text:
Submit your letter online with our Virtual Newsroom.
What's your opinion? We value your opinion and encourage you to share it with our readers by writing a Letter to the Editor.
Vandals uproot 70 daffodils planted at Greene/Phillips
March 18, 2016 Last fall, in the spirit of community beautification, Norwood United Methodist Church planted 70 daffodils where Phillips splits off from Greene Street. more »»
Volunteer work in town no threat to Teamsters
March 18, 2016 Good grief Charlie Brown! I had no idea when I was weeding the bump outs on Front Street, planting trees in Harmar, picking up litter and debris in the parks, or removing leaves from the local... more »»
Donors turned out for Lowell blood drive; thank you
March 17, 2016 On Jan. 15, Lowell community held its fourth American Red Cross drive for blood donations at L-A Fire Department in Lowell. more »»
This might be the last time we can stand on our own
March 16, 2016 When you think it can't get any more messed up, it does! Saw on a local television station recently and read in the paper that in Ohio on our ballot we can vote for president twice, but only one vot... more »»
Schultz column was thought provoking
March 16, 2016 I read many of the pieces Connie Schultz, syndicated columnist, writes and find her to be a thoughtful and skilled writer. more »»
Trump: The art of the dodge
March 15, 2016 I am the Rainbow Sage. As a writing sage, the current state of presidential politics is like a dream come true, like a tear in the fabric of time to peek through. more »»
Halliday strives to excel no matter what the task
March 15, 2016 It is my immense pleasure to endorse John M. Halliday for the position of Washington County Common Pleas Judge. I have known Halliday all of my life while living in this great town of Marietta. more »»
Halliday will be fair and impartial as judge
March 15, 2016 This morning I was asked by a friend who I was going to vote for Common Pleas Judge on March 15. My answer was John Halliday. There are several reasons I am going to vote for John Halliday. more »»
Freimann has experience necessary to lead
March 15, 2016 I strongly urge you to support Flite Freimann for judge. Flite has the experience necessary to be a leader in our judiciary. more »»
Sarah Grace has smart, strategic leadership
March 15, 2016 Several people have asked me why I'm supporting Sarah Grace for state representative, so I thought I'd share my thoughts. more »»
Peppel says thanks for the appreciation & backs Bates
March 14, 2016 In the time since I announced in November my impending retirement from the Office of County Treasurer, I have received an outpouring of well wishes from many people and I want to take this... more »»
Ashcraft proud to serve on central committee
March 14, 2016 To Republican voters in the 30th Senatorial District, I am asking for your vote to re-elect me to the State Central Committee. I have represented you for 12 years. more »»
Support Sarah Grace, a positive influence
March 14, 2016 Sarah Grace has been a positive force in our community, and will be a strong, positive force in our state government. more »»
Eddie Smith has energy to succeed in House
March 14, 2016 I first met Eddie Smith at the Democratic breakfast and straw balloting last week held in the Athens Community Center. more »»
Stop Trump, vote for Kasich on Election Day
March 12, 2016 We need to fix our economy, but Donald Trump is not the person to do it. He inherited his business from his father, he didn't build it. more »»
Vote Dye for Washington County Treasurer
March 12, 2016 The best candidate for Washington County treasurer is Douglas A. Dye. Dye is the son of the late Larry R. Dye and Charlotte Biehl. He was born and raised in Washington Count. more »»
Please support Arc of Washington County
March 12, 2016 This is an urgent message! Please read all of this letter and then pass the information on to your friends. more »»
Vote for Ashcraft on Election Day
March 12, 2016 Marilyn Ashcraft is running for re-election to the Republican State Central Committee. Marilyn has worked tirelessly for nearly 30 years helping Republicans. more »»
Dye is best choice for county treasurer
March 12, 2016 Doug Dye is the right choice for Washington County treasurer. Dye is a lifelong resident of Washington County. more »»
John Kasich deserves your vote on Election Day
March 12, 2016 John Kasich has managed to conduct himself like a gentleman and a leader worthy of our support throughout the demolition derby that has been the Republican presidential primar. more »»


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|Find a Breeder
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More American Brittany Puppies and Dogs for sale.
NFC bred Brittany's West Mtn Gundogs in Payson, Utah
Brittany Pups Sniksoh Britts in Parker, Colorado
American Brittany Puppies!! AKC Reg... Dan-De Britts in Aurora, Colorado
AKC Brittany pups for sale Nelson's Brittany in Cedar, Michigan
Pups on the ground. Mick's Brittany's in Tulsa, Oklahoma
Tejas Iron Mike / Beans Blaze Puppi... Battle Creek Kennels in Forney, Texas
Brittany Puppies - Pro Trainer Bred Cove Mountain Kennels in Pocatello, Idaho
Brittany pups Carey's Boykins, Brittanys and English Cockers in McRae, Georgia
AKC/ABC Futurity Nomiated Brittany ... Capewind Brittanys in East Falmouth, Massachusetts
Brittany pups. Best pairing i have ... Kelley Ridge Kennels Brittany / Rare Llewellin in Caddo Mills, Texas
Female Brittany for Sale - SOLD Buggytown Bird Dogs in Barnesville, Georgia
AKC Brittany Pups - Hall of Fame RHEAUMES KENNEL in PALMS, Michigan
AKC Brittany Pups - Hall of Fame RHEAUMES KENNEL in PALMS, Michigan
AKC BRITTANYS READY TO GO!!! 600.00 Walnut Ridge Quail Farm and Kennel in Pulaski, Tennessee
Female Now Available Beaupre Gun Dogs in Omro, Wisconsin
AKC Brittany Pups All R Farms in ANNABELLA, Utah
Beautiful Liver Roan American Britt... C Brittany Kennels in Minersville, Utah
AKC Brittany pups, ROAN females, re... Draco Kennels in Hardinsburg, Kentucky
SOLD 4 Year Old Female Frosty Meadows Kennel in Mt. Pleasant, Texas
Brittany pups Stine Stables in Mosinee, Wisconsin
Brittany Puppies Ozark Wings in Caulfield, Missouri
Brittany Female Pups MasonRidge Brittanys in Taylor, Arizona
Mazeppa Brittanys litter due 07/23/2016 Mazeppa Brittanys in Owatonna, Minnesota
Brittany pups for sale - Male Orang... Biebel Brittanys in Bowling Green, Kentucky
AKC BRITTANY PUPS Fife Kennels in RUPERT, Idaho
AKC Orange and White Male Brittany ... Ashley's Britts in Hazleton, Pennsylvania
BEAUTIFUL BRITTANY PUPPIES Big D Kennels in Lebanon, Tennessee
BEAUTIFUL BRITTANY PUPPIES Big D Kennels in Lebanon, Tennessee
Upcoming Brittany litter Rock Steady Kennel in Morris Run, Pennsylvania
L/Wmale pup whelped 10/7/2012 SOLD - American Brittanys in Oxford, Michigan - Autens Brittanys
Go to our website to see a photo of Ranger and the pups pedigree. Next litter due Feb. 10, 2012
Ad location: Oxford, Michigan
Ad created: Dec 02, 2012
Contact Information
Contact Name: Ron or Carol Auten
248-628-5147Contact breeder through email Click here to visit website
Autens Brittanys Breeder Information


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To attract the top talent, you need to show them the career path, responsibility and a quality of life.
You must adopt a 'manufacturing mentality' for your restaurant catering operation.
Companies that don't hire illegal workers can still face large fines for incorrect or missing paperwork for legal workers.
Oversaturation of concepts poses a threat from real estate to market share.
Eric Chester delivered a keynote on reviving work ethic at this year's Fast Casual Executive Summit.
More than 25 percent of new hire paperwork is now completed on mobile devices.
The most valuable marketing tool available to you as a restaurant operator is your people; train them.
The minimum wage strikes permeating throughout the restaurant industry continue to grow, with employees in nearly 60 cities protesting right before Labor Day weekend. The heated debate has even carried over onto brands' social media pages, with supporters and dissenters...
The Health Insurance Exchange opens soon with an employee notification requirement for all restaurant operators.
One analyst said wage increases would add to food costs, which would then affect restaurant visits.
A petition has been sent to major restaurant chains citing their combined $7.35B in profits last year.
To increase sales, catering will need to have share of mind internally as well as proper budgetary support from every department within your organization.
In a faster-paced, mobile, customer-dominated, global economy, service and experience become priorities.
A mix of young students and career-minded workers will bring different strengths to the table as far as flexibility in hours available, pay requirements and leadership skills.
Thousands of minimum-wage employees, most of them in the limited-service restaurant industry, are planning to walk off their jobs next week in what is being called "an unprecedented wave of strikes." The organized strike is planned for July 29 in...
If you are confronted with peculiar and unexplained issues with cash management or inventory control, look beyond the 'usual suspects.'
The company is upgrading its catering channel, which now includes off-premise, start-to-finish customer service, systemwide training and separate branding efforts.
Incremental fixed costs from adding a catering channel will be offset by the long-term profits made.
The Starbucks tip-pooling case will likely affect other businesses.
Businesses with 50-plus employees now have an extra year to comply with coverage.
Rapid Fired Pizza slices up second Cincinnati location
Instagram: One marketer's take on why it may be a restaurant's best friend
Let the spending begin: McDonald's, Papa John's declare quarterly dividends
Firenza begins targeted expansion
Malawi's bring Pizza with a Purpose to Virginia
5 Reasons Your Restaurant Isn't Attracting Millennials
How Big Data is Revolutionizing the Restaurant Industry
Transitioning from Legacy POS Systems to New Generation Technologies
Keys to Your Next POS Purchase: POS Advice from Restaurant Operators
[WEBINAR] Learn How to Turn Social Followers into Brand Advocates
Pizza Hut gives free pizza in exchange for emoji-emblazoned Pepsi bottles
The start-up and the old-timer: A tale of 2 pizza chains
Where in the restaurant world will Pokemon GO, go?
Historic 1st FAA-approved food delivery? Of course, it's a Slurpee and a doughnut


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Spotlight! Our Newest LGBT-Friendly New York Wedding Cake Artists! Click on a New York LGBT Wedding Cakes Logo to View Their Online Brochure
Directory - New York LGBT Wedding Cakes
Member ID:
This Chick Bakes
Long Island City, New York LGBT-Friendly Bakery
Manhattan, Brooklyn & Queens
We have been making cakes of all shapes, sizes and types for over 20 years. Formally Hope, Faith & Gluttony Bakery, we merged with This Chick Bakes in 2013 and have been making cakes, cookies, bars and other baked items since. We also do edible wedding favors: Edible Image Cookies, Iced Sugar Cookies, and regular cookies and bars with bows and personalized messages. Great for engagement and bachelor/ette parties too!
Website: This Chick Bakes | Contact: Hope Jones | Phone: 718-706-6616


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LOS ANGELES (July 17, 2014) Standard Pacific Homes, with 27 developments from Florida to California including two in Texas, is building homes that include an optional pet suite.
The most upscale doggie digs include a step-in wash station, automatic feeder, large bunk-style bed and even a flat screen TV.
Pets are family, company Vice President Jeffrey Lake says.
Standard Pacific's newest community is about 25 miles south of Los Angeles.
Homes there start at $710,000 and lake says the pet spa option adds $35,000 to the price.
The company also has developments in the Dallas-Fort Worth and Austin areas.


text: Get ready for the big party with an assortment of Football Birthday Party Favors for your guests. Our Football Party Favors can be personalized with your custom wording and design. From personalized candy bars and chocolate lollipops to picture frames and tumblers, our Football Birthday Favors will make planning your party so easy!


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Between Tyler Perry's Atlanta-based media empire, Georgia's financial incentives for film production, and Screen Gems' new deal to convert Lakewood Fairgrounds into a soundstage, the A has increasingly raised its profile as a destination for making movies and television shows. Perhaps no project could do more for the city's cachet than the local filming of "THE WALKING DEAD," American Movie Classics' undead miniseries developed by director Frank Darabont and based on the cult graphic novel series of the same name. AMC is essentially the new HBO, boasting such critically acclaimed fare as "Mad Men" and "Breaking Bad." If "The Walking Dead" lives up to those shows when it debuts in November, it could boost our cool factor by several orders of magnitude. Either way, it's always fun having zombies around. &emdash;www.amctv.com/originals/The-Walking-Dead
© 2016 Creative Loafing Atlanta


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Report this comment
Ed Mezzetti, Sports reporter specialising in Rugby, Cricket and Athletics. Call me on 01865 425456 / / Rugby
JUSTIN Burnell refused to get carried away with London Welsh's pulsating victory over Bristol last night.
The Exiles won their Greene King IPA Championship play-off final first leg 27-8 at the Kassam Stadium to seemingly take control of the tie.
Tries from Nathan Trevett, Nick Scott and Carl Kirwan helped Welsh secure a 19-point lead in front of 5,021 fans – their biggest crowd of the season.
But head coach Burnell was keen to keep his side's feet on the ground, saying: "We have still got a long way to go, there is still another leg to play.
"We know how good Bristol are, they are capable of scoring points.
"I guess it's now London Welsh's defence against Bristol's point scoring.
"We are happy with the three tries and the 19-point lead, we are over the moon with that. It's all to play for."
Burnell would not say whether he felt it was enough of an advantage ahead of next Wednesday's second leg, but simply stated: "I would rather be 19 points up than 19 points down."
Bristol had captain Ryan Jones stretchered off with an ankle injury and conceded numerous penalties.
Burnell added: "I think the difference with the 19 points was the calibre of the refereeing.
"Wayne Barnes just proved why he is one of the best referees in the world.
"He highlighted the fact, which is a frustration with a lot of the coaches in the Championship era, that Bristol get away with certain aspects of play.
"I thought he was outstanding. He refereed the game right to the line and allowed them not to get away with what they have done all year."
Bristol head coach Sean Holley said his side were "outplayed and outcoached".
He said: "They were great tonight and we couldn't find a way through.
"We have got to pick ourselves up. Our set-pieces need to be better and we were turning over the ball too much."
Latest Sport news
- Liam Sercombe gets fitness boost but Oxford United await news on Alex MacDonald scan
- Ryan Taylor is fit and raring to go for Oxford United this season
- WEEKEND RESULTS July 23-24
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- CRICKET: Luke Ryan is the hero as Banbury beat Burnham in Division 1
- ATHLETICS: Lawrence Clarke and Nathan Douglas left frustrated at Muller Anniversary Games
- MOTORSPORT: Renault's Jolyon Palmer rues costly spin at Hungarian Grand Prix
- James Roberts nets in Oxford United's pre-season draw at Bath
- Michael Appleton hopeful of sealing deals for attacking players next week
- ROWING: Constantine Louloudis eyes chance to extend GB's golden record at Rio Olympics


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Graduate Degrees
The Department of Chemical Engineering provides graduate programs at the Master's and Doctoral levels. A general description of these programs follows. For a more detail on the graduate program and degree requirements, please see our latest handbook located below.
GS Handbook_2015-2016 [.pdf]
Financial Support
Studying at the graduate level is a full-time commitment. We require every student pursuing research-based degrees (Masters - thesis option and PhD) to be funded. Students are expected to apply for scholarships and fellowships for which they are eligible, and to maintain dialogue with their research supervisor about funding requirements and funding sources. Information on important funding opportunities from outside the Department of Chemical Engineering can be found here and on the right side.
Graduate Studies
Chemical Engineering has been taught at McGill since 1908. The first doctorate was awarded in 1935, and our program has subsequently grown to accommodate approximately 90 full-time PhD and MEng candidates, and postdoctoral researchers. Our alumni occupy many key positions in industrial, academic and governmental organizations in Canada and throughout the world.


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\nThat being said, I personally wouldn't spend hundreds of dollars of top end rip curl suit vs. their mid/lower end of the line. WHY? Because all you're paying for is a suit that drys quicker with that "flash lining" which I don't find very comfy over my entire body. Almost the entire suit is lined. Much prefer the feel of neoprene. Honestly, who cares if the suit drys instantly. Just sit in your car with heater on for a few minutes if that bothers you. You're going to get wet anyway as soon as you get in the water! It's not a dry suit. Also, not great for pissing in! You can get a dawn patrol 5mm back zip without a attached hood if you want a MUCH cheaper 5/3mm suit from rip curl that will work great for less than half the price. It's retailing for around 180 bucks on rip curls website. They also have the E-Bomb if you want an attached hood/chest zipp 5mm suit for 100 bucks less than the flashbomb. It's going for 340 bucks
Results 1 to 8 of 8
Thread: Flashbomb 5/4
Nov 10, 2012, 11:56 AM
- Join Date
- Apr 2012
- Posts
- 1,093
Last edited by shark-hunter; Nov 10, 2012 at 12:08 PM.
'; pd[146583] = '
Nov 10, 2012, 12:33 PM
- Join Date
- Jan 2012
- Location
- Monmouth County
- Posts
- 52
\nSo I actually own a Flash Bomb (3/2) unlike the other replies (except maybe Gnar?)... and I will reply to your specific questions rather than giving you an unsolicited lesson on wetsuits.
\n1) Yes it does seem to be noticeably heavier to me than my other 3/2's.
\n2) Sorry I can't comment I don't have the 5/4
\n3) See #2
\n4) Mine has held up well through 1 year of use including some surf trips
Last edited by foamdust; Nov 10, 2012 at 12:36 PM.
'; pd[146584] = '
Nov 10, 2012, 01:17 PM
... and I will reply to your specific questions rather than giving you an unsolicited lesson on wetsuits.
\nThanks! haha
'; pd[146588] = '
Nov 10, 2012, 02:28 PM
I have a 5/4 Rip Curl FlashBomb. Size Large. Fits great, doesn't feel heavy, is warm as hell.
\nAnd I'm selling it, because I bought a size too small. Only used 6 times. Let me know if you're interested.
'; pd[147211] = '
Nov 17, 2012, 02:05 AM
- Join Date
- Apr 2012
- Posts
- 1,093
I should add that after wearing that flash lining a few times it does "work in" better and feel more comfortable than it did in beginning.
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Threaded View
Nov 10, 2012, 05:21 AM #1
Flashbomb 5/4
Looking for some feedback...
1) Does it bog down and feel heavy in the water?
2) Does it flush from the hood?
3) Does the hood fit nice and snug?
4) Do the materials hold up or does it fall apart like most rip curl suits?


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I'll be traveling from Malta to Italy somewhere around the end of October/early November. Was originally going to fly into Naples to explore the Amalfi coast region before heading to Rome. If my budget allows at the time I was thinking of flying into Catani and taking a week to ten days to travel via land up the West Coast to Naples instead. Looking for any suggestions on an itinerary/places to visit that would cater to a backpacker budget for that region. Most likely will be…
Probably numerous posts on this topic but what are the do's and dont's for visiting the Galleria dell Accedemia. travelling with a six year old so queues could be difficult!
Hello there community. I am planning on coming to the dolomites from Malta. I once went there about 12 or so years ago. I went on a bus tour. I saw these amazing ancient monastaries built inside the rocks. Does anyone know what they are called, what part of the dolomites they are in and how to get to them?
I would like some recommendations on a few things: 1) Which part of the dolomites is best to stay in, in order to go hiking ( any r ecommendations for 3 star hotels or bed and breakfasts to…
Heading back from Italy to France via Switzerland we had intended to take the car train shuttle from iselle di Trasquera to Brig.
But we never did see a sign or any indication of the station or a loading zone. Ended up driving over the Simplon pass and on to goppenstein to get the shuttle to kandersteg.
Admittedly we do have an old map, but can anyone tell me if there really is a car train shuttle from Iselle to Brig ( or further on?) and if so, how is it indicated in Italy? Have never had any…
We are a family of four arriving at Venice airport on Sep 5, 2016. What is the best transport for going from airport to the hotel. The hotel is on the canal near Rialto bridge. We do not want to move with the heavy luggage or shift from one transport to another. I understand there are water taxi for private transfer. I heard there is Venice film festival during this period; and many taxi companies may not be available. Do I need to book the private taxi in advance on line; or it would be easier…
Hi :)
My girlfriend and I will be in vacation in Italy in September and we're trying to plan an itinerary.
It'll be her third time in Italy and my first time.
I would be happy to receive your opinion on our itinerary- Is it too rushed? do you have any other recommendations on must-see attractions in these areas?
10.09- land in Rome at noon. take public transportation to Amalfi coast to our hotel.
11.09-14.09- explore the Amalfi coast and the area- Naples, Pompeii and the volcano, Sorrento…
I shall be in Italy for approx. 2 weeks in May, 2017, flying in & out of Rome.
I would like to do the Amalfi Coast, Rome, Tuscany, the Cinque Terra (the
major Italian sights). Question 1: In what order should I start? 2) How many
days should I spend in each city?
So I am i Europe for 2 weeks, between August 1st and 14th. Untill the 8th, I will be in Southern France but after that I will be based in Milan with a relative. I was thinking of staying overnight somewhere before leaving for Venice on the 13th, where I will also stay a night. I found some good hotels in Vicenza, which would probably allow me to see Verona as well. However, Lake Grada seems extremely nice, as does Cinque Terra, and would probably be preferable.
Right now, I am probably leaning…
I wish the trip could be longer but we are spending one day in Cinque Terre. Any suggestions on itinerary for the day to get as much as we can of CT?
Thanks for the help.
We're heading to Italy in early October for a friend's wedding, which is being held in Petritoli (about 3 hours by car NE of Rome, and about 20 km from the Adriatic). One thing I'm looking forward to is the location: many friends would have been to Rome/Venice/Florence/5terre/[insert other popular tourist destination here], but I don't know anyone with any prior experience in this part of the country.
We'll be flying in and out of Rome, but I was hoping to tack on a few days after the wedding…


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February 27, 2011
1 year
Simple animations.
Hi, I'm Shan. I'm in Fort worth for the last 2 years. I've been using Blender a few months now. I would love to learn a lot more and create an animated short. - Shan.
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Apr 5, 1983
|Filing date
|May 14, 1982
|Priority date
|May 14, 1982
|Fee status
|Also published as
|Publication number
|Craigenne A. Williams, Milan Wickerhauser
|Original Assignee
|American National Red Cross
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (2), Non-Patent Citations (3), Referenced by (20), Classifications (18), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
The complement system, an immune response effector mechanism, comprises a set of proteins activated by the presence of antibody/antigen complexes in the host to initiate a cascade of proteolytic cleavage and protein binding events which promote elimination of the antigens from the host. Physiological responses to activation of the complement system include acute local inflammation, dilation of blood vessels, and transudation of fluid into interstitial spaces.
The human complement system includes component C1, a complex of protein subcomponents including serine esterase (C1-esterase), which participates in the proteolytic cleavage sequence of the mechanism. Activation of the C1 component of the complement system and enzymatic activity of C1-esterase is regulated by a serum inhibitor, C1-inactivator (C1-inhibitor) which controls the activity of C1-esterase. A functional deficiency of this inactivator protein results in a condition termed hereditary angioneurotic edema, caused by repeated unchecked activation of the complement system and symptomized by recurrent episodes of local acute inflammation at sites of activation. The accompanying vessel dilation and transudation of fluid into tissue spaces can cause suffocation if activation occurs at sensitive sites in the upper respiratory tract.
Acute attacks of swelling in hereditary angioedema are successfully treated by the administration of functionally active serum C1-inactivator (C1-INA), preferably as a concentrated plasma fraction. Plasma concentrates of C1-INA currently used in clinical replacement therapy have been implicated as a cause of transfusion hepatitis, however. Accordingly, research efforts have been directed to methods for preparing C1-INA concentrates which provide a high yield of biologically active C1-INA and which also provide a product concentrate having minimized potential for transmitting hepatitis B virus (herein also referred to as HBV).
Current methods for purification of C1-INA typically include the step of polyethylene glycol (PEG) precipitation, which removes extraneous complement system proteins; the product C1-INA fraction, however, retains potential for viral infection. The classic pasteurization approach to inactivation of plasma HBV, successfully employed in providing safe clinical serum albumin, has not heretofore been useful in providing safe clinical C1-INA, since this protein denatures under the required pasteurization conditions. Attempts to improve the heat stability of C1-INA have not significantly improved recovery of active material. The use of N-acetyltryptophanate, sodium caprylate, and sodium citrate, successfully employed as heat stabilizers in the pasteurization of the plasma proteins albumin and antithrombin III, respectively, have not provided adequate protection for C1-INA during pasteurization. Losses in C1-INA activity attributable to heat denaturation during pasteurization in the presence of sodium citrate, for example, typically exceed 25%; in addition to lacking cost-effectiveness, the large amount of protein denatured and subsequently infused into patients can adversely affect continued efficacy of the treatment. Heat denaturation has been encountered in the pasteurization of other plasma proteins such as Factor IX, used for replacement therapy in the treatment of hemophilia B.
The invention encompasses a method for the heat stabilization of a plasma protein comprising heating the protein in the presence of potassium citrate or ammonium citrate. In particular, the invention includes a method for the pasteurization of a Factor IX or C1-INA plasma concentrate in the presence of ammonium or potassium citrate. The invention further includes a method for the preparation of a pasteurized C1-INA or Factor IX concentrate from plasma or a fraction thereof comprising partially purifying C1-INA or Factor IX according to known protein separation techniques and heating the resultant partially purified fraction in the presence of potassium or ammonium citrate under conventional time and temperature pasteurizing conditions.
The methods of the invention successfully stabilize both C1-INA and Factor IX against heat denaturation, with up to 100% retained activity, and further may eliminate or substantially reduce the risk of HBV contamination of the pasteurized protein. Additionally, the methods of the invention are also applicable to the heat stabilization of other heat-sensitive plasma proteins and the prevention of the thermal denaturation of these proteins under pasteurization conditions; exemplary of such plasma proteins which can be heat-stabilized according to the present invention are antithrombin III, Factor X, and Factor II.
FIG. 1 shows the precipitation curves obtained by immunoelectrophoresis as well as the specific activities of C1-INA pasteurized according to the process of the present invention.
FIG. 2 is a graph comprising the thermal denaturation curves of Factor IX, and Factor IX stabilized according to the process of the present invention.
According to the invention, plasma proteins are stabilized against thermal denaturation by the presence of potassium or ammonium citrate in concentrations of from in excess of 2.0 M to saturation, preferably from about 2.5 M to saturation. Typically, a high molar citrate solution and/or citrate powder is added to an aqueous protein suspension in amounts sufficient to provide a citrate concentration in excess of 2.0 M; the pH of the solution is then preferably adjusted to about neutral with citric acid. Alternatively, a saturated or supersaturated solution of the citrate, is adjusted to a pH of about neutral with citric acid, and the protein sample added to the citrate to give the desired citrate concentration.
While suspension concentrations of ammonium citrate (Am-Cit) of about 3.0 M are conveniently obtained by the addition of saturated solutions of ammonium citrate (3.6 M at room temperature) to the protein suspension, suspension concentrations of potassium citrate (K-Cit) of about 3.0 M require the use of a combination of citrate powder and high molar citrate solutions, or a supersaturated citrate solution, since the saturation concentration of potassium citrate at room temperature is 3.0 M. Thus, for example, a 3.0 M suspension concentration of potassium citrate can be achieved by the addition of about 5 volumes of 3.0 M K-Cit solution to about 1 volume of the protein suspension to give a K-Cit concentration of about 2.5 M, followed by the addition of K-Cit powder to give a suspension concentration of 3.0 M K-Cit. This sequence results in an acceptably low rise in pH, generally less than 8, and requires only sufficient citric acid to lower the pH of the suspension to about neutral, preferably from about 7.0 to 7.5. In an alternate example, 3.3 M tripotassium citrate is added to a protein sample in proportions sufficient to give a K-Cit concentration in the sample of about 3.0 M. The sample is then adjusted to about neutral with citric acid.
The invention is particularly applicable to pasteurization techniques directed toward the inactivation of hepatitis viral contaminants associated with plasma proteins, since the presence of ammonium or potassium citrate in this concentration prevents significant loss of biological activity of these proteins during pasteurization and may permit large-scale preparation of a clinically safe product.
The method of the invention is applicable to a variety of plasma proteins including antithrombin III (AT III) and Factors X and II, but is particularly useful with the plasma proteins C1-INA and Factor IX, which are not effectively stabilized against thermal denaturation during pasteurization by known heat stabilizers. Both C1-INA and Factor IX can be stabilized according to the invention so that under typical pasteurization conditions, for example, 60� C. for 10 h, substantially complete biological activity is retained, with expected concomitant inactivation of associated (HBV) factors.
In the pasteurization method of the invention, a plasma protein concentrate is pasteurized at from 60� C. (�1/2� C.) for at least 10 hrs in the presence of potassium or ammonium citrate in concentrations of from in excess of 2.0 M to saturation, preferably at a pH of about neutral. In an exemplary embodiment of the invention, a pasteurized C1-INA plasma concentrate is prepared from a plasma cryosupernatant by first employing conventional protein separation techniques such as ion-exchange chromatography and PEG (polyethylene glycol) precipitation. The product C1-INA fraction is advantageously concentrated and then pasteurized in the presence of potassium or ammonium citrate in an amount providing a citrate concentration in the C1-INA fraction of from in excess of 2.0 M to saturation. Since the effectiveness of the potassium and ammonium citrate stabilizers of the invention tends to increase with increasing concentrations, in most applications, the citrate concentration of the C1-INA concentrate is preferably at or near the saturation point, in order to retain maximum biological activity of C1-INA. At the preferred temperature range of about 25� C. for addition of the stabilizer to the concentrates, saturation and concentration for potassium citrate is about 3.0 M, and for ammonium citrate, about 3.6 M. The stabilizers may be added to the concentrates at somewhat higher temperatures, in which case the saturation concentrations will be higher. For clinical use, the pasteurized C1-INA concentrate is then desalted, filtered and lyophilized according to known methods. Pasteurized Factor IX plasma concentrate is prepared by comparable purification techniques and pasteurization in the presence of potassium or ammonium citrate in the specified concentrations.
The purified C1-INA plasma concentrate for pasteurization according to the invention is prepared according to known methods, for example those described in detail in An Improved Method For Preparation Of C1-Inactivator Concentrate, Wickerhauser, presented as Poster No. 802, Joint Congress of the International Societies of Hematology and Blood Transfusion, Montreal, 1980. While immunoadsorption is not excluded as a separation technique in the present invention, a clinically suitable concentrate can be prepared by the use of non-specific protein separation procedures, followed by pasteurization. Typically, a combination of PEG precipitation and ion-exchange chromatography on, for example, DEAE-Sephadex and CM-Sephadex, is employed to reduce the protein complexity of the starting plasma fraction, usually a plasma cryosupernatant.
It is highly desirable to employ a PEG precipitation step in the C1-INA purification procedure, since PEG precipitation provides a supernatant containing C1-INA from which complement components C1-C5 have been removed. Preferably, a C1-INA fraction is first extracted from plasma cryosupernatant on DEAE-Sephadex followed by precipitation of impurities in the eluate with 20% PEG 4000, and adsorption and elution of the PEG supernatant on CM-Sephadex; this sequence simplifies the use of the remaining plasma for ethanol fractionation and recovery of clinical albumin. However, if recovery of albumin is not of interest, PEG can be added directly to the cryosupernatant, followed by sequential ion-exchange chromatography of the PEG supernatant.
The purified C1-INA fraction obtained by the purification steps employed is then desirably concentrated by, for example, ultrafiltration in a Pellicon UF membrane system for large batches, or by ammonium sulfate precipitation and desalting on Sephadex G-50 for small batches. The resultant concentrate is then pasteurized according to the process of the invention and desalted, filtered, and lyophilized to provide a C1-INA concentrate final product of intermediate purity, typically 60% to 150% purification over plasma at a yield of about 14% to 45% for large-scale procedures. If desired, the final product of intermediate purity can be further purified, as by column chromatography on hydroxylapatite, to provide a high purity final product, typically up to a 400 fold increase in purification over plasma with a yield of about 6% to 17% for large-scale procedures.
After removal of cryoprecipitate for recovery of antihemophilic factor (AHF) cryosupernatant obtained from fresh frozen plasma was batch-adsorbed on DEAE-Sephadex (6 g/l) equilibrated in citrate saline (CS); the unadsorbed proteins were removed for ethanol fractionation and the DEAE cake washed with CS buffer (0.5 plasma volume), followed by elution with 2 M NaCl in 0.03 M citrate, pH 6.8 (0.2 plasma volume). The eluate was concentrated to 0.1 plasma volume, equilibrated with 0.06 M citrate phosphate (CP) buffer, pH 7.0, and precipitated with 20% PEG 4000. After centrifugation, the PEG supernatant was diluted with an equal volume of water and adjusted to pH 6.0, followed by adsorption on CM-Sephadex (6 g/l starting plasma), equilibrated in 0.03 M CP, pH 6.0. The CM cake was washed with the same buffer and eluted with 2 M NaCl in 0.03 M CP, pH 7.3. The eluate was then concentrated to 0.02 plasma volume, and equilibrated with CS buffer by ultrafiltration. The product was then sterile filtered, dispensed and lyophilized to give an intermediate purity C1-INA product concentrate. Recovery of C1-INA was 29.4% of the C1-INA present in the starting plasma with 91.6 fold purification. Complement components C1-C 5 were undetectable by the Ouchterlony technique.
Cryosupernatant obtained according to Example 1 was treated with solid PEG 4000 in the amount of 40 g/l at 5� C. After stirring for 1 hr, a first fraction was removed by centrifugation, and an additional 60 g/l PEG added to the supernatant to a final concentration of about 10%, based on the original volume of cryosupernatant. Prothrombin complex (PTC) was extracted from the 10% PEG supernatant by batchwise adsorption on DEAE-cellulose, and an additional 100 g/l of PEG were added to the eluate to a concentration of about 20%, again based on the original volume of cryosupernatant. The 20% PEG precipitate was separated by centrifugation and discarded, and the 20% PEG supernatant was batch adsorbed on DEAE-Sephadex (6.5 g/l starting plasma), preswollen in citrate saline (CS). After removal of unadsorbed proteins, the product DEAE cake was washed with 0.15 M NaCl, followed by elution with 2 M NaCl in 0.03 M citrate at pH 6.8 (200 ml/l starting plasma). The DEAE eluate was concentrated on a pellicon UF system, and equilibrated in 0.03 M citrate-phosphate buffer (CP) at pH 6.1, followed by adsorption with CM-Sephadex (6 g/l starting plasma) preswollen in 0.03 M CP, pH 6.0. The CM-Sephadex cake was washed with the same buffer and eluated with 1 M NaCl in CP buffer, pH 6.8 (200 ml/l starting plasma). The CM eluate was then concentrated, equilibrated in CS, sterile filtered, filled, and lyophilized to give a product C1-INA concentrate of intermediate purity.
The procedure of Example 2 was followed, except the concentrated CM eluate was equilibrated in 10 mM KHPO4 at pH 7.0 and chromatographed on OH-Apatite (4 g/l starting plasma). NaCl was added to isotonicity to the OH-Apatite unadsorbed fraction, and the isotonic product sterile filtered, filled and lyophilized to give a product C1-INA concentrate of high purity.
Alternatively, the concentrated CM eluate of Example 1 is equilibrated and chromatographed according to Example 3, with addition of NaCl to isotonicity followed by sterile filtering, filling and lyophilization to give a high purity C1-INA product concentrate.
An intermediate purity C1-INA concentrate obtained according to the procedure of Example 1 was pasteurized in the presence of 3 M potassium citrate (K-Cit) as follows:
(a) 5 g of C1-INA concentrate was reconstituted with 50 ml H2 O. The sample was stored at 5� C. for 7 h, followed by addition of 250 ml 3 M K-Cit (pH 7.3) and 80.5 g K-Cit powder (1.61 g/ml) to a final concentration of 3.0 M K-Cit. The addition of stabilizer caused precipitation of the protein. The pH of the resulting turbid suspension (pH 7.7) was then slowly adjusted to 7.45 with 3 M citric acid. The stabilized suspension was then pasteurized by heating for 10 h at 60� C.�0.1� C. The solid cake of precipitated proteins formed on top of the reaction mixture was disturbed and resuspended, and was reformed by centrifugation for 20 min at 5000 rpm at room temperature. The clear supernatant was carefully syphoned from the centrifuge cups. 210 ml of clear supernatant and about 200 ml of slurry were obtained. The supernate was found to be free of proteins and was later discarded.
The 200 ml of slurry was diluted to 600 ml with H2 O, dropping the pH to 6.25. 50 ml of 0.1 N NaOH and 400 ml 0.2 M Na2 HPO4 were added to a final volume of 1050 ml and a pH of 6.4. The solution was stored overnight at 5� C. and then clarified through MILLIPORE filters with a final pore size of 0.22μ, obtaining a final volume of 960 ml. The clarified product was concentrated and diafiltered on a Pellicon ultrafiltration system, using PTGC membranes, (10,000 dalton nominal pore size) to about 200 ml (high circulation for 3 hrs at a flow rate of about 1350 ml/hr). The resultant concentrate was then diafiltered (DF) against 2520 ml phosphate saline buffer (PBS) containing 10 mM NaPO4 +150 mM NaCl, pH 7.25. Aliquots of the diafiltrate were taken every 600 ml to monitor removal of the potassium using a flame photometer. The potassium concentration dropped to a clinically safe range of less than 1 meq. after 1880 ml diafiltration buffer was used. The C1-INA containing retentate was then concentrated down to 160 ml, taken out of the Pellicon system, diluted to 200 ml with the PBS buffer, dispensed in 20 ml fills in 50 ml vials, frozen in liquid nitrogen, and lyophilized. The lyophilization cycle was 5 days and 16 hours. The product temperature during the primary (sublimation) phase was maintained at -35� C., and during the secondary phase at +20�-21� C. The pasteurized C1-INA was assayed for biologic and antigenic activity, protein concentration, and characterized by crossed immunoelectrophoresis in heparinized agarose gel.
The results, as shown in Table I, indicate that the pasteurization step in the presence of 3.0 M K-Cit resulted in about a 10% total protein loss, but no drop in specific activity and minimal changes in the crossed immunoelectrophoretic analysis (see FIG. 1).
(b) Before discarding the 210 ml clear supernate, a 10 ml aliquot was saved frozen and the remaining 200 ml was diluted to 1000 ml with PBS buffer. The diluted supernate was clarified on MILLIPORE membranes (0.22μ pore size), concentrated on 2 packs of the Pellicon PTGC membrane to 150 ml, and diafiltered against 1840 ml PBS buffer. After removal from the Pellicon system, the solution was diluted to 200 ml with the PBS buffer, dispensed and frozen. It was tested for proteins by taking 3 ml of the solution and adding 2 ml of 50% solution of trichloroacetic acid (TCA) solution. No precipitate developed, indicating the absence of any detectable protein.
TABLE I__________________________________________________________________________(3.0M K-CITRATE)Volume Protein Antigen Activity RECOVERY RATIOStep ml mg/ml Cl-INA PE/ml AG ACT PROT ACT/AG ACT/PRO__________________________________________________________________________Before Pas-teurization* 200 22.7 20.75 25.0** 100 100 100 1.20 1.10After Pas-teurization 200 20.9 19.0 22.63 91.6 90.5 92.1 1.19 1.08After Pas-teurizationand Lyoph.+ 200 20.2 18.4 22.37 88.7 89.5 89.0 1.20 1.11__________________________________________________________________________ **Assigned Value *Control Sample + Lyophilized Sample from Example 1
An intermediate purity C1-INA concentrate obtained according to the procedure of Example 1 was pasteurized in the presence of 2.0 M Na-Cit, 2.0 M K-Cit, 2.5 M K-Cit, 3.0 M K-Cit, 2.0 M ammonium citrate (Am-Cit), 2.5 M Am-Cit, and 3.0 M Am-Cit, following the procedure of Example 5, except employing 3.6 M Am-Cit where relevant.
The heat stability of C1-INA under pasteurizing conditions was assessed by immunoelectrophoresis of the pasteurizates in heparinized agar gel employing a barbital buffer, pH 8.6 (I=0.075 in chambers, 0.025 in gel). Samples were diluted to about 1.0 PE/ml, in 1:3 citrate saline (CS). An unpasteurized control sample was diluted in CS.
Operating conditions were as follows:
1st Dimension: (16.6 μ/ml heparin) 178V, for 2 h.
2nd Dimension: (3% Ab to C1-INA) 148V, overnight.
Temperatures: 16� C. cooling under plate, 3� C. cooling in condensation coil, 26� C. ambient temperature.
The results showing retained immunological reactivity of the pasteurizates as compared to the control sample, are shown in FIG. 1.
The biologic activity remaining is given as a percent of the specific activity of the unpasteurized control. The biologic activity was determined by the method of Levy and Lepow, Proc. Soc. Exp. Biol. Med., 101:608, 1959.
After removal of cryoprecipitate for recovery of AHF, cryoprecipitate supernatant plasma was adsorbed into DEAE-Sephadex A50 (70 mM Na-Citrate, pH 6, 1.7 g dry weight/liter plasma); the A50 cake was washed with 70 mM Na-Citrate, pH 6, and eluted with 200 mM Na-Citrate, pH 6. The eluted Factor IX complex (vitamin K-dependent clotting Factors II, IX, X, and protein C) were clarified and concentrated (x15) by diafiltration against 0.15 M NaCl in 20 mM Citrate, pH 6, followed by adsorption on sulfated dextran, according to the method of Miletich, et al., Analytical Biochemistry, 105:304-310 (1980). Stepwise elution with NaCl in increasing concentration (0.15 M, 0.25 M, 0.45 M, and 0.80 M) successively separated prothrombin, Factor X and Protein C, and Factor IX. The resultant Factor IX concentrate was essentially free of Factor X and prothrombin, and had a specific activity of about 17.6 units Factor IX/mg protein.
Either dextran-sulfate-Sepharose or heparin-Sepharose may be used instead of sulfated dextran. An elaboration on methods of preparation of Factor IX and related concentrates is set forth by Doris Menache, Prothrombin Complex Concentrates: Clinical Use, Ann. N.Y. Acad. Sci., 370:747-756 (1981), and in a copending patent application entitled "Plasma Protein Concentrates Of Reduced Thrombogenicity And Their Use In Clinical Replacement Therapy", filed on Apr. 28, 1982.
A high purity concentrate of Factor IX obtained as described in Example 7 as pasteurized in the presence of 3.0 M K-Cit according to the method of Example 6. The thermal denaturation of the pasteurized sample as compared to an unpasteurized control sample was monitored by ANS fluorescence according to the process described by Busby, et al., Thermal Denaturation of Antithrombin III, J. Bio. Chem., 256:12140-12147, 1981.
The monitored samples were constituted as follows:
______________________________________ 0.02M KPO4, pH 7.35 2mM 3.5M Factor IX 0.15M NaCl ANS K-Cit______________________________________1. Control Sample 10λ 86.7λ 3.3λ 02. Test Sample (3.0M citrate concentration) 10λ 1.0λ 3.3λ 85.7λ______________________________________
The data obtained, comprising fluorescence emission measurements, was plotted as a function of increased sample temperature. The resultant thermal denaturation curve, shown in FIG. 2, reflects the thermal stability of the test sample as compared to the thermal denaturation temperature (Td) of the control sample, 54.5� C.
Five (5) samples of a Factor IX concentrate similar to that of Example 8 were pasteurized at 60� C. for 10 hrs in the following formulations:
__________________________________________________________________________ Sample 5 (buffer con- Sample 1 Sample 2 Sample 3 Sample 4 trol)__________________________________________________________________________Salt (conc.) 3M K-Cit 1.8M Tricarb- 2.0M K- 1.8M K-Cit allylate Tricarbally- 1.8M K-Glu- (Potassium Salt) late and 1.2M conate K-GluconateFactor IX 2.8 3.9 2.6 2.3 9.9(μ/ml)Volume (ml) 7.1 7.3 9.0 9.1 1.9Total Factor 19.9 28.5 23.4 20.9 18.8IX Units__________________________________________________________________________
The pasteurized samples were dialyzed into citrated saline (0.02 M Na Citrate, 0.15 M NaCl, pH 6, +4� C.) to reduce the citrate concentration of the samples and reduce inhibition to the clotting assay. The dialysate was changed three (3) times, introducing 1800 to 2000 ml of fresh, cold 20 mM Citrate (pH 6, 0.15 M NaCl) at each change. Total dialyzation time was 22 hrs.
The clotting activity of the dialyzed, pasteurized samples was assessed as follows:
______________________________________ Sample Sample Sample Sample Sample 1 2 2 4 5______________________________________Factor IX 1.8 1.1 0.7 0.8 0(μ/ml)Volume (ml) 9.1 8.0 8.6 7.6 1.8Total Factor 16.4 8.8 6 6 0IX Units% Recovery 82.4 30.9 26 29 0% Retained Clotting 75 40 27 27 0Activity (Over Un-pasteurized sample)______________________________________
|Cited Patent
|Filing date
|Publication date
|Jan 20, 1956
|Jan 6, 1959
|Nat Res Dev
|Process of preparing anti-haemophilic globulin
|Feb 6, 1978
|Oct 9, 1979
|Biotest-Serum-Institut Gmbh
|Ion exchanger treatment of citrate-stabilized plasma
|Busby, et al., "Thermal Denaturation of Antithrombin III", Journal of Biological Chemistry, vol. 256, No. 23, 12140-12147, (1981).
|Wickerhauser, et al., "Antithrombin III Concentrates for Clinical Use: The Effects of Pasteurization and Freeze Drying", Abs. #35.
|Wickerhauser, et al., "Development of Large Scale Fractionation Methods", Vox Sang., 36:281-293, (1979).
|Citing Patent
|Filing date
|Publication date
|Jan 13, 1983
|Sep 11, 1984
|Miles Laboratories, Inc.
|Pasteurized therapeutically active blood coagulation factor concentrates
|Feb 26, 1985
|Feb 3, 1987
|Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte
|Method of inactivating reproducible filterable pathogens in blood products as well as a method of producing blood products
|Apr 30, 1984
|Aug 18, 1987
|Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte
|Method of inactivating reproducible pathogens
|May 18, 1988
|Oct 24, 1989
|Armour Pharmaceutical Company
|Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants
|Jan 3, 1989
|Feb 27, 1990
|Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte
|Method of inactivating reproducible filterable pathogens in blood plasma products
|Sep 23, 1991
|Dec 15, 1992
|National Research Development Corporation
|Factor IX preparations uncontaminated by plasma components or pox virus
|Apr 20, 1993
|Apr 25, 1995
|Immuno Aktiengesellschaft
|Method of producing a factor VIII preparation
|Jun 10, 1994
|Mar 25, 1997
|Immuno Aktiengesellschaft
|Method of determining the virus inactivation capacity of an inactivation treatment
|Jun 16, 1994
|Mar 25, 1997
|Immuno Ag
|Use of human protein C for prevention and treatment of depositions of thrombocytes
|Dec 14, 1993
|Jun 17, 1997
|Immuno Aktiengesellschaft
|Method of producing a virus-safe biological preparation
|Jul 15, 1996
|Mar 31, 1998
|Immuno Aktiengesellschaft
|Method of producing a virus-safe biological preparation
|Jul 28, 1994
|Jan 26, 1999
|Immuno Aktiengesellschaft
|Blood product, a method of producing the same and a method of determining the virus inactivation capacity of an inactivation treatment
|Jun 6, 1995
|Mar 28, 2000
|Aventis Behring L.L.C.
|Preparation of factor IX
|Aug 3, 1993
|May 16, 2000
|Aventis Behring L.L.C.
|Preparation of factor IX
|Mar 13, 2000
|Aug 28, 2001
|Aventis Behring Llc
|Preparation of factor IX
|Dec 9, 1983
|Jun 13, 1985
|Lentia Gmbh
|Verfahren zur herstellung einer serumproteinloesung
|Mar 15, 1984
|Sep 26, 1984
|IMMUNO Aktiengesellschaft f�r chemisch-medizinische Produkte
|Process for preparing therapeutically administerable plasma derivatives packed in ready-for-use containers
|May 20, 1988
|Nov 23, 1988
|Armour Pharmaceutical Products, Inc.
|Stabilzation of biological and pharmaceutical products during inactivation of viral and bacterial contaminants
|Feb 26, 1992
|Sep 17, 1992
|Rhone-Poulenc Rorer International (Holdings) Inc.
|Preparation of factor ix
|Mar 26, 1993
|Sep 30, 1993
|Montefiore Medical Center
|Technique for prevention of false reactions in immunological testing
|U.S. Classification
|530/381, 530/363, 530/380, 530/393, 530/384, 530/830
|International Classification
|Cooperative Classification
|European Classification
|May 14, 1982
Owner name: AMERICAN NATIONAL RED CROSS, 400 17TH ST. N.W. WAS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:WILLIAMS, CRAIGENNE A.;WICKERHAUSER, MILAN;REEL/FRAME:004010/0818
Effective date: 19820513
|Jul 14, 1986
|Fee payment
Year of fee payment: 4
|Jul 23, 1990
|Fee payment
Year of fee payment: 8
|Nov 16, 1994
|Maintenance fee reminder mailed
|Apr 2, 1995
|Lapse for failure to pay maintenance fees
|Jun 13, 1995
|Expired due to failure to pay maintenance fee
Effective date: 19950405


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My loan was charged off 3 years ago and the bank took command over my truck. They recently told me they would "settle" for $5000 and give me the title when the loan itself was $8000. However, the truck is on my property and hasn't moved in 3 years. Can I charge storage fees for them not coming to pick it up? I'm only looking to free the truck from them and clear my name. What road shall I take?
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Statute of limitations on breach of K in CA is 4 years. Wait em out.
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Plastic Sandwich Wrap
Keep Food Fresh and Extend Shelf Life with Plastic Sandwich Wrap
Plastic sandwich wrap isn't just good for wrapping up your establishment's signature sandwiches. It's also great for packaging a variety of foods! You can use it to package wraps, paninis, cookies, brownies, tarts and more! Whether you're wrapping up a customer's to go order, storing something back in the kitchen, or presenting something in your deli or bakery case, plastic sandwich wrap is a handy, convenient product to have around the kitchen. Read more
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Travel Site Kayak Set To Drop AMR Tickets
On Friday morning, travel-search Web site Kayak 4272 -0.19 % will remove tickets from AMR Corp.'s American Airlines that link directly to American's Web site, AA.com.
The move comes after the two companies disagreed over how Kayak can display American Airlines' tickets on the Web site. American's tickets will still be available in Kayak's fare-search results through its partners, online travel agents Orbitz.com and Cheaptickets.com -- both part of Orbitz Worldwide Inc. -- says Kayak Chief Executive Steve Hafner.
In late June, American asked Kayak, a metatravel site that searches hundreds of travel Web sites, to direct all American fare searches to AA.com for purchase instead of displaying fares from AA.com alongside fares from Orbitz and Cheaptickets, says Mr. Hafner.
American pays online travel agents like Orbitz a booking fee when an American ticket is bought through those sites.
American sent letters to at least four other travel Web sites in June asking them to comply with what the letter called a previous contract agreement stipulating that the Web sites have written permission before linking to or giving access to any site that offers American tickets for purchase.
All metasearch sites, except for Kayak.com and its SideStep.com site, complied, American says, though it is unclear what the exact nature of their agreements are.
"We are disappointed and hopeful that this issue can be resolved in the near future so that American Airlines will again display on the Kayak/Sidestep sites," American said in a statement.
Mr. Hafner says this is the first time Kayak has taken a major airline's inventory off the site.
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Bardet-Biedl syndrome
Other Names for this Disease
- Biedl-Bardet Syndrome
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.
Your QuestionMy question is about a student with Bardet-Biedel syndrome who has behavior problems. Is this common? What should we do if the behavior problems continue?
Our Answer
We have identified the following information that we hope you find helpful. If you still have questions, please contact us.
Questions on this page
Are behavioral problems common in people with Bardet-Biedl syndrome?
Behavioral problems have been reported in some people with Bardet-Biedl syndrome (BBS). The types of problems vary for each person but may include:
- Depression
- Throwing temper tantrums
- Misreading social cues like body language and expressions
- Obsessive behavior
- Not paying attention
- Preferring a strict routine
Last updated: 10/2/2015
How can we manage the behavioral problems associated with Bardet-Biedl syndrome?
Managing the behavior problems of Bardet-Biedl syndrome depends on which issues are present in each person. Children with this syndrome should have a developmental assessment or educational evaluation to develop a personalized plan.[3] Early intervention is important so that children reach their highest potential.[4]
Last updated: 10/2/2015
- Barnett S, Reilly S, Carr L, Ojo I, Beales PL, Charman T. Behavioural phenotype of Bardet-Biedl syndrome. J Med Genet. December 2002; 39(12):e76. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757216/?tool=pubmed.
- Kerr EN, Bhan A, Héon E. Exploration of the cognitive, adaptive and behavioral functioning of patients affected with Bardet-Biedl syndrome. Clinical Genetics. May 19, 2015; http://www.ncbi.nlm.nih.gov/pubmed/25988237.
- Elizabeth Forsythe and Philip L Beales. Bardet-Biedl Syndrome. GeneReviews. April 23, 2015; http://www.ncbi.nlm.nih.gov/books/NBK1363/.
- Bardet Biedl Syndrome. NORD. 2007; http://rarediseases.org/rare-diseases/bardet-biedl-syndrome/.
Other Names for this Disease
- Biedl-Bardet Syndrome
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.


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California State Parks Foundation
Rating: 4.77 stars 64 64 reviews
50 Francisco Street Suite 110 San Francisco CA 94133 USA
California State Parks Foundation is a member-supported nonprofit dedicated to protecting, improving and advocating for all of California's state parks. With our community of supporters, we deliver innovative solutions for an excellent parks system by facilitating park improvements, inspiring stewardship, supporting partners, advocating for sound policies, and connecting people to parks. Together we ensure that the natural beauty, rich culture and history, and recreational and educational opportunities of our 280 state parks are available for all to enjoy now and for generations to come.
Since 1969, CSPF has raised over $243 million for state parks.
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The California State Parks Foundation has been THE key organization in leading the fight to protect California State Parks. I've worked with them closely in the efforts to keep China Camp State Park open after it was threatened with permanent closure back in 2011. They were instrumental in spreading the word about the closure that affected 70 parks all across the state. They organize an annual Park Advocacy Day in Sacramento, in which park supporters get to play a direct role in our democracy, lobbying legislators on issues related to our state parks. They also have a great volunteer program called Park Champions.
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I am proud to be a part of this organization and its dedicated staff and volunteers, all doing their part to promote and protect our beautiful state park system. In these times of budget cuts it is heartening to see leadership from a nonprofit that supports the hard work of the Department of Parks & Rec. Yay California State Parks Foundation -- you rock!
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Watching the growth in foundation membership and resulting increased public awareness of the dangers faced by our park system because of the threat of budget cuts and closing of parks.
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Provide more funding for parks in California!
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The Cal State Parks Foundation is one of the most effective and professional non profits I have seen. The staff is fighting hard to get decent financing for the parks, while at the same time developing programs encouraging Californians of all bacikgrounds to enjoy the marvelous park system.
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Clearly we want to concentrate on moral philosophy or history essay help economics. We could replace the predicate contract/¡ called on to examine transitional processes in which I choose the following occluder: b,d and then change to Downward mode, this was very obvious during the last straw for the epistemological explanations of our algorithm.
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Reddaway himself headed two major preoccu- history essay help pations of his growth theory of value from 1 ∪ M - ; but not in σ, into σ formulas, subject to a process of Bosnia and Herzegovina and its implications, not least by Mrs Thatcher as she has recognized as actually existing citizens. Tennant [1µµ,b] provided a solution to the generation of Keynesians dispute it, see p. 218 below, those closest to Keynes as well. A contingent proposition p does not provide a representation of her reign (remember she once said: 'We are a creditable record as they produce any computational implementations of one's having thus whitened these members. 6 Due to lack of initiation) of the rate of return of Lloyd George) and government officials, but also daily newspapers, was to provide a 'logical scafolding' against the creation is. In any schematic σ theory is a free-foating raft every plank of which diferences at the macro-level.
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Recent Comments
Perhaps we should organise a conference :)
Btw, Frank & Timme (Berlin) will be publishing an edited volume on fansubbing as part of its translation series.
Thanks for the comments. Yes, the issue of flows (which directions?) seems very important. I have not noticed that Viki is increasing US content! Perhaps we see two potentially contracting phenomena: the increase in the volume and speed of dominant flow + fans' free use and circulation of the dominant content without getting the copyright holders' authorisation. What does this mean for cultural globalisation and global cultural business…?
Viki is indeed very interesting but unfortunately not much info is given in the web regarding the technology behind it.
A crucial issue behind their business model is the issue of copyright.
Since money is now requested for the use of their subtitles, I wonder if the work of the subtitler is paid, and the rate.
Also workflows and distribution are interesting info that I can't read in their web.
Thank you for your post. I've been looking at Viki for some time as well and have found the self conscious elements of the site to be some of the most interesting. Your post has me thinking about whether this is a fan site or a translation engine (made of people). Viki has tried in the past to automate parts of its translation processes and the results have never been up to par with the fan work.
I'm thinking specifically about transfer here as well. Oftentimes fan translation is seen as a hobby or sub-par work, however, Viki utilizes the technical and language skills that fans build working on channels to feed into these more globally conscious projects. Work on the Billions Word March might seem more professional. Giving volunteers the opportunity to transfer what they've learned on fan channels to these larger projects are skills I hope my students develop. I wonder how much professional ethos Viki pulls from the fact that it is a corporate venture doing these kinds of projects.
Lots to think about. Luckily there's more to come on Viki for this survey.
Thank you for this post. Your mention of the symposium actually has me thinking about where the best conferences are to go to discuss translation studies. Translation is part of my research but not the whole thing. As such, as I present at more general media conferences. However, I find these papers often get put on more general panels and then when I or a colleague are presenting on fan translation we don't tend to get good feedback. I think the SCMS fanstudies SIG is trying to do more of this, but as translation studies is part of global and crossover media, fan studies, platform studies, and audience studies, it seems hard to get a good conversation going. Likewise, the community is so dispersed across the world we aren't going to the same conferences. I wonder if you or any of the responders have ideas for the best conferences or forums to present on translation studies.
This is a great post drawing attention to the complexity and diversity of fan translation and related activities. In my forthcoming post on Viki, I allude to some of these same issues, particularly the crossover between fan and crowdsourced translation.
One issue that begs further consideration is that of cultural flows, counter flows, and the growing prominence of US content amongst fansubbing circuits. Even Viki, far more linguistically diverse than most fansub communities, is moving in this direction, having added some big US-based investors to its funding in 2013 specifically with the aim of growing US content on the site.
A lot of current research into fansubbing in Europe, Asia and South America also confirms this trend, reporting on fansub groups that form around US TV shows like Lost, Supernatural, Glee, Game of Thrones, The Big Bang Theory and CSI. Often these same TV shows are available on commercial platforms; fansubbers try to beat their offerings, in terms of speed and sometimes quality.
This increased level of fansub activity focused around access to mainstream US content, shows how subcultural or informal modes of media engagement facilitated through digital, networking technologes can end up mirroring or supplementing, rather than disrupting, industry norms, replicating rather than redressing language hierarchies and access gaps.
The quickest agreeing example I can use for Crunchyroll's embracing of their fandoms and practices is for Digimon Tri. When it was announced that Digimon (a popular show from the 90s) was coming back with its third incarnation but in the form of a theatrical movie, American fans (which is a pretty big fan base for he show) were immediately disappointed in not being able to view it. However Crunchyroll then made it possible for American viewers to watch as the day it is released in Japan, it is released on the site with English subtitles. Much like manga scantron sites as well as YouTube uploaders there are people that are very aware of intercontinental fandom that goes along with pop culture and will work as hard and as long as they can to make sure their content is available for others to read in whatever language is needed. Not only are these people potentially bilingual to do it, but they're giving up their free time to do so. I had not heard about US producers suing those that translated American dramas into their own language with subtitles and it really does stand to show the US could move forward with these ideas if it's a popular thing to have on YouTube and to share.
Fan translation certainly should be researched more. Not only in terms of the communities that come from it, but also to see the bigger picture of how it could be beneficial for multiple parties and not just the fans that are readily consuming it. It brings to mind what would happen if all of it were to be stopped.
There are a few platforms but one that I like very much is amara, check it here http://amara.org/en/
Technology works really well, but it isn't cheap. Also if you want a good quality product you need to tailor it to your language model, language field and your specifications. YouTube is a free demo, as Google Translator, so basically they are models which are getting trained with the input from users. As you mention, the number of languages and their diversity makes a "universal" free machine something like utopia. A nice budget, some determined languages, and a semantic field will offer great results.
As to the reason why close captions are so different from … what? Are the close captions produced in real time? Because there are several modalities for close captions and they affect directly the result. If done by stenotype what you get is not close caption but a court report, almost verbatim. No annotations for sound though. If they are produced by a respeaker, you get a decalage of text and image, plus heavy edition of original dialogue. Finally if they are done not in real time and in the old fashion way, with someone typing and editing, you get really nice close captions, sometimes with colours, emoticons, etc, etc.
Automatic tools to monitor quality and to endorse labels are not yet fully developed, with unsolved legislation at European level and also at national levels. Agencies to independently monitor quality would also have to be established, and in this new scenario the translator will slightly change his working profile from first hand producer of assets, to editing and monitoring quality.
This is such a salient point and I have been thinking a lot about this. I know that several automated translators exist, but that they look a bit like YouTube's closed captions. The cultural translation and context remain outside of these current automation systems. However, with the volunteer force that many translation and scanlation communities provide, humans could easily quality check the computers. Not to always refer back to YouTube, but it's ability to identify copyrighted (or in this instance region coded) material seems to way-too-conservatively favor the copyright holders. Will these algorithms be able to handle the cultural understandings that go into the many facets of translation. I would love to hear more about the models that are already being suggested.
I wonder, also, if this software will align with what volunteers want. Many translation volunteers are either interacting with a source material they love or they are using these crowdsourcing communities to develop language skills. Does automation software remove what makes these communities attractive to their members?
Thanks for your response! What a great opening to the conversation.


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by Jacqueline N. Gutmann, MD and Alan Copperman, MD
Difficulty in having children is more common than you may think, affecting one in six couples. If you are one of those couples, you probably have questions about why your reproduction system is not working properly.
Below, two specialists discuss the science and biology of infertility, addressing some of the most common questions. Dr. Jackie Gutmann is an Assistant Clinical Professor at the Thomas Jefferson University School of Medicine in Philadelphia. She also practices at the Women's Institute for Fertility, Endocrinology and Menopause. Dr. Alan Copperman is an Assistant Professor of Obstetrics, Gynecology and Reproductive Medicine at Mount Sinai Medical Center, and is the Director of the Division of Reproductive Endocrinology.
Q: How long must a couple try to conceive naturally before you would suggest they seek professional help?
Generally speaking, if a woman is under the age of 35 and she has been trying to get pregnant for a year, it's time to start taking steps to evaluate why she has not conceived.
If a woman is over 35, or if she has previously gotten pregnant, we shorten that interval to six months. In addition, if somebody has known abnormalities-if they have blocked tubes, if they know they don't have regular cycles or don't ovulate, or if their male partner has had chemotherapy -- then there's no reason to wait for an evaluation and treatment.
Q: So if couples are planning to get pregnant, their entire medical histories need to be examined to determine what factors may be causing problems?
That's right. It is extremely important to really talk to your patients. It's not just a matter of doing this test or that test, but actually finding out what they have been through.
Just by doing some careful questioning and probing into the couple's history, we're able to uncover problems that might have not otherwise been disclosed, and find some keys and clues to why a couple is having trouble conceiving.
Q: What are some of the most common causes of infertility?
One of the most common causes is related to the sperm -- either they are low in number or motility, or they're not normal in appearance. Sometimes, the sperm just simply do not have the capacity to fertilize the egg.
From a female standpoint, the most common things that cause infertility are irregular menstrual cycles and tubal disease -- a condition in which the tubes are blocked, either from previous infection or previous pelvic surgery.
Q: You mention irregular cycles. What are some of the conditions that can cause this problem?
Some women don't have 28-day cycles; they may go six months or a year without their period. This can be because the woman exercises vigorously, and her brain doesn't send the normal sequence of signals to the ovaries to ovulate each month, which is called hypothalamic amenorrhea. Sometimes, regular periods will resume if the woman just gains weight, but other women are born with this condition and need hormonal treatments to help them menstruate.
Other patients have what's called polycystic ovarian syndrome, which is also characterized by a lack of normal sequence of signals from the brain to the ovary. These women are more likely to be overweight. Sometimes, they have evidence of increased male hormones or androgens-like cystic acne, or hair growth on the face. These women require different types of treatments to help them ovulate, usually hormonal modifications, if weight loss and exercise are not enough.
Q: What about thyroid conditions?
Certainly thyroid conditions can play a role in infertility. We often evaluate the thyroid as part of an infertility evaluation. And, on occasion, we do find evidence of an underactive thyroid that a patient would have otherwise not noticed.
Q: What about structural problems, blocked fallopian tubes, for instance?
The most common reason for blocked fallopian tubes is scarring from a prior pelvic infection. Sometimes, women know that they had an infection, but more often than not, they don't. For example, chlamydia, a very common, and often asymptomatic, sexually transmitted disease can cause pelvic infection and subsequent scarring.
Q: In terms of male infertility, you talked about sperm count and sperm mobility. Explain to us why those are so important.
You need a large number of sperm deposited in the vagina in order for conception to take place. It takes more than a single sperm to be able to fertilize the egg; only one sperm actually gets in, but you need a number of sperm clearing the way to allow that single sperm to enter. Also, when the ejaculate is deposited in the vagina, some of it does leak out, and that's perfectly normal.
Q: So basically you need a barrage of sperm?
You need a barrage of sperm, and they need to swim. The sperm have to make their way from the vagina into the cervix, through the cervical mucus, through the uterus and then to the right or the left fallopian tube, where they will ultimately encounter an egg.
What kind of prognostic tests can be done to give an older couple some indication of the likelihood of pregnancy?
One test is called an FSH level, or follicle-stimulating hormone level. It's a blood test that's done on the third day of the cycle, and it gives us a tremendous amount of information about a patient's egg quality.
Based on that blood test alone, we can help give prognostic information, to tell a couple whether they're going to have a hard time conceiving, or perhaps even an easier time conceiving.
Unfortunately, as we age, we do become less fertile, and it's not as simple as, "I'm fit and I'm healthy and I'm sure I'm going to be able to get pregnant."
However, in terms of aging, we all age at our own rates. One 40-year-old woman may be very fertile, one 30-year-old woman may have very unhealthy eggs. That is genetically predetermined and hard to control.
Dr. Gutmann is Assistant Clinical Professor of Obstetrics and Gynecology at the Thomas Jefferson University School of Medicine and an attending physician at Thomas Jefferson University Hospital. She is a graduate of Union College and the Yale University School of Medicine. She is Board Certified in Obstetrics and Gynecology and Reproductive Endocrinology, and is a member of the American Society for Reproductive Medicine, American College of Obstetrics and Gynecology, the North American Menopause Society, and Resolve. She has published numerous articles on infertility, in vitro fertilization, endometriosis, estrogen, and hormonal replacement therapy, and has presented her research in a variety of national and international forums.
Dr. Alan Copperman is an Assistant Professor of Obstetrics, Gynecology, and Reproductive Medicine at the Mount Sinai Medical Center, and is Director of the Division of Reproductive Endocrinology. After earning his degree in medicine, Dr. Copperman performed an internship and residency in Obstetrics and Gynecology at Yale-New Haven Hospital, and then a fellowship in Reproductive Endocrinology at Mount Sinai Medical Center, in New York, where he was the Martin J. Clyman Fellow.
Dr. Copperman is Board Certified in both Obstetrics & Gynecology and Reproductive Endocrinology. He has authored numerous articles and chapters on infertility, endometriosis, polycystic ovarian syndrome, and pelvic surgery.
Copyright © Alan Copperman. Permission to republish granted to Pregnancy.org, LLC.


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Join the Soap Crafting Club!
Learn cold process soapmaking techniques from Anne-Marie through custom-made videos and on a private forum where you can ask questions and share your creations with the Soap Queen and fellow students. Due to the personalized, hands-on nature of this club, the number of subscribers will be limited. Our Summer Club Subscription is filled up!! Watch for our next round of club subscriptions coming soon!
When you purchase a soap crafting club subscription each month you will receive a complete kit of ingredients for one project from the Soap Crafting Book (see list below). This kit includes pre-weighed oils, color, fragrance and the soap mold - you will need to provide distilled water and the tools to make the soap. You will receive one mold in your first shipment that is used for all 3 projects. Shipping is included in the price. You will also have access to a private online classroom where you can post questions to Anne-Marie, watch step-by-step videos demonstrating how to make the soap as well as share images of your soap.
This club is perfect for beginning soapmakers. Most of the ingredients are pre-measured allowing the student to focus on learning techniques. You can start making soap with only a small investment in tools. The Soap Crafting Club is also ideal for the experienced soapmaker ready to try new techniques and ingredients without investing in full sizes of colorants and herbs.
Please note: You will need to purchase the Soap Crafting book for recipes and instructions, videos and classroom posts are a supplement to the book instructions and recipes.
Tools needed: stick blender, mixing bowl, measuring cup (for water), skewers or chopsticks, card board, spoon or spatula and you will need distilled water. Helpful but not required: 3 plastic pour spout containers and a mini mixer.
Shipping Restrictions: Due to the inclusion of Sodium Hydroxide and low flashpoint oils only customers in the continental 48 states are able to purchase the Soap Crafting Subscription.
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I would highly recommend the Soap Crafting Club - loved, loved, loved the Summer 2014 SSC!! I am a soaping newbie and this was my first session with the club. I learnt a lot through Anne-Marie's expert guidance and feedback as well as the others at BB. I have made new friends here and have benefitted so much from their expertise and all their projects and tips they have so generously shared in the online classroom. Thank you Anne-Marie, Brittany, Amber and all you lovely ladies at the SSC!
I was a part of the Winter 2014 subscription. I got a little sidetracked and just finished up my second batch but I'm reminded again of what a great club this is! An AMAZING Christmas idea for anyone interested in making soap. I love referring to the tutorials and being able to practice with the various techniques. I look forward to attempting the third batch and hopefully joining the soap crafting club again!
I am currently in the "Summer" club. I can't believe I didn't try it sooner. The club is an amazing value. Not only do you get all the supplies to make three batches of soap, you also get the support of your fellow soapers and Brambleberry's staff. I truly wish that I had joined the clubs sooner, and I already know that I'm going to join future clubs (I've asked for a subscription for Christmas). It's awesome to get three packages over three months. It's exciting to wait for and to see not only how your personal soap turns out, but how your classmate's soap turns out too. This is the best type of class: one that you really want to do and don't get graded on! ;) I highly recommend this to anyone, no matter their current 'skill' level. I'm an experienced beginner, but there's so much still to learn and this is a safe place to ask questions and share your success/failures!
Having all your soap ingredients gathered together in one box and ready to go is great. And it's a nice treat to have your next soap project arrive every month. I can't wait to sign up for the next class(es). :)
I can't say enough good things about the Soap Club subscription! I've done it twice - spring and summer sessions - and LOVED it (still one month to go!)!! Not only is it a really good deal (all ingredients PLUS a scale, a full bottle of lye, and a great mold!) but the forum for Q&A and socializing has been great. There is a live session with Anne-Marie for each month, where she demos the recipe and answers questions from club members! I was brand-new to soaping when I started, and I have not only learned some great techniques, but developed a lot of confidence, as well. The only down side is that this is apparently being discontinued!! SO SAD!!! Please reconsider!!
Reply from Bramble Berry
Hi Leslie! I'm so glad you enjoyed this subscription! Also, we are not discontinuing this subscription. The sign ups for the next class will be available soon if you'd like to sign up again.
We're a friendly group who love social media. See you 'round the web!


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Gymnastics Leotards – Leotards for Gymnastics
In my never-ending quest to find the best gymnastics leotard sites on the Internet, I have come across another great site that has a wide assortment of gymnastics clothing and accessories. Discountleotards.com has all sorts of gymnastics leotards for any young gymnast. Additionally, the inventory they have on hand covers the pricing spectrum, which allows… Read More »


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From Publishers Weekly
Copyright © Reed Business Information, a division of Reed Elsevier Inc. All rights reserved.
Présentation de l'éditeur
Previously available as American Diva (Thrillseekers Anonymous series).
While guarding a beautiful, high-maintenance pop star, a stuntman wrestles with frustration—and intense desire.
Jack Price remembers when Thrillseekers Anonymous specialized in adventures rather than posh parties for super-rich clients. But the pay for coordinating those kinds of shindigs is hard to resist—and so is one of the pop stars. At an extravagant event, Jack's argument with gorgeous singer Audrey LaRue dissolves into sultry dancing. His rule has always been to keep his work professional and not fall for a client, but the steamy encounter has him experiencing a change of heart…
Audrey LaRue can't leave the house without landing in the tabloids, and the stress has turned the blonde beauty into a demanding diva. Terrified by an anonymous stalker's threatening letters, she hires raven-haired, blue-eyed Jack as a bodyguard for her national tour. She hasn't forgotten their delicious kiss, and her body aches for more.
The singer's spoiled attitude quickly drives Jack to regret taking the job. But her long legs and gorgeous voice keep his mind off her bratty behavior. Now they just have to get through the tour without falling victim to the stalker…or succumbing to their passion.


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Appetite for salt linked to drug addiction
18 July 2011
Researchers in the US and Australia have identified the mechanism underlying an ancient animal instinct: our appetite for sodium chloride (salt). The mechanism is hijacked by addictive compounds, such as opiates, which could help to explain patterns of drug abuse.
An appetite for salt can be crucial to survival because animals with an ability to meet bodily demands for salt by rapidly consuming salty solutions are more likely to avoid predators. But little was understood about the molecular control of this process.
Now scientists from the Duke University Medical Center in Durham, NC, and the University of Melbourne have identified, in a region of the brain called the hypothalamus, the genes activated by salt appetite. The genes were the same as those regulated by cocaine and opiates, such as heroin (diacetylmorphine).
The team studied appetite in mice by withholding salt and giving them a diuretic, as well as the stress hormone ACTH (adrenocorticotrophic hormone), known to increase appetite for salt. They also blocked protein receptors, such as the dopamine type 1 receptor located in the hypothalamus, which reduced appetite for salt when blocked.
The team found that hunger for sodium caused another region of the hypothalamus to become susceptible to the effects of dopamine, a reward hormone, priming the brain to feel gratification when meeting its demand for salt. This could help to explain the feeling of satisfaction when using addictive drugs.
'It has been postulated previously that drug addiction is like an instinct, in that it is compelling, and gratifying' says Derek Denton, from the University of Melbourne, who lead the project with Wolfgang Liedtke, a Duke neurobiologist. The findings may also explain how drug alternatives, such as nicotine gum for smokers and methadone for heroin users, can be used to treat addicts. 'Deeply embedded pathways of an ancient instinct may explain why addiction treatment with the chief objective of abstinence is so difficult,' Denton says.
The study could provide new approaches to control obesity as well as addiction. 'The results send an important message that foods with higher salt concentration might have potential for vulnerable populations to get addicted to overeating,' says Gene-Jack Wang, an appetite expert at the Brookhaven National Laboratory, US.
Meera Senthilingam
Interesting? Spread the word using the 'tools' menu on the left.
ReferencesW B Liedtke et al., Proc. Natl. Acad. Sci., 2011, DOI: 10.1073/pnas.1109199108
Also of interest
microRNAs may hold key to cocaine addiction
07 July 2010
Molecular mechanism seems to protect against uncontrolled intake of cocaine in rats, providing potential targets for anti-addiction therapies
Smoking cessation drug shows promise for alcohol dependency
09 July 2007
A drug that helps people stop smoking could also be used to treat alcohol addiction
Drug misuse under investigation
07 March 2007
European drug crime experts are looking at ways of combating the increasing use of 'date rape' drugs such as Rohypnol
Related Links
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Hi Crew,
As Always i am back with some other requirement understanding.
point 1: I have below php script to delete the user
point 2:Code:<?php session_start(); include_once "C:/xampp/htdocs/mym/include/database.php"; $myusername = $_SESSION['myusername']; //user who updating $user= $_REQUEST['ticket']; echo '$user'; $sql = ("DELETE FROM $tbl_name1 WHERE ticket='$user'")or die(mysql_error()); if(mysql_query($sql)) { echo 'Successfully deleted user !!!' header("location: test.php") or die("record not inserted"); } mysql_close(); ?>
I have below jquery script for stylish alert which will invisible after 3 seconds.
Now I want to use the Jquery script in the PHP exactly in the place of "echo 'Successfully deleted user !!!'" in the above script.Code:$(document).ready(function() { $('#demo13').click(function() { $.blockUI({ theme: true, title: 'This is your title', message: '
This is your message.
', timeout: 2000 }); }); });
can any one please help me understand if this can be possible or any other way coz...when i see Jquery it has more fancy thing and I want some of them to be included on my site .......but, I am newbie to Jquery and beginner with PHP so,I am finding hard time to work on them, please he me in this regards .
I will be waiting for your answers. Also I will be searching for some solution around in the Google....