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Improving your skin is so easy you can do it in your sleep.
Sleep helps to restore your skin's natural balance. However, when you don't get enough of it, your complexion could be a telltale sign, appearing dull and puffy after only one night of interrupted shuteye.
Inevitable? Sure. But don't make restless nights a habit. Chronic sleep depravation can cause premature aging, stress and fatigue.
Like the rest of our bodies, skin needs that special "shut down period" in order to stay hydrated and refreshed for the next day.
As you may have heard, doctors recommend eight hours of sleep per night to look and feel your best. Even missing out on a measly 60 minutes a night adds up to almost a full night's sleep in just a week. And trust us, your skin will do the math.
Clocking a full 8 hours might take some practice. Be sure to avoid alcohol, coffee and tea 4-6 hours prior to bedtime, get regular exercise, and infuse a "wind-down hour" into your nightly routine. Once the lights go out, keep them out—cell phone and laptop screens are proven to negatively affect sleepiness.
Make the most of your rest by understanding the body's natural behavior. Skin acts like a sponge while you sleep, absorbing ingredients during the nightly renewal process. Because it's so accessible during this time, skin care products formulated for night, like Revitalift Anti-Wrinkle + Firming Night Cream, work great. This product works while you snooze to increase cell turnover, reduce the appearance of lines, and plump skin for a more youthful look.
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America's Civil War Magazine
Really! Get a no-fuss refund for all undelivered issues. Enjoy the price savings of a subscription while keeping complete flexibility.
8,000,000+ Satisfied Customers
Over 8,000,000 customers and a continuous A+ rating from the Better Business Bureau since 1999. We do whatever it takes to take care of our customers.
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Additional Information
About America's Civil War
Each issue contains well-researched articles about the war's key battles, leaders, strategies and locations. Written by historians and leading experts, the magazine provides complex insight into the Civil War. Each issue also reveals period photos, maps, historical relics and little-known facts about the tumultuous and trying period.
America's Civil War magazine gives readers an insider's look at the issues that caused the war, the military geniuses who strategized for the war, and the individuals who were involved in it. History enthusiasts of all ages will look forward to each new issue of America's Civil War. Packed with stories about important battles and key moments, it's the perfect magazine for anyone who wants to know more about the Civil War.
Automatic Renewal Service:For your convenience, this publication is part of the Automatic Renewal Service. You will receive all the benefits of our automatic renewal program. 100% Satisfaction Guarantee - cancel at any time!
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Each issue brings you American Indian history, contemporary arts, Native film, theater, music, culture, Native American recipes, pow-wows & events in North & South America in exquisite full-color.
Internal Medicine Coding Alert cuts through the confusion of correctly billing insurance companies and Medicare for internal medicine claims. This resource helps accurately code for E/M services, electrocardiograms, ESRD, and more.
Military Spouse magazine is the only national magazine that is by, for, and about U.S. Military Spouses. Military Spouse magazine incorporates all aspects of life in the military.
Martha Stewart Weddings is a bridal and weddings magazine that caters to engaged couples who want to create unique, personalized celebrations that everyone will remember.Since 1994, Martha Stewart Weddings has been providing soon-to-be brides and grooms with information, ideas and ...

subset: commoncrawl


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Advil Liquid Capsules contains a liquid centre of ibuprofen inside of a soft capsule shell; therefore making it easier to breakdown inside of the body and is absorbed a lot faster than a standard tablet, providing quick relief to where it is needed most.
Advil Liquid Capsules work locally at the site of mild pain, providing an anti- inflammatory effect effectively reducing fever and relieving pain where inflammation is present.
Advil Liquid Capsules can be used for:
* Headache
* Back Pain
* Muscle Pain
* Period Pain
Always read the label. Use only as directed. Incorrect use could be harmful.
Consult your healthcare professional if symptoms persist.
For information on warnings, precautions and contraindications consult your healthcare professional or refer to product packaging.
Each Advil Liquid Capsule Contains 200mg of Ibuprofen.
Customer Reviews
Orders within Australia – Regular Post
Orders will be delivered by Australia Post.
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Crafted from soft jersey cotton, this long-sleeved top from Joules will ensure warmth and comfort between the sheets. Decorated in a vintage-style buck print, the cheeky tagline is sure to raise a smile.
Thank you for visiting Joules Julian Buxk Long Sleeve Jersey T-Shirt, Navy Marl on shoppingfind.co.uk
We bring the products from many websites to one website for you to search, save and compare.


text: Jenny Sanford: "Nobody Wants Their Children To Read Smut Like That About Their Father...From Their Father."Hortense Smith2/06/10 1:30pmFiled to: notes on a scandalJenny sanford 20/20Jenny sanford barbara waltersJenny sanfordPolitics134EditPromoteShare to KinjaToggle Conversation toolsGo to permalink On last night's 20/20, Jenny Sanford sat down with Barbara Walters to discuss her husband's affair and the subsequent toll the extremely public fallout took on their marriage and their children. Clip after the jump. Sanford notes that the e-mails, which her children have read, were the final straw that caused her to leave the marriage, and that though Sanford has tried to reconcile with her, she is determined to get divorced: When asked by Walters if she knows whether Sanford is still in touch with his mistress from Argentina, Sanford insists she doesn't want to know, because she wants to move on. "I would say that I have acted honorably in our marriage," she says, "and I've been the best wife I can be. But now I'm looking forward to whatever comes next."Jenny Sanford On Decision To Divorce [ABCNews]Reply134 repliesLeave a reply


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Whole Living magazine provides smart ideas on taking care of yourself, your family and the planet in ways that are natural and sustainable. Whole Living magazine promotes wellness, fitness and beauty, balance, community and living green.
Do we need a discount code? This comes up on the site as $29.90.
it's MYBARGAINBUDDY
Thank you!! 🙂
Oops! Forgot to put that in there. 🙂
I'm with Lavender. Maybe we missed the opp? Would love to get it!
The deal is back!
I must have been late ordering, they said the discount code was invalid. So sad.


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St. Patrick's Day Celebration
March 17, 2017River Falls
Follow the rainbow to downtown River Falls and celebrate St. Patrick's Day! Kick off the festivities with the Pot 'O Gold Medallion Hunt as clues are revealed throughout the day. Partake in the Poker Walk and indulge in the Potato Soup Cook-off by sampling delicious, comforting soups from participating businesses. Cheer on favorite teams as beds race through historic River Falls. Sponsored by the River Falls Area Chamber of Commerce & Tourism Bureau.
Event Date Detail
Mar 17, 2017
Fair/Festival Type
- Holiday


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Toyota Corolla Verso (2002 to 2004)
Click on thumbnails or names for further information.
>> Car boot organisers:
>> Carbox Form low liner:
Carbox LS Toyota Corolla Verso (02 to 04) JV20-8091
Low Short boot mats fit behind the rear seats
Low Short boot mats fit behind the rear seats
>> Carbox Classic high liner:
Carbox HS Toyota Corolla Verso (02 to 04) JV10-8098
- This high-sided liner fits behind the rear seats.
- A Carbox high-sided liner will help to keep your car boot in immaculate condition, and protect its resale value.
All our prices include VAT at 20%


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PRO+ Premium Content/E-Books
Access your Pro+ Content below.
Introduction to virtualization: Hypervisors
Sponsored by SearchServerVirtualization
This chapter is included in the Introduction to virtualization for administrators E-Book.
Virtualization technology isn't complete without a hypervisor. This final chapter of the Introduction to Virtualization e-book explains some hypervisor basics—highlighting the differences between bare-metal and hosted hypervisors—and lists some features that you should look for when selecting one for your virtual environment.
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Be prepared with server benchmarking, documentation toolsDownload
VMware Virtual Volumes provide path out of legacy storageDownload
Virtualization containers aren't the nightmare you might imagineDownload
Storage may be to blame for that I/O bottleneckDownload


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Lexington Partners Said to Near Three Fund MilestonesKiel Porter
Lexington Partners Inc., one of the largest firms dedicated to buying private-equity interests, is set to complete fundraising for two pools this year before seeking investors for its next flagship vehicle in 2014, according to two people with knowledge of the plans.
Lexington is to finish fundraising on its third co-investment fund, Lexington Co-Investment Partners III LP, of about $1.5 billion by the end of June, said the people, who asked not to be identified because the talks are private. Secondaries funds such as those run by Lexington buy investors' commitments in private-equity funds rather than purchasing companies directly.
Previously, Lexington co-investment funds were backed largely by just two institutions, the Florida State Board of Administration and the New York State Teachers Retirement System. The new fund, which invests directly in companies owned by private-equity managers, will feature a wider investor base, one person said.
Separately, New York-based Lexington held a first close, the point at which a fund can begin to invest, for its third mid-market fund, Lexington Middle Market Investors III LP, in April and is expected to hold a final close at its $750 million target by the end of 2013, the people said.
With marketing for these funds completed, Lexington is expected to begin raising a successor to its main vehicle, Lexington Capital Partners VIII LP, in early 2014, the people said. The fund is expected to have a similar target to its predecessor, which closed at $7 billion in 2011, one person said.
A spokesman for Lexington declined to comment.


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Moody College of Communication Scholarship Application
By completing our application, students are considered for any of our scholarships for which they are eligible.
What questions will I have to answer in the application?
Click here to review the full details of the scholarship application.
What are the criteria for the scholarships?
A full list of the scholarships awarded through this single application can be found here.
Am I eligible to apply?
Eligibility criteria are listed here.
Summer scholarships: The Moody College offers six scholarships that may be used for summer internships or projects. Full details are available on this webpage.
Jesse H. Jones Fellowships
The Moody College of Communication annually awards the Jesse H. Jones Endowed Centennial Fellowships to graduate students who possess exceptional ability in advertising, communication sciences and disorders, journalism, radio-television-film, or communication studies. The fellowships are awarded each Spring for the following academic year. The fellowships are open to masters or doctoral students who are enrolled in a Moody College graduate program at the time of application, or were enrolled in a Moody College graduate program during the prior long semester; applicants must be seeking funding for the second or subsequent year of their programs. Preference is given to candidates with a strong, interdisciplinary track record. Click here for more details.
Students can apply for a Jesse Jones Fellowship by completing the Moody College of Communication's Scholarship Application.
Wofford Denius Music Industry Internship Grants Program
The Wofford Denius Music Industry Internship Grants Program is a special program that grants financial assistance to Moody College of Communication students pursuing summer internships in the music industry in Los Angeles, New York City and Nashville.
Other Resources
Undergraduate Research Fellowship program
The Undergraduate Research Fellowship program provides support for specific scholarly research projects conducted by full-time UT undergraduate students enrolled in any department. These fellowships are intended to cover costs associated with academic research projects proposed and written by student applicants and undertaken with the supervision of a university tenured or tenure-track faculty member, lecturer, senior lecturer or full-time research scientist/engineer. Some restrictions apply. See current application for more information.
The application for Fall 2017/Spring 2018 is now open. Click here to apply. The deadline is noon (CT) on February 28, 2017. Late materials will not be accepted.
December 2017 graduates may apply.
All scholarships for Fall 2016 and Spring 2017 have been awarded.
Follow us on Facebook to learn about scholarship opportunities
Whenever we learn about a scholarship opportunity that Communication students can apply for, we'll post it on Facebook.


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Twisted snaffles are more severe than regular jointed snaffles. The ridges caused by the twisting make pressure points on the bars of the mouth. Obviously, the more twisting, the more severe, and for that reason, the twisted wire snaffle is more severe than the bit shown on this page and a double twisted bit is even more severe.
For a horse that, for whatever reason, has become unresponsive to a regular snaffle, twisted bits are perhaps an option. A slow twist like this might be useful when taking a horse out in company, where he might tend to get strong.
I'm not a fan of twisted bits. I've seen instances where the pain caused by the use of progressively more severe bits has actually caused worse behaviour from the horse. Taking the horse back to the simplest, most gentle bit and going back to basics with his training may alleviate the need for such strong bits as the double twisted wire snaffle.
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Sorry! The position you're looking for is no longer available. Check out other Legal internships in Chicago, IL below.
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WKPOP — Chicago, IL
February 27 2017
WKPOP is a new kind of dancing/ fitness program for women and girls of all ages to have fun and get fit through the power of kpop dancing. As we combine kpop dancing and exercising into an all-fun jam…
Application Deadline: Available Year-round
Full time
Combined Insurance — Chicago, IL
February 17 2017
ombined Insurance is a leading provider of individual supplemental accident, disability, health and life insurance products. We pride ourselves on being customer-centric, people-driven, accountable, p…
Application Deadline: 3/3/2017
Full time Paid
Sales / Business Development Strategies for New Car Sharing Start-up
Quanticleap — Chicago, IL
December 10 2016
QUANTICLEAP, LLC is a very early stage start-up founded by serial entrepreneur Jason Randolph focusing on leveraging data to better optimize auto rentals and sharing. We maintain a fleet of luxury SUV…
Application Deadline: Available Year-round
Part time Paid
Social Media Intern
Origin Development & IT — Chicago, IL
November 30 2016
Origin Development is a small, fast, fun company that provides technology solutions. Most of our work involves web application development and we traditionally support clients in the live events indus…
Application Deadline: Available Year-round
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Paralegal Internship
McCready, Garcia & Leet — Chicago, IL
November 29 2016
McCready, Garcia & Leet is a personal injury law office on the south side of Chicago. We are looking for an intern's assistance while they earn credits for school. The intern would have a flexible sch…
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Legal Intern/Volunteer to assist victims of domestic violence
Mil Mujeres — Chicago, IL
November 11 2016
Mil Mujeres, a non-profit organization dedicated to providing comprehensive immigration legal services to Spanish-speaking survivors of domestic violence, physical assault, sexual assault and human tr…
Application Deadline: Available Year-round
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Front of House Restaurant Internship
Entertainment Cruises — Chicago, IL
September 10 2016
We are offering an Internship program from May 15, 2017 August 11, 2017 that will provide students with the opportunity to expand their knowledge in the field of hospitalityand determine whether they…
Application Deadline: 4/30/2017
Full time Paid
Chicago Loop Paralegal Internship
Dworkin and Maciariello — Chicago, IL
September 06 2016
Dworkin and Maciariello a Workers Compensation/Personal Injury law firm in the loop, is looking for interns to assist us while earning credits for school. The internship would be Monday to Friday hour…
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Record Label Artist & Repertoire (A&R)
Maek — Chicago, IL
August 18 2016
As an A&R representative, you will be responsible for talent scouting and overseeing the artistic development of our artists. You will act as a liaison between artists and the record label and be invo…
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SQL and Data Analyst
Prosperoware LLC — Chicago, IL
August 07 2016
Founded in 2009, Prosperoware has developed the industrys most comprehensive set of integrated software platforms to streamline business processes, manage risk, and improve profitability for legal and…
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Industrial Psychology Programs in Wyoming
The information below is designed to help people explore potential careers, and find information about colleges offering related educational programs. If interested,each individual may contact multiple schools.
Also try online schools for industrial psychology, for more choices and flexibility.
Featured Industrial Psychology Programs in Wyoming
Kaplan UniversityCampus
- Locations:
- Fort Lauderdale, FL
Grand Canyon UniversityCampus
- Locations:
- Phoenix, AZ
Colorado Technical University OnlineCampus
- Locations:
- Colorado Springs, CO
Colorado State University-Global CampusCampus
- Locations:
- Englewood, CO
Baker College OnlineCampus
Baker College is proud to be the largest independent college in Michigan with the most focused approach to education and training available. With one of the highest graduate employment rates in the country, our mission is to help our students find meaningful employment.
- Locations:
- Willis, MI
Keiser University Graduate SchoolCampus
For over 35 years, Keiser University has maintained a practical, hands-on approach to career education to help our students achieve their personal and professional goals.
- Locations:
- Fort Lauderdale, FL
Northcentral UniversityCampus
Earn your graduate degree online with Northcentral University.
- Locations:
- San Diego, CA


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They've been rammed, beaten, dropped, run over, and even decapitated, all in the name of automotive safety. Join us as we track the evolution of the crash test dummy, one spectacular car wreck at a time. We examine each member of the dummy family tree, from 1948's Thin Man, the grandfather of them all, to 1976's industry standard Hybrid III, to today's THOR, the $750,000 god of safety. We also sit in on recent crash test experiments to show how, even decades later, these heroes of the highway show no signs of slowing down.
Engineer Jem Stansfield investigates how the crash test dummy has become an icon for safety. For 65 years he has been crashed, smashed and impaled, evolving from a simple military mannequin into a highly sophisticated measuring tool.
God Shuffled His Feet is the second album by the Crash Test Dummies, released in 1993. It features their most popular single, "Mmm Mmm Mmm Mmm". The cover art superimposes the band members' faces over the figures of Titian's painting Bacchus and Ariadne. It was their most successful album commercially.


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But fear not - there is plenty to explore...Shop all K2 Shop sale K2
If pitted with the difficult task of finding a one-ski quiver, the K2 Shreditor 112 Skis are one of few that truly fit the bill. Wide enough to handle any soft snow conditions with aplomb, but not too cumbersome to rip on the hardpack, the Shreditor 112's are K2 s most versatile quiver-of-one choice for the steep and deep aficionado who also has to ride with the fam and shralp a few blues. The mountains we ride and conditions we ride in aren't always consistent, but with the K2 Shreditor 112 Skis you'll be shredding hard regardless.
All-Terrain Rocker Designed for all ability levels, All-Terrain Rocker adds versatility and ease in all snow conditions. This profile features an elevated tip and tail for variable and soft snow performance, as well as camber underfoot for power, energy, and edgehold in firmer conditions.
Medium Flex
Freestyle Baseline 2.0 By designing a ski's profile (rocker and camber) to work in combination with it's overall shape (top shape and sidecut) K2's engineers are able to create skis specifically targeted for a desired type of terrain, ability level, snow condition, and even skiing style.
Tapered Tip A tapered shifts the widest part further back to reduce tip weight and deflection in soft and variable snow conditions. A tapered tail allows for easier release as you exit the turn for a more playful yet predictable and trusted feel.
Forebody Tapered, blunted powder focused tip for predictability in soft and variable conditions.
Midbody Medium to wide waist widths range from 102 to 120 mm for float with a moderate sidecut for quick, medium turn shapes.
Tail Tapered, blunted twin tips for a looser more playful feel.
Fir / Aspen Core
Triaxial Braid A K2-patented machine interlocks strands of fiberglass around a milled core for pronounced torsional strength, while retaining the lively flex patterns inherent in a wood ski.
TwinTech Sidewalls A unique blend of sidewall and cap constructions for accuracy and power underfoot combined with lightness, chip resistance and smooth turn initiation.
Swap Base K2 maximizes base material usage by alternating the contrasting die cut pieces - your base may be the reverse of what you see pictured.
We recommend a brake width equal to or at most 15 mm wider than the ski waist width.
|Size (cm)
|Tip Width (mm)
|Waist Width (mm)
|Tail Width (mm)
|Turning Radius (m)
REVIEW SNAPSHOT®by PowerReviews
Best Uses
Reviewed by 3 customers
Best Uses
Comments about K2 Shreditor 112 Skis 2016:
Awesome ski hands down. Not too far to rip groomers but not to skinny to float in the powder. The tapered nose and tail make it a very playful and surfy ski perfect for getting lost in the white room and numerous nose butters. The camber underfoot, however, not a lot, is just enough to keep an edge and make this a true all mountain ski. It's exceptional at nothing but truly above average at most things. Get this ski now.
Best Uses
Comments about K2 Shreditor 112 Skis 2016:
These are the best one ski quiver for me. I'm 165lbs 6 feet tall got the 189, it is perfect length and I mounted them -1.5cm from true center. I use these skis mainly for park and powder, if I had a ski just for park I would go skinnier, but these are the best if your like me you're in the park when the conditions aren't very good but you live for the powder days. Overall the flex is nice it isn't too soft, it is good for park but if you charge a lot then this isn't the ski for you. In powder this thing is sick, i can do 360s and huck small cliffs, but if you huck big cliffs I would get a stiffer ski. The flotation is superb, it is as much as you need maybe you will want wider for the deepest days, but these are a one ski quiver for me so they cant be perfect for everything.
Best Uses
Comments about K2 Shreditor 112 Skis 2016:
Pretty fun ski for playing around but was surprised at how soft it was when I got it. It is extremely chatery at high speeds. Also fun for jumps. First day ever using them however the edge and 6 inches of sidewall under the foot blew out. It was early season but I hadn't hit anything major on the way down, at most scraped against a log. I somehow got it fixed which last me a while but all the edges started to crack very easily the rest of the season.


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Theodore Roethke
Theodore Roethke Poems
My Papa's Waltz
The whiskey on your breath
Could make a small boy dizzy;
But I hung on like death:
Such waltzing was not easy.
We romped until the pans
Slid from the kitchen shelf;
My mother's countenance
Could not unfrown itself.
The hand that held my wrist
Was battered on one knuckle;
At every step you missed
My right ear scraped a buckle.
You beat time on my head
With a palm caked hard by dirt,
Then waltzed me off to bed
Still clinging to your shirt.
The Geranium
When I put her out, once, by the garbage pail,
She looked so limp and bedraggled,
So foolish and trusting, like a sick poodle,
Or a wizened aster in late September,
I brought her back in again
For a new routine--
Vitamins, water, and whatever
Sustenance seemed sensible
At the time: she'd lived


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This series is a form of creative writing known as fan fiction. Detective Robert Goren is a regular character on the Dick Wolf television show, Law & Order: Criminal Intent. What follows is one longtime viewer's breath of life into an already popular character.
I'm waiting to hear back from my mother's doctor. After her recent break they've tried lowering her meds back down a bit. The thinking was to stabilize her and then try to get her back to the lower dosage. Last night she had a setback. The problem is nothing appeared to trigger it. She was alone in her room and basically just collapsed mentally all over again. She slept last night and woke this morning in the same fragile state. They opted to pump her full of those damn drugs again and she'll be down for the day. I'm not sure what the next step is. Keeping the meds elevated leaves her really lethargic at best. But does she need a higher dose. Is it better for her to be unaware of her inner demons? I just don't know what to even hope for. Whatever is in her best interest is best. Escaping her inner torture is a blessing I'm sure. I know that. But what quality of life is that? Not that a mental break every few weeks is better. It's beginning to feel like a lose/lose situation. She has been slipping away from me for most of my life. I've watched it, seen the gradual mental decomposition and it… Hurts, but she has always known me. An increase at this point means she won't always communicate or even realize I'm in the room. If she does realize I'm there she may not know who I am.
The lesser of the evils… for her. How do I know what that even is?
All the thinking, trying to figure out what is really best has made me really look at my mom's life overall. I could say upping meds so that she is lethargic if not catatonic is lousy, but is it better than her moment by moment reality when she is clear and alert? No one but her can really answer that. Clear-headed but haunted, or spacey and at peace? I think it's one of those situations where you think you know what you'd rather but when presented with the situation for real, your mind could change.
When I think about her relationship with my father… I wonder if she just couldn't handle him. Did she start backslidding mentally because it was better, easier than staying in the present. Was it easier to get lost in her own psychosis than it was to really admit how lousy her life with her husband was? Even when I was a kid and they'd fight, I knew what he did was wrong. I blamed her for him leaving, but I also thought he treated her badly. He was always so self- important and self-absorbed. Every conversation was turned into something about himself. He had a way of doing that and it drove everyone nuts. You always felt like he was superior, not because he really was, but because he needed to believe he was. His own arrogance led him to believe that he could say whatever the hell he liked to anyone at all – but if they responded, well. How dare they? How dare anyone say anything negative about him?
A fine example of a man who could dish it but couldn't handle getting back what he brought on himself.
In many ways they were polar opposites. Mom wanted peace and calm while dad thrived on chaos and drama. Two radically different sets of needs trying to coexist in a merged world. I can to this day remember mom trying to talk to him and feeling… less than him. Or that's how she believed he saw her. One night not long before he left us I heard them fighting. I didn't understand it very much then. Now as a grown man it kills me. She was asking for the simplest of things. Emotional support. She felt doomed in his presence. He wanted particular things accomplished then slammed her when she tried to do them. The gist was if you can't be supportive then at the very least, stop dragging me down.
"If you love me why do you take so much pleasure in insulting me just for kicks?"
I can still hear her saying that. How did he respond to her request to back off and stop being so hurtful? By slinging more insults. Pushing more buttons. Belittling her for things undone and insulting anything accomplished. Hitting raw nerves one at a time until she finally snapped and punched him.
I can still see the big, pompous, self-important man on the living room floor choking my mother while I watched from the next room. Mangling the body of the woman who was half his size. Sealing the deal, showing her exactly what type of dirt beneath his shoes he thought her to be. She was good enough to carry his children, cook his meals, cater to his insane extended family, but how dare she… How dare she ask that he treat her with the same respect that she instinctively tried to give him? The nerve of her to initiate a conversation where she simply asked to be treated with a little bit of kindness. A reminder that she needed to feel supported and held up by someone and as her husband, shouldn't he be the one to want to do that?
My father left that night after finally letting mom go. He was gone for a few hours and I'm sure she prayed he would drive his sorry, drunken ass into a telephone pole. She was oblivious to me even being there. She was just lost in her own thoughts. I lost count of how many times I heard her tell herself out loud that she hated him.
"I hate him. I hate him. I hate him."
It was almost like a chant.
The next morning she was withdrawn from everything. Bruised and slow moving. She looked defeated physically but emotionally I think he did choke some of the life from her. That was a clear turning point in her sickness. If she stayed lost in her own head, if she withdrew into her own deluded world – well maybe those delusions were better than reality. Maybe in her delusions she fits in. Maybe the people who live in her head, maybe they treat her with kindness. Maybe she is treated like a human being there and maybe she believed that no one on the outside, no one in the real world, would ever treat her well for very long. So she retreats back into her own created safety zone.
All she wanted was to have a husband that adored her and instead I think he truly broke her.Powered by Sidelines


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For those of you who have an interest in Heraldry, we will mention that this item bears the arms of Blackwill. And also Bonvill, Fisher, Fulcher, Halliday, Miles, Peck, Shields, Trant and Twedie.
Stone's workshop made this item in at least four sizes. The larger two required substantial time in the making, and are scarce by comparison to their smaller peers. It is also unusual find an example which has never been engraved, since these were most often made as presentation pieces.
Over the years, we've handled many many pieces of Martelé, and if you dear reader will forgive me for a bit of crudeness, most of them are "trashed." Specifically, the detail is severely worn away, leaving the beauty of the overall design still appreciable but no longer intact...
Compare other examples such as items 361767311810 (1875.00) and 131490471803 (2550.00) on the Big Bad auction page...
As our friend Don Soeffing has recounted in "The Battle of the Birds" (Silver Magazine, November/December 1995), production of this pattern was short lived, because W & H lost this particular battle against Tiffany for infringement of their design pattern...
Though not a "first demand" pattern, the Antique Ivies were made by several manufacturers, and involved extensive skill and hand work to produce. Expensive when first sold, they are members of a dying breed, as most flatware of this quality has now been consigned to the melting pot...
Please note that each bird is slightly different in form, and that only one bears Adler's mark. However, we do believe them to be of a pair.
Marguerite was design...
For those of you who favor comparison shopping, a similar though slightly more fatigued example with pitting in the bowl recently sold on ebay (item 281610340194) @157.50
This piece bears the craftsman's mark of both Robert Bean and Fletcher Carter. Also, let's give a shout out to the good folks at ONC, still going strong in Amesbury after one hundred years, who were kind enough to identify this cup as the "Roly Poly cordial."
The perfect gift for your wine loving friend, who will appreciate that the muslin ring remains present, when the time comes to decant that special bottle of port...
It is an unusual pleasure to find an object which is engraved ("J. Diprose, EsqR / from J.J.G. Bombay") with both a name and a location, to lend it an added sense of history.
This item is superb in both design and execution. Though we always hesitate to say "flawless condition," one would be hard-pressed to find fault...


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Kris Groberg wrote:
> Anyway, don't worry about the power. Kris
Hi Kris
I am not too worried, they just said it could interrupt power and
communications on the news. I will still sleep fine though.<g>
Bob Bob Axmear 208 2nd St Ne Waukon, Ia 52172
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text:
Andrew Barber
Andrew Barber [Andrew Vernon Barber] (16 August 1969 / Wisbech)
Comments about Andrew Barber
When shadow casts and time seems long,
When all seems lost and hope has gone.
I think of thee and words now said,
Your voice, your lines, the path we tread.
And in my soul, when darkness roam,
There comes a light to guide me home.
With faith I give, while love you bring,
In mind, in flesh, in joy – we sing.
Through temperance, with truest heart,


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Pam Grier net worth and salary: Pam Grier is an American actress who has a net worth of $10 million. Pam Grier was born on May 26, 1949 in Winston-Salem, North Carolina. She is of mixed racial heritage with Hispanic, Chinese, and Filipino in her background as well as an African American father and Cheyenne Indian mother. Due to her father's career in the Air Force, she moved around a lot as a child and eventually settled in Denver, where she attended East High School, appeared in a number of stage productions and participated in beauty contests to raise money for college tuition at Metropolitan State College. Grier moved to Los Angeles in 1967 to become an actress. Grier got her break in the early 1970s after starring in a string of moderately successful women in prison and blaxploitation films like "The Big Bird Cage", "Coffy", "Foxy Brown", and "Sheba Baby". In 1997 she made a comeback in the Quentin Tarantino film "Jackie Brown", for which she received a Golden Globe nomination for Best Actress. Grier portrayed Kate "Kit" Porter on the television series "The L Word" for six seasons. Tarantino has said that Pam Grier may have been cinema's first ever female action star.
Pam Grier net worth
Pam Grier
Date of Birth
May 26, 1949 (67 years old)
Actor, Voice Actor
United States of America
5 ft 7 in (1.727 m)
More Actors
All net worths are calculated by applying a proprietary algorithm. The results are then fact checked and confirmed by a team of editors. We scan all publicly available data and resources and work diligently to ensure that our numbers are the most accurate and up to date net worth data you will find anywhere on the internet.


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|Publication number
|Publication type
|Application number
|Publication date
|Feb 27, 1990
|Filing date
|Mar 20, 1987
|Priority date
|Apr 17, 1985
|Fee status
|Publication number
|C. Garrison Fathman
|Original Assignee
|The Board Of Trustess Of Leland Stanford University
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (4), Non-Patent Citations (32), Referenced by (19), Classifications (28), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
The Government has rights in this invention pursuant to NIH Grant No. A1-18716 awarded by the Department of Health and Human Services.
This is a continuation-in-part of United States Serial No. 724,063 filed Apr. 17, 1985 now U.S. Pat. No. 4681760.
The invention relates to methods of modulating a specific immune response, including control of unwanted immune reactions to pharmaceuticals, allergic reactions, and organ allograft tolerance inductions. In particular, binding moieties which react with that T cell differentiation antigen of the subject species which corresponds to the murine differentiation antigen L3T4 are useful in preventing both primary and secondary immune responses to an immunogen administered simultaneously, or within the period of depletion of L3T4 antigen-bearing T cells.
The efficient functioning of the immune system is a double-edged sword. Its ability to provide a defense against invasion by hostile foreign organisms such as infectious bacteria, viruses, or even malignant cells is relied upon by vertebrate organisms for their health; indeed, their viability depends upon the success of this protection. On the other hand, there are some undesirable side effects to this efficiency, even as it relates to foreign substances encountered by the host. Not all intrusions of foreign tissue are necessarily hostile. Problems encountered in rejections of skin grafts for burn victims has a long history; the more recent proliferation of procedures which involve organ transplants has brought the problem of foreign tissue rejection to the attention of the general public.
Furthermore, it has come to be understood that allergic responses result from operation of the immune system. Allergens apparently trigger responses which culminate information of antibodies. Some (IgE) are capable of binding to mast cells to elicit the unpleasant symptomology associated with allergies. These symptoms may be merely unpleasant, or may be severe, as are those encountered in patients allergic to certain medications, such as penicillin. The advent of pharmaceutical compositions containing peptide molecules large enough to be immunogenic has magnified the importance of this problem. Peptide pharmaceuticals useful in a variety of treatments such as antiviral and anticancer therapies have recently been made much more readily available through recombinant techniques.
It is common knowledge that attempts to prevent unwanted immune responses have not been particularly successful. For example, efforts are made to match transplant recipients with donors so as to minimize the amount of immunogenic response to foreign materials. Only in the case of identical twins can reasonable success be certain. The limitations of such an approach are so apparent as to warrant no further comment. Alternatively, brute force efforts to suppress the immune system in general, such as administration of anti-mitotic agents, may prevent rejection at the expense of the recipient's life due to the resulting susceptibility to infection.
An alternate approach applicable only to preventing tissue rejection is passive immunization of recipients with antibodies directed against the histocompatibility antigens (Davies, D. A. L., et al, Transplant Reviews (1979) 30:18-39). Other approaches also applicable only to the transplant rejection problem have employed treatment of the donor tissue. These are based on the assumption that the rejection response is caused by the histocompatibility antigens on the surface of passenger leukocytes carried on the transplant which leukocytes are not an essential part of the desired tissue per se. In vivo culture of the donor transplant tissue has been used to eliminate passenger leukocytes (Surgery (1977) 81:74-79; Science (1980) 209:283-285; Trans Proc (1982) 8:1094-1098). The donor tissue has also been treated directly with suitable antibodies (Faustman, D., et al, Transplantation (1982) 34:302-305). EPO Publication No. 0140109, published 8 May 1985, discloses the use of immunotoxins formed by conjugating antibodies with a cytotoxic moiety for pretreatment of donor tissue.
Methods to prevent immune responses to soluble antigens have been largely confined to avoidance of exposure. Patients allergic to certain drugs are treated with alternative formulations when available; hay fever sufferers attempt to stay away from the immunogenic pollen. If avoidance is impossible, one must resort to treating the symptoms.
What is desired is a specific immuntolerance with respect to a particular antigen, leaving the general competence of the immune system intact. None of the foregoing approaches achieve such a selective immunosuppression of the subject. Treatments employed to prevent transplant rejection which are directed toward the host per se generally depress the entire system; treatments of the donor tissue alter the nature of the foreign material introduced. In the case of allergic responses to drugs or to environmental antigens, alteration of the foreign material is either undesirable or impractical. In the present invention, the immune system of the host is selectively and specifically suppressed with respect to a particular immunogen without impairing general immunocompetence. The invention achieves this result by virtue of its specificity for a differentiation antigen on the surface of helper T cells, thus preventing those cells from participating in mounting an immune response against a specified antigen introduced simultaneously, or at least within the period of helper T-cell recovery.
The present invention provides a method for suppressing undesired immune responses, such as allergic reactions, to antigens whose administration to the subject is either desired, or is inevitable but otherwise harmless. It also provides a method for inducing tolerance to tissue transplants.
In one important application, the advent of recombinant technology has made available a substantial number of potentially powerful therapeutic polypeptides such as, for example, the interferons or interleukins, which often elicit an unwanted immune response. Of course, allergic reactions to more commonly used drugs are not unknown, but the new polypeptide pharmaceuticals, presumably because of their size, are more troublesome in this regard. The invention permits the subject to experience the desirable therapeutic effects of a desired drug without the immunologic reaction.
Another application is to the problem of allergies to foods or materials in the surroundings. Millions of individuals are subjected to severe symptomology in response to otherwise perfectly harmless components of the environment, for example, ragweed or other pollens. The method of the invention can prevent or diminish this immune response which results in widespread discomfort.
A third application, to reduce the incidence of tissue rejection in transplant procedures, is significant in making these often life saving procedures safe and practical. These procedures could, in this era, otherwise be straightforward absent the problems of incompatibilty.
A fourth application is to allow the use of foreign proteins such as xenogeneic monoclonal antibodies for therapy of certain diseases such as cancer.
The method of the invention resides in the co-administration of the antigen for which immunotolerance is sought and an antibody which is specific for the "L3T4-equivalent" differentiation antigen on T cells, thus preventing these helper T cells from participating in the immune response otherwise concurrently mounted against the particular co-injected or co-administered antigen. The protective antibodies may be administered directly, or these antibodies or L3T4-equivalent binding portions thereof may be conjugated with cytotoxic moieties to obtain immunotoxic conjugates. The cytotoxic moieties may aid in the destruction of the helper T cell function which is also prevented by reaction with the antibodies or fragments alone. The essential component of the protective composition is the moiety specifically binding the L3T4 or its equivalent.
Two general situations are of interest. One relates to a naive subject, previously unexposed to the antigen of concern. This is commonly the case with respect to transplant hosts or patients who are to be treated with new or infrequently administered drugs. The other relates to individuals previously exposed to the same antigen. This is most often the case for allergic responses to components of the environment.
With respect to defensive immunosuppression against a previously unencountered agent, such as a new pharmaceutical or transplant, it is sufficient to suppress the primary immune response to introduction of the foreign substance. In the method of the invention, this primary response is suppressed by administration of the foreign substance simultaneously with the administration of the binding moiety, e.g., the antibody or immunotoxin that is specifically immunoreactive with the differentiation antigen corresponding to the murine L3T4 surface glycoprotein in the subject species (i.e., an "L3T4-equivalent") or within the helper T-cell recovery period thereafter. Accordingly, the invention in one aspect relates to a method of preventing or ameliorating the immune response to an immunogen by properly timed coadministration of the anti-L3T4-equivalent binding moiety and the immunogenic substance.
With respect to alleviation of responses to previously experienced immunogens, the technique is the same although the history of the subject, and therefore the subject itself, is different. The nature of the response is also different. While the most frequent instance of such prior exposure is in the case of environmental allergens, this aspect of the invention is not limited to such allergens per se. Previous exposure to the same allergen is the norm, and the invention is particularly useful in this application. Even this response to a secondary challenge with the immunogen can be mitigated by administration of the moiety binding L3T4-equivalent simultaneously with or just before the "booster" exposure. The immunogen can also be deliberately administered at the appropriate time to confer future immunity along with immediate suppression. Accordingly, the invention in another aspect relates to amelioration of a secondary immune response, most commonly, an allergic response, by administering to a subject, previously exposed to an immunogen, a moiety specifically binding to the relevant L3T4-equivalent in appropriate combination with exposure to immunogen.
In another aspect, the invention contemplates kits containing compositions suitable for effecting the method of the invention.
FIG. 1 shows the total specific anti-myoglobin immunoglobulin levels obtained in mice with and without simultaneous injection with GK1.5 monoclonal antibody (Mab).
FIG. 2 shows the levels of antimyoglobin IgG in the bloodstream of mice with and without injection of GK1.5 Mab.
FIG. 3 shows the depletion and recovery of helper T-cell population with administration of GK1.5 secreted Mab.
FIG. 4 shows a comparison of suppression of the immune response to myoglobin and to KLH.
The method of the invention depends on the interruption of a specific immune response by crippling the participation of a subclass of T lymphocytes, the helper cells, and permitting these cells to regenerate in the presence of an immunogen. These T-cells are recognized by a surface-borne glycoprotein differentiation antigen, designated L3T4 in the murine system.
Briefly, it has long been established that two major types of lymphocytes participate in the immune response--T cells, which differentiate to various effector functions, and B cells, which differentiate so as to secrete specific antibodies to the antigen. In a very general way, the primary function of the B lymphocyte differentiated cells (plasma cells) is to secrete antibody; the differentiated T cells provide effector functions such as those of the killer cells, helper cells, and suppressor cells. T cells, in addition to antigen-specific recognition sites, contain differentiation antigens characteristic of their particular subtype. Accordingly, the method of the invention influences the course of the immune response by blocking the characteristic differentiation antigen of the helper T cell subtype, thus inhibiting the effector function of the helper T cells.
The helper cells apparently interact with B cells to "help" effect B cell differentiation and proliferation; in addition, they "help" in the differentiation of T cells into their effector roles, e.g., as killer cells. A majority of these helper T lymphocytes (HTLs) contain a surface differentiation antigen designated in the murine system as L3T4. This differentiation antigen is a glycoprotein of apparent molecular weight 52,000 (Dialynas, D. P., et al, J Immunol (1983) 131:2445-2451) and is apparently analogous to the Leu3 or T4 differentiation antigen on human helper T cells. Monoclonal antibodies (Mabs) specific to the L3T4 differentiation antigen have been prepared (Dialynas, D. P., et al, (supra)). A hybridoma secreting such monoclonal antibodies, designated GK1.5, was obtained from a fusion of a mouse nonsecretor myeloma SP2/0 with spleen cells from a rat that had been injected with a cloned T cell line. The Mabs secreted are rat IgG2b antibodies specific against L3T4.
Others have investigated the effect of the injection of GK1.5 Mabs on the immune response. Wofsy, D., et al, in a paper presented to WSCI, Feb. 4-6, 1985, reported that weekly injections of anti-L3T4 antibody into a strain of mice prone to develop autoimmune disease decreased the circulating levels of L3T4-positive cells by 90%-95% and suppressed the development of autoimmunity. They further observed that the mice developed little or no antibody to the rat IgG. Woodcock, J., et al, in an abstract submitted to Western AFCR Feb. 4-6, 1985 disclosed that intravenous injection into mice of the GK1.5-derived IgG2b monoclonal antibody 3 days before a xenogeneic skin graft delayed the time of rejection. The injected mice showed a reduction of L3T4-positive cells even after 28 days. Additional administrations of the monoclonal antibody enhanced the reduction of circulating L3T4-positive cells. The results are consistent with those of Cobbold, S.P., et al Nature (1984) 312:548-551, which show that IgG2b antibodies are successful in eliminating T cell subsets bearing this marker in vivo.
Wofsy, D., et al, in abstract submitted to the Western AFCR, Feb. 4-6, 1985, report the effect of GK1.5-secreted Mab injection on the immune response to a soluble antigen. Mice injected with bovine serum albumin (BSA) normally produced anti-BSA IgM immediately followed by a rapid increase in the level of anti-BSA IgG antibodies. The IgG response could be prevented by a single injection of the GK1.5-secreted Mabs within 48 hours of immunization, but suppression of IgG function did not occur if injection was made more than 48 hours after the administration of BSA. Wofsy also observed that injections of GK1.5 Mabs into mice did not elicit an immune response, whereas treatment with other rat IgG2b Mabs did stimulate high titers of anti-rat antibody.
A. Definitions
As used herein "simultaneously" when referenced to injection of antigen and L3T4-equivalent binding moiety refers to injection or administration of one within approximately 24-48 hours of the other. Either may be administered first. It is preferable, however, that the administration of the moiety binding the receptor be carried out substantially contemporaneously with or within 48 hours prior to injection or other administration of the antigen.
"Helper T-cell recovery period" refers to the time period required after binding moiety administration for L3T4-equivalent-bearing helper cells to be restored to their approximate normal levels, preferably, in the context of the invention, to 50% of their normal levels.
"Binding moiety to L3T4-equivalent" refers to a substance which is specific to the differentiation antigen corresponding in the subject species to the L3T4 surface differentiation antigen of murine HTL cells. Some moieties may be immunoreactive against a determinant on these differentiation antigens which makes them cross-reactive with the correspondant differentiation antigens on HTL cells in several species. In general, because of the powerful immunosuppressant activity of the antibodies useful in this invention, it is not necessary that they be derived from the subject species. For example, the rat IgG2b monoclonal antibody GK1.5 is reactive against murine L3T4 and these Mabs are convenient for use in murine test systems since they do not raise antibodies to rat Ig in mice. Other commercially available monoclonal antibodies, such as Leu3 (Becton Dickinson) or T4 (Ortho) are reactive against human Leu3 or T4 differentiation antigen. Various alternative hybridoma lines producing monoclonal antibodies which specifically react with the corresponding differentiation antigens in T cells of the subject are suitable in the method of the invention.
It is not, of course, necessary that monoclonal antibodies be used as the L3T4-equivalent binding moiety. Monoclonal antibody preparations have the advantage of higher affinities and homogeneity, but polyclonal preparations may be used. Also, fragments of immunoglobulins which retain target specificity, for example, F(ab)2 or Fab fragments are usable as well. In addition, antibodies specific against L3T4-equivalents or fragments thereof may be conjugated with cytotoxins. The construction of immunotoxins using various cytotoxic moieties, such as whole ricin, ricin A, diphtheria toxin, pokeweed antiviral protein (PAP) or other naturally occurring or artificial toxins are by now well understood in the art. For reviews, see Thorpe, P. E., et al, Immunol Revs (1982) 62:119-158; Jantzen, et al, (ibid) pp 185-216; Olsnes, S., et al, Pharm Ther (1982) 15:335-381.
Thus, in summary, the term "moiety binding to L3T4-equivalent" refers to monoclonal or polyclonal antibodies or fragments thereof or any of these bound to cytotoxins, so long as the specific ability to bind the L3T4-equivalent in the species of interest is retained.
"Specific antigen" refers to the immunogenic substance of interest. Thus, specific antigens include globular proteins, glycoproteins such as immunoglobulins, materials carried on particles such as pollen proteins, polypeptides intended for therapeutic use such as interferon, interleukin-2, or tumor necrosis factor, hormone replacements, such as leutinizing hormone or its analogs or antagonists, and the like. Synthetic peptide analogs of protein therapeutic agents which are used for receptor blockade are another important class of soluble antigen. Still another important subclass is that of allo-antigens, i.e., those which are products of the major histocompatibility complex. It is these allo-antigens which are presumably responsible for rejection of foreign tissue in tissue transplants or skin grafts.
A significant aspect of the invention is that it is efficacious regardless of whether or not the subject has been previously exposed to the antigenic substance because it provides immunotolerance to a specific antigen upon secondary as well as primary exposure. Primary responses to antigens generally involve formation of quantities of IgM antibodies specific to the antigen. "Booster" exposures to the antigen (or, indeed, the delayed response to the initial administration) result in a secondary response--comparatively dramatic increases in the IgG, IgA, and IgE population specific to the antigen. In other words, the secondary response is characterized by an increase in specific IgG, IgA, and IgE levels, The IgM population fairly quickly diminishes and is again supplemented only when an additional administration of the antigen is made; IgG, IgA, and IgE levels are maintained for longer periods. Previous exposures to the same antigen result in enhanced secondary response upon subsequent exposure.
B. General Method
The essential feature of the invention is administration of the binding moiety of correct specificity to block the subject's "L3T4" differentiation antigen or, more precisely, the subject species' correspondant surface glycoprotein either simultaneously with administration of the specific antigen or previous to antigen administration, wherein the antigen is administered during the recovery period. The actual effect of the binding moiety may be to kill the L3T4-equivalent-bearing cells or to block the effector function of these cells in some non-cytotoxic event, in either case permitting regeneration of normal helper T-cell moieties over a period characteristic of the species--about 2 weeks to 1 month in mice. While not intending to be bound by any particular theory as to the mechanism of operation of the invention method, Applicants believe helper T-cell regeneration in the presence of a particular antigen results in its being recognized as self.
It may enhance the effectiveness of the L3T4-equivalent binding moiety to prepare it as an immunoconjugate with a cytotoxic material. The cytotoxin will thus be directed specifically to the target T-helper cells.
The L3T4-Equivalent Binding Moiety
The dosage of the moiety binding to L3T4-equivalent which is administered will depend on its form, on whether or not it is converted to an immunotoxin, on its mode of administration, and on the condition of the subject. Clearly the most preferred mode of administration is by injection, preferably intravenous injection. Typically, the subject to be thus specifically immunosuppressed is injected with about 200 mg-5 g, preferably about 1-2 g of L3T4-equivalent binding moiety in a suitable excipient, such as physiological saline, in a single injection intravenously or intraperitoneally.
The antibody portion of the desired binding moiety is obtained by conventional procedures. L3T4-equivalent sera may be obtained from immunized subjects. For the Leu3 or T4-equivalent human differentiation antigen, antisera may be prepared from subject mammals such as mice, horse, goat, rabbit, sheep, or rats by injecting with human helper T cells and collecting the sera from the immunized host. Since the L3T4-equivalent binding moiety confers selective specific immunosuppression, the use of non-human antisera is permissible. Antibodies desired for other mammalian subjects may be similarly derived using injections of helper T cell subpopulations from these mammals.
Monoclonal anti-L3T4-equivalent antibodies may also be made by the somatic cell hybridization procedure first described by Kohler, G., et al, Nature (1985) 256:495-497. The immortalizing cell lines, reagents, and conditions used in this procedure are well known. Briefly, the procedure involves immunizing the host as above, collecting antibody-producing cells and fusing these cells with an appropriate immortalizing cell line using a fusogen such as polyethyleneglycol, growing the cells in selective medium to eliminate unhybridized partners, identifying hybridomas that produce antibodies against the immunogen, culturing these hybridomas and collecting the Mabs from the resulting culture fluid. The immortalizing partner used for the fusion also need not confer characteristics on the Mab which are compatible with the subject, because of the specific immunosuppression conferred. As stated above, anti-L3T4-equivalent monoclonal antibodies are available commercially for humans and for a number of other species.
Antigen binding fragments (F(ab), F(ab'), F(ab')2, F(v)) of polyclonal or monoclonal antibodies are made by digesting the whole immunoglobulin with an appropriate protease, for example, papain in the case of F(ab) and pepsin in the case of F(ab')2. The class (and subclass) of the antibody used is not critical. Polyclonal antisera presumably are mixtures of Ig classes; Mabs produced are of a single subclass.
If the L3T4-equivalent binding moiety is administered as an immunotoxin, the antibody portion is conjugated using standard conjugation techniques to a cytotoxin. Thorpe, P. E., et al (supra); Olsnes, S., et al (supra). Typical coupling agents include, for example, 3,3'-dimethyl-dithio(bis)propionate, and N-succinnimidyl-3-(2-pyridyl-dithio)propionate (SPDP) which yield a reducible disulfide bond; and, for example, the N-hydroxysuccinnimidyl esters of, for example, 6-maleimidylcaproic acid which yield thioethers. Other coupling agents, such as glutaraldehyde or carbodiimides yield alternate chemistries.
The cytotoxin moiety may, for example, be a bacterial or plant toxin, or a portion thereof that includes is enzymatically active fragment or a similarly active protein. Examples of such toxins are diphtheria toxin, Pseudomonas exotoxin, ricin, abrin, momordin, gelonin, and the like. The toxins and proteins may be extracted from bacteria or plants or may be synthesized using known peptide synthesis techniques (if relatively short) or by recombinant techniques if the gene sequence are available.
The Specific Antigen
The amount and nature of the material used for simultaneous injection to confer the desired specific immunosuppression depends on the type of antigen.
For allergens, whether environmental or deliberately administered soluble antigens, such as drugs, the antigenic component may be conveniently administered intravenously in suitable excipients in amounts of 10 μg-1 mg. Alternatively, for environmental allergens, exposure may mimic "natural" exposure and employ aerosols or oral compositions and quantities approximating the estimated degree of exposure are appropriate. For example, one might use a "field of flowers" approach in protecting a subject against an immune response to a naturally occurring pollen. That is, at the beginning of the acacia blooming season, for example, the subject is placed in proximity to the offending blooms while simultaneously being administered protective binding moieties or within the recovery period after such administration. Gradations between these natural exposures and the highly artificial method of isolating the specific allergen and injection with or just after the binding moiety administration may also be used. The formulation of appropriate pharmaceutical compositions to administer the antigen is well known to those in the art.
If the allergen is a therapeutic agent, amounts of antigen approximating those intended to be administered and a similar route of administration may be used. In general, this protection affords a simpler problem as generally speaking the antigen is already available in a suitably formulated pharmaceutical composition and the levels of exposure expected and expected routes of administration are already known.
For suppression of rejection in the case of transplanted tissue, specifically, with respect to allografts, a variety of modes of administration are feasible. Allografts are multiplicities of cells or associated cells that define a tissue or organ from an individual of the same species as that of the intended recipient, but which derive from an individual genetically dissimilar from the recipient. These cell multiplicities themselves, include vascularized organs such as heart, kidney, liver, lungs, etc. Endocrine glands (pituitary, thyroid, adrenal, parathyroid, and pancreas) or skin grafts may not contain the major histocompatibility antigens which are responsible for triggering the rejection of the transplant. These antigens are carried by passenger cells such as leukocytes which are included in the transplanted cells as impurities.
Two general approaches may be used: the transplant materials can themselves be used as a source of antigen, or the particular histocompatibility antigens may be obtained separately and administered alone or as cells bearing the histocompatibility antigens of the transplant donor, i.e., peripheral blood lymphocytes. A major antigen responsible for tissue rejection carried o such passenger leukocytes is the murine Ia-equivalent antigen which in humans is designated HLA-DR (MHC class II antigens). Human HLA-DR antigens have been subclassified and if the donor has been typed, suitable antigen, e.g., peripheral blood lymphocytes, associated with the donor tissue is conveniently obtainable and injected prior to transplant along with or within the recovery period of administering the L3T4-equivalent binding moiety. The perhaps more crude, but effective, manner of administration is simultaneous injection of the L3T4-equivalent binding moiety along with or just before the transplant itself or a pre-transplant simultaneous injection of a portion of the tissue suitably finely divided and formulated along with the protecting binding moiety.
As seen from the previous paragraphs, each specific antigen offers alternative routes for administration appropriate to its nature. All offer the possibility of obtaining purified antigen and utilizing intravenous administration. In certain instances, it is also possible to inject a composition containing a mixture of the specific antigen along with the binding moiety in a suitable pharmaceutical composition.
In summary, for antigens in general, while intravenous administration is most convenient, other forms of administration are useful as well. Other routes of parenteral administration include subcutaneous, intraperitoneal, or intramuscular injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. For substances intended to stimulate the immune system, such as the specific antigen administered in the method of the invention, an adjuvant, such as complete Freund's adjuvant is generally used.
An additional approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained.
Systemic administration may be effected via suppository. For such formulations, traditional binders and carriers include, e.g., polyalkalene glycols or triglycerides. Such suppositories may be formed from mixtures containing L3T4-equivalent binding moiety or antigen in the range of 0.5%-10%; preferably 1%-2%.
For aerosol administration, the antigen is preferably supplied in finely divided form along with a surfactant and a propellant. Typical percentages of active ingredients ar 0.01% to 20% by weight, preferably 0.4% to 1.0%. Surfactants must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids, such as caproic or octanoic acids, polyols such as mannitol or sorbitol, or their anhydrides or esters and their polyoxyethylene and polyoxypropylene derivatives. Preferred surface-active agents include the oleates of sorbitan, e.g., those sold under the trademarks "Arlacel C", "Span 80", and "Span 85". The surfactant may constitute 0.1%-20% by weight of the composition, preferably 0.25%-5%. The balance of the composition is ordinarily propellant; for example the lower alkanes, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes, such as are sold under the trademark "Freon". In producing the aerosol, a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divided active ingredient and surfactant. The ingredients are thus maintained at an elevated pressure until released by action of the valve.
Solid compositions of antigen or L3T4equivalent binding moiety may be used if administered orally or if reconstituted for administration. Conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. The corresponding liquid pharmaceutically administerable compositions can be prepared by dissolving, dispersing, etc, the antigen or binding moiety above and optional pharmaceutical adjuvants in a carrier as described above.
Actual methods of preparing the above dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, latest edition. The composition or formulation to be administered will, in any event, contain a quantity of the binding moiety or antigen in an amount effective to obtain the desired specific immunosuppression.
It is convenient to package the specific antigen and protective L3T4equivalent binding moiety into kits for administration of the treatment. Thus, for example, kits for the treatment of allergy would comprise containers with, preferably, unit dosage levels of allergen such as ragweed protein, milk protein, or other allergenic material in suitable excipients including most preferably adjuvant preparations such as Freund's complete adjuvant. An additional container would supply, e.g., suitable monoclonal antibodies specific for L3T4 or immunotoxins derived from them in form for administration such as suspension in physiological saline or other pharmaceutical excipient or in solid form to be reconstituted. For certain antigen/binding moiety combinations, these components may be supplied as a mixture. Additional components of such kits might be sterile disposable syringes. All materials may be packaged in convenient containers for administration as is known in the art, along with instructions for their use.
C. Examples
The following examples are meant to illustrate and are not intended to limit the invention.
Sperm whale myoglobin was used as a antigen in Balb/C mice, and the ability of GK1.5-secreted Mab to produce specific immunosuppression with respect to this antigen was verified using four protocols. The four protocols differed only in the timing of the injections of the antigen and protecting antibody. In each protocol, one experimental group consisting of three 6-8 week old mice, and two control groups consisting of three similar mice were used. One control group received corresponding injections of α-Thy Mab instead of GK1.5-secreted Mab at identical times and in the same amounts. The other control group received injections of corresponding volumes of buffer solution. All groups in all protocols received 100 μg myoglobin in complete Freund's adjuvant on day 0 and booster injections of 50 μg myoglobin in the adjuvant every 14 days thereafter. Sera were collected on day 7 and day 10 after each immunization and assayed for the presence of anti-myoglobin total immunoglobulin (including both IgM and IgG) by ELISA as described in Example 3 below. The specific protocols are as follows:
______________________________________Protocol 1: (Antibody and antigen were injected intraperitoneally.)Antibody: 200 μg on days -1 and 0; 100 μg on days 1 and 2.Antigen: 100 μg on day 0, 50 μg every 14 days thereafter.Protocol 2: (Antibody and antigen were injected intravenously.)Antibody: 100 μg on day 0.5, 1, 1.5, and 2.Antigen: 100 μg on day 0, 50 μg every 14 days thereafter.Protocol 3: (Antigen and antibody were injected intravenously.)Antibody: 100 μg on day 0, 1, and 2.Antigen: 100 μg on days 0, l, and 2, 50 μg every 14 days thereafter.Protocol 4: (Antigen and antibody were injected intravenously.)Antibody: 100 μg on day 0, 1, and 2.Antigen: 100 μg on day 0, 1, and 2, and 50 μg every 14 days thereafter.______________________________________
FIG. 1 shows the results obtained on typical bleeding for mice in each of the 4 protocols. Results are given in ELISA units (see Example 3, below) as a function of serum dilution. The data shown were taken 9 days after six 14-day intervals post day 0 but are typical of results obtained upon earlier bleeding. The open circles show the levels of total immunoglobulin specific against myoglobin in the α-Thy injected controls. The closed circles show corresponding results for the experimental group at two serum dilutions.
All four protocols gave similar results. The controls show high levels of specific antimyoglobin immunoglobulins correlating with serum dilution. Antimyoglobin antiserum is absent from the GK1.5-secreted Mab-injected groups.
Experimental and control groups of three mice each were similar to those used in Example 1. All groups received 100 μg myoglobin on day 0 and booster injections of 100 μg myoglobin every 14 days thereafter. On day 14, 100 μg of GK1.5-secreted Mab or control injections were administered and sera were withdrawn at various intervals and assayed by ELISA for IgG specific against myoglobin. The results are shown in FIG. 2, where ELISA units are plotted against time.
The open circles joined by dotted and solid lines show the levels of antimyoglobin IgG in the sera of buffer and α-Thy-injected controls respectively. The solid circles show the IgG levels in the sera of mice injected with GK1.5-secreted Mab. The IgG levels of the control mice rise monotonically as the animals are boosted. However, the mice injected at day 14 with GK1.5 fail to show the IgG secondary response to the boosting antigen injections.
For total antimyoglobin Ig: microtiter plates (Dynatech Laboratories, Alexandria, VA) were coated with 100 μg/ml sperm whale myoglobin in PBS for 1 hour at room temperature or overnight at 4� C., and washed with PBS. The remaining nonspecific binding sites were saturated with 3% BSA in PBS, and the plates were washed. Fifty μl of the serum dilutions were added, and the plates incubated for 2 hr at room temperature, and then washed with washing buffer containing Tween 20.
Bound Ig was detected using 100-200 μl diluted peroxidase-coupled goat anti-mouse Ig (GAMIg), incubating at 2 hours at room temperature, and then washing 3 times with washing buffer. The detection solution, OPD/H2 O2 was added to each well and incubated for 5 min, and the OD492 of each well was measured by a Dynatech ELISA reader. OD units were correlated with μg protein by standard procedures.
For IgG: the procedure was identical to that above except that labeled goat anti-mouse-IgG was used instead of total goat anti-mouse-Ig.
Balb/C mice were injected with 200 μg of GK1.5-secreted Mab in Freund's complete adjuvant on each of three consecutive days intraperitoneally. The lymph node cells of three mice were pooled, and the cell surface phenotypes were analyzed by two color FACS analysis, using Lytl as a global T cell maker. Lymph node cells staining for L3T4 and Lyt2 make up the entire T cell population in mice, and the amounts of each are expressed as percentages of total T lymphocytes in FIG. 3. As shown in FIG. 3, upon administration of the antibody, the L3T4 population drops drastically in favor of Lyt2, and recovers almost linearly over a period of 37 days, reaching, at that point, about 50% of its former value.
Ability of GK1.5-secreted Mab to produce specific immunosuppression with respect to sperm whale myeoglobin in comparison with a stronger immunogen, keyhole limpit hemacyanin (KLH) was obtained by the procedure and protocols of Example 1 but measuring IgG against these proteins periodically. The results are shown in FIG. 4. Mice injected with anti-L3T4 were able to maintain low antibody titers against the weaker antigen sperm whale myeoglobin through the test period of 56 days despite periodic boosts with the antigen. For the stronger antigen, KLH, immunoresponsiveness resumed after the recovery period for the helper lymphocytes as determined in Example 4.
Balb/C mice were rendered diabetic by intravenous injection of 55 mg/kg streptozotocin. Within 1 week after treatment, elevated glucose levels showed that the mice were in fact diabetic. Using comparison groups of five mice each, it was demonstrated that syngenic transplants of islets of Langerhans prepared by disecting the islets from pancreatic tissue of littermates is able to reverse the diabetes so that the survival times of the mice exceed 100 days from the administration of 1800-2000 islets. (The islets are isolated by a modification of the technique disclosed by Lermarck, A., et al, J Cell Biol (1976) 71:606.) Similar islet preparations from allogenic species were prepared, and when administered at similar levels to the diabetic subjects, were uniformly rejected, resulting in survival times of less than 10 days.
Three additional groups of five mice were administered Mab secreted by GK1.5 days -1, 0, +1, and +2 from administration of the islets, wherein a total of 350 μg was administered at 100 =g on the first three days and 50 μg on the last. Groups thus treated and then transplanted with 600-800 islets showed survival times comparable to the syngenic treated group, as did those administered 850-1200 islets. Preliminary data indicate that administration of more than 1500 islets also will result in similar survival times.
Lymph node cell suspensions of normal and treated mice were prepared in PBS containing 2% FCS and 0.1% sodium azide and depleted of erythrocytes by gradient centrifugation on Ficoll-Hypaque. 5�105 cells were incubated in 25 μl of pre-titered conjugated antibody for 30 min on ice and washed twice. For two color analysis, green fluorescence was derived from directly FITC-conjugated reagents (anti-L3T4, anti-Lyt2) In a second incubation, Texas Red labeled avidin was added and bound to biotinylated first-step antibody (anti-Lytl). As controls for bacground fluorescence levels, control cell preparations which were either unstained or incubated with an isotype matched irrelevant antibody were analyzed. Flow microfluorometry analysis was performed on a modified FACS II system (Becton-Dickinson, Mountain View, CA) equipped with logarithmic amplifiers. Data analysis was as described by Hyaka, K., et al, J Exp Med (1988) 157:202. Dead cells were excluded from analysis by the scatter gating method and additionally by propidium iodine staining at a final concentration of 1 μg/ml. Data are presented on log10 scales of increasing green and red fluorescence intensity and are shown as contour plots.
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|Anti-cancer drugs for the treatment of leukaemias I, constituted by the chain A of ricin and a specific monoclanal antibody
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|The Board Of Trustees Of Leland Stanford Junior University
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|Citing Patent
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|Oct 31, 1989
|Apr 7, 1992
|Du Pont Merck Pharmaceutical Company
|Pyrimidine biosynthesis inhibitors useful as immunosuppressive agents
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|Oct 6, 1992
|The Beth Israel Hospital Association
|Induction of tolerance to a foreign antigen IL-2 receptor-binding substances
|Jun 5, 1995
|Apr 29, 1997
|Neorx Corporation
|Clearing agents useful in pretargeting methods
|Sep 16, 1994
|Apr 6, 1999
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|Jun 1, 1999
|Joslin Diabetes Center, Inc.
|Antigen associated with Type I diabetes mellitus
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|Aug 10, 1999
|The United States Of America As Represented By The Department Of Health And Human Services
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|Dec 7, 1994
|Jun 13, 2000
|Neorx Corporation
|Small molecular weight ligand-hexose containing clearing agents
|Sep 15, 1993
|Jul 4, 2000
|The United States Of America As Represented By The Department Of Health And Human Services
|Interleukin-2 stimulated T lymphocyte cell death for the treatment of autoimmune diseases, allergic responses, and graft rejection
|Jun 6, 1996
|Jan 9, 2001
|Neorx Corporation
|Cluster clearing agents
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|Jul 9, 2002
|Neorx Corporation
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|Jun 21, 2005
|Aletheon Pharmaceuticals, Inc.
|Cluster clearing agents
|Jun 6, 1995
|Aug 16, 2005
|Joslin Diabetes Center, Inc.
|Antigen associated with type 1 Diabetes Mellitus
|Jun 9, 1993
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|THE UNITED STATES OF AMERICA, as represented by the Secretary of the Department of Health and Human Services
|Interleukin-2 stimulated t lymphocyte cell death for the treatment of autoimmune diseases, allergic disorders, and graft rejection
|Jun 9, 1993
|Nov 19, 1997
|Us Army
|Interleukin-2 stimulated t lymphocyte cell death for the treatment of autoimmune diseases, allergic disorders, and graft rejection
|Oct 29, 1992
|May 13, 1993
|Joslin Diabetes Center
|Antigen associated with type i diabetes mellitus
|Feb 25, 1993
|Sep 2, 1993
|The Board Of Trustees Of The Leland Stanford Junior University
|Early antigen for autoimmune diabetes
|Aug 2, 1994
|Feb 9, 1995
|The Board Of Trustees Of The Leland Stanford Junior University
|Methods for b-cell population control
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|U.S. Classification
|424/154.1, 424/275.1, 435/810, 436/506, 530/868, 436/547, 424/184.1, 436/548, 436/512, 530/388.75, 530/391.7, 424/183.1, 436/808, 514/885
|International Classification
|Cooperative Classification
|European Classification
|Mar 20, 1987
Owner name: BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:FATHMAN, C. GARRISON;REEL/FRAME:004709/0109
Effective date: 19870313
|Aug 4, 1993
|Fee payment
Year of fee payment: 4
|Aug 14, 1997
|Fee payment
Year of fee payment: 8
|Sep 18, 2001
|Maintenance fee reminder mailed
|Feb 27, 2002
|Lapse for failure to pay maintenance fees
|Apr 23, 2002
|Expired due to failure to pay maintenance fee
Effective date: 20020227


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|Scorpion Power
Senior Heliman
Brownsville, Texas
I have a Blade 300x for sale. I only hovered it three times to try out the FBL! It comes with the AR7200 FBL Unit. The heli flies rock solid! I was very happy with it but down here by the coast its always windy and I dont think i will get to fly it very often. So Im sticking with bigger helis for now.I have everything like new in the original box with the manual. I got this new from a local hobby shop when I traded in a gasser airplane. The hobby shop gave me some spare parts to cover the value of the airplane. I will throw those in as well. (two main shafts, two head spindles and linkages)I also changed the connectors to Dean's connectors and purchased two extra turnigy nano tech batteries. so It will come with 3 batteries total.I will post pics later today.Priced to sell at 325.00 shipped and paypal'd.No Trades !!!!!
|08-19-2012 Over year old.
Senior Heliman
I wish I could buy this bird again. Great price and great guy to deal with.
Champion,Magic,MiniBoy,Xcell60+50,Intrepid,Intrepid Gas,Baron30,Whisper,300X,mCPXv1v2,Concept,Nexus
|08-28-2012 Over year old.
|1 page 1126 views
|Hitec RCD
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Posh Salon in Brentwood, California is an upscale hair salon specializing in all of the latest trends in hair color, hair cuts and styles, Hotheads Extensions, and specialty hair services.
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Are there any MMORPGs anymore that don't use instances?
It really cheapens the MMO experience. I was kind of hoping games would use the old EQ model where nothing is an instance. At least when there are no instances, people compete with other players over the same farms, etc. and guilds are competing to be the first to down raid NPCs. People want to kill NPCs in non-instanced MMORPGs.
People shouldn't put up with these instancing systems, can hardly call it an MMO when you have your own private zones that are magically separated from the rest of the world.
darkfall is instance free, so no instances anywere playing it atm halfscreen, having a blast )
FFXI isn't instanced.
I dont' know.
But I'm not sure the playerbase which want non instanced MMORPGS is actually the majority.
Darkfall use non instanced I think. I'm not sure there are other theme park game other than EQ which is non instanced.
Originally posted by Rajen
FFXI isn't instanced.
In a way FFXI does have instances, but the thing is one 1 group can do that insance at a time. Dynamis, limbus, BSNM, KSNM, its all instances but like I said only 1 group can be doing it at 1 time.
Waiting for:EQ-Next, ArcheAge (not so much anymore)
Now Playing: N/A
Worst MMO: FFXIV
Favorite MMO: FFXI
see signature
the only "instances" are player flats and guild halls.
WWIIoL is non instanced.
Nothing says irony like spelling ideot wrong.
Instances are not evil per se but they shouldnt be abused. They can become very convenient when you have several groups of people trying to run the same content.
Just to make things clear...
I speak for myself and no one else, unless i state otherwise mine is just an opinion. A fact is something that can be independently verified, you may challenge such but with proof. You have every right to disagree with me through sound argument, i believe in constructive debate, but baseless aggression will warrant an unkind response.


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By Brian Mansfield, USA TODAY
Elliott Yamin estimates he has recorded 35 songs for the follow-up to his 2007 debut. "Obviously, not all of them are going to make the record," says the Season 5 American Idol finalist, "but I've had time to branch out and work with as many people as possible."
For the untitled album, due May 5 on Hickory Records, Yamin has been in the studio with producers including Jermaine Dupri, J.R. Rotem, Eman, Harvey Mason Jr., Steve Russell and Stargate.
IDOL CHATTER: Follow the new season's action in our blog
"I've been working with people who've done a lot of contemporary stuff," says the 29-year-old singer.
Yamin hasn't picked a first single, but has couple contenders. "There's a song called You that I did with Stargate. … Then there's Know Better that I did with this really talented production team called Midi Mafia. It's a really hot track — it's got single potential written all over it."
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Lot 1286: Restored Original M&S 80 Texaco Fire Chief Pump
Annual Fall Classic Auction - Day 1
by Donley Auction Services
November 10, 2016
Union, IL, USALive Auction
Looking for the realized and estimated price?
Description: Restored Original M&S 80 Texaco Fire Chief Pump. Measures 20 1/2"W x 62 1/2"H x 16 1/2"D. See Pictures for Details on Condition.
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Georgetown keeps rolling
Otto Porter Jr. overcame foul trouble to score 16 points, and No. 15 Georgetown wasted a 12-point lead in the second half before rallying for its seventh consecutive victory Friday night, 62-55, over host Cincinnati (19-7, 7-6).
Markel Starks, who had 17 points, hit a go-ahead 3-pointer with 5:35 left and made five free throws in final minute, helping the Hoyas (19-4, 9-3) stay atop the Big East.
In Pac-12 women's games:
No. 6 Cal 79, No. 15 UCLA 51: Gennifer Brandon scored 16 as the Bears (22-2, 12-1) handed the Bruins (19-5, 10-3) their first home loss this season.
No. 4 Stanford 79, USC 55: At Los Angeles, Chiney Ogwumike had 26 points and 15 rebounds for her record-setting 20th double-double of the season, and the Cardinal (23-2, 12-1) beat the Trojans (8-16, 5-8) for the 12th consecutive time.
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