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Apply Now for the AAA Visa® credit card! Receive a $100 statement credit^ after you make at least $500 in purchases within the first 90 days!
Whether at home or on the road, the AAA Member Rewards Visa® credit card gives members the security and value needed in a credit card.
The AAA Member Rewards Visa credit card provides 24-Hour Customer Service, around the clock fraud protection, and secure online access to your account information at
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How You Earn Points: You earn points when you use your card to make purchases, minus returns, credits and adjustments ("Purchases"). The following transactions are not considered Purchases and will not earn points: Balance Transfers and Cash Advances (each as defined in your Credit Card Agreement), fees, interest charges, fraudulent transactions and certain other charges. 1 Point: Earn 1 point (base point) for every $1 of Purchases charged to the credit card each billing cycle. 2 Points: Earn 2 points (consisting of 1 bonus point and 1 base point) per $1 for Purchases made with the card at any eligible gas, grocery store or pharmacy retail merchant categories as designated by Bank of America. 3 Points: Earn 3 points (consisting of 2 bonus points and 1 base point) per $1 for Purchases made with the card through any participating AAA Club when AAA is the merchant of record, or at eligible retail travel merchant categories as designated by Bank of America. Points Expiration: Points expire 5 years after the month they were earned. Rewards Program Rules: Program Rules containing additional details will be sent to you with your new account materials. Other significant terms apply. Program subject to change.
^You will qualify for a $100 statement credit if you use your new credit card account to make any combination of Purchase transactions totaling at least $500 (exclusive of any fees, returns and adjustments) that post to your account within 90 days of the account open date. Limit one (1) statement credit per new account. This one-time promotion is limited to new customers opening an account in response to this offer. Other advertised promotional statement credit offers can vary from this promotion and may not be substituted. Allow 8-12 weeks from qualifying for the statement credit to post to your account. The statement credit will generally be applied to your existing balance with the highest APR before being applied to any balances with lower APRs. Receipt of a statement credit does not affect your responsibility to pay your Total Minimum Payment shown on each Statement you receive from us. The value of this reward may constitute taxable income to you. You may be issued an Internal Revenue Service Form 1099 (or other appropriate form) that reflects the value of such reward. Please consult your tax advisor, as neither we, nor our affiliates, provide tax advice.
This credit card program is issued and administered by Bank of America, N.A. Visa and Visa Signature are registered trademarks of Visa International Service Association and are used by the issuer pursuant to license from Visa U.S.A. Inc. ©2017 Bank of America Corporation ©2017 AAA. AAA.com/CreditCard


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Jim Shore's Bugs Bunny Personality Pose captures the essence of that wascally wabbit with Jim's signature colors and unique folk art style.
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Performed by The American Military Band, the Music of the Marines CD features 15 tracks that are sure to pump up your patriotic spirit. The collection will send some sweet smiles to any Marines- former or active. Likewise, friends and family of U.S. Marine Corps members will appreciate and enjoy the rich and unique lyrics and the smooth arrangement of each song.
Play List:
1. Semper Fidelis
2. Theme From Superman
3. Washington Post March
4. America the Beautiful
5. Al Capitan March
6. The Thunderer
7. American Patrol
8. Stars & Stripes Forever
9. Waltzing Matilda
10. Liberty Bell
11. Picador March
12. An American Tribute
13. The Marine's Hymn
14. The Star Spangled Banner
15. Taps


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A Graver Jackson's Cry: Overcome the Violence!
By DON TERRY,
Published: November 13, 1993
WASHINGTON— The Rev. Jesse Jackson's star has dimmed a bit. At 52, he is graying at the temples, and his heart seems heavier than it was in the 1970's, when he sought to sway a generation of black teen-agers to believe, and repeat, "I am somebody." When he talks with teen-agers these days, it is not about the promise of tomorrow but about the dangers of today.
"Stop the violence!" Mr. Jackson thunders. "Save the children!"
Until then, hope will have to wait.
Mr. Jackson says he cannot remember a time when so much of black America was in such deep danger and despair because of drugs and violence, unemployment and disease. Part of Culture, He Says
Poverty and racism still do their devil's work. But nowadays the threat to life and limb and liberty often grows up just down the street. Young black men and boys are killing one another, Mr. Jackson says, in a storm of "self-destruction." Baby sister and little brother are dying in the crossfire.
But this isn't happening in a vacuum; the violence among blacks, he says, is rooted in a national culture -- shared by people of every color in the country's rainbow -- that is drawn to the power of the gun, particularly as a means to settle disputes, big and small, in the street and in the home.
For Mr. Jackson and a growing number of prominent black clergy members, writers and community leaders, ending the violence has become a crusade. He calls it the "new frontier of the civil rights movement."
Long-term answers will have to include jobs and schools, the nuts and bolts of life, Mr. Jackson says, but in the meantime people are dying.
Mr. Jackson has been traveling the country preaching to black audiences to do-for-self, to take responsibility for ending the carnage in their streets. And lately, he has been getting a lot of attention from news organizations and even from President Clinton.
"No one else will do it for us but us," he says. It is a sentiment passed down from generation to generation, like the family Bible. For Mr. Jackson it is a self-evident truth.
"When it's black on black, there seems to be a zone of permissiveness about crime," he says. "That has got to stop."
But he says permissiveness and acceptance of killing has also seeped into the souls of too many black people, and that troubles him the most. He wants black students to be on the front lines in the war on guns, self-hate, greed and violence, much as their parents' generation was in the forefront when the enemies were Klansmen, dream-crushing laws and governors blocking the schoolhouse door.
The man who spent recent years telling students to "keep hope alive" is now telling them to stand up to the thugs among them and to break the student "code of silence" that allows Johnny to sit in class with a pocket full of dope and a 9-millimeter pistol in his waistband. Turn Johnny in, he says.
"It's not snitching," he recently insisted to a group of skeptical students at Roosevelt High School in Washington. "It's self-defense."
A senior, DeMone Perry, shook his head at what he later said was Mr. Jackson's naivete or "old age" about what it takes to survive in the streets. "You need some kind of protection," the youth said, "because nobody else is going to stop a bullet for you."
He said almost everyone he knew carried a gun or a knife to school, including some teachers. He said he would not "snitch" because the police had their own code of silence that protected crooked officers and allowed them to rob, cheat, steal and sell drugs like criminals.
"I'm sorry, sir," the youth told Mr. Jackson. "This is 1993, not 1963. I don't know where you've been."
Mr. Jackson put his hand on the student's shoulder and said, "I've been to a lot of teen-age funerals." Recapturing Spotlight
Mr. Jackson has also been to a lot of news conferences.
Adolph L. Reed Jr., a political science professor at Northwestern University who wrote "The Jesse Jackson Phenomenon," a book published in 1986 by Yale University Press, says that now, with attention on a new group of more moderate black political leaders, Mr. Jackson's talk of self-help to fight crime is one sure way to recapture the spotlight that dimmed so much for him last year during the Presidential election campaign.
"Jackson has been marginalized within the Democratic Party," Mr. Reed said. "He's been trying to figure out for some time what to do with himself and how to assert his presence on the national stage."
Not long after the Presidential campaign, he failed to recapture that spotlight when at the 11th hour he withdrew from consideration as executive director of the National Association for the Advancement of Colored People. Although Mr. Jackson was clearly the most well-known of the candidates, questions were raised about whether he was best suited for the post.
For others, Mr. Jackson's current campaign comes dangerously close to blame-the-victim oratory, and it lets the bigger -- and whiter -- society off the hook of responsibility.
Richard Majors, a psychologist on leave from the University of Wisconsin and a founding member of the National Council on African American Men, said Mr. Jackson and other leaders must be careful not to put too much of the burden for change solely on the weary shoulders of black America.


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|Coordinates: 54°02′00″N 9°19′20″W / 54.0333°N 9.3222°WCoordinates: 54°02′00″N 9°19′20″W / 54.0333°N 9.3222°W
|County Mayo
|47 m (154 ft)
|Population (2011)
|• Total
|Time zone
|• Summer (DST)
|Irish Grid Reference
Lahardane (Irish: Leathardán) is a small village in the parish of Addergoole, County Mayo, Ireland, adjacent to Lough Conn and to Nephin, and close to the towns of Crossmolina, Castlebar and Ballina. Population in 2011 was 156 .[1]
Historically, the people of Lahardane and the surrounding area helped the French army under General Humbert during the 1798 uprising when the local priest, Fr Andrew Conroy, led French and Irish forces to Castlebar though the Windy Gap, a passage through the Mountains. The British forces had been expecting the French to go to Foxford first, and were caught off-guard. This led to the Races of Castlebar.[2] After the uprising was put down, Fr Conroy was hanged on the Mall in Castlebar, and buried probably in the old abbey in Addergoole cemetery. A Celtic cross now stands proudly in Lahardane as a memorial to his bravery. The cross was erected in 1937 by Michéal Ó Tiomanaidhe,[3] the famous Gaelic scholar, Irish writer and folklore collector who was born in Cartoon in the parish of Addergoole on 20 September 1853.
Addergoole parish suffered the largest proportionate loss for any locality probably in the world when the RMS Titanic sank in 1912. The Addergoole Fourteen boarded the ship at Queenstown (Cobh). Three survived the disaster. There is a plaque in St Patrick's Church, Lahardane to the memory of the fourteen, as well as a memorial garden filled with sculptures to honour their memory.
Lahardane Fair Day on 15 August[edit]
The history of the Lahardane Fair goes back to around the turn of the century, that is 1900, so it is a tradition of perhaps 100 years. It was a traditional Harvest Festival, as was practised in the West of Ireland at the time and it was always held on 15 August, a feast day. It is a religious holiday as well.
At that time, it would be noted for its tradition of hiring of the young folk to various farmers and was often known as the 'Hiring Fair'. This tradition, of course died out when Ireland became independent in 1922 and it became a traditional day for the sale of cattle and sheep. This situation prevailed for the following 70 to 80 years but in the seventies, it fell into disrepute because in the streets, there was very little selling going on of the traditional kind, that is sheep and cattle, because the marts had taken over all this business, and it had degenerated into a pitiful gathering of people trying to maintain an old tradition.
The Lahardane Parents Council, that is the parents of those children attending the National School, decided to revive the Fair Day and make it a worthy occasion, when people could be enticed to visit the village for one day of the year. They agreed to continue the traditional day of 15 August and resisted the temptation to move it to the nearest weekend as most other communities have done with their particular festivals throughout the year. Instead, the Lahardane Fair Day always falls on 15 August, regardless of whichever day that is.
2008 was the 18th year of the revived fair and with each and every passing year, it has proved more and more successful. The number of people attending the village for the day is extraordinary. Essentially, the day is used to raise funds for the Lahardane National School. To date, perhaps, over €60,000 has been raised to help support the school. These particular finances have been well spent, in agreement with the Board of Management and the Parents Council with the recent extension of the school, that is the new roof, the new rooms, extra class room and activities room, plus the provision of an enclosed basketball court and the updating of all the surrounds of the school. Within the school, there has been the provision of more modern furniture, fittings for the school, audio-visual equipment, computers and photocopiers and other such appliances, which are now the norm in a progressive school. Finances have also been provided for school tours and recreational activities for all the pupils. Also, as originally promised by the parents when they started off, money was put forward towards the development of the Lahardane Community Centre and approximately €11,000 was given towards the building this year. Other projects have also been funded by the Lahardane Parents Council, that is the Nephin Climb, which is always held on the first Sunday of August, the week after the Reek climb.
When the Fair Day was inaugurated in 1968, Lahardane was the first community in Ireland to use the idea of a Cow Pat Lottery. People of this community were the first community to come up with this idea and use it as a means of raising funds. It attracted amazing attention at the time and for the following number of years. The idea was a brilliant idea for fund raising through selling tickets and it was a most unusual way of doing things, and it certainly caught the public imagination! However, it has been more than well played out at this stage and the Cow Pat Lottery has been dropped.
On the streets of Lahardane on Fair Day, you still have the idea of a sale of animals, as was the case for the last hundred years. The animals may have changed somewhat, in that it is lambs and sheep for sale in the morning, plus all the other associated animals you find in a farmyard, that is chickens, ducks, geese, the odd turkey, puppies, cats, birds of other descriptions and various farm produce. This is as it should be at a traditional fair day in the West of Ireland, and the Lahardane Parents Council are delighted to have revived this tradition and maintain what has been a fashion for the Lahardane Fair Day for over 100 years.
The Lahardane Fair has also been associated with the revival of an old tradition - the Donkey Fair. The Donkey Fair is always held on the Sunday before 15 August, and is now in its third year. It is designed to promote the idea of bringing back the donkey to the street for one day of the year, and it involves the show of donkeys, that is mares, foals, jack donkeys, mules, jennets and in particular a display of donkey carts. The idea of getting the donkey cart back again is because this particular item is practically gone off the face of the earth, so an idea was put forward that they should be brought back and put on display on one day, and that children might get the once-in-a-lifetime chance of a trip in a donkey cart. It is a wondrous sight to see several carts going around a circuit in the field at Lahardane Fair. Hopefully, in time to come, this particular item will gain in popularity, and make Lahardane, perhaps the donkey capital of the country.
Lahardane in fiction[edit]
Lahardane is the name of the house in the 2002 novel, The Story of Lucy Gault, by William Trevor. The novel is set on the south coast of Ireland and, other than the name, there is no connection with the Mayo village.
External links[edit]
- http://www.addergoolefourteen.com
- http://www.addergoole-titanic.com
- http://www.podcasts.ie/2010/04/titanic-bell-ringing-ceremony-2010/


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Kukla's Korner Hockey
Not A Thing Wrong With Iginla
by Paul on 02/14/09 at 11:30 AM ET
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from Eric Francis of the Calgary Sun,
Scoreless in his last six outings and the author of just two goals his last 18 outings, Iginla will be asked 14 different ways to account for his pause in production. Never mind the fact he has 14 points during his "slump" to remain amongst league scoring leaders—everyone wants to know "what's wrong with Iggy?"
Given the character of the game's ultimate captain, No. 12 will undoubtedly answer by suggesting he'd like to be scoring more and is expecting more of himself as the team's leader.
However, the answer he should give is simple: Nothing.
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Download PC games new latest full
|ArcadeBelieve In Santa Read reviews, rate games, download free trials/versions.
Believe In Santa
Reviewed by Yuri Storchak
Genre and what to do:Arcade . Meet a lovely girl, named Sandy who visits her grandma just before Christmas and finds out that adorable granny has 10000$ dept. The loan must be paid off within ten days otherwise the bank expropriate the gift shop. She despairs deeply but suddenly, like in a fairy tale Santa appears in front of her and promises her to give two Elves for help. So our hardworking girl starts working in the gift shop, serving customers. To serve a customer Sandy should take appropriate toy from the conveyer, give it to Elves for painting, deliver the gift to the customer, pack it if customer wants and take money. She has to do everything quickly since customer won't wait long and leave. But Sandy may make clients happier, by giving them sweets and magazines. To complete a level, our heroine must earn the required sum of money, which isn't as easy as it may seem. New décor upgrades become available with advance in the game. If Sandy becomes skilled enough Santa will invite her on Christmas Eve.
Style and atmosphere inside the game:Believe In Santa is a fast-paced game that helps you to feel cheerful Christmas atmosphere. It features bright colorful graphics, diverse sound effects and Christmas music. Storyline begins with comics-like introduction and continuous in numerous cut scenes between levels. You start game with short learning curve that explains nut and bolts of game play. As for graphics, it is very colorful and detailed; customers are amazing and well done, decorations are amazing especially when you upgrade them. All-in-all, Believe In Santa is an exciting game with high quality presentation and unique Christmas atmosphere that you surely like.
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About MeHi I'm Joshua Pharris! I am a painter in Fort Collins CO, but never turn down interesting creative projects! I love to paint but I enjoy acting; theatre and video, modeling, fashion design, anything I can get my creativity into and grow from!
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Definition of stroppy
Examples of stroppy in a Sentence
There's no need to get stroppy with me.
Origin and Etymology of stroppy
perhaps by shortening & alteration from obstreperous
First Known Use: 1951
STROPPY Defined for English Language Learners
Definition of stroppy for English Language Learners
: easily annoyed and difficult to deal with
Learn More about stroppy
See words that rhyme with stroppy Britannica English: Translation of stroppy for Arabic speakers
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Mount View Road, Crouch End N4
£899,950 Asking price
- Flat
- Bedrooms: 4
- Reception rooms: 1
- Bathrooms: 2
Property features
Property description
Four bedroom split level flat with its own entrance, south facing garden and roof terrace offering stunning views over London's skyline, set within an imposing double fronted property.
Situated close to local transport links, this fine home offers over 1400 sq ft of accommodation, and an early viewing is highly recommended.
Additional information
- Four bedroom flat
- Light and airy
- Private southerly garden
- Roof terrace
- Stunning views
- Two bathrooms
- Close to St Aidans School
- Excellent transport links
Local authority
Haringey Borough Council
Share of Freehold
- Harringay (0.3 miles)
- Crouch Hill (0.4 miles)
- Harringay Green Lanes (0.6 miles)


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Speculation surrounding the future of Lewis Hamilton came to an end today with the announcement that the former world champion is to join Mercedes.
The 27-year-old from Stevenage has signed a three-year deal with the Brackley based team, ending a 14-year association with McLaren.
Today's announcement appears to spell the end of Michael Schumacher's disappointing comeback, with the seven-time world champion due to retire for a second time. Nico Rosberg, a close friend of Hamilton's, will remain at Mercedes.
Meanwhile, McLaren have been quick to announce Hamilton's replacement at Mclaren, so quick in fact it was announced before Hamilton had officially revealed he had left the Woking based side. Their new driver is Mexican Sergio Perez, with the 22-year-old, who is yet to win a Grand Prix, joining Jenson Button.
Rumours have been flying around about Hamilton's future for months, although a move to the Silver Arrows still represents something of a shock. Hamilton was signed up to McLaren's driver development program at the age of 13 and it was Ron Dennis' team that provided him with a drive in Formula One and powered him to an incredible world title triumph in 2008. Yet it would appear a change weighed more heavily for Hamilton than remaining loyal to McLaren.
"It is now time for me to take on a fresh challenge and I am very excited to begin a new chapter racing for the Mercedes Formula One Team," Hamilton said today.
"Mercedes-Benz has such an incredible heritage in motorsport, along with a passion for winning, which I share.
"Together, we can grow and rise to this new challenge. I believe that I can help steer the Silver Arrows to the top and achieve our joint ambitions of winning the world championships."
The move to Mercedes will see Hamilton team up with Ross Brawn, the man behind Button's title triumph in 2009 and Ferrari's incredibly successful spell during Schumacher's better years.
"I am delighted to welcome Lewis Hamilton to our team," Brawn said today.
"The arrival of a driver of Lewis' calibre is a testament to the standing of Mercedes-Benz in Formula One and I am proud Lewis shares our vision and ambition for the success of the Silver Arrows.
"I believe the combination of Lewis and Nico will be the most dynamic and exciting pairing on the grid next year, and I am looking forward to what we can achieve together.
"Over the past three years we have been putting in place the foundations and building blocks that are needed to compete regularly for the world championship.
"Behind the scenes, we have assembled a team that is technically stronger, more experienced and better resourced, thanks to the support of Petronas and all of our loyal team partners.
"The potential is now there to match any other team on the grid, which is the minimum standard for a Mercedes-Benz works team.
"Our task is now to translate that potential into on-track performance for next season and beyond."
It is understood that Mercedes offered Hamilton a better deal than McLaren, particularly in terms of the freedom for the driver to pursue other sponsorship deals.
In terms of their on track offer, Mercedes represents something of a risk with the team having only won one of 52 races since they took over Brawn GP at the end of the 2009 season, but the core of people behind the scenes is second to none.
Importantly, with new engine regulations due to come into force in 2014 as F1 switches to a new turbo era, Mercedes should have an advantage as a manufacturer and with McLaren as a customer.
Hamilton will continue to race for McLaren this season where he currently lies fourth in the world championship standings, 52 points behind leader Fernando Alonso.
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Portal dos Borbas
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Je suis Ca Va La Bibliotheque
... couples start dancing salsa barefoot In the street to the restaurant's live music and got ourselves some bracelets from a street vendor to match our chilled out, happy moods. The next day, the French girls left for Paraty and myself and Niamh went on a hike to a waterfall and then Found a beach to go swimming. We went out for dinner that night, grabbed a few beers at the hostel and then retired to the hostel hammocks to plan our next stop which would be Paraty. Before taking ...
Clara an her dad picked me up from the airport that afternoon. They have a beautiful house! The only Brazilian house I've visited so far. (Not counting the favela house) most people in Rio live in apartments. We had rice and this yellow stuff which wasn't bad for dinner. Me and Clara caught up a bit on life and she had to go to bed early for school which starts at ...
Brazil's finest beaches, bums and bikinis
... where we stuggled to find a decent looking cafe for lunch and even then the food was mediocre. It nicely confirmed our reasons for choosing a much more discreet place on the other side of the island to stay at. After lunch we stopped at the north of Ilha Grande at a place called Lagoa Verde; a protected bay for snorkelling. We were unsure what kind of life we would see because after snorkelling with sharks, stingrays and penguins in the ...
... loud they might cause damage and streets instantly several inches deep in water. Were stuck at the top of town where nothing was open and there was no shelter, so soaked through by the time we found an open restaurant. I was ready for that all-you-can-eat
wood fired buffet by then. Was a food chance to try feiojada, a very bland beany dish, one of many it seems, ...
Urban Jungle to Jungle Trekking
... are allowed on the island. It's probably only a matter of time until things change but for now, the island remains relatively unscathed by modern transportation. I arrived by wooden yacht, ferrying produce to locals from the mainland. The trip cost around £3 and involved lying on top of milk and vegetable (and drink!) crates, whilst taking in the incredible views of Isla Grande on the horizon. In terms of ecosystem, you couldn't get much more diverse than this. Isla ...


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It's often said that what matters is the singer, not the song, which is why music fans are still moved by Bing Crosby's rendition of "99 Bottles of Beer." Savour a voice that could sing the phone book with this GrouponLive deal for a G-Pass to see Martina McBride at the Harrah's Casino Tunica Event Center on Friday, October 12, at 9 p.m. Doors open at 8 p.m. Because the ticket is a G-Pass, Groupon customers can use it to enter the venue directly; they will not need to redeem their Groupon at will call. Choose from the following seating options:
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Grammy winner Martina McBride has never shied away from heavy topics, leavening the domestic abuse in the poignant story-song "Independence Day" with an irresistible slide-guitar riff or the depression in "When God-Fearin' Women Get the Blues" with a survivor's twangy honky-tonk snarl. The country legend brings the same sensibility to the six tracks she penned on her latest album, Eleven. Martina's powerful voice soars through the ups and downs of surviving breast cancer in "I'm Gonna Love You Through It," which celebrates the human support network that keeps people going through the "forced smiles and baggy T-shirts." "Teenage Daughters" turns a wry eye to the emotional rollercoaster of that child-rearing phase where communication slackens, disagreements rise, and the potency of the liquor cabinet's vodka mysteriously weakens. "I think it peels back a layer and lets people see more of my personality," McBride said to the United States' CMT cable channel of her songwriting, "especially the playful and fun side." During her live shows, Martina delves into 20 years' worth of chart-topping material that dates back to her debut album, The Time Has Come and runs through her pop-infused follow-up discs and increasingly cinematic lyrical scope.
Due to security restrictions, G-Passes must be printed out and presented in person at the event. They cannot be redeemed through Groupon's mobile app.
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Turning Point
this is the turning point
where the fires burns out
where our battle crumbles into
a mutual surrender
slowly, a tear muanders down your bruised face
my legs wither
there is no running anymore
Watch as we cling to the one thing
we still have
a voice.
My earS explode as you SCREAM your point of veiw
i whisper under what is left of my breath,
" What good is yelling to the deaf? because i can't hear you , I don't fear you anymore"
This is the turning point
where night blossoms into day
the point where i can safly say
I put my claws away
i can see in your blood shot eyes
I don't need to ask you to stay


text:
In the coming months the Canada will send troops to Ukraine, SIA informs with reference to CTV TV channel.
"While the government is still working out the details, sources tell CTV News a training mission is one of the options on the table. Canada will likely work closely with American allies who are already in the region," the TV channel website, CTV's Mercedes Stephenson reported the news Friday on Power Play.
Stephenson said senior Conservatives have been hinting at the possibility of an expanded mission for weeks, and the move will emphasise "Canada's strong anti-Putin stance and help shore up the Ukrainian government."


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Progesterone tablet
Hi.. I am 8 weeks pregnant. Previously i had two miscarriages. Where the first was ectopic pregnancy and the second pregnancy was wrongly diagonised as ectopic and treated with Methotrexate... now again I hav conceived and evrythng is fine but m taking naturogest 300 mg twicw daily. I feel vomiting, stomach burn and giddiness. So m in confusion whether t continue this or to stop. Pls advice.
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Dear Practo user, It is common to have these symptoms in early pregnancy. One should have small frequent feeds. Don't take large meals. Don't fast. I hope, it has been confirmed that this time tgat it is intrauterine pregnancy. You must be taking Folic acid. Your Doctor must have prescribed you drug for vomiting; most probably combination of Doxylamine and VitB6. Usually, your symptoms should gradually subside with these measures only. If still persisting, you can try reducing the dose of Naturogest to 200 mg.
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Sea Kayak Rescue Book
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Item: 65050.01 | Product Details »
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The nimble sea kayak is inherently unstable--so it's just a matter of time before you find yourself in the drink! Your ability to right the kayak and reenter it quickly and easily can spell the difference between a dunk and a disaster. Let expert instructors Roger Schumann and Jan Shriner show you the full range of kayak rescues, suitable for beginners and experts alike. From the basic Self-Paddle float Rescue and T Rescue to the more advanced Eskimo Rolls, this manual includes every technique you will ever need to rescue yourself--and others in all sea kayaking conditions.
Authors: Roger Schumann & Jan Shriner
Copyright: 2001
Size: 7.5" x 9"
Pages: 126
Authors: Roger Schumann & Jan Shriner
Copyright: 2001
Size: 7.5" x 9"
Pages: 126
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|Roger Schumann & Jan Shriner
|7.5" x 9"


text:
Digital Vets has launched a new range of low-cost CR digital x-ray scanners built on pioneering technology.
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Love and Robins: The History of Tim Drake and Stephanie Brown
MAXIM.COM's Exclusive Preview of ANIMAL MAN #2
This afternoon, MAXIM.COM published their exclusive preview of the second issue of ANIMAL MAN, the critically acclaimed and fan favorite title from DC COMICS-THE NEW 52. ANIMAL MAN #2, written by Jeff Lemire and illustrated by Travel Foreman, goes on sale tomorrow.
DETECTIVE COMICS #1 and SWAMP THING #1 Head Back to Press for Third Printings
DETECTIVE COMICS #1, by Tony S. Daniel and Ryan Winn, and SWAMP THING #1, by Scott Snyder and Yanick Paquette, two of the most critically acclaimed and fan adorned titles in DC COMICS-THE NEW 52, are heading back to press for third printings.
2nd Stop on the DC Comics-The New 52 Art Tour with Francis Manapul and THE FLASH
Despite the cold and rain on Friday in Toronto, there was a terrific turn out as fans of Francis Manapul and THE FLASH made it out to the Toronto Cartoonists Workshop for another successful event on the DC Comics-The New 52 Art Tour. Francis' incredible original art lined the long walls.
(Everybody's Talkin' About) DC Comics-The New 52, Monday Evening (ET) Edition
(Everybody's Talkin' About) DC Comics-The New 52, Tuesday Morning (ET) Edition
The previews for the second issues of DC COMICS-THE NEW 52 continue to roll in. Take a look at what people are saying about the books on sale tomorrow:
DC Comics-The New 52 Art Tour on The Source with Cliff Chiang
You've heard that retailers across the country are hosting artists from DC Comics-The New 52 and displaying process pieces from their new comic book series. Well, for those of you who can't make it to the events we thought we'd bring a version of it right here for you to see.


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Altered Traveling Wave Propagation and Reduced Endocochlear Potential Associated with Cochlear Dysplasia in the BETA2/NeuroD1 Null Mouse
- First Online:
- Received:
- Accepted:
DOI: 10.1007/s10162-007-0092-9
- Cite this article as:
- Xia, A., Visosky, A.M.B., Cho, JH. et al. JARO (2007) 8: 447. doi:10.1007/s10162-007-0092-9
- Citations
- 555 Downloads
The BETA2/NeuroD1 null mouse has cochlear dysplasia. Its cochlear duct is shorter than normal, there is a lack of spiral ganglion neurons, and there is hair cell disorganization. We measured vertical movements of the tectorial membrane at acoustic frequencies in excised cochleae in response to mechanical stimulation of the stapes using laser doppler vibrometry. While tuning curve sharpness was similar between wild-type, heterozygotes, and null mice in the base, null mutants had broader tuning in the apex. At both the base and the apex, null mice had less phase lag accumulation with increasing stimulus frequency than wild-type or heterozygote mice. In vivo studies demonstrated that the null mouse lacked distortion product otoacoustic emissions, and the cochlear microphonic and endocochlear potential were found to be severely reduced. Electrically evoked otoacoustic emissions could be elicited, although the amplitudes were lower than those of wild-type mice. Cochlear cross-sections revealed an incomplete partition malformation, with fenestrations within the modiolus that connected the cochlear turns. Outer hair cells from null mice demonstrated the normal pattern of prestin expression within their lateral walls and normal FM 1-43 dye entry. Overall, these data demonstrate that while tonotopicity can exist with cochlear dysplasia, traveling wave propagation is abnormally fast. Additionally, the presence of electrically evoked otoacoustic emissions suggests that outer hair cell reverse transduction is present, although the acoustic response is shaped by the alterations in cochlear mechanics.
Keywordscochlea cochlear malformation cochlear mechanics incomplete partition hearing loss cochlear partition
Cochlear dysplasia (or malformation) is usually, but not always, associated with hearing loss (Bamiou et al. 1999; Coticchia et al. 2006; Jackler et al. 1987; Schuknecht 1993). While commonly identified clinically during the evaluation of a patient with congenital hearing loss, the effects of dysplasia on cochlear mechanics have not been well defined. In the mammalian cochlea, progressive changes in the mass and stiffness of the basilar membrane determine the resonant frequency map of the cochlea (Geisler 1998). The apex of the cochlea is tuned to low frequencies, and the base of the cochlea is tuned to high frequencies. Sound pressure waves enter the cochlea by vibration of the stapes at the oval window and create a traveling wave that propagates up the cochlear duct to maximally stimulate the area of the cochlear partition tuned to that frequency. Frequency tuning is sharpened and vibrations are enhanced by outer hair cells, a process called the cochlear amplifier (Davis 1983; Rhode 1971; Ruggero and Rich 1991). Somatic and stereociliary motility have both been proposed as the basis of cochlear amplification (Brownell et al. 1985; Chan and Hudspeth 2005; Fettiplace and Hackney 2006; Jia and He 2005; Kennedy et al. 2006).
BETA2/NeuroD1 is a basic helix-loop-helix transcription factor initially found to be important in pancreatic and brain development. Together with the Math and Neurogenin subfamilies, they belong to the Drosophila proneural Ath group. The gene was cloned when it was discovered that it upregulates insulin gene expression and was named Beta cell E-box Transcriptional Activator 2 (Beta2; Naya et al. 1995). The same year, it was independently cloned based on its requirement for neuronal differentiation and named NeuroD (Lee et al. 1995). The transcription factor is now referred to as BETA2/NeuroD1, and it is important in both cell cycle withdrawal and cell differentiation.
While BETA2/NeuroD1 heterozygotes have normal cochlear anatomy, null mice demonstrate substantial cochlear dysplasia (Kim et al. 2001; Liu et al. 2000a). The cochlear duct is shortened, with growth halted at 1.25 turns compared to the normal 1.75 turns (Morsli et al. 1998). However, the tectorial membrane, the stria vascularis, and Reissner's membrane are histologically normal. The most striking finding is an almost complete absence of spiral ganglion neurons. The sensory epithelium within the cochlear partition is present, but there is hair cell misalignment that is presumably the result of defects in migration of neuronal precursors. In particular, some inner hair cells are found within the region of the outer hair cells.
Herein, we assessed the impact of the BETA2/NeuroD1 null cochlear dysplasia on several aspects of cochlear physiology. Although the cochlear partition could be stimulated to vibrate in a tonotopic manner, traveling wave propagation was abnormal. Our data also suggest that outer hair cells are able to generate force within this dysplastic cochlea.
MATERIALs AND METHODS
The study protocol was approved by the Baylor College of Medicine Institutional Animal Care and Use Committee. The BETA2/NeuroD1 transgenic mice were generated and then bred into a 129SvJ background to reduce the rate of perinatal lethality due to diabetes as described previously (Liu et al. 2000b). This permitted survival of 60–70% of the null mutants into adulthood. All mice used in this study were bred from F2 and F3 heterozygotes and were between 4–8 weeks old. The data presented in this manuscript came from studying a total of 74 mice.
Measurement of vertical tectorial membrane movements
An excised cochlear preparation was used to measure movements of the cochlear partition in response to mechanical vibration of the stapes. Specifically, we measured vertical displacements of a silver-coated bead placed on top of the tectorial membrane. Studies were performed in a standard extracellular solution. This was similar in composition to perilymph, and contained, in mM: 152 NaCl, 6 KCl, 1.5 CaCl2, 2 Na-pyruvate, 10 HEPES, and 10 glucose. The pH was 7.35, and the osmolality was 315 mOsm/kg.
While this preparation has not been described before using the mouse cochlea, similar preparations using excised guinea pig and gerbil cochleae have been described (Chan and Hudspeth 2005; Gummer et al. 1996; Mammano and Ashmore 1995; Morioka et al. 1995; Nowotny and Gummer 2006). The temporal bones were harvested after the mouse was killed by cervical disarticulation while under a surgical plane of anesthesia. In standard extracellular solution, the bulla was dissected open and the cochlea exposed under a dissecting microscope (Stemi-2000C, Zeiss, Germany). The incus was carefully disarticulated from the stapes and removed. The cochlea was then glued upright into a chamber (Iso-Dent, Ellman International, Oceanside, NY). A small section of the otic capsule bone overlying the scala vestibuli was removed with a fine knife. Reissner's membrane was then perforated and the organ of Corti visualized. Care was taken not to touch the tectorial membrane. Roughly 4–5 silver-coated glass beads about 15-25 μm in diameter each (Conduct-O-Fil S3000-S3N, specific gravity 2.5 g/cc, Potters Industries, Carlstadt, NJ) were carefully dropped onto the tectorial membrane.
The chamber was then moved to our experimental upright microscope (Axioskop 2 FS plus, Zeiss) and fixed securely in place. By illuminating the cochlea from below, we could visualize the organ of Corti and the hair cells using a 40× water immersion objective (Achroplan, NA = 0.8, Zeiss). A 4-cm length of tungsten wire (0.005 in. diameter, A-M Systems) glued to a piezoelectric actuator (PA8-12, piezosystem jena) was advanced through the external solution with a micromanipulator until it gently contacted the stapes capitulum. A laser doppler vibrometer (OFV-5000, Polytech PI) attached to the trinocular port of the microscope was focused on the bead to measure vertical movements of the tectorial membrane. The velocity output was low-pass filtered at 100 kHz and digitized at 100 kHz for offline analysis. The magnitude and phase responses between 1–40 kHz were calculated by FFT analysis and referenced to stapes motion, measured in a similar fashion using a bead placed on the anterior crus. The data were smoothed using a three-point boxcar filter, and the baseline of the phase response was zeroed at the low-frequency baseline.
When designing this setup, we verified that the preparation was securely fixed by measuring the vertical velocity of a bead placed on the osseous spiral lamina near the site of the tectorial membrane bead. In all five preparations examined, we found that the velocity was at least 30 dB less than that of the tectorial membrane over the frequency range of 1–40 kHz. This suggests that the tectorial membrane response was not significantly contaminated by movement of the entire preparation.
In vivo experiments
Procedures performed on anesthetized mice included measuring the auditory evoked brainstem response (ABR), distortion product otoacoustic emissions (DPOAEs), the cochlear microphonic (CM), the endolymphatic potential (EP), and electrically evoked otoacoustic emissions (EEOAEs). Mice of either sex were anesthetized using ketamine (100 mg/kg) and xylazine (5 mg/kg). Supplemental doses of anesthesia were administered to maintain areflexia to paw pinch.
Sine wave stimuli were generated digitally using MATLAB (Release 13, The Mathworks, Natick, MA), converted to analog signals using a digital-to-analog converter running at 200 kHz, and then attenuated to the appropriate intensity according to our experimental design (RP2 and PA5, Tucker-Davis Technologies; Oghalai 2004). To generate the acoustic stimuli, two different speaker systems were used: high frequency piezoelectric speakers for the ABR and DPOAE measurements (EC1, Tucker-Davis Technologies) and a supertweeter (Radio Shack) for the CM. The speakers were connected to an earbar inserted into the ear canal and calibrated from 4 to 95 kHz by a probe-tip microphone (type 8192, NEXUS conditioning amplifier, Bruel and Kjar, Denmark) inserted through the earbar. The tip of the microphone was within 3 mm of the tympanic membrane.
ABR measurements
The ABR signal was measured with a bioamplifier (DB4, Tucker-Davis Technologies) from a needle electrode positioned at the ventral surface of the tympanic bulla referenced to an electrode placed at the vertex of the skull, as previously described (Wenzel et al. 2006). A ground electrode was placed in the hind leg. The stimulus was a 5 ms sine wave tone pip of alternating polarity with cos2 envelope rise and fall times of 0.5 ms and a repetition time of 50 ms. The stimulus intensity ranged from 10 to 80 dB SPL in 10 dB steps. The frequency range studied was 4 to 80 kHz. Two hundred and fifty ABR responses were sampled at 25 kHz over the 50 ms repetition time and averaged. Thresholds were calculated offline. At each frequency, the peak-to-peak voltage of the ABR waveform was measured, and the data interpolated over the range of stimulus intensities. The threshold was determined to be when the ABR was four standard deviations above the noise floor. If no ABR response was detected even at our equipment limits of 80 dB SPL, we arbitrarily defined the threshold to be 80 dB.
DPOAE measurements
DPOAEs were measured as previously described (Paylor et al. 2006). Briefly, the stimuli for eliciting DPOAEs were two sine wave tones of differing frequencies (F2 = 1.2 × F1) of 1-s duration with F2 ranging from 4 to 43 kHz. The two tones were presented at identical intensities, which ranged from 20–80 dB SPL in 10 dB increments. The acoustic signal picked up by the microphone in the earbar was digitized at 200 kHz and the magnitude of the 2 × F1 − F2 distortion product determined by FFT. The surrounding noise floor was also calculated by averaging 20 adjacent frequency bins around the distortion product frequency. DPOAE thresholds were calculated offline by interpolating the data and identifying when the signal was >−5 dB SPL and greater than two standard deviations above the noise floor. If no DPOAE response was detected even at our equipment limits of 80 dB SPL, we arbitrarily defined the threshold to be 80 dB.
CM measurements
The CM is a field potential that reflects the summation of hair cell transduction currents primarily from outer hair cells of the basal turn of the cochlea (Cheatham and Dallos 1982; Cheatham and Dallos 1997; Dallos 1975; Patuzzi and Moleirinho 1998; Patuzzi et al. 1989). After rigidly securing the mouse in a head holder, a ventral incision was made. This was extended dorsally to the scalp, and the pinna was resected. The bulla was carefully opened medial to the tympanic annulus to expose the round window. The stapedial artery was preserved. The earbar was then inserted into the ear canal and secured. The CM was measured from the ball-ended tip of a Teflon-coated silver wire (0.003 in. diameter, A-M Systems, Carlsborg, WA) advanced onto the round window membrane with a micromanipulator. The signal was referenced to a silver wire inserted under the skin near the vertex of the skull. The ground electrode was placed in the hind leg. A bioamplifier was used (DB4, Tucker Davis Technologies) to amplify the signals. The signal was amplified 100 times and no filtering was used. However, the bioamplifier system does not pass DC signals (corner frequency <20 Hz). Additionally, it has a flat frequency response until its innate corner frequency of about 22 kHz.
The stimulus was a 30 ms 6 kHz tone, repeated every 1 s. Its intensity ranged from 35–90 dB SPL. By measuring the speaker output with the probe tip microphone in the earbar, FFT analysis demonstrated that all stimulus harmonics and noise at all other frequencies were at least 50 dB below the primary signal at all stimulus intensities. The CM signal measured by the bioamplifier was digitized at 200 kHz, and the magnitude of the response at 6 kHz determined by FFT.
EP measurements
After opening the tympanic bulla, the cochlea was backlit using a fiberoptic cable to highlight the region of the spiral ligament. The bone overlying the basal turn was thinned with a microknife very close to the stapedial artery to expose the spiral ligament. A glass micropipette pulled to a tip diameter of about 1 μm filled with 150 mM KCl was advanced up to the spiral ligament with a micromanipulator. The voltage was measured every 1 s referenced to a silver wire placed under the skin near the vertex of the skull (Axoclamp-2, Axon Instruments). The baseline bias voltage was compensated for by determining the zero-current potential of the extra-cochlear fluids outside of the spiral ligament, before entering scala media. After entering the endolymphatic space, the EP was recorded until the measurement stabilized (usually about 5–10 s). Then, the micropipette was withdrawn from the cochlea and the voltage of the extra-cochlear fluids re-measured to verify that no baseline drift occurred.
EEOAE measurements
EEOAEs were measured by injecting a constant current sine wave stimulus into the cochlea and measuring the acoustic response by a microphone in the ear canal (Hubbard and Mountain 1990; Mountain and Hubbard 1989; Nuttall et al. 2001; Ren and Nuttall 1995, 2000; Xue et al. 1993). The surgical preparation was similar to that used for measuring the CM. However, the stimulus was a 212 μA rms sine wave (Linear Stimulus Isolator, WPI, Sarasota, FL) that ranged from 4–40 kHz. The current was passed through the cochlea via a ball-ended Teflon-coated silver wire placed on the round window membrane. The actual current delivered was verified by measuring the voltage drop across a 1 kΩ resister placed in series. The ground return was a silver wire inserted under the skin near the vertex of the scalp. The acoustic response was measured by the microphone in the earbar and digitized with a sampling rate of 100 kHz. The magnitude of the response at the stimulus frequency was determined by FFT, and the surrounding 20 frequency bins were averaged to calculate the noise floor.
Cochleae were isolated and fixed in 4% paraformaldehyde overnight. They were then placed in a 0.12 M EDTA for 3–7 days, dehydrated in ethanol, and embedded in paraffin. Serial paraffin sections (7 μm) were cut. The hematoxylin and eosin staining procedures have been described previously (Liu et al. 2000a). For immunofluorescence studies, the sections were deparaffinized and washed with phosphate buffered saline containing 0.1% Triton X-100 (PBST) for 1 h. The sections were then blocked for 1 h in normal serum at room temperature and incubated with the primary antibody, polyclonal goat anti-prestin diluted 1:400 (Santa Cruz Biotechnology, USA), overnight at 4°C in a humidified chamber. Sections were washed three times with PBST and then incubated with the secondary antibody, Alexa Fluor 594 mouse anti-goat IgG diluted 1:500 (Molecular Probes/Invitrogen), at room temperature for 1 h. After washing with PBST again, the sections were covered with fluorescence mounting medium and nail polish (Biomeda gel/mount, Foster City, CA) and imaged using an epi-fluorescence microscope (Axioplan 2, Zeiss).
FM 1-43 dye application
FM 1-43 dye (Molecular Probes/Invitrogen, USA) was diluted to 2.5 μM in standard extracellular solution. For certain experiments, 100 μM streptomycin sulfate (S-6501, Sigma-Aldrich, St. Louis, MO) was also included. The dye was applied to the excised cochlear preparation for 20 s. FM 1-43 dye quickly enters hair cells through non-specific cation channels (Meyers et al. 2003). The application time was short to minimize signal contamination by dye entry through apical endocytosis (Gale et al. 2001; Griesinger et al. 2002; Griesinger et al. 2004; Griesinger et al. 2005; Kaneko et al. 2006; Meyers et al. 2003). The dye was then rinsed away under constant perfusion for another 20 s. FM 1-43 fluorescence within the organ of Corti was visualized using the 40× water immersion objective using a mercury arc lamp and a filter set (XF21, Omega Optical, Brattleboro, VT). Grey scale images were captured using a digital camera attached to the trinocular port (A101, Basler, Germany). Images were taken immediately following washout.
Statistical analysis
Data were analyzed with SPSS (11.0 for Windows) and plotted with SigmaPlot (9.0, Systat Software). Statistical significance was assessed using the Student's non-paired two-tailed t test. P values <0.05 were considered statistically significant. All presented values are mean ± SEM.
Measurement of tectorial membrane motion
Representative raw velocity magnitude data from the apex of a wild-type mouse (Fig. 1d) and from the base of a heterozygote mouse (Fig. 1g) are presented. The resonant frequencies were about 6 and 22 kHz, respectively. Stapes velocity magnitudes for each preparation are also shown and demonstrated resonances at about 28 and 24 kHz, respectively. This reflects the innate resonance of the loaded piezoelectric actuator. Both the tectorial membrane and the stapes responses were >20 dB greater than the noise floor plus three standard deviations.
To compensate for frequency dependent variations of the stimulus amplitude, the magnitude of the tectorial membrane velocity was divided by the magnitude of the stapes velocity. This gives the unit-less response ratios (Fig. 1e and h). To compensate for frequency-dependent variations in the phase of the stimulus, the phase of the stapes was subtracted from that of the tectorial membrane (Fig. 1f and i). This procedure was performed individually for every cochlea studied so as to minimize frequency-dependent contamination of the tectorial membrane responses by the stimulus resonance.
Comparison of the magnitude of tectorial membrane motion
At the base, the resonant frequencies ranged between 14.6 and 26.4 kHz for all 23 tuning curves measured among the three genotypes. The average resonant frequencies of wild-type and heterozygous mice were not statistically different from that of the null mice (wild-type: 18.8 ± 0.8 kHz, n = 10; heterozygous: 23.9 ± 1.1 kHz, n = 5; null: 16.6 ± 1.4 kHz, n = 8; p > 0.1). Overall, the resonant frequency values measured were within the range of what would be expected according to the mouse place-frequency map with no cochlear amplifier present, causing the normal frequency of resonance to drop by about 0.5–1 octave (Cody and Johnstone 1980; Liberman 1982; Muller et al. 2005; Ou et al. 2000).
Comparison of the phase of tectorial membrane motion
Phase responses measured at the same time as the previously described magnitude responses are shown for all three genotypes at the apex and at the base (Fig. 2d–f). Both wild-type and heterozygous mice demonstrated phase lag accumulations of >600° above the resonant frequency at both the base and the apex. In contrast, at the apex, only minimal phase lag accumulation was found in null mice, typically <250°. At the base of the null cochlea, larger phase lag accumulations were present, although they still did not reach that of wild-type or heterozygote mice. The differences in phase between the genotypes was quantified using averaged, normalized data (Fig. 3c and d). There was significantly less phase lag accumulation in null mice compared to wild-type or heterozygous mice (p < 0.05 for nearly every tested frequency above resonance). This effect was larger in the apex than in the base.
In vivo electrophysiology
As previously reported, no ABRs could be detected to equipment limits in null mice (Kim et al. 2001; Liu et al. 2000a). This was found across the frequency spectrum of 4–80 kHz, and the differences from wild-type and heterozygous mice were statistically significant at every frequency (p < 0.001). These results are not surprising given the lack of spiral ganglion cells.
DPOAE thresholds were also measured for each genotype and there were similar thresholds between wild-type and heterozygous mice (Fig. 4b). No statistically significant differences between the thresholds of wild-type and heterozygous mice were found at any frequency (p > 0.1). Null mice lacked DPOAEs at all frequencies to equipment limits, and the differences from wild-type and heterozygous mice were statistically significant between 10–36 kHz (p < 0.01).
Next, the amplitude of the cochlear microphonic at 6 kHz was measured at stimulus intensities ranging from 35–90 dB SPL (Fig. 4c). Normal responses were found in wild-type mice, with the compound action potential dominating the signal at the onset (see raw data inset). Louder intensity stimuli generated larger cochlear microphonic responses that saturated at stimuli >75 dB SPL. There were only minimal responses in null mice. The slight response measured at 80–90 dB remained below threshold (three standard deviations above the noise floor). All cochlear microphonic responses in null mice were statistically less than the responses in wild-type mice at the same stimulus intensity (p < 0.001).
Wild-type and heterozygous mice had normal endocochlear potentials (wild-type: 93.2 ± 3.2 mV, n = 5; heterozygous: 98.5 ± 2.6 mV, n = 6; Fig. 4d). No statistical difference was found between these two groups of mice (p > 0.1). In contrast, null mice had almost no endocochlear potential (2.0 ± 1.0 mV, range: 0–6 mV, n = 6), which was statistically different from those of wild-type and heterozygous mice (p < 0.001).
A representative example of the response from the same mouse and from a null mouse using current stimuli ranging from 1 to 40 kHz is shown in (Fig. 5b). There were emissions across the entire frequency spectrum, and the characteristic EEOAE fine structure of multiple peaks and valleys in the responses were noted (Ren and Nuttall 2000). Removal of the tympanic membrane reduced the responses to the level of the noise floor across the frequency spectrum. Across the measured frequency spectrum, null mice were found to have generally lower responses than wild-type mice (Fig. 5c). The differences were larger and tended to be statistically significant at frequencies >10 kHz (p < 0.05).
Serial sections through wild-type (n = 3) and null (n = 3) cochleae oriented along their central axis were evaluated. After staining with hematoxylin and eosin, every section was examined in sequence. A detailed histological description of the development of the BETA2/NeuroD1 null cochlea has been reported previously (Liu et al. 2000a). Additionally, histological studies on heterozygous mice were not performed as their cochleae have already been shown to be similar to cochleae of wild-type mice.
FM 1-43 dye entry
The BETA2/NeuroD1 null mouse has altered cochlear biomechanics
BETA2/NeuroD1 null mice have a severe cochlear dysplasia. One feature is that there are large connections between the perilymphatic chambers through the central core of the cochlea. This malformation is associated with broader tuning than normal at the cochlear apex and a reduced accumulation of phase lag at both the base and the apex. As a progressive phase delay is characteristic of traveling wave propagation (Patuzzi 1996), we conclude that traveling wave propagation is substantially faster with this malformation.
Preparation-induced artifacts due to mechanical loading or poor surface adhesion by the reflective bead (Khanna et al. 1998; Nuttall et al. 1991), having an opening in the cochlea (Cooper and Rhode 1996; Ulfendahl et al. 1991), and the innate resonance of the piezoelectric actuator may affect these data to some degree. However, the high degree of similarity between the responses we measured in control wild-type and heterozygote cochleae to normal responses reported in the literature argue against significant contamination. For example, the tuning curves from wild-type and heterozygous mice were comparable to tuning curves measured in vivo, such as in mice where the cochlear amplifier was absent due to tectorial membrane malformations (Legan et al. 2000; Legan et al. 2005). Additionally, the sharpness of the tuning curves we measured were similar to those described for other mammalian species in which the cochlear amplifier was inhibited (Cooper and Rhode 1995; Hemmert et al. 2000; Robles and Ruggero 2001). Consistent with these findings, we found the expected accumulation of phase lag with increasing stimulus frequency (Geisler 1998; Robles and Ruggero 2001). Thus, we believe that the mechanics data reported herein reflect predominantly cochlear physiology and not artifact.
Why the incomplete partition malformation hastens the traveling wave is not obvious. Our current understanding of normal cochlear mechanics is that immediately after a movement of the stapes, a "fast" compression wave occurs because the fluid within the cochlea is essentially incompressible (Chadwick et al. 1980; Geisler 1998). Thus, the entire length of the cochlear partition is exposed to the sound pressure wave stimulus in a near-simultaneous fashion. However, the distributed variation in the innate mechanical properties of the cochlear partition produces a graded response pattern. This creates the appearance of a "slow" traveling wave (Ren 2002; Ruggero 1994; von Bekesy 1960). A key factor behind the production of a normal traveling wave is the concept that the impedance of the fluids within the cochlea are in series with the cochlear partition impedance. Thus, the fluid impedance sums from the oval window to the region of best frequency along the cochlear partition, and then back again to the round window. In this way, there is more fluid impedance influencing tuning at the cochlear apex than at the base. Historically, this is the main difference between the traveling wave theory of von Bekesy (von Bekesy 1960) and the earlier independent resonator theory of Helmholtz (Helmholtz and Ellis 1954).
Another potential explanation for the reduced phase accumulation in the BETA2/NeuroD1 null is that the basilar membrane itself may be different in the mutants. Indeed, our findings are quite similar to that found in the base of the developing gerbil cochlea where the passive mechanics needed to sustain traveling wave propagation were found to progressively mature between postnatal days 14–20 (Overstreet et al. 2002). During this time period, the maximal phase lag accumulation progressively increased from about 180° to the adult level of roughly 600–800°. Abnormal basilar membrane development, which may alter its stiffness, is likely associated with the shortened cochlear duct in the BETA2/NeuroD1 null mouse. However, the fact that the apex and the base are tonotopically tuned to different, but appropriate, resonant frequencies at least suggests that there are regional variations in its physical properties.
While we consider these two explanations to be reasonable interpretations of our data, other possibilities should be considered. Recent modeling studies suggest that the cochlear coiling can impact cochlear micromechanics, particularly at the apex, by redistributing energy wave density (Cai et al. 2005; Cai et al. 2004; Manoussaki et al. 2006). However, the effect of the altered cochlear geometry of the BETA2/NeuroD1 null in these models is unknown. Finally, although the cochlear partition of the BETA2/NeuroD1 null is firmly fixed along its lateral edge (as in the wild-type), perhaps its medial edge is not as firmly fixed and causes abnormal radial motion to occur. Our measures of vertical motion would not detect this type of activity.
The reduced endocochlear potential
The BETA2/NeuroD1 null mouse has severe hearing loss because of the lack of spiral ganglion cells and our ABR results confirm previous reports (Kim et al. 2001; Liu et al. 2000a). However, the nearly 100-fold reduction in CM magnitude in null mice is also consistent with a more proximal defect, namely, the reduction in the endocochlear potential and the reduction in numbers and the disorganization of the hair cells.
The reason for the reduced endocochlear potential is unknown. However, there are previous reports of mutant mice with an endocochlear potential of zero or close to zero (Schrott et al. 1990; Steel and Barkway 1989; Steel et al. 1987). This appears to occur in mice with neural crest defects and reduced melanocyte counts within the stria vascularis, although a recent paper argues against the theory that melanin production is important to production of the endocochlear potential (Ohlemiller 2006; Ohlemiller et al. 2006). While light microscopy did not demonstrate any major anatomic defects in the BETA2/NeuroD1 null stria vascularis (Fig. 6), a specific assessment for the presence or number of melanin-containing cells was not performed. Certainly, the BETA2/NeuroD1 mutation affects neural development and cell migration, and thus, the mutation itself may be implicated in this pathophysiologic process.
Another possibility is that the anatomy of the cochlear dysplasia could lead to a reduced endocochlear potential. It is conceivable that the lack of or degeneration of modiolar precursors during development could create cracks in scala media, connecting the endolymph with the perilymph. Additionally, because the intracranial, sub-arachnoid space connects directly to the interior of the cochlea with this malformation, changes in intracranial pressure during straining could potentially damage the intracochlear structures. A classic clinical scenario in patients with cochlear malformations is that subtle head trauma causes a sudden, substantial sensorineural hearing loss. This has been hypothesized to represent rupture of the membranes of the inner ear (Cremers et al. 1998; Jackler and De La Cruz 1989; Stinckens et al. 2001).
Reverse transduction in the mutant mouse
Laser doppler vibrometry measures indicate that there are movements of the tectorial membrane in response to stapes displacement in the BETA2/NeuroD1 null. However, this experimental paradigm does not permit an assessment of the impact of these movements on the hair cells. An indirect measure of this, the cochlear microphonic, could not be studied because of the reduced endocochlear potential. Another way to test the connection between outer hair cells and cochlear partition movements is to study reverse transduction. Indeed, electrically evoked otoacoustic emissions could be measured, suggesting that the movements of the cochlear partition could be evoked by an electric field in the BETA2/NeuroD1 null.
While the exact site from which the movements originated was not assessed in this study, the most likely source of force generation would be from outer hair cells (Halsey et al. 2005; Liberman et al. 2004). Force generation by outer hair cell somatic electromotility and/or stereociliary motility within the normal organ of Corti in response to electrical stimuli is called reverse transduction, and these processes have been postulated to underlie the cochlear amplifier (Fettiplace and Hackney 2006). In order for somatic electromotility to function normally, the prestin protein must be present in the lateral wall of outer hair cells (Liberman et al. 2002; Zheng et al. 2000). Our immunolabeling in the BETA2/NeuroD1 null is consistent with this, however subtle regional differences of prestin expression between outer hair cells of wild-type and null mice might not have been detected. In order for stereociliary motility to be functional, hair cell mechanoelectrical transduction channels must be functional. We showed that hair cells from null mice permit FM 1-43 entry in a fashion similar to that of hair cells from wild-type and heterozygous mice. However, it is important to note that normal FM 1-43 dye staining does not prove that mechanoelectrical transduction is normal. Direct measurements of somatic electromotility and transduction currents under whole-cell voltage-clamp are indicated to definitively assess this issue, but are beyond the scope of the present work.
One reason why electrically evoked otoacoustic emissions were lower in null mice compared to wild-type mice is likely related to the hair cell misalignment and the reduced numbers of outer hair cells. Fewer hair cells in the base of the cochlea could certainly explain the larger differences at higher frequencies. Future studies to quantify hair cell numbers along the length of the cochlear duct would be needed to assess this concept. Another possibility is that null mutant outer hair cells are shorter than wild-type or heterozygote outer hair cells, and the amplitude of electromotility depends on cell length (Dallos et al. 1993). A third reason is that the biomechanics of the cochlear partition as a whole are likely to be different in the null mouse. It is also possible that the electrical field generated passive movements of the tectorial membrane or basilar membrane directly, rather than outer hair cell force production. Even so, the fact that movement of the cochlear partition in the null mouse can elicit sound emission from the ear confirms the reciprocity between movements of the cochlear partition and movements of the stapes footplate in this dysplastic cochlea.
Normal cochlear function in heterozygous mice
Lastly, we found that the ABR and DPOAE thresholds of BETA2/NeuroD1 heterozygous mice are normal. A possible explanation for why we did not observe a difference between the cochlear function in wild-type and heterozygous mice in our study, as compared to the partial hearing loss found in the original ABR recordings by Liu et al. (2000a) is genetic drift. The mice in this study were from F3 and F4 generations, while the mice in the previous study were F1 and F2 generations. It is possible that a mild difference in hearing may have been lost as breeding modified the genetic background of the mice. However, it is also possible that the original 15 dB threshold shift found in heterozygous mice measured before was not accurate. The ABR data presented herein were collected using frequency specific stimuli, permitting a more refined and precise analysis of cochlear function than the previously used click stimuli recordings. It should be noted that our ABR and DPOAE data confirm each other in that neither demonstrated differences between wild-type and heterozygous mice. Additionally, our results correlate with the fact that wild-type and heterozygous cochleae are morphologically identical.
Potential clinical implications
The cochlear dysplasia found in the BETA2/NeuroD1 null mouse has many similarities with congenital cochlear malformations found in humans. One of the most common findings is Mondini dysplasia, more precisely termed the incomplete partition malformation. Patients with an incomplete partition malformation commonly have mild-to-moderate sensorineural hearing loss that often progresses to deafness (Bamiou et al. 1999; Coticchia et al. 2006). In this disorder, the cochlea is shorter than normal (only 1.5 instead of the normal 2.5 turns in humans) and its central modiolus is thin or missing (Schuknecht 1993). However, the auditory nerve is typically present. It is possible that progressive loss of the endocochlear potential may in part explain why humans with an incomplete partition malformation have progressive hearing loss.
Additionally, if these patients also have reduced phase accumulation, the delays associated with normal traveling wave propagation would not be present. This may adversely impact the central nervous system's ability to analyze complex signals, and would likely manifest as reduced speech discrimination in noise. If so, a hearing aid that could simulate a traveling wave by delaying low-frequency sounds relative to high-frequency sounds may provide clinical benefit.
The authors wish to thank William E. Brownell, Ph.D., Ruth Anne Eatock, Ph.D., and Robert Raphael, Ph.D. for helpful advice, and Haiying Liu, Wen Chen, and Xue-Fei for technical support. The artwork is by Scott Weldon. This project was funded by NIH grant DC006671 (to JSO) and DC04585 (to FAP).


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University Of Minnesota Army ROTC
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University of Minnesota Army ROTC
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University of Minnesota Army ROTCon 7 January 2015
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