mar 2008
|Poly-Med, Inc.
|Segmented copolyesters as compliant, absorbable coatings and sealants for vascular devices
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|3 Jan 2012
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|20 Dec 2016
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|U.S. Classification
|428/423.1, 606/77, 525/415, 623/23.59, 606/76, 528/81, 602/41, 623/22.11, 528/73
|International Classification
|Cooperative Classification
|European Classification
|1 Mar 2010
|Fee payment
Year of fee payment: 4
|2 Oct 2012
Owner name: COVIDIEN LP, MASSACHUSETTS
Free format text: CHANGE OF NAME;ASSIGNOR:TYCO HEALTHCARE GROUP LP;REEL/FRAME:029065/0448
Effective date: 20120928
|5 Dec 2013
|Fee payment
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text:
New research suggests that women who take hormone replacement therapy in the early stages of menopause may have a reduced risk of heart attack, heart failure or dying.
This apparent benefit comes without a heightened risk of cancer or blood clots, the Danish researchers said. These health risks have long been a concern of menopausal women and their doctors when considering hormone therapy.
The study, published Oct. 9 in the BMJ, even found evidence of a trend toward a lower risk of breast cancer, although this was not statistically significant, said study author Dr. Louise Lind Schierbeck.
However, two doctors not associated with the study said the findings weren't enough to convince them to recommend hormone replacement therapy (HRT) to head off heart problems. But they -- and many doctors -- would prescribe low doses of the therapy for short durations to treat menopausal symptoms such as poor sleep or hot flashes.
The new study comes on the heels of two other studies, one finding that HRT was safe for the heart and the other concluding that it did not worsen memory in younger women taking it.
Women have shied away from hormone therapy since the landmark Women's Health Initiative study found elevated risks of breast cancer, heart disease and other health problems among women taking estrogen plus progestin, a synthetic form of progesterone. That study was halted early because of the results, published in 2002.
For this latest study, about 1,000 women aged 45 to 58 who were recently menopausal or had perimenopausal symptoms, such as hot flashes and irregular periods, were randomly selected to receive either HRT or an inactive placebo.
Participants took the therapy for an average of a decade, at which point they had a 50 percent decreased risk of a cardiovascular event or death, said Schierbeck, who is with Bispebjerg Hospital in Copenhagen. Six years after women had stopped taking HRT, the risk was still reduced 40 percent, she added.
Schierbeck conducted the study while at Hvidovre Hospital, also in Copenhagen. She said that longer follow-up research is needed to verify the breast cancer results.
This study differs from the Women's Health Initiative (WHI) in several important ways. The women in this study were much younger than in the WHI (an average age of 50 versus 64) and were given a differently formulated estrogen.
The difference in age and time since menopause were probably the main reasons for the differences in the studies, Schierbeck said.
But one analysis from the WHI, which only looked at women younger than 60, also found a reduction in heart disease and death, albeit one that was not statistically significant.
HRT has been shown to lower cholesterol levels, improve blood vessel function and keep body weight down, all of which might contribute to a reduction in heart disease.
Dr. Suzanne Steinbaum, director of women and heart disease at Lenox Hill Hospital in New York City, said the new study can offer a "little bit of peace of mind" to women who are "recently postmenopausal who are really symptomatic with mood swings, hot flashes and difficulty sleeping and concentrating."
But, she would not prescribe HRT to prevent heart disease based on these results.
Dr. Mary Ann McLaughlin, director of the cardiac health program at Mount Sinai Medical Center in New York City, agreed. "I don't think this is enough to change recommendations," she said.
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text:
Scott set to rejoin Rays on Tuesday
Scott set to rejoin Rays on Tuesday
Scott played in eight games for Class A Charlotte, hitting .308 with a pair of homers and six RBIs. He saw some action at first base during the stint, which concluded with a pair of multihit games for the Stone Crabs.
"Everything's feeling good, I'm ready to go," Scott said. "It's good to see the team is playing well, and I'm excited to be back."
Manager Joe Maddon said that there is a possibility of Scott playing first base at times, but he'll see much of his time as a DH whenever Evan Longoria is unable to play.
"I'll do whatever they want me to do," Scott said.
With Scott's return, the team must clear a space on the roster as well as in the lineup. Maddon said that there is some flexibility on the horizon, as Longoria may start seeing time at third base as early as the current six-game homestand, thereby opening the DH slot.


text:
Portland, ME — Despite the recent lack of snow and beyond frigid temps the Ragged Mountain stop of the Scion High Rollerz Snowboard Series once again delivered a solid contest venue and some very progressive riding. 62 riders from all over New England and one dedicated east coaster from Philly showed up and displayed what the east coast is known for. Commitment.
In the mens pro division Vermonter Chris Rotax stuck some of the most difficult tricks of the day, took home first place and the big $. Second place went to the, "new old man of the mountain Mike Baker who went bigger and badder in his styly leather jacket than anyone on the mountain. Coming in third was another Vermonter Ryan Hryckiewicz and rounding out the top five were Kosh Kennedy and Yale Cousineau.
The women in the pro division showed that the east coast ladies can ride with the best of em. Taking first and the green was Eliza Green who came all the way from Chester Vermont to stomp everything she tried. High Rollerz regular Megan Burke busted big airs and a solid repertoire of rail antics to take second. Coming in third was "Jersey Girl" Kristy Link and Jenny Buono ended up in a solid fourth place.
The guys in the am men division showed once again that they are hungry with points leader Lucas "The Goon" Magoon taking first place honors for the second time in the series. Ted Borland riding for Artec project out of Massachussetts came in a close second with Vermonter Zach Friedline taking third. Jereme Leafe and Chu Thiv completed the top five in this heated division.
The am women showed compassion and guts for their fellow competitor when points leader Nelly Ward riding for Winterstick went down during the qualifiers with a knee injury. Second place finisher Becky Slattery riding for Gould Academy and third place finisher Nora Connors riding for Manitoba harvest decided to battle it out for second and third in the finals and graciously decided to give the first place honors to Nelly without making her compete on a bum knee in the final jam.
Overall, everyone gave 100% including shop sponsor Eastern Boarder and the Fringe/High Rollerz staff. No one complained and the High Rollerz Series moves on to Blue Hills, MA on February 21 for the next stop in this heated east coast points race.
This series is sponsored by: Scion, Burton Snowboards, Artec, Transworld Snowboarding, Winterstick Snowboards, Smith Optics, Eastern Edge, Oakley, Smuttynose Brewing Company, Scott, Eastern Boarder, Pioneer's Board Shop, Sunny Breeze, NOTB snowboards, EE, Givo Brand Wear, Rye Airflield, Vew Dew, Atomic, Giro, Drop and Flow.
This series was conceived and put into action by Fringe Marketing and Boston based pro snowboarder Andrew Mutty www.andrewmutty.com
Those interested in participating can get more information and an entry form at www.highrollerzsnowboarding.com.
Fringe Marketing is a Portland Maine based youth and action sports marketing, consulting and event management firm. For more information on Fringe go to www.fringemarketing.com


text:
Alcohol Consumption and Sickness Absence: Evidence from Panel Data
This paper examines the relationship between alcohol consumption and sickness absence. We use regional panel data from Finland over the period 1993-2005. The data on individuals' health that we are using originates from Health Behaviour and Health among the Finnish Population conducted by the National Public Health Institute. The results show that alcohol consumption is associated with sickness absence, and particularly so for men. Therefore, the earlier aggregate time-series evidence from Sweden is largely confirmed in a regional panel data setting.
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|Date of creation:
|19 Dec 2007
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| Postal: Ludwigstraße 33, D-80539 Munich, Germany
Phone: +49-(0)89-2180-2459
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- Jan Erik Askildsen & Espen Bratberg & Øivind Anti Nilsen, 2005.
"Unemployment, labor force composition and sickness absence: a panel data study,"
Health Economics,
John Wiley & Sons, Ltd., vol. 14(11), pages 1087-1101.
- Askildsen, Jan Erik & Bratberg, Espen & Nilsen, Øivind Anti, 2002. "Unemployment, labour force composition and sickness absence. A panel data study," Working paper Series 0205, Department of Economics, University of Bergen.
- Askildsen, Jan Erik & Bratberg, Espen & Nilsen, Øivind Anti, 2002. "Unemployment, labour force composition and sickness absence. A panel data study," Working Papers in Economics 05/02, University of Bergen, Department of Economics.
- Askildsen, Jan Erik & Bratberg, Espen & Nilsen, Øivind Anti, 2002. "Unemployment, Labour Force Composition and Sickness Absence: A Panel Data Study," IZA Discussion Papers 466, Institute for the Study of Labor (IZA).
- Christopher J. Ruhm, 2000. "Are Recessions Good for Your Health?," The Quarterly Journal of Economics, Oxford University Press, vol. 115(2), pages 617-650.
- Christopher J. Ruhm, 1996. "Are Recessions Good For Your Health?," NBER Working Papers 5570, National Bureau of Economic Research, Inc.
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text:
Joshua Shawn Harris, 10, of 6421 Georgia Highway 320, died Sunday, April 21, 2002.
A native of Hart County, Joshua was a son of Jeffery Monroe Harris and Connie Kay Banks Harris, Toccoa. He was a special education student at Carnesville Elementary School. He attended New Bethel Baptist Church.
Services will be at 3 p.m. Tuesday at New Bethel Baptist Church with the Revs. Tommy Childress, Bruce Moore and Duane Eller officiating. The body will be placed in the church at 2:30 p.m.
Survivors, in addition to his parents, include a brother, Jeffery Trent Harris, Toccoa; his maternal grandmother, Idell Banks, Tallapoosa; and his paternal grandmother, Myrtle Harris, Lavonia.
The family is at the residence of Dykes Dalrymple, 4635 Georgia Highway 198, New Bethel Community, and will receive friends from 2-4 and 7-9 p.m. today at Hamby Funeral Home, Lavonia.Athens Banner-Herald, Monday, April 22, 2002
Published in the Athens Banner-Herald on Monday, April 22, 2002.
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text:
Surprising news for Bridget Jones star Hugh Grant!
The British actor, 51, became a dad for the first time, welcoming a baby girl in early October, Us Weekly reports.
"I can confirm that Hugh Grant is the delighted father of a baby girl," a rep for the About a Boy actor said in a statement. "He and the mother had a fleeting affair and while this was not planned, Hugh could not be happier or more supportive. He and the mother have discussed everything and are on very friendly terms."
The identity of the baby's mother has not yet been revealed. Although in April, Grant was romantically linked to stunning Chinese actress Tinglan Hong.
"He's going to be a great dad!" the source tells Us. "He's beaming about his daughter. He's not with the mum anymore but he's absolutely thrilled."
In 2007, Grant opened up to Vogue about wanting to become a father. "As much as I adore myself, I'm quite keen to find someone else to care about more. I remember reading a Warren Beatty quote when he finally had children and said what a relief it was to not be all me, me, me."
The Love Actually star famously dated model mom Elizabeth Hurley for 13 years before parting amicably in 2000.