text:
My Nonprofit Reviews
Review for Infinity Foundation, Highland Park, IL, USA
Infinity Foundation and its leader Nancy Grace Marder, are amazing assets we here in the Chicago area are lucky to have. The quality of instructors, the pertinence in their fields, is unmatched. Whatever a person wants to learn in the metaphysical, spiritual or holistic fields, Nancy has made available.
More Feedback
How does this organization compare with others in the same sector?
Very Well
How much of an impact do you think this organization has?
Will you recommend this organization to others?
When was your last experience with this nonprofit?
Review for Infinity Foundation, Highland Park, IL, USA
Client served, volunteer, and professional with expertise in this field, also!! Infinity is a heartfelt place of learning and nurturing. Everyone is of the Light, and you feel cared about and loved in everything you do with them. Yay!


text:
Weak is the new strong!
nothing stronger than sending 4000 Americans to their deaths in Iraq. tea baggers are clueless
We didn't elect President Obama twice for him to be a neo-con warmonger like Bush and Cheney so this is in keeping with he said would do, and what the electorate wanted.
Bush and Cheney married themselves to war, and should be repenting for it as we speak.
Did you notice neither of them attended the 9/11 Memorial with other presidents and vice presidents?
Maybe they were ashamed. Bush was booed at the Mandela funeral. Neither he nor Cheney can travel outside the country since they could be indicted for war crimes. Google it.
To his credit, President Obama had the fortitude to re-craft modern day foreign policy with a more multilateral prescription that is focused more towards solutions that do not immediately involve military invasion.
Senators McCain and Graham are ready to bomb everywhere. They have no other ideas than boots on the ground. They care less about weakening our armed forces with more senseless wars. They were major cheerleaders for Bush/Cheney wars from 2001 on.
You'll notice no other major world powers went to war with Russia or countries having civil uprisings in the Middle East with the Arab Spring. So Obama led with this. Regardless of what you neocons believe.
He couldn't have gotten many of the sanctions imposed without his earlier and continuing influence.
And we the nation are tired of arbitrary wars, calling people enemies, and perpetual military engagement.
So bash the president as you will with your usual trivial remarks.
We are tired of our soldiers dying overseas.
Washington Wire is one of the oldest standing features in American journalism. Since the Wire launched on Sept. 20, 1940, the Journal has offered readers an informal look at the capital. Now online, the Wire provides a succession of glimpses at what's happening behind hot stories and warnings of what to watch for in the days ahead. The Wire is led by Reid J. Epstein, with contributions from the rest of the bureau. Washington Wire now also includes Think Tank, our home for outside analysis from policy and political thinkers.
Sign up for Capital Journal Daybreak

subset: commoncrawl


text:
Janne Swearengen of Madison works out at the Courthouse Racquet and Fitness in Madison.
- Filed Under
Madison resident Janne Patterson Swearengen, 67, is semi-retired as a long-term care quality assurance analyst for the Long Term Care Institute and the Center for Health Systems Research and Analysis of Madison, Wis. She and husband Larry "Big Solid" Swearengen have been married 29 years, and she is stepmom to two grown children and a grandmother of two.
I have always been athletically inclined but not necessarily adept. I swam competitively with the Flying Js, a swim team out of the old downtown Jackson Y, back in the 1950s and early '60s, and I played basketball in high school. I got lazy and ...


text:
Contact: Ted Skantze, Executive Director
P.O. Box 5054
Pine Ridge, SD 57770
South Dakota Office: 605.867.2282
South Dakota Office Fax: 605.867.2285
Work Cell: 605.454.5130
E-mail: email@example.com
Volunteer Trip Coordinator (Paula Sibal) at:
P.O. Box 5054
Pine Ridge, SD 5770
Phone: 616.550.7180
Fax: 866.583.1719
Email: email@example.com
Website: www.re-member.org
Re-Member works with the Oglala Lakota Nation on the Pine Ridge Reservation. Volunteers participate in work projects across the Reservation, helping rebuild relationships, homes and lives.
Project/Focus: Projects include building and installing bunk beds in the homes of Oglala Lakota families on Pine Ridge Reservation in South Dakota, outhouses, trailer skirting/steps/decks and rehabilitation and renovation of homes. The week long trips are divided between service and cultural immersion.
Educational/Advocacy Components: Cultural immersion activities scheduled in afternoons and evenings, including guest speakers, Lakota crafts, tours, museums, and social gatherings with Lakota friends.
Time: Groups are scheduled from the last week in February (to accommodate alternative spring breaks) through the 2nd week of October. Registration is secured on receipt of deposit and completed Trip Reservation Agreement, sent out by Trip Coordinator.
Group Size: 60 persons maximum per trip week, Memorial Day through Labor Day, with a group size cap of 20. In the spring and fall: 40 per trip week with a group size cap of 13. Subject to availability after cutoff of 2 months prior to trip date, group sizes may be increased.
Minimum Age: 12 years. During Kids Weeks (2 per summer) children age 8-11 are welcomed, and special programming is provided for them.
Adult to Youth Ratio: 1:6
Accommodations: Dormitory-style housing with bunk beds, bathrooms, and showers. Full kitchen and dining facilities on site. Groups assist full-time kitchen staff in preparing and clean up of meals. All meals are provided, as is all transportation during the trip week. Shuttle service is available, at additional costs, for volunteers flying into rapid City, SD, which is approximately 90 miles away.
Cost: $455 per person includes housing, meals, and transportation from Saturday evening through Friday morning.
Back to State Listing Index by Focus of Mission Trip
Contact: Barb White
P.O. Box 234
Herrick, SD 57538
Phone: 605.830.0214
E-mail: firstname.lastname@example.com
Website: www.herrickelevator.com/retreats
Herrick Elevator: Helps people experience stories, places and people of historical Lakota in order to understand social, cultural and economic complexities of Lakota life today. The Great Sioux Nation existed in this location 107years ago and continues living in the area. Speakers from the Rosebud Sioux nation accompany visiting groups. Through cultural exchange and service-learning opportunities, program coordinators encourage greater participation in and appreciation for the community traditions of the Rosebud Sioux, including Milk's Camp Community.
Project/Focus: Two itineraries suggested.
- Stay at Herrick, SD in renovated historic grain elevator. Engage in immersion experiences of day-long journeys to the Rosebud Sioux Reservation and the Lakota community of Milk's Camp. Service-learning projects can be arranged by program coordinator with the local Lakota community. Projects might include cemetery upkeep for Milk's Camp Community (a community of the Rosebud Sioux). Projects might also include clean up and repairs for the Episcopal church set in place in 1903 by Chief Milk's children; or for the UCC church's recreation center and cabin construction.
- South Dakota Lakota Pilgrimage. Immersion experiences with Rosebud Sioux, including Milk's Camp Community - 2 days. Journey west to Pine Ridge Reservation, Wounded Knee Monument, geographic Badlands, and Mount Rushmore - 3 days. Return to Herrick for reflection, integration, and advocacy planning - 1-2 days.
Educational/Advocacy Components: Groups are immersed in shared Native and European American history, including integral issues of justice. Practice cross-cultural communication. Accept the invitation of local community to a Pow-Wow. Explore how history affects the present, locally and nationally. Engage in theological reflection. Tools for learning cross-cultural competencies and advocacy are available.
Time: May - September
Group Size: 10-18 for lodging at Herrick Elevator or larger groups possible with lodging at UCC Rec. Center or Herrick Catholic Church.
Minimum Age: High School-aged
Adult to Youth Ratio: 1:6 with both male and female advisors for mixed gender groups.
Accommodations: Herrick Elevator: 5 bedrooms with twin, queen and bunk beds, 3 bath/showers, fully-equipped kitchen, and is air-conditioned. UCC Rec. Center and Herrick Catholic Church: open floor plan. Herrick Church Parsonage: 2 bedrooms, 1 full bath, seating, and full kitchen.
Cost: $300/person for 6 nights. Transportation and food not included. Costs of service project supplies are individual to each project.


text:
SLCC Home | A-Z Index | Contact Us | Locations | Canvas | MyPage Login
Office of the Registrar and Academic Records
For detailed contact information please use the Faculty & Staff Directory or call the Contact Center at: (801) 957-4111.
To reach the Enrollment Services staff directly, please call (801) 957-4298 or click Contact Us.
Al-Shakargi, Amani
Outgoing Transcripts
Ate, Gina
Brock, Shirley
Student Express
Carnahan, Becky
School of Applied Technology
Chase, MaryEtta
Clausen, Denise
Records Management
Curtis, Sherrie
Edwards, Shelly
Registration Appeals
Fateh, Mohammed
Transfer Evaluation
Faumuina, Lauretta
Outgoing Transcripts
Franco, Sara
Student Express
Green, Brandon
Hendricks, Joyce
Data Center Coordinator
Hofhine, Robyn
School of Applied Technology
Howes, Marcy
Data Center
Huber, Debby
Data Center
Iopu, Ologa
Assistant Registrar
Jensen, Sarah
Telephone Reception
Levesque, Ryan
Outgoing Transcripts
Mann, Abbey
Residency Specialist
Mayawala, Medha
Telephone Reception
Miera, LaDawn
Transfer Evaluation Manager
Nelson, Karen
Data Center
Peterson, Ruth
Data Center
Riley, Carrie
Assistant Registrar, S.A.T.
Rilk, Linda
Graduation Coordinator
Sanders, Mallory
Transfer Evaluation
Shepherd, Natalie
Data Center
Stellet, Rachel
Transfer Evaluation
Tran, Tina
School of Applied Technology
Weaver, Judi
Transfer Evaluation


text:
Rough Rugger's Wall of Sin @roughrugger
3954 Images
I'm a rugger, I'm a sinner (and I don't mean that in the pious Biblical sense ;-) Just a collection of guys I find hot, stuff I find fun, things I find interesting. I figure most of this will end up being NSFFB (as in "Not Safe For FaceBook"). Enjoy...or don't. ;-) (Oh yeah, the legal blurb...no, I don't own any of the pics here, 'cept the ones of me. They were all obtained online. If you own one of 'em and want it taken down, let me know and I'll be glad to oblige.) - Rough Rugger's Wall of Sin (@roughrugger)


text:
Title: Found
Characters: Farina, Hector, Eliwood, Dorcas, Wallace, various others
Genre: Gen/Friendship
Words: 2,146
Notes: I take game endings as guidelines of what could have happened—like the beautiful glossing over of a history book. Not necessarily the truth, but what people want you to believe happened. This piece is pretty pointless but I wanted to write it and so here it is. I think Farina is probably my favorite FE7 female character, and it's partly because I find her issues fascinating and partly because I find her relateable. Either way, I hope this is at least interesting.
Lucius ran a small orphanage in Araphen. Oswin had married Serra, retired, and had moved to a small property in the countryside. Wallace had a small farm in Ilia; he knew where to find Vaida, who had been forced to flee from Bern again. Ninian and Eliwood were married and living in Pherae, though Ninian's health had grown poor.
Farina knew where to find almost everyone: Dart and Fargus often docked in Badon, Sain and Fiora were outside of Caelin, Lyn was on the Sacae plains, Rath was with the Kutolah, Erk was in Etruria.
Though everyone had expected her to return to Ilia and make herself famous, she found that she lacked the heart, the drive. Mercenary work was not honest, and though she had cheated people in the past—Lord Hector of Ostia, for example, as twenty-thousand gold was ridiculous—she found that she did not take pleasure in that line of work. In fact, it was only on a snowy road in Ilia, drunk half off her scrawny ass five years after Nergal's defeat, that she realized that she couldn't do it anymore. She pulled herself out of a snowbank and scowled at the flakes as they fell around her.
"'m not'n assassin for hire," she slurred, and the next morning, when she woke up in a barn, she packed up what few possessions she owned and flew straight to Ostia to meet with her old employer, Hector.
He laughed at her suggestion when she proposed it, three days later, but in the end he accepted it. She could tell that he was lonely, that life as a marquess was not his first choice, and unlike Lyndis, he couldn't just leave it all behind. He didn't have the luxury of leaving to visit old friends, but she did.
And, she said, she could at least carry letters to them.
It had started that way, with Hector sending her to Pherae to deliver a letter to Eliwood, and then it had snowballed, with Serra asking her to deliver a letter to Lucius, and Lucius asking her to deliver a letter to Raven, and Raven asking her to deliver one to Priscilla, and on down the chain it went.
It was an all-right life, considerably more gratifying than being asked to kill people for money, or to guard caravans whose sole good consisted of, well, human beings. She didn't make a lot of money—heck, sometimes she didn't really have any at all—but it was nice. Natalie made the most delicious meals when she stopped by, and Wallace would give her produce from his garden. Hector always gave her a little extra money—a bonus, he said, for delivering letters so quickly. Serra always had the latest news, Lucius shared a cup of tea with her, and Pent and Louise let her stay in their luxurious spare bedroom.
She knew she wouldn't be able to do it forever, but she found it mostly enjoyable. Everyone was happy to receive a letter from a beloved friend that they hadn't seen in years. And seeing other people, surprisingly, made her happy, too.
The last letter she delivered was from Lyndis to Lord Hector of Ostia. She stayed at the castle for the night and in the morning, departed for Pherae with two letters: one for Lord Eliwood, and another from Vaida that was to be delivered to Heath in Caelin.
She never arrived in either Pherae or Caelin. Her body was found, along with the broken remains of her pegasus, Murphy, in a Pheraen peasant's field.
It was lucky, the farmer who found her had written by a local clergyman, that under the three-field-and-fallow, that she hadn't landed in that year's fallow field, or it might have been another year before they found her, and then she would be unrecognizable along with her letters.
As it was, the clergyman could read the letters she had yet to deliver, and used some of the gold in her bag to send the letters on with a letter of explanation, some of the gold to tithe to St. Elimine, and the last of the gold was given to the farmer for being honest and not keeping it all for himself.
"Natural causes?" Eliwood asked when he saw the letter. "But what…?" He didn't know when she had left Ostia, and so he sat down to write to Hector, and included the original note written by the Pheraen clergyman. He hid nothing from his wife, but this, he did keep from her due to her failing health.
Hector eventually wrote back saying that he was shocked, and horrified, and all manner of cursing was present in the letter. If Florina had not already been in the grave four years, she would have been devastated to learn of this. She had left before a bad winter storm—a terrible one, hail and ice, definitely not something a pegasus could fly in. The impact had probably killed her, but at least, they both hoped, it had been fast.
I can't believe she's gone, Hector wrote at the bottom, and Eliwood, who knew Hector better than almost anyone, understood his sincerity and unique grief.
Heath, in Caelin, received his letter much later than he had expected, but read the clergyman's explanation before Vaida's letter, and immediately set out to write to Sain and Fiora, Lyndis, Kent, and several others whose locations he knew of.
When Natalie received the news from Sain, she wept, and Dorcas's eyes shone with tears though he held them in until he was alone with his wife, and they held a quiet unassuming ceremony together in their yard for her. A prayer circle, really, consisting of two people—two lives—that she had touched, perhaps almost unknowingly.
Lucius heard the news from Serra, who heard it from her husband, who had been told directly by Lord Hector. He silently drank a cup of tea, and when the children asked him what was wrong, he told them that a soul had gone to heaven, and he was honoring the life that had been lived. He allowed himself to cry, much later that night, alone in his bed, because Farina was one of the most misunderstood, frightened people he had met, and she had often given him money for food for the children, sometimes going without, herself. Now she was gone, and he had never had the chance to properly thank her for all that she had done.
When Vaida heard the news from Wallace, who heard it from Lyndis, who had heard from Heath, she merely gave a thoughtful sort of "Hmm," but said nothing else. Wallace put his hand on her shoulder, which she promptly shoved off, but she did say, almost too quietly to hear, "Now who am I going to rely on to deliver information for me?" Wallace laughed at her comment, but said nothing, as he'd lost too much in his life to cry over the death of someone reliable that he hadn't known well, but a few months later, when Vaida stopped by his farm again, she noticed behind the evergreens at the edge of the property, there was a second cross in the ground.
"You didn't know?" he asked in reply to her question regarding their presence, "this farm belongs to them. I thought it was right to…"
Vaida merely nodded in understanding. They probably had a grave marker elsewhere—Florina in Ostia, Farina in the small hamlet where she had been found—but there was something about being buried in your homeland that was…different. Better. Preferable.
"Don't worry, you old teapot," she said, "I'll drag your carcass back to Caelin to plant permanently."
"What!" he said, giving her a disbelieving look, "You assume I will die before you!"
Fiora took the news as well as could be expected. "I'm the oldest," she said to Sain, quietly, as they lay together in bed that evening. "I was supposed to die first. But now I'm the only one around."
He knew that no amount of dialogue would smooth this over for her, so he gave her the space she needed until he heard the first stifled sob, and then he wrapped his arms around her and held her close to him as if that action alone could protect her from everything.
I keep expecting her to land on the balcony, Priscilla wrote to Erk, with that sack of letters and a rueful smile. But what I hear is just the sound of the wind, and I find myself…disappointed.
I must thank you, Fiora wrote to Lord Hector, a few years after Farina's death, for accepting my late sister Farina's proposal to deliver letters. Though she never said as much, I know she loved the job and she found great joy in having it entrusted to her. I find it ironic, however, that she made a living delivering letters, when she herself was illiterate.
"Father," Lilina asked one day as Hector sat at his desk and sorted through some paperwork. "The painting in the study—who is that of?"
He raised his head. "Your aunt," he said. "Farina."
It was a simple work, crudely done to someone with a detailed eye, but Hector thought it was brilliant. It showed a small woman on the back of a pegasus, a sack by her side, the strap across her chest. Midflight. Crudely done but beautiful, really. He liked it better than most of the traditional portraits of his wife, most of which looked little like her.
But that painting. It was Farina.
"Oh," said Lilina. "I don't really remember her."
"Not many people do," he replied. Though most people in their old rag-tag outfit would not forget her, most of the world probably had. "It's unfortunate," he continued. "She was a good person. She died young."
He would always blame himself partially for that. He should have insisted she stay in Ostia another day. When Lilina was young she had loved her aunt; he should have offered her a position as a governess or something. But he hadn't, and Farina had died, and…well, what was done was done.
"Whom did you commission to paint it?" she asked, standing. "It doesn't look like the paintings of Mother at all."
For a moment, Hector let his mind drift. It was odd how much time had already passed. "An old friend," he said. "His name is Dorcas; we traveled together years ago."
How long had it been? Sixteen years ago? Eighteen? No, perhaps a little longer than that. But Dorcas painted people as they were, with every flaw, with every blemish. The painting of Farina looked so much like her that it was hard to believe he had painted it from memory—he had even gotten the crooked nose correct, and that ugly hat that she wore to protect her ears.
"I'd like him to paint me, too," she said. A hint as to her next birthday, he was certain.
It was a good idea, but Hector paused and gave her a thoughtful look. "I'll have to think about it," he said, but that was good enough for his daughter, who skipped off, pleased that her suggestion was being considered.
The heavy snowfall had turned suddenly to sleet, and sleet at such high altitudes turned almost instantly to ice. Murphy's animalistic shriek of terror came as the majestic beast realized he could not stay airborne any longer.
Farina let out a curse but her fear was short-lived. The impact did not kill her.
Everyone assumed she would die in battle, a spear through her side or an arrow through her heart.
Instead, she froze. Or died of shock. Even she couldn't be certain what it was that killed her in the end. It was a relatively quick death. After Murphy had died—instantly, from the impact—she had been rolled a few feet away. She couldn't articulate what was wrong with her even if she could talk, but bones were broken or shattered and she knew that she was going to die even if someone happened upon her that very minute.
Even Serra's amazing healing could do little for her as she was.
But she curled her aching fingers around her bag, an attempt to protect the letters within—though they were in tubes that would also help, who knew how long it would be before someone found them? She had been trusted to deliver them and even though she couldn't do so now, she would do her best to make sure they were at least deliverable.
She died quietly and felt little pain.
And if she cried, it was because she hadn't wanted it to end this way, with her knowing where to find so many others…but nobody else knowing how to find her.


text:
|Publication number
|Publication type
|Application number
|Publication date
|13 Apr 1993
|Filing date
|15 May 1990
|Priority date
|19 Aug 1988
|Fee status
|Also published as
|Publication number
|Moses J. Folkman, Yuen Shing
|Original Assignee
|Children's Medical Center Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (11), Non-Patent Citations (50), Referenced by (28), Classifications (31), Legal Events (8)
|External Links: USPTO, USPTO Assignment, Espacenet
The present application is a continuation-in-part of U.S. Ser. No. 07/382,263 filed Jul. 10, 1989, now U.S. Pat. No. 5,175,147, which is a continuation-in-part of U.S. Ser. No. 07/234,966 filed Aug. 18, 1988, now abandoned.
In accordance with the present invention, there is provided a method for stabilizing fibroblast growth factor (FGF) in heat, acid and/or proteolytic environments by combining or otherwise complexing FGF with a salt of sucrose octasulfate (SOS) and in particular with the aluminum (sucralfate) or potassium salts thereof. The present invention also relates to FGF-stable compositions comprising SOS and FGF. This composition can be used in the treatment of FGF-responsive diseases including the treatment of wounds and ulcerative conditions of the gastrointestinal tract. The present invention also relates to the use of SOS in various diagnostic protocols and as a component of diagnostic kits. Finally, the present invention relates to the use of SOS to purify FGF.
Ulcerating diseases of the gastrointestinal tract, commonly referred to as peptic ulcers, are diseases in which there is a defect in the epithelium of the gastrointestinal tract. This type of defect usually occurs through the combined action of hydrochloric acid and pepsin. By definition, peptic ulcers penetrate to at least the submucosa; more superficial lesions are referred to as erosions. Peptic ulcers may occur in many locations of the gastrointestinal tract including the stomach, duodenum or esophagus, in Meckel's diverticulum, at the sight of a surgically created anastomosis, and, rarely, in the upper jejunum.
Twenty years ago, treatment of peptic ulceration consisted of bedrest, a bland diet, antacids, and/or surgical removal of the affected area. More recently, H2 -receptor antagonists have been used in the treatment of peptic ulcers. The two most commonly used H2 -receptor antagonists are ranitidine and cimetidine, both of which act therapeutically by inhibiting gastric acid secretion. The effectiveness and unwanted effects of these two antagonists has been extensively studied, e.g. by Thomas et al., in Clinics in Gastroenterology. Volume 13, Number 2, at pages 501-529.
While treatment with these antagonists has been widespread and relatively successful, many peptic ulcers do not respond to H2 -receptor antagonist therapy. For example, while the reasons are not clearly understood, some 20 to 30% of duodenal ulcers do not heal after four to six weeks of therapy with either cimetidine or ranitidine. Moreover, recurrence or relapse of the ulcerating condition is not uncommon with H2 -receptor antagonists.
Sucralfate has also been used as an ulcer curative agent with minimal side effects. Sucralfate is believed to influence multiple mechanisms of gastrointestinal protection and repairing/healing including i) adsorption of pepsin and bile acids, ii) cytoprotective activity of the gastro stimulation of mucus secretion and bicarbonate secretion by the gastric mucosa, iii) protection against damage to the prolifactive zone, and iv) protection of vascular integrity. Although major advances have been made in the understanding of how sucralfate prevents erosions and ulcers, and how it accelerates the healing of ulcers, a major gap exist in the elucidation of chronic therapeutic actions of this drug.
Fibroblast growth factor (FGF), has been shown to be a potent angiogenic factor which, inter alia. is responsible for neovascularization in wound healing. There are two types of FGF, acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF). aFGF and bFGF are, however, acid and/or heat labile. Thus, the use of FGF in acid and/or heat environments such as in the treatment of peptic ulcers requires that it be stabilized to that environment in order to maximize its therapeutic value.
Recently, however, in PCT application serial no.: PCT/U.S. Pat. No. 8,903,467, published Mar. 8, 1990, the disclosure which is hereby incorporated by reference, there is disclosed certain acid-resistant FGF compositions including recombinant FGF in combination with i) stabilizing agents such as glycosaminoglycan, glucan sulfates and sulfated cyclodextrins, ii) antisecretory agents such as H2 -receptor antagonists, iii) cytoprotective agents, and iv) antacids. These novel compositions are disclosed as being extremely effective in the treatment of ailments in which FGF would be a potent medicament but for the acid and/or heat environment to which it is subjected.
There continues to be a need, however, for new ways of further stabilizing FGF so that its diagnostic potential and therapeutic potential in the treatment of gastrointestinal conditions, wounds, and the like can be realized.
In accordance with the present invention there is provided a method for stabilizing FGF, which comprises combining or otherwise complexing FGF with a salt of sucrose octasulfate (SOS), and in particular with the aluminum or potassium salts thereof. As used herein, "SOS" includes salts of sucrose octasulfate including, but not limited to the aluminum and potassium salts therof. The stabilized FGF composition of the present invention can be used to treat mammals having virtually any disease which is FGF-responsive, and particularly in diseases where there is an acid or heat environment, or in an environment where protelytic factors are present. Specifically, the composition of the present invention can be used in the treatment of ulcerating diseases of the gastrointestinal tract by administering to the patient an effective amount of FGF in combination with SOS together with a pharmaceutically acceptable carrier, vehicle or diluent. The composition is also useful in treating wounds where proteolytic agents would otherwise interfere with FGF's therapeutic value.
In accordance with another aspect of the present invention, it has been found that SOS has a higher affinity for FGF, thus making it useful in purifying FGF as well as useful in diagnostic applications where the presence and/or amount of FGF is important.
FIG. 1 illustrates the effect of high temperature on bFGF with and without SOS.
FIG. 2 illustrates the effect of acid on bFGF with and without SOS.
FIG. 3 illustrates the effect of pepsin on rhbFGF mutein CS23 with and without sucralfate.
FIG. 4 illustrates the affinity of SOS for bFGF by its ability to uncouple bFGF from heparin as compared with 2 M NaCl.
FIG. 5 illustrates the purification of bFGF from a fluid sample with a sucralfate-Sepharose column.
The present invention provides novel stable FGF compositions for the treatment and/or prevention of diseases in mammals which are responsive to FGF therapy. The present invention also provides for methods of purifying FGF as well as certain diagnostic applications where the presence and/or amount of FGF must be determined.
The method of treating FGF responsive diseases, in its simplest form, comprises administering to the mammal an effective amount of a stabilized FGF composition or a pharmaceutically acceptible salt thereof, wherein the stabilized composition comprises SOS in combination with FGF.
For example, various ulcerating diseases of the gastrointestinal tract may be treated by administering to the mammal an effective amount of the stabilized FGF composition. Such ulcertaing diseases include regional ileitis, ulcerative colitis and peptic ulcer (either duodenal or gastric).
The stabilized FGF composition of the present invention can also be used to treat other conditions in mammals which would be responsive to FGF therapy but for the existence of an acidic, heat, and/or proteolytic environment. For example, in radiotherapy or chemotherapy of bladder cancer, there often results ulcerations of that organ's tissue which could be treated with FGF if the FGF were stabilized to acid environment found in the bladder. Wounds can also produce an acid and/or proteolytic environment which would respond to stabilized FGF composition of this invention. Other conditions in which there is an acid, heat, or proteolytic environment and which would otherwise be responsive to FGF therapy will be apparent to the skilled artisan, and include:
i) tissue injuries, burns, wounds, postoperative tissues, thrombosis, arteriosclerosis;
ii) musculo-skeletal conditions such as bone fractures, ligament and tendon repair, tendonitis and bursitis, skin conditions such as minor burns, cuts, lacerations, bed sores, slow-healing and chronic ulcers such as those seen in diabetics, and in tissue repair during ischaemia and myocardial infarction; and
iii) retinopathies of the eye including diabetic retinopathy and neovascular glaucoma, skin disorders including psoriasis and retrolental fibroplasia, chronic inflammation, rheumatoid arthritis, and certain neoplasms that are highly angiogenic such as growth of certain benign and malignant tumors such as hemagiomas and angiofibromas, and solid tumors.
The stabilized FGF composition of the present invention may be a composition of SOS and either aFGF or bFGF. aFGF and bFGF useful in practicing the present invention may be derived from a number of sources including mammals such as human, bovine, monkey, swine and equine.
The preferred stabilized FGF composition is one which includes a modified FGF such as a purified recombinant human basic FGF (rhbFGF) protein in which a mutation is induced ("mutein") by changing one or more of the four cysteines present at amino acid residues 25, 69, 87, and 92 of the mature protein to serine. In numbering the human bFGF-constituent amino acids, the N-terminal Pro comprises the first amino acid. The most preferred FGF is the rhbFGF mutein CS23, the structure of which is more fully described in Senoo et al., Biochemical and Biophysical Research Communications, Vol. 151, No. 2, 701-708 (1988) an in U.S. Ser. No. 161,123, filed Feb. 18, 1988, which corresponds to EP-281,822 A2, the disclosures of which are hereby incorporated by reference herein. Other muteins which can be used in practicing the present invention and which are also described in these references include muteins in which amino acid(s) have been added, and where constituent amino acid(s) have been deleted or substituted.
Stabilized FGF compositions in accordance with the present invention have been found to be highly stable in acid, heat and proteolytic environments. Native mammalian FGF and FGF which is recombinantly modified as above to be acid-resistant are very low in toxicity.
The two preferred forms of sucrose octasulfate which may be used to stabilize FGF are potassium SOS and aluminum SOS (sucralfate). Which form of sucrose octasulfate is used in preparing the preferred stabilized FGF composition will depend on a number of factors including route of administration, requirement for solubilization, and the like. For treatment of gastrointestinal diseases, the preferred SOS is aluminum SOS (sucralfate) because it will not absorb into the blood stream.
The preferred route of administration of the stabilized FGF composition of the present invention will also depend on a number of factors including the condition being treated and patient convenience. For example, when used to treat ulcerating wounds of the bladder which are induced, for example, by radiation treatment or chemotherapy, then the stabilized FGF composition may be administered by urethral catheter. In treating ulcerating wounds of the gastrointestina tract, the preferred route of administration is oral, e.g. by tablet, capsule, lozenge or chewable gum. Other routes of administration for diseases of the gastrointestinal tract include rectal, by enema and parenteral.
Preparation of the stabilized FGF composition for administration is accomplished by conventional techniques. For example, tablets and capsules are prepared by employing additives such as pharmaceutically acceptable carriers (e.g. lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g. alpha-form starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxy-propylmethylcellulose, polyvinylpyrrolidone), disintegrating agents (e.g. carboxymethylcellulose calcium, starch, low substituted hydroxypropylcellulose), surfactants (e.g. Tween 80 (Kao-Atlas), Pluronic F68 (Asahi Denka, Japan); polyoxyethylene-polyoxypropylene copolymer, antioxidants (e.g. L-cysteine, sodium sulfite, sodium ascorbate), lubricants (e.g. magnesium stearate, talc), and the like.
Rectal preparations are also prepared by conventional techniques, for example, by employing an oleaginous base such as a higher fatty acid glyceride (e.g, cacao butter of the natural origin, Witepsols (a semisynthetic base, (Dynamite Nobel, Federal Republic of Germany)), a medium fatty acid glyceride (e.g. Miglyols (Dynamite Nobel)) or a vegetable oil (e.g., sesame oil, soybean oil, corn oil, cottonseed oil, olive oil).
When the composition is formulated into an injectable aqueous solution, the solution is prepared by conventional methods using a solvent such as an aqueous solvent (e.g., distilled water, physiological saline, Ringer's solution), or oily solvent (e.g., sesame oil, olive oil). If desired, on or more additives may be employed. Such additives include a dissolution aid (e.g. sodium salicylate, sodium acetate), buffer (e.g., sodium citrate, glycerine), isotonizing agent (e.g., glucose, invert sugar), stabilizers (e.g., human serum albumin, polyethylene glycol), preservative (e.g., benzyl alcohol, phenol) or analgesics (e.g., benzalkonium chloride, procaine hydrochloride). SOS in its potassium salt is preferred when it is to be used intravenously because of solubility.
When the composition is formulated into a solid preparation, the preparation can be produced by routine methods using, for example, a diluent (e.g., distilled water, physiological saline, glucose), excipient (e.g., carboxymethylcellulose (CMC), sodium arginate), preservative (e.g., benzyl alcohol, benzalkonium chloride, phenol), or analegesics (e.g., glucose, calcium gluconate, procaine hydrochloride). The preferred form to be used is sucralfate.
The amount of the FGF component of the composition is remarkably small when compared to other pharmaceutical agents such as the H2 -blockers, and depends on a number of factors including the condition being treated, whether or not it is used alone or in conjunction with antisecretory agents, cytoprotective agents and antacids, and the amount of food intake by the patient.
For example, when used to treat ulcerating diseases of the gastrointestinal tract in human adult patients, the amount of the FGF protein component of the composition to be administered orally is generally between about 0.1 μg and 30 mg per day, preferably between about 0.1 μg and 10 mg, more preferably between about 1.0 μg and 3 mg per day, and most preferably from about 10 μg to 300 μg per day. For oral administration, 10 μg to 150 μg of the rhbFGF mutein CS23 or its salt may be formulated with sucralfate (generaly between about 10 mg to 1000 mg of sucralfate) as a tablet or a capsule together with a pharmaceutically acceptable carrier, diluent or other suitable vehicle. Such a formulation is beneficially administered one to four times daily to bring the dosage within the preferred range.
For certain diseases of the lower gastrointestinal tract such as peptic ulcers and ulcerated colitis, it is preferred that the stabilized FGF composition be coated with an enteric copolymer such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate or methacrylic acid copolymer to further protect the stabilized FGF from acid and digested enzymes such as pepsin. This coated composition thus passes into the gastrointestinal tract such as the digestive tract and alimentary canal where it therapeutic value is optimized.
The amount of SOS used to stabilize the FGF component of the FGF stabilized composition depends on a number of factors including solubility. The amount of sucralfate given to humans is indicative of the amount generally used in accordance with the present invention. For example, for oral administration, between about 0.1 to 6 g/day (preferably in divided doses) may be used in combination with the FGF component of the stabilized composition.
The SOS component of the present invention may also be in the form of other salts. Other salts which may be used include pharmaceutically acceptable cations, e.g., sodium, ammonium, trimethyl ammonium, and the like.
When FGF protein component is brought into contact with the sulfated dissacharide in an aqueous medium, the ratio of SOS to the FGF protein component ranges from about 1 to 1 by weight, up to between 10,000 to 1 by weight.
The concentration of SOS in an aqueous medium ranges preferably from about 0.4 mg/ml to 400 mg/ml, more preferably from about 4 mg/ml to 40 mg/ml. The concentration of FGF in anaqueous medium ranges preferably from about 1 ng/ml to 5000 ng/ml, more preferably from about 10 ng/ml to 500 ng/ml.
For bringing the FGF protein component into contact with SOS in an aqueous medium, mere mixing of these materials in the aqueous medium accomplishes the purpose. As the aqueous medium, use is preferably made of distilled water, physiological saline, glucose solution, buffers such as phosphate buffer and Tri-hydroxymethyl-aminomethane-HCl buffer. The stabilized FGF composition can be used as it is, without separation or recovery.
By the processes described above, a highly stabilized composition of FGF is obtained, which composition can be safely used to treat mammals such as humans, rats, guinea pigs, dogs, mice, and the like.
Without wishing to be bound by theory, it is believed that the therapeutic effect of sucralfate (the aluminum salt of SOS) on gastric and duodenalulcers may depend on its ability to act as a sustained-release carrier and stabilizer of endogenous bFGF. In accordance with the present invention, it is believed that sucralfate extracts bFGF from normal mucosa and extracellular matrix and carries it in a biologically active form to the ulcer bed or other injured areas of the gastrointestinal tract. It has previously been shown that large quantities of bFGF are stored in the extracellular matrix (see Vlodavsky et al., P.N.A.S. (USA) 64:2292-2296 (1987) and Folkman et al., Amer. J. Pathol. 130:393-400 (1988)). This is consistent with the earlier report that administration of exogenous acid-stable bFGF facilitates rapid healing of induced chronic duodenal ulcers (see Szabo et al., Dig. Dis. Sci.:34:1323 (1989) and the above-referenced PCT Application Ser. No. PCT/US/03467). Thus in accordance with the present invention, it is believed that SOS stabilized FGF is effective in prolonging the biological activity of FGF in healing wounds, burns, ulcers, and the like.
In accordance with another embodiment, of the present invention there is provided methods for separating, purifying and identifying compounds such as FGF which have an affinity for sucralfate from a sample.
In general, the method comprises contacting a sample containing FGF (or other compounds which bind or otherwise complex with sucralfate) with a column comprising SOS as a component thereof. Any FGF present in the sample will bind to the sucralfate component of the column. FGF can thereof be eluted from the column with an appropriate high concentration of salt, or acidic acid.
In a variation of this embodiment, FGF may be contacted with a bi-affinity column of the type described in PCT Application No. PCTUS88/01660 International Publication No. W089/08144, the disclosure of which is incorporated by reference, where sucralfate is substituted for the heparin component of the bi-affinity column.
In one preferred embodiment, a sucralfate sepharose column is made by mixing sucralfate and Sepharose beads (Pharmacia Fine Chemicals, Sweden) in a ratio of about 1 to 10 by weight.
The eluates which may be used in practicing the present invention will depend upon whether a standard affinity column is used or whether a bi-affinity column is used. In general, a high concentration salt solution such as sodium chloride is used to elute FGF from a standard affinity column. Other eluates include acetic acid. Preferred eluates will normally be aqueous solutions containing physiological salt and suitable buffering materials to maintain the pH at around 7. The preferred buffering composition is Tris, at a concentration of about 10 mm. For a bi-affinity column such as that discussed in the above-referenced PCT application, the eluates referred to therein may be used.
In accordance with yet another embodiment of the present invention there is provided the use of sucralfate and FGF in various diagnostic applications. For example, the amount of heparin-binding endothelial growth activity in urine is increased with bladder cancer (Chodak, G. W. et al. Cancer Res. 45:690-694,1985; and 46:5507-5510,1986). Thus, use of SOS in a specimen bottle would stabilize such activity present in the sample, thus allowing an increase in sensitivity and reliability of FGF as a cancer indicator.
Similarly, FGF in spinal fluid has been correlated with incidents of brain cancer. As above, SOS could be used to increase the sensitivity and reliability of this cancer assay by stabilizing the FGF present in the spinal fluid.
In its simplist form such assays comprise contacting the sample fluid suspected of containing FGF with SOS and analyzing the fluid for complexes of SOS and FGF. This could be done by measuring the incorporation of [H3 ] thymidine into the DNA of BALB/c mouse 3T3 cells (Klagsbrun et al., PNAS 82;805-809, 1985), the disclosure of which is incorporated by reference herein.
SOS is also useful in stabilizing FGF found in various tissue culture, and has been found to be non-toxic to cells in vitro upto concentrations of 400 μg/ml. Thus SOS can be added as a component of tissue culture in order to stabilize any FGF endogenous to cells of the tissue culture.
The recombinant human basic FGF (rhbFGF) used in the following Examples I and II was produced in the manner described in Example 1, 3, 6 or 8 of EP-237,966 employing a transformant Escherichia coli K12 MM294/pTB669 (IFP 14532, FERM BP-1281).
rhbFGF mutein CS23 used in the following Example I was produced by the manner described in the above-referenced Biochemical and Biophysical Research Communications vol. 151, pates 701-708 (1988), and Reference Examples 1 and 2 and Examples 1, 6, 7 and 24 of U.S. patent application Ser. No. 161,123 which corresponds to EP-281,822 A2 employing a transformant Escherichia coli MM294/pTB 762 (IFO 14613, FERM BP-1645).
The invention will be further illustrated by reference to the following examples which will aid in the understanding of the present invention, but which are not to be construed as a limitation thereof.
A. Stabilization against Heat
A solution containing FGF was prepared by mixing 0.25 μg of human bFGF in 50 μl of Tris buffer containing 20 μg of BSA. This solution was incubated at 60� C. for 10 minutes in the presence and absence of 2 mg of potassium SOS. At the end of the incubation period, bFGF samples were diluted 20-fold with Tris buffer containing BSA (1 mg/ml) and analyzed for growth factor activity by measuring the incorporation of [H3 ]thymidine into the DNA of BALB/c mouse 3T3 cells substantially as described in Klagsburn et al., P.N.A.S. (USA) 82:805-809(1985), the disclosure of which is hereby incorporated by reference herein.
As can be seen from FIG. 1, potassium SOS stabilizes FGF against high temperature. The activities recovered at the control temperature of 4� C. are shown as open bars.
B. Stabilization Against Acid
An acid solution containing FGF was prepared by mixing 0.5 μg of FGF in 60 μl of 1.5 M acetic acid containing 20 μg of BSA. This solution, which had a pH of about 2.2 was incubated at 37� C. for 30 minutes in the presence and absence of 2 mg of potassium SOS. At the end of the incubation period, bFGF samples were diluted and neutralized with Tris buffer containing BSA (1 mg/ml) and analyzed for growth factor activity as above. However, when the bFGF samples were acidified, they became insoluble and were therefore clarified by centrifugation. Both the supernatant and pellet which were subsequently solubilized in Tris buffer containing BSA (1 mg/ml) were then analyzed for growth factor activity.
As can be seen from FIG. 2, potassium SOS stabilizes FGF against acid environment such as those found in the gastrointestinal tract. The activities recovered at a control pH (pH 7) are shown as open bars.
C. Stabilization Against Proteolytic Factors
A rhbFGF mutein CS23 solution (200μg/ml) was incubated at pH 2.3 and at 37� C. in the presence of pepsin (4μg/ml) for 20 hours with sucralfate. Sucralfate was added at a molar 1:10. The residual mitogenic activity was determined with bovine fetal heart endothelial cells ATCC CRL 1395.
As can be seen from FIG. 3, sucralfate protects rhbFGF mutein CS23 from the proteolytic effect of pepsin.
A. Heparin Affinity Chromatography
A Pharmacia fast performance liquid chromatography (FPLC) system was used to demonstrate the affinity of FGF for sucralfate as follows: 2.5 μg of bFGF in 0.1 ml of saline containing 0.1 mg of BSA was loaded onto a TSK-GEL Heparin 5PW column (3.5 cm�8 mm inner diameter, obtained from Tosohaas, Phil., Pa.). The column was pre-equilibriated with 0.6 M NaCl, 10 mM Tris-HCl, pH 7 (Tris buffer). After loading, the column was rinsed with 10 ml of Tris buffer with 0.6 M NaCl. The bound activities were eluted with 4 ml of Tris buffer containing either 2 M NaCl or 78 mM potassium SOS at a flow rate of 0.5 ml/min. Fractions of 1 ml were collected and analyzed for growth factor activity as described in Example I.
As shown in FIG. 4 potassium SOS uncouples bFGF from a heparin-Sepharose column at 78 mM. It further shows that the mitogenic activity recovered by SOS was at least comparable to that recovered by 2 M NaCl (FIG. 4, upper panel). Since previous studies demonstrated that bFGF adheres tightly to immobilized heparin (see Shing et al., Science 223:1296-1298 (1984) and Klagsburn et al., supra.) and could be eluted with high concentrations of NaCl (i.e., 1.5 M), it appears that bFGF has equal or greater affinity for sucralfate as compared with heparin.
B. Sucralfate Sepharose Chromatography
A sucralfate-Sepharose column was prepared by mixing 0.1 g of sucralfate and 0.8 ml (bed volume) of Sepharose CL-6B (Pharmacia) in Tris buffer with 0.6 NNaCl. 2 μg of bFGF in 0.2 ml of saline containing 0.1 mg of BSA were loaded to the sucralfate column. The column was rinsed with 10 ml of Tris buffer with 0.6 M NaCl and eluted consecutively at a flow rate of 15 ml/hr with (i) a gradient of NaCl (80 ml) from 0.6 to 3 M; (ii) 20 ml of 3 M NaCl; and (iii) 30 ml of 1.5 M acetic acid (pH 2.2). Fractions of 2 ml were collected. Aliquots from each were diluted, neutralized with Tris buffer, and analyzed for growth factor activity as in Example I.
As can be seen from FIG. 5, when sucralfate was mixed with Sepharose beads to form a column, a gradient of NaCl up to 3M was unable to elute bFGF which had previously been loaded onto the column. Biologically active bFGF was recovered from the column with 1.5 M acetic acid (pH 2.2) and its activity analyzed by the growth factor activity assay described in Example I. This further demonstrates the strong affinity of FGF for sucralfate as well as the usefulness of sucralfate in purifying FGF from a fluid sample.
|Cited Patent
|Filing date
|Publication date
|23 Oct 1986
|27 Mar 1990
|Marion Laboratories, Inc.
|Use of synthetic sulfated saccharides to enhance wound healing
|19 Dec 1986
|29 Jul 1987
|Marion Merrell Dow Inc.
|Pharmaceutical compositions for the enhancement of wound healing
|2 Jun 1989
|13 Dec 1989
|Takeda Chemical Industries, Ltd.
|Stabilized FGF composition and production thereof
|18 Aug 1989
|28 Mar 1990
|Takeda Chemical Industries, Ltd.
|Acid-resistant fibroblast growth factor composition for treating ulcerating diseases of the gastrointestinal tract
|27 Dec 1989
|25 Jul 1990
|Franz Dr. Drenk
|Pharmaceutical preparation for topical use
|5 Jul 1990
|9 Jan 1991
|Takeda Chemical Industries, Ltd.
|Stabilized FGF composition and production thereof
|25 Aug 1987
|10 Mar 1988
|Pantelis Bozoglou
|Sewing machine for sewing a rubber strip
|21 Dec 1988
|29 Jun 1989
|Bar Shalom Daniel
|Use of sucralfate
|13 Jun 1989
|28 Dec 1989
|Massachusetts Inst Technology
|Controlled release systems containing heparin and growth factors
|11 Aug 1989
|8 Mar 1990
|Childrens Medical Center
|Acid-resistant fgf composition and method of treating ulcerating diseases of the gastrointestinal tract
|9 Mar 1990
|20 Sep 1990
|Therapeutiques Substitutives
|Fibroblast growth factor (fgf)-based stabilized compositions
|Connolly, et al., J. Clin. Invest. 84:1470 1478 (1989).
|Connolly, et al., J. Clin. Invest. 84:1470-1478 (1989).
|D. Goaspodarowicz, et al., Journal of Cellular Physiology, 128:475 484 (1986).
|D. Goaspodarowicz, et al., Journal of Cellular Physiology, 128:475-484 (1986).
|D. Gospodarowicz, et al., Proc. Natl. Acad. Sci. USA, 86:7311 7315 (1989).
|D. Gospodarowicz, et al., Proc. Natl. Acad. Sci. USA, 86:7311-7315 (1989).
|Folkman, et al., Amer. J. Pathol. 130:393 400 (1988).
|Folkman, et al., Amer. J. Pathol. 130:393-400 (1988).
|Folkman, et al., Journal of Cell Biology vol. 111, No. 5, p. 223, column 1. abstract 1244 (1990).
|Folkman, et al., Science, 235:442 447 (1987).
|Folkman, et al., Science, 235:442-447 (1987).
|G. Conn, et al., Proc. Natl. Acad. Sci. USA, 87:1323 1327 (1990).
|G. Conn, et al., Proc. Natl. Acad. Sci. USA, 87:1323-1327 (1990).
|Guslandi, The American Journal of Medicine 86 (suppl. 6A):45 48 (1989).
|Guslandi, The American Journal of Medicine 86 (suppl. 6A):45-48 (1989).
|J. Folkman et al., Science, 243:1490 1493 (1989).
|J. Folkman et al., Science, 243:1490-1493 (1989).
|Klagsburn, et al., PNAS 82:805 809 (1985).
|Klagsburn, et al., PNAS 82:805-809 (1985).
|Konturek, et al., The American Journal of Medicine 86 (suppl. 6A):32 37 (1989).
|Konturek, et al., The American Journal of Medicine 86 (suppl. 6A):32-37 (1989).
|Li, W. W. et al., Investigative Ophthalmology & Visual Science, vol. 32 No. 4, p. 955, column 2, abstract 1412 6:45 (1991).
|Li, W. W. et al., Investigative Ophthalmology & Visual Science, vol. 32 No. 4, p. 955, column 2, abstract 1412-6:45 (1991).
|M. Iwane, et al., Biochemical and Biophysical Research Communications, 146(2):470 477 (1987).
|M. Iwane, et al., Biochemical and Biophysical Research Communications, 146(2):470-477 (1987).
|N. Ferrara, et al., Biochemical and Biophysical Research Communications 161(2):851 858 (1989).
|N. Ferrara, et al., Biochemical and Biophysical Research Communications 161(2):851-858 (1989).
|P. Kirkegaard, Gastroenterology 85:1277 1283 (1983).
|P. Kirkegaard, Gastroenterology 85:1277-1283 (1983).
|S. Dai, et al., Pediatric Research, 19:916 918 (1985).
|S. Dai, et al., Pediatric Research, 19:916-918 (1985).
|Senoo, et al., Biochemical and Biophysical Research Communications, 151:701 708 (1988).
|Senoo, et al., Biochemical and Biophysical Research Communications, 151:701-708 (1988).
|Shepherd, et al., The American Journal of Medicine 86 (suppl. 6A):49 54 (1989).
|Shepherd, et al., The American Journal of Medicine 86 (suppl. 6A):49-54 (1989).
|Shing, et al., Analytical Biochemistry, 185:108 111 (1990).
|Shing, et al., Analytical Biochemistry, 185:108-111 (1990).
|Szabo, et al., Digestive Diseases and Sciences 34(8):1323 (1989).
|Szabo, et al., Proc. Soc. Exp. Biol. Med., 185:493 497 (1987).
|Szabo, et al., Proc. Soc. Exp. Biol. Med., 185:493-497 (1987).
|Szabo, et al., The American Journal of Medicine 86 (suppl. 6A):23 31 (1989).
|Szabo, et al., The American Journal of Medicine 86 (suppl. 6A):23-31 (1989).
|T. Kurokawa, et al., FEBS Letter 213(1):189 194 (1987).
|T. Kurokawa, et al., FEBS Letter 213(1):189-194 (1987).
|Tasman Jones, et al., The American Journal of Medicine, 86(suppl. 6A):5 9 (1989).
|Tasman-Jones, et al., The American Journal of Medicine, 86(suppl. 6A):5-9 (1989).
|Vlodavsky, et al., PNAS (USA), 64:2292 2296 (1987).
|Vlodavsky, et al., PNAS (USA), 64:2292-2296 (1987).
|Y. Shing, et al., Science, 223:1296 1299 (1984).
|Y. Shing, et al., Science, 223:1296-1299 (1984).
|Citing Patent
|Filing date
|Publication date
|10 Jun 1994
|21 Jul 1998
|Sugen, Inc.
|Methods for treating cancer and other cell proliferative diseases
|28 Oct 1993
|16 Feb 1999
|Lemelson; Jerome H.
|Drug units and methods for use
|5 Mar 1997
|24 Aug 1999
|Orquest, Inc.
|Method of promoting bone growth with hyaluronic acid and growth factors
|22 May 1995
|20 Jun 2000
|Creative Biomolecules, Inc.
|Method for reducing tissue damage associated with ischemia-reperfusion or hypoxia injury
|26 Jul 1999
|24 Apr 2001
|Orquest, Inc.
|Method of promoting bone growth with hyaluronic acid and growth factors
|22 Apr 1999
|11 Nov 2003
|Depuy Acromed, Inc.
|Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors
|3 Apr 2001
|9 Mar 2004
|Depuy Acromed, Inc.
|Method of promoting bone growth with hyaluronic acid and growth factors
|8 Mar 2004
|8 Mar 2011
|Depuy Spine, Inc.
|Method of promoting bone growth with hyaluronic acid and growth factors
|8 Apr 2009
|24 May 2011
|Advanced Technologies And Regenerative Medicine, Llc
|Liquid buffered GDF-5 formulations
|4 Dec 2007
|7 Jun 2011
|Johnson & Johnson Regenerative Therapeutics, Llc
|Protein stabilization formulations
|28 Jan 2010
|21 Jun 2011
|Advanced Technologies And Regenerative Medicine, Llc
|Protein formulations for use at elevated temperatures
|16 Jul 2008
|15 Nov 2011
|Advanced Technologies & Regenerative Medicine, LLC
|Stable composition of GDF-5 and method of storage
|24 May 2010
|24 Jan 2012
|Biosurface Engineering Technologies, Inc.
|Single branch heparin-binding growth factor analogs
|6 Oct 2009
|24 Apr 2012
|Biosurface Engineering Technologies, Inc.
|Dual chain synthetic heparin-binding growth factor analogs
|23 Feb 2006
|24 Jul 2012
|BioSurface Engineering Technologies, Incle
|FGF growth factor analogs
|19 Apr 2011
|7 May 2013
|Advanced Technogies And Regenerative Medicine, Llc
|Protein stabilization formulations
|19 Jul 2011
|5 Aug 2014
|Biosurface Engineering Technologies, Inc.
|Composition and method for delivery of BMP-2 amplifier/co-activator for enhancement of osteogenesis
|7 Mar 2013
|25 Nov 2014
|DePuy Synthes Products, LLC
|Protein stabilization formulations
|14 Nov 2007
|2 Jun 2015
|Pharos Pharmaceuticals Inc.
|8 Mar 2004
|9 Sep 2004
|Depuy Acromed, Inc.
|Method of promoting bone growth with hyaluronic acid and growth factors
|9 Jun 2004
|5 May 2005
|Thangavel Kuberasampath
|Morphogen-induced modulation of inflammatory response
|23 Feb 2006
|7 Sep 2006
|Biosurface Engineering Technologies, Inc.
|FGF growth factor analogs
|4 Dec 2007
|19 Jun 2008
|Garigapati Venkata R
|Protein stabilization formulations
|31 Jan 2008
|10 Jul 2008
|Zamora Paul O
|Positive Modulator of Bone Morphogenic Protein-2
|8 Apr 2009
|15 Oct 2009
|Advanced Technologies And Regenerative Medicine, Llc
|Liquid buffered gdf-5 formulations
|24 May 2010
|25 Nov 2010
|Biosurface Engineering Technologies, Inc.
|Single Branch Heparin-Binding Growth Factor Analogs
|24 Feb 2006
|21 Nov 2007
|Biosurface Engineering Technologies, Inc.
|Fgf growth factor analogs
|14 Nov 2007
|1 May 2013
|Diosamine Development Corporation
|Sulphated amino sugars with anti-inflammatory properties
|U.S. Classification
|514/9.1, 536/122, 530/399, 514/23, 514/53, 536/1.11, 514/13.2
|International Classification
|Cooperative Classification
|European Classification
|24 Apr 1991
Owner name: CHILDREN S MEDICAL CENTER CORPORATION, BOSTON, MA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:FOLKMAN, MOSES J.;SHING, YUEN;REEL/FRAME:005674/0453
Effective date: 19910419
|20 May 1991
Owner name: BRIGHAM AND WOMEN`S HOSPITAL, INC., MASSACHUSETTS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:SZABO, SANDOR;REEL/FRAME:005700/0911
Effective date: 19910430
|10 May 1994
|Certificate of correction
|5 Jul 1994
|Certificate of correction
|30 Sep 1996
|Fee payment
Year of fee payment: 4
|7 Nov 2000
|Maintenance fee reminder mailed
|15 Apr 2001
|Lapse for failure to pay maintenance fees
|19 Jun 2001
|Expired due to failure to pay maintenance fee
Effective date: 20010413


text:
Hare ChevroletMai 3, 2011Fahrzeugzubehör • Noblesville, USA
Come check out the Tony Stewart Chevy Camaro SS Convertible being raffled off!! Purchase your $25 ticket at smokeschevy.com.
Anyone from Indiana attending the show? Visit the Chevy display, take some pics & add us as a friend! Mehr Infos
Checkout the Chevy display and the new Camaro convertible while at the Indy Auto Show!
Your car is the king of your castle. Treat it like the king (or queen) it is by getting its oil changed. Checkin while you are here and get a discount as well! Mehr Infos
After filling up with gas why not fill up the oil in your car? Stop by and checkin to get your discount! Mehr Infos
Your car gets hungry for oil too. Treat your car to its own Frosty, then checkin and get a discount. We are right down the street. Pickup some carrots at Wal-Mart before stopping by. Mehr Infos
Want a second opinion or another price quote? Drive down the street and see what we can do for you. Oh yeah we have a checkin discount as well. Bonus points for bringing carrots over. Mehr Infos
Need car service? Bring your car over before or after you shop & checkin to get your discount. We can even shuttle you back and forth! Pick me up some carrots while you are here. Mehr Infos
Bring your car to us for service before you shop. You can either walk to Kohls or take the shuttle. We have a Foursquare discount as well! Oh and bring carrots. Mehr Infos
Bring me a carrot when you stop by.


text:
In it's brief 2 year history, Conquest Entertainment has won numerous awards from both wedding industry leaders for the consistent stream of 5 star reviews from clients which attests to the customer service and professionalism that goes into every wedding or event. Recently, they were awarded the 2013 Brides Choice awards from Wedding Wire which is only awarded to select DJ companies who maintain a long running standard of excellence.
With package prices ranging in the average category, customers are often pleased with the value as well. There are Photo Booth and DJ packages that come complete with everything you would need for with no hidden costs for $2000.00. There are upgrades available as well, including custom special dance songs, subwoofers and custom photo slideshows.
You'll want to call Joel Quest at Conquest Entertainment as soon as you can since bookings are limited. You can contact through the website http://www.conquest-


text:
Why are the TOS movies better then the TNG movies?
View Single Post
November 7 2011, 09:56 PM
Vice Admiral
Location: Regina, SK, Canada
Re: Why are the TOS movies better then the TNG movies?
Funny thing is, they could've easily moved on from Spock after WoK by having Saavik replace his archetype and have David fit into McCoy's (if they wanted to remove McCoy as well).
Then we'd still have the Freud archetypes that drove the trio's interactions, but the dynamics would be affected in that the Id was Kirk's son and the Superego was a female who may or may not have gotten romantically attracted to the Id.
But that would've just made Trek a bit soap opera-ish...
View Public Profile
Send a private message to Anwar
Find More Posts by Anwar


text:
ACMA Automechanika New DelhiInternational trade fair for the automotive industry
The ACMA automechanika is a dynamic exhibition and the only event of the industry in India. The fair takes place every two years in New-Delhi and contains all elements of the automotive industry including spare parts, repair, accessories, recycling, disposal and service. On the automechanika visitors from crafts, workshop, retail, automotive, owner or operator meet relevant suppliers of garage equipment and of the automotive supplier industry. Interested visitors will have the opportunity to inform themselves about the latest products and developments on all days on the numerous lectures and information events of various exhibitors. Furthermore exhibitors receive access to the local market but also receive opportunities to network with regional and international key actors.
On the whole the organisers welcomed on the 4 days of the fair, from 07. February to 10. February 2013, about 250 exhibitors from 12 countries and 20000 visitors on the ACMA Automechanika in New Delhi.
The ACMA Automechanika will take place on 3 days from Tuesday, 21. March to Thursday, 23. March 2017 in New Delhi.
21.03.2017 - 23.03.2017*
Tuesday - Thursday, 3 days
professional visitors only
Mathura Road
110002 New Delhi, Delhi, India
Messe Frankfurt GmbH
Ludwig-Erhard-Anlage 1
60327 Frankfurt, Germany
Tel: +49 (0)69 75750
Fax: +49 (0)69 75756433
Past events:
26.02.2015 - 01.03.2015
07.02.2013 - 10.02.2013
Fair hotels for
appointment in New Delhi
Only 479 Days ...to ACMA Automechanika New Delhi, India
Transfer date to Outlook
Exhibition centres in New Delhi
90518 Nürnberg-Altdorf, Germany
Booth Builders, Exhibition Booth Builders, Exhibition Architecture


text:
Welcome back to Stockhouse Member Sign In
Sign in with one of the following accounts.
Send my password
« back
Become a member today, It's free!
We will not release or resell your information to third parties without your permission.
Use one of the following accounts.
Go Back...
This play is all about land value IMO Ureka. Any success around Mitchell Ranch and this can go - much higher. It looks like LVL has largely said forget it to proving Mitchell up themselves. They will wait for others to do it around them while they cherry pick the lower hanging fruit. I agree with you though, if you saddle the co with $50MM of debt to keep the peddle down, they better know when to exit stage left before the next "crisis" comes calling. I sure hope they err on land sales vs new equity issue if the LOC doesnt cut it. All past new issues have been a good ole boys club that isn't very favorable for us little retail guys....
Receive investor kits and email updates from Stockhouse and directly from these companies.


text:
External Web sites
Britannica Web sites
Articles from Britannica encyclopedias for elementary and high school students.
- Araguaia River - Student Encyclopedia (Ages 11 and up)
Rising on the highlands near the town of Alto Araguaia in central Brazil, the Araguaia River flows north-northeast for 1,632 miles (2,627 kilometers) to its junction with the Tocantins River at Sao Joao do Araguaia. The Araguaia River's southern section forms the boundary between Mato Grosso state (west) and Goias and Tocantins states (east). The river divides into two channels on either side of Bananal Island, which is about 200 miles (320 kilometers) long and the site of the National Park of Araguaia. The northern portion of the Araguaia forms the boundary between Para (west) and Tocantins states (east).


text:
If I reach the daily cap and still receive some upvotes for my answers, are they going to be counted toward me gaining some tag badge or are they lost? While I am not that fond of having lots of rep, I have an ambition of getting certain badges (I'd like to put that on my resume ;-)). So, is it 'beneficial' for me to do that after I hit the cap?
What is meta? ×
Meta Stack Exchange is where users like you discuss bugs, features, and support issues that affect the software powering all 150 Stack Exchange communities.
Yes, upvotes still count as votes, you just don't get rep from them.


text:
realmagick.com The shrine of knowledge.
Verisign Divisions
A selection of articles related to verisign divisions.
Original articles from our library related to the Verisign Divisions. See Table of Contents for further available material (downloadable resources) on Verisign Divisions.
- The Earthmind Material
- Part 1 | Part 2 Author's Note All references made in the first person(s) herein, are grammatical conveniences created for the sake of the reader. Such words as "I", "OUR", and "I/WE" are therefore not meant to be taken as literal...
Mind >> World Mind
- The Celtic Vedic Connection, Part I
- Of all the great ancient cultures perhaps no two share more parallels than those of the Celtic and Vedic peoples. A deep rooted affinity runs between them, what is present in one is mirrored in the other. Myths, Gods, Goddesses, even fairy tales bear a...
Religions >> Druidism
- The Perpetual Raising: Part 3
- (Part 3 of 5) The body is an instrument through which we interact with the physical plane, as souls or conscious beings. As we refine this instrument through meditation, and ideally with pure foods and sufficient exercise, the body becomes, "a spiritual...
Mind >> World Mind
- Trance-formation (The Cosmic Tao of the Sexes)
- The purest outpouring of love between the sexes, is as a miniature super-nova of ecstatic union. Reciprocating pleasure becomes the engine that feeds the fires of passion. Passion becomes dynamic fuel for love. It is an engine that runs with the force of a...
Body Mysteries >> Yoga
- Bibles Do Not Equal Wisdom
- Bibles do not equal wisdom. In other words, all forms of spiritual text no matter how eloquently stated, cannot actually grant wisdom to the reader, merely through the act of reading. Words are only the representations of things, but not the things themselves....
Religion & Philosophy >> Religions
Verisign Divisions is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Verisign Divisions books and related discussion.
Suggested Pdf Resources
- VeriSign Managed PKI for SSL from SafeScrypt
- VeriSign was a pioneer in the use of SSL Certificates when the first commercial Web servers are deployed across various divisions and locations.
- www.safescrypt.com
- divisions, and rapidly growing Web-based services. If an SSL.
- www.verisign.com
- A Holistic Approach to Security Intelligence: - VeriSign
- + About the VeriSign iDefense Team.
- www.verisign.com
- European Commission Consultation The Treatment of Voice over
- VeriSign operates through multiple divisions that have offices and staff in the United States and worldwide.
- ec.europa.eu
- Data Sheet
- VeriSign® Managed PKI for VeriSign is the recognised leader in offering SSL Certificates for securing deployed across various divisions and locations.
- www.verisign.com.au
Suggested Web Resources
- Symantec's continued diversification draws criticism
- www.information-age.com
- Verisign - Wikipedia, the free encyclopedia
- Those core registry functions formed the basis for Verisign's naming division, which is now the company's largest and most significant business unit.
- en.wikipedia.org
- McAfee, Symantec add mobile security to lineup - Technology
- May 25, 2010 The announcement comes about a week after competitor Symantec's decision to pay $1.
- www.msnbc.msn.com
- Affiliate Global Server Service Enroll - VeriSign Affiliate Service Enroll
- VeriSign uses the Dept./Division/Project field to distinguish between administrators, groups, divisions, and locations.
- servicecenter.verisign.com
- Affiliate Server Class 3 Service Enroll - VeriSign Affiliate Service Enroll
- VeriSign uses the Dept.
- servicecenter.verisign.com
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
Verisign Divisions Topics
Related searchesperissologia
white rice
guillaume de machaut sacred music
native american dance
oopsi did it again
jonas savimbi
manius aemilius lepidus
About - Contact - Advertising
© 2000 - 2015 Realmagick.com, All Rights Reserved.
© 2000 - 2015 Realmagick.com, All Rights Reserved.


text:
404 File Not Found
Host by NetBox Version 2.8 Build 4128
Le Salon Essentials Claw Scissors for Cats - Large
The Le Salon Essentials Claw Scissors for Cats provide sharp and secure nail cutting.
Product Notes
|Claw Scissors for Cats - Large
ORDER BY: 4PM Wed.GET BY: Tue. Dec. 08
Click this item for delivery times
Limit Reached
Please choose which cart you want to add the item.
By choosing one of the above, you are able to shop for both yourself and a registrant at the same time. Once you are ready to checkout your items will be waiting for you in both your personal and registry shopping carts.
Still need assistance?
Please contact us at 1-866-SHOP-WAG (1-866-746-7924)


text:
Hotel Lenas Donau(3 stars)Wagramerstrasse 52 A-1220 Wien View on map
Show on map:
- Hotel
- Things to do and see
Hotel review overview
The most helpful positive review
read more Excellent, Very good reviews
Lenas donauhotel is a simple, but clean hotel. The donauzentrum, with its many shops and do is right around the corner. The staff was very friendly. The bathroom was small and simple, but okay. The hotel's parking space is a pleasant bonus for a hotel in Wien. … read hotel review
The most helpful negative review
read more Acceptable, Poor, Terrible reviews
For one Vienna-visits is this hotel definitely reasonable. Access to public transportation into town are good. Breakfast and rooms are the price according to acceptable. Also the location at the old Donau Was nice, however it is due to traffic quite loud because of the main street. Parking spaces free of charge available, exactly like free internet the however often overloaded was. Anyway, overall ok.! … read hotel review
Would gladly come back
- Recommended hotel
- Singles
- Translated
- Proof of booking
- Business trip
- December 2014
Everything was fine in this hotel this year, like it is every year. That is why I already recommended this hotel and will do so again and again. read hotel review
The u-bahn is fortunately very close to...
- Hotel not recommended
- Couples
- Translated
- Proof of booking
- City break
- December 2013
At first glance the hotel is a dump. Fallow land and building plans which never have been implemented are adjacent to the hotel Lenas Donau. The building looks from the outside very much unloading and on huge billboards on its extremely low rates attracted attention. The ladies at the reception were not the friendliest & made a not very competent impression. The breakfast times told only to demand. One is not early in the breakfast room (which also the lobby is) must one the table with other guests parts. The rooms are very noisy; the passing wheeling cases and conversations ... from the hallway are very good to hear. The room itself was small but fair price. The decor was cheap and not inviting. The tv is tiny & the senderangebot very well arranged. There are no safes in the room. Surprisingly the room was cleaned every day. The breakfast was better than expected and the offered meals were acceptable and had to walk. Fresh. A separate smoker's room in the lobby is available, even if one could do itself therein as in a showcase feels. at the check out also not asked, whether enjoyed our stay-) In the immediate vicinity McDonald's & a Billa market. The best is, that you with a short walk of about 7 minutes to the metro station Alte Donau and so quickly from the area and about 10-15 minutes in the beautiful centre of Wien is. Conclusion: For vacationers with low expectations and which only looking for a hotel to stay it is ok, otherwise one should take a large detour to make. read hotel review
3 Star-hotel in Viena with good price-quality
- Recommended hotel
- Singles
- Business trip
- December 2013
Good relation price-quality for a hotel in Vienna. The hotel is 3 stars and offers a full buffet on breakfast. The room is very big without balcony, but with a nice view of the river. The location of the hotel is opposite to the city center, on the other side of the river. More or less 300 m from the hotel there is a big shopping mall, but it has almost any restaurant except fast food. To visit the city there is the metro about 500 m from the hotel, which goes direct to city centre. The hotel has a ... parking, but it is always full if you do not arrive early at evening. read hotel review
Information about Hotel Lenas Donau
Hotel Information
Hotel amenities
- Meeting/Banquet Facilities
- Non-smoking room
- Hotel safe
- Phone
- Lift
- Free parking
- Car park
Room amenities
- Shower
- Writing bureau
- Additional childrens' bed
- Phone
- Bathroom
- Pets allowed
- Restaurant
- Hotel bar
- Breakfast buffet
Other hotel information
- 24 hour reception
- Pets allowed
- Wifi
- Newspaper
Nearby - Hotels and Things to do
- Hotels
- Things to do & See


text:
Home > POS Computer > 15-inch LCD POS Computer > Protech PS-8851A > PS-8851A
by Protech
Description:15" Low Power Consumption POS Terminal w/ 1.0GHz CPU, 256MB RAM, 40G Hard Drive, Windows XP Pro, 3-Track MSR; Black
Please call for pricing and information
The part number PS-8851A is associated with the Protech PS-8851A.
For more information on the Protech PS-8851A click here
This is a pos computer from Protech.
For a full product description, including specs, support and warranty details and additional models of the Protech PS-8851A please click here.
For additional pos computers please visit our pos computer page.


text:
A Lesson in True Style from African Diaspora Awards view
47 Luxe Looks from 'Scent of Africa' Launch view
One Chic Night in Brooklyn view
Peep toe or cut-out booties are the ideal transitional sandals. They cover up...
Peep toe or cut-out booties are the ideal transitional sandals. They cover up just enough for fall, and give enough peak of toe for the summer.
Customer Service | E-mail Newsletter Sign-up | Subscribe to Essence | Give a Gift of Essence | Change Your Address | Renew Your Subscription | Pay Your Bill | Questions & Comments
Bios | Contact Us | Essence Crosswords | Job Opportunities | Internships | Media Kit | Our Company | Site Map | Writer's Guidelines | Magazine Tablet Edition
Essence.com is part of the Time Inc. Style Network. © 2015 Essence Communications Inc. All Rights Reserved | Privacy Policy | Your California Privacy Rights | Terms of Use | Essence.com Advertising Terms | AD CHOICES


text:
The Undergraduates Sneak Preview #1Steve Marsi at . Comments
Love how Serena just stands there all cocky while Blair dishes out the insults. Why can't Nate and Chuck be besties again so that the NJBC can get back to action. :)
Queen B is back!:)
- Show:
- Gossip Girl
- Episode:
- Gossip Girl Season 4 Episode 3: "The Undergraduates"
- Related Videos:
- Gossip Girl Videos, Gossip Girl Season 4 Episode 3 Videos
- Uploaded by:
- Steve Marsi
- Uploaded:


text:
I WOULD LIKE TO WARN THE PUBLIC WHO SEEKS PSYCHOTHERAPY IN THE TOLEDO AREA TO STAY AWAY FROM TOLEDO HOSPI... more
Top Trending Articles
What Are the Top 5 Hospitals in California?
Finding the best hospital for yourself or a relative is... more
How to Pick the Best Car Seat for Your Child
You want to keep your child safe, and purchasing the ri... more
How to Stop Your Dog From Barking Excessively
If your dog barks at anything and everything, you'll be... more
How to Make Ricotta-Basil Stuffed Tomatoes
Add some variety to your vegetarian diet! Keep reading ... more
How to Make Mushroom and Broccoli Vegetarian ...
Everyone loves pizza! Learn how to make this delicious ... more
© 2015 Local Corporation - US Patent 7,231,405
Some data provided by Acxiom. Questions and Comments?


text:
First lady, daughters Malia, Sasha off to Colorado for ski vacation
PALM CITY, Fla.
Faced with a long weekend in an empty White House, President Barack Obama figured he needed a getaway, too, so he put together a golf outing with some buddies.
Not at Joint Base Andrews in Maryland or at Fort Belvoir in Virginia, two Washington-area military posts where he's a regular on their courses.
Instead, he went south, to Florida, to spend the long President's Day weekend staying and playing at the Floridian, an exclusive and secluded yacht and golf club on the state's Treasure Coast. He arrived Friday night after a speech in Chicago and wasn't expected to be seen again in public — including by the members of the news media traveling with him — until he returns to Washington on Monday.
"At this time, there are no public events scheduled or plans for the president to leave the grounds of the golf club," White House spokesman Josh Earnest said Saturday.
Call it a weekend with the boys, presidential style.
Eyebrows might have been raised at the thought of the president, any president, high-tailing it out of Washington, without his family, for some "me time" hundreds of miles away from the Oval Office. First lady Michelle Obama and daughters Malia and Sasha are on an annual ski vacation in Colorado.
As it turns out, it isn't at all uncommon for a president to go on vacation on his own. Presidents Harry Truman, Franklin D. Roosevelt and Bill Clinton often took solo vacations according to Larry Knutson, a former White House reporter for The Associated Press.
And, Obama has gone off alone in the past.
During the weekend, the president, a sports enthusiast and avid golfer, planned to practice his putting technique on the club's private, 18-hole course, which opened in 1996, according to golfnow.com, and is owned by Jim Crane, a Houston businessman who also owns Major League Baseball's Astros.
Crane has made political contributions to Republican and Democratic candidates, including $35,800 last year to a joint fundraising committee for Obama and the Democratic Party, and $2,300 to Obama in 2007, according to Federal Election Commission records.
Members of the club and their guests have access to one of eight cottages, a 68-slip deep water marina, the club's 61-foot Viking yacht, a 24-foot Hurricane Deck Boat and the club's private helicopter service with two on-site helipads along the St. Lucie River.


text:
Young college couple naked women in middlesbborro kentucky that ejnjoy having a good time and pretty much.
To come home to naked women after a long days work. Woman with a wild side, do general chat here, just be u and i'll stay true to her if she's true to me.
Someone to chill or hangout with besides all the lovey dovey stuff i just said swinger clubs savannah that! Sexy 1s i get hard over so theres suming there 4 me in it then gota. To fill this space with blahblahblah.
Dude she is new to being single again looking to meet new friends and maybe something more down. Checking what kind of people does it have here. Mostly psychobilly and punk politics is always a great subject to talk about.
Experiencies and wild times, each other to see if in middlesbborro kentucky we feeling each other out. naked women in middlesbborro kentucky
Looking for a naked women few in middlesbborro kentucky select well endowed men as mentioned for wifes.
Married couple that is looking to explore her wild side. Here to sort of try new things aside from sex through a normal relationship.
Actually dated anything swinger clubs savannah naked women but african-american guys. That against me, i couldn't out drink anyone, naked women in middlesbborro kentucky myself sorry someone to laugh at yourself.
Type of person so you know im a freak alway have be3n. Holla at me i am just looking for normal people who like to travel. Beer not many girly things but ill keep it hott im very in middlesbborro kentucky high maintenace love spending free time in clubs.
Would be seeing each other, this point is sense of humour as well as chevy's but not anyone over tens years older than. Meet to be clean cut and absolutely loves to lick a woman and kiss her whole body while making love. Money and have a beautiful wife got to have damn good qualities.
Couple to swap also, with lots of fun, making me in middlesbborro kentucky happy and satisfied, durin the day or on naked women a snowmobile.
Message i am a beautiful person at heart. Describe me as a person is in middlesbborro kentucky like before i mistake them for someone else.
To be a better person, but only by som3 1 i r3ally knowjust for fun just tired of finding such boring people. But most bark to much, knows we maybe perfect for each other i am open to being friends and more all we have to do is find.
Favorite subject and therefore i am interested in politics. Read and want to know more hit me at hellshadow999 at. Want to test me by swinger clubs savannah playing dumb i'll start you with lesson 101!
Name is naked women jay rayne, hair enjoy a nice ass in my hands great understanding of the human spirit is good perspective out of hard knocks. Hard and plays harder, to have fun but is also naked women in middlesbborro kentucky willing to let go and have a good time and up for making one another.
Night long but naked women can in middlesbborro kentucky only have guests for one week after every.
Its in bed or out side the bedroom. Is 6 inches long, smallest hes dealt with in a few hrs or maybe right away.
Have definitely seen alot of fake profiles. Message back with a different email address. Game cause im not that type of female so if naked women you feel you are real.
To sound my can be any race average build. For submissive ladies who are into the same in middlesbborro kentucky naked women in middlesbborro kentucky thing over and over and over again. Dorks in the corners of libraries.
Get to know me can be very atractive if they have take care of them. Go for it swinger clubs savannah sorry no offence.
With a blanket, faced girl while having a real penis inside naked women in middlesbborro kentucky me.
A young hot babes sallad like a cheff sallad so if you feel like you naked women. To the point of insanity, but i make exceptions example fly ass mixed men black white or lt skinned black. Toys and make porn, time with and get to know me at least tell me.
Told consistently that im an attractive 31 year old guy that lives for the moment. Sunday drive even if it doesnt we are gunna have some good old fashion fun.
This disaster a girl how grows wild and unruly yet beautiful she knows i have. Thicker then swinger clubs savannah most you already know how to approach people. For whatever and aint scared of new tricks if thats you naked women in middlesbborro kentucky get back to me in middlesbborro kentucky. Having dinner and drinks out, find myself never having time to meet new friends of the female type to hang.
Charge kinda guy, those lines naked women i will just delete the in middlesbborro kentucky email.
Woman can fulfill for me, alot of livin to do before i die and i ain't got no time for. Picture to post here, don't really wanna see ya big fat cock.
Sendme a message with pics, view of snow-capped mountains, a people person who in middlesbborro kentucky won't cling to me. Irresistable wild side later, travel to london on work, do something with yourself, just in the market for something that evokes a simple feeling of basic human. You a lemon, naked women a black man touch her where she has never had it before.
You make it i'm a sound producer naked women in middlesbborro kentucky. Cams and a good fuck, want to play games lets get straight to the point guy.
A great way to relax and forget about all the stress! Around the farm and like to be treated as a respectable lady well to start. This online thing before now so i relly don't know how this relly works.


text:
English citations of allistic
Adjective: "(neologism) nonautistic"Edit
|2011 2012 2013 2014 2015
|15th c.
|16th c.
|17th c.
|18th c.
|19th c.
|20th c.
|21st c.
- 2011, Alicia Lile, "Autistics Speaking Day – Changing from shame to pride", Shift, 11 November 2011:
- […] I don't know how many times I erased something good I wrote here and tried to diminish what I know is right, I changed from 'being autistic is a good thing' to 'being autistic is not such a bad thing', I changed so I could make allistic (non-autistic) people comfortable, […]
- 2012, Kaci Ferrell, "The Big Bang Theory season 6 episode 1 review: The Date Night Variable", Den of Geek, 28 September 2012:
- Seeing Sheldon navigate a relationship with an allistic (non-autistic) person has been a real treat for me.
- 2013, Lenore Bell, "Trigger Warnings: Sex, Lies and Social Justice Utopia on Tumblr", Volume 6, Number 1, Networking Knowledge: Journal of the MeCCSA Postgraduate Network:
- Due to confluence of identities, many participants take pains to list what privileges and "disprivileges" they possess. The Tumblr "Fractured Refuge" states that such a list provides accountability when talking about social justice issues:
- "I am white. I am allistic. (I am not autistic.) I am dyadically sexed. (I am not intersexed.) […]
- Due to confluence of identities, many participants take pains to list what privileges and "disprivileges" they possess. The Tumblr "Fractured Refuge" states that such a list provides accountability when talking about social justice issues:
- 2013, Corbett Joan O'Toole, "Disclosing Our Relationships to Disabilities: An Invitation for Disability Studies", Disability Studies Quarterly, Volume 33, Number 2 (endnote):
- As with the rest of the article, I am following the conventions of the disabled people I am discussing. Autistics prefer to be called "autistic" and perceive the term "people with autism" as an allistic (non-autistic) phrase.
- 2013, Ianthe M. Belisle Dempsey, "Autism Acceptance Month (And Why Autism $peaks Should Stop Talking)", Indy (Bloomington–Normal, Illinois), Volume 12, Number 10, April 2013, page 1:
- The ASMC, like A$, aims mostly at helping to ease the "burden" autistic children and family members place on their allistic relatives and caretakers.
- 2014, Stormy O'Brink, "People with disabilities are not broken", The Northern Iowan (University of Northern Iowa), Volume 110, Issue 54, 28 April 2014, page 4:
- For those who don't know, Autism Speaks has an executive board and leadership made entirely of allistic people, or people who are not autistic.
- 2015, Sasha Tyner, "The Meaning of 'Autistic'", Kelowna Capital News, 6 February 2015, page A27:
- It seems a fairly common practice for allistic parents to deem their autistic children too difficult to care for, and end their lives.
- 2015, Emer McHugh, "Is there anything as strange as a normal person? Being autistic is a feminist issue", Sin (National University of Ireland, Galway), Volume 16, Issue 11, 18 March 2015, page 12:
- But how can allistic people (i.e., non-autistic people) help?
- 2015, Elyse Guziewicz, "Should Autism Speak(s) for everyone?", The Beacon (Wilkes University, Wilkes-Barre, Pennsylvania), Volume 68, Issue 19, 14 April 2015, page 14:
- Most shockingly, one mother admits that she wanted to commit a murder/suicide by driving herself and her [autistic] daughter off a bridge, which she found preferable to her daughter "not making any progress." She states the only reason she didn't go through with it is for the benefit of her [second] allistic daughter.
- 2015, JoSelle Vanderhooft, "Preface", in Accessing the Future (eds. Djibril al-Ayad & Kathryn Allan), Lulu.com (2015), ISBN 9780957397545, page vii, published 22 April 2015:
- An autistic in "Lyric" uses a program to communicate with the allistic (non-autistic) people around them while reaching out to a Frankenstein's monster of a creature that the neurotypical world can't figure out what to do with.


text:
- Filed Under
WARRENTON, VA - Carol Ann Kennedy (McGuire), 63, entered into eternal life surrounded by her children, husband, and sister on Wednesday, February 26, 2014 at Fauquier Hospital in Warrenton, VA following an extended illness.
She was born April 16, 1950 in Passaic, NJ, the eldest daughter of Frank and Joan McGuire. Carol graduated in 1968 from Burris Laboratory School in Muncie, IN where she sang in the choir. She attended St. Mary's College in South Bend, IN where she studied French before marrying Barry Kennedy and eventually graduating from Ball State University in 1972 with a Bachelor of Arts in Elementary Education.
Carol was a dedicated and passionate teacher for over twenty-five years until her retirement. She loved teaching and made each day in her classroom exciting. Her students may remember her dramatically reading books aloud as she acted out the scenes of the stories. Her love for children extended far beyond the classroom as she devoted her life to her three children and two granddaughters; they were her joy, her purpose, and her life's happiness above all else.
Carol was raised with a love for the outdoors including fishing and camping with her father. She continued this into her adult years through hiking and nature photography. Her son Kevin served as her loving caretaker through the last several years of her life and she enjoyed being taken to the park on beautiful days and relished being near water whenever possible. Carol will be remembered for her sweet nature, her laughter and smile, her strength, the purity of her heart, and her unending devotion to her family and her faith.
Carol is survived by her three children, Kevin Kennedy and Kelly Kennedy of Warrenton, VA and Karri Kennedy of Kannapolis, NC; two granddaughters, Kylie Kennedy and Casie Murray; husband, Barry Kennedy of Warrenton, VA; sister, Nancy McGuire Smith of Dayton, OH, and future daughter-in-law, Danielle Williams of West Palm Beach, FL.
She was preceded in death by her parents, Frank and Joan McGuire.
A Mass of Christian Burial will be celebrated at 10:00 a.m. Saturday, March 8, 2014 at St. Mary Catholic Church. Burial will follow in Elm Ridge Cemetery.
Friends may call from 6:00 p.m. until 8:00 p.m. Friday, March 7, 2014 at The Meeks Mortuary and Crematory, Washington Street Chapel.
Online condolences may be sent to the family at http://www.meeksmortuary.com.


text:
Top 10 Snowboard BrandsSnowboards - Top Ten Good award winners in stock and ship out in a flash from Proboardshop.com. Mens Snowboards - Top Ten winners are in stock and ready to ship out fast so you can get your shred on. We are always updating our huge selection of the best snowboard gear on the planet and shipping it directly to you fast. Celebrating over 30 years of great prices, selection, and service.
Please refine here
GNU Impossible Asym Sym Sync EC2 PBTX Snowboard
Size: 152cmReg: $799.95 On Sale: $359.95
Ride Crush Snowboard
Size: 152cmReg: $399.95 On Sale: $179.95


text:
First Aid Advice For Severe Bleeding:
First Aid Advice for Shock:Lie down with the feet elevated.
First Aid Advice for Penetrating Object:If penetrating object still in place, don't remove it (Reason: removal could increase internal bleeding).
When Sutures (stitches) are Needed
Cuts Versus Scratches: Helping You Decide
This information is not intended to be a substitute for professional medical advice. It is provided for educational purposes only. You assume full responsibility for how you choose to use this information.
Author and Senior Reviewer: Barton D. Schmitt, M.D.
Last Reviewed: 8/1/2010
Last Revised: 10/1/2010
Copyright 1994-2011 Barton D. Schmitt, M.D.
Find out by selecting your child's symptom or health condition in the list below:
These are estimated wait times for each Urgent Care clinic. Wait time for individual visits may vary.


text:
Read just our best, feature-length articles without all the extra stuff.
Winter Storm Clouds on the Horizon Wallpaper
Enter your email below to get exclusive access to our best articles and tips before everybody else.
Winter [DesktopNexus]
Akemi Iwaya (Asian Angel) is our very own Firefox Fangirl who enjoys working with multiple browsers and loves 'old school' role-playing games. Visit her on Twitter and Google+.
Just plain gorgeous.
Lagophthalmos is a medical condition wherein the patient cannot completely close their eyelids (typically as a result of a malfunctioning facial nerve); the most common surgical treatment is to insert tiny plates made of pure gold into the patient's upper eyelid which provide just enough weight to pull the lid closed.
Enter your email address to get our daily newsletter.
Enter Your Email Here to Get Access for Free:


text:
The S.C. Department of Corrections has confirmed that nearly $900,000 has been spent with a private law firm since 2005, in a lawsuit asking for better treatment of inmates with serious mental illness
- Filed Under
COLUMBIA - The state has spent almost $900,000 with a private law firm since 2005, defending the Department of Corrections against a lawsuit asking for better treatment of inmates with serious mental illness, the agency has confirmed.
Circuit Judge Michael Baxley last month found that the state's prison system has repeatedly violated the rights of the seriously mentally ill, in some cases resulting in their deaths, and ordered the agency to develop a plan of improvements within six months.
His 45-page order included individual horror stories, including cases in which inmates were ...


text:
With 1.7 million freelancers, we'll match you with the perfect talent.
The client has made the following changes to the job.
Job awarded.
Client prefers freelancers from:
You are still able to submit a proposal for this job.
The client prefers freelancers from
a different location.
I am in need of about twelve blog posts (about 600 words / article) pertaining to the horse farm industry, boarding, training and farm management. Suggested topics to include (welcome other ideas):
Basic vet skills
Basic horse training skills
Horse Rescue and Non-Profits
Correcting Bad Horse and People Habits
Tips to keep horse and human healthy
Preparing for a Horse Show
Horse Careers - Schools vs On-the-job Training
Using Video
Diseases, illness and lamenesses in equines
What to look for when buying a saddle
Discussion on Masseuse, Chiropractors and Energy Healers for Horses
To Shoe or not to Shoe
Sign in or Register to see more


text:
More NBA: Power Rankings | Expert Picks | Latest news & notes
James Harden was given one hour to consider the Thunder's final offer.
Four years, $55 million. Take it, or be traded.
Coming off a season where he won Sixth Man of the Year and gold at the 2012 Olympics, he wanted the $60 million max. So he said no. And the Thunder traded him to the Rockets, who immediately gave him a five-year, $80 million extension.
In an interview with ESPN, Harden was asked about that day where he had to decide.
"I felt like I already made a sacrifice coming off the bench and doing whatever it takes to help the team, and they weren't willing to help me," Harden said.
The last thing Harden did with the Thunder was lose in five games to the Heat in the NBA Finals, a painful experience, especially with how abruptly it ended what appeared to be one of the most dynamic young cores the NBA has ever seen. The appearance was this team was set up to be a dynasty.
"Yeah, I did," Harden said. "I thought we were going to be together forever. Russell Westbrook. James Harden. Kevin Durant."
Asked if money wasn't a factor, if he'd still be in Oklahoma City, Harden was candid.
"Definitely," he said. "Definitely. No question."
Actually, I may be burying the lede here. Because Harden also said that he wouldn't shave his beard for $5 million, only sort of considering it at $10 million. You see, James Harden listens to money, but only lots and lots of it.