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Christian Living
Road Warrior
How to Keep Your Faith, Relationships, and Integrity When Away from Home
Are you more and more disconnected from your real life?
Forced to face a battle with the lonely road?
Business travel has become more costly than ever–and not just financially. The mental and emotional pricetags bring you and your family under attack, threatening to distance you ...read more
Experiencing the Resurrection
The Everyday Encounter That Changes Your Life
Experience the powerful reality of Christ's resurrection in your life. Moment by moment, day by day.
Two thousand years ago, God raised Jesus Christ from the dead. But that isn't a mere historical event. It isn't simply a theological doctrine. It is rather a "huge moment" that ...read more
Experiencing the Resurrection Study Guide
The Everyday Encounter That Changes Your Life
The study guide that will help you experience the powerful reality of Christ's resurrection. Moment by moment, day by day.
What does the resurrection of Christ really mean for us? What does it reveal about the heart and mind of God? And what real differences can the miracle of the resurrection make in ...read more
The Next Level
A Parable of Finding Your Place in Life
Business degree in hand, Logan enters the immense Universal Systems building and is hired as an organizational analyst — a trouble-shooter. His job: evaluate the company's five divisions, each on a separate level and each operating on startlingly unique principles. Which set of principles is successful? Why is ...read more
Closer Than Your Skin
Unwrapping the Mystery of Intimacy with God
If you crave the real experience of God's presence in your daily life…
If you sense there's more to Christianity than service, study, and superficial spirituality…
If you're ready to go beyond knowing about God
to truly knowing ...read more
One Month to Live
Thirty Days to a No-Regrets Life
"If you want new urgency, fresh purpose, and a sharper focus for your life, then this book is for you. Read it and your future may be changed forever!"
—Lee Strobel, best-selling author of The Case for Christ and The Case for the Real Jesus
Are ...read more
Leading with a Limp
Take Full Advantage of Your Most Powerful Weakness
Put your flawed foot forward.
Pick up most leadership books and you'll find strategies for leveraging your power and minimizing your areas of weakness. But rather than work against your weakness, why not draw from a deeper well of strength? God favors leaders who make the most of the power that comes ...read more
101 Cups of Water
For every time you've tried too hard, fell too far, or struggled too much, the refreshing cups in this book–or reminders of God's infinite grace and mercy–will renew you like cool, clear water after a long, dry walk on a dusty, pitted, uphill road.
"I've been a believing Christian ...read more
Surviving Your Baby's First Year Without Losing Your Cool
Welcome to the Adventure of Motherhood
Clutter? Chaos? Exhaustion got you down? You must be a mom. And you're not alone. Perhaps you thought you had it all together…then your baby was born and your world was turned upside down. If new motherhood has you filled with doubt, guilt, and confusion, Trish Berg ...read more
Unlimiting God
Increasing Your Capacity to Experience the Divine
People have their limits. Some choose to ignore them.
God's power and love have no limits. So why do Christians put limits on their relationship with Him? We could be pursuing greater knowledge, experiencing deeper intimacy, and abiding in freer joy… and yet we routinely settle for mediocrity in our ...read more
How to Get Your Husband to Listen to You
Understanding How Men Communicate
You talk for thirty minutes, telling him every detail of your day. He has three great ideas for how to fix your problems.
"Why can't you just listen to me?" you ask. You pull back, he gives up, and your marriage suffers.
The problem? He's a man. And you expect a ...read more
Generation NeXt Marriage
The Couple's Guide to Keeping It Together
Do you still find yourself humming the love songs of the 80s and 90s?
Do you still believe that every marriage should be between soul mates?
But...do you wonder how you can succeed at love and marriage when the generation you grew up in didn't?
Marriage isn't what it used to ...read more
How Would Jesus Vote
How your faith should inform your vote.
The 2008 election is shaping up to be one of the most important political contests in American history. In fact, Dr. D. James Kennedy believes it will be a watershed moment that could impact our very survival as a nation under God.
Values ...read more
No More Dreaded Mondays
Ignite Your Passion--and Other Revolutionary Ways to Discover Your True Calling at Work
Beloved career coach, talk show host, and best-selling author Dan Miller has devoted his life to helping people across the country who are frustrated with their careers to stop dreading Mondays, once and for all. In No More Dreaded Mondays, he shares the inspirational advice and specific, practical steps you can use ...read more
How We Love
Discover Your Love Style, Enhance Your Marriage
Identify the source of missteps in your marriage–and learn
exactly what you can do about it!
Tired of arguing with your spouse over the same old issues?
Longing for a marriage with less conflict and more intimacy?
Struggling under a load of resentment?
In How We ...read more
How Did I Get So Busy?
The 28-Day Plan to Free Your Time, Reclaim Your Schedule, and Reconnect with What Matters Most
If you can't remember the last time you had time to read,
then this book is for you.
Are you exhausted from rushing through your days in a flurry of activity, then dropping into bed only to find your mind racing ahead to the next day's to-do list? Are you constantly playing catch-up at work and ...read more


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Uh oh: LeBron James Broke Royal Protocol by Not Showering and Touching Duchess Kate
The British are angry that NBA Superstar LeBron James broke royal protocol when he met the Duke and Duchess of Cambridge last night.
The Carters Meet the Royals
It was a night of firsts for British Royal couple Prince William and his pregnant wife, Duchess Kate Middleton. The Royal couple attended their first NBA game on Monday night at the Barclays Center in Brooklyn, where they met America's self-appointed royal couple Beyonce Knowles-Carter, 33, and her husband, rapper Shawn "Jay Z" Carter, 45.
Cavaliers and Nets Players Wear 'I Can't Breathe' Tees Before NBA Game
In 2005, the NBA implemented a strict dress code to combat image problems caused by young black players wearing hip hop attire popularized by street dealers and rap stars. The dress code called for NBA players to wear "business casual" attire before and after NBA games — even if a player was sitting on the bench.
But before last night's Cavaliers vs Brooklyn Nets game at the Barclays Center, Cleveland Cavaliers stars LeBron James and Kyrie Irving, as well as members of the Brooklyn Nets, donned black t-shirts bearing the words "I can't breathe," to support the family of Eric Garner who was suffocated by a NYPD police officer.
Celebs Out & About: Beyonce Knowles-Carter
Pop singer Beyonce Knowles-Carter, 33, and her androgynous daughter Blue Ivy Carter were spotted out and about in NYC on Tuesday. Beyonce was caught on video 'tweaking' at the Brooklyn Nets' NBA home opener game on Monday.
Was Beyonce Tweaking at Brooklyn Nets Game?
After years of persistent rumors about pop icon Beyonce's alleged drug use, a video has surfaced that seems to confirm the rumors.
LeBron James and His Mom Celebrate Miami Heat's Victory Over Brooklyn Nets
The Miami Heat defeated the Brooklyn Nets in game 5 of the NBA playoffs in Miami last night to advance to the Eastern Conference Finals for the 4th consecutive year. Team co-captain LeBron James celebrated the team's big win with his favorite girl, his mom Gloria James.
After a much needed rest, LeBron and his teammates will take on the hapless Indiana Pacers on Monday or Tuesday.
Jay Z and Beyonce Sit Courtside at Miami vs Nets Game 4
Rap mogul Jay Z and his wife, singer Beyonce were escorted into the Barclay Center by a phalanx of bodyguards to attend game 4 of the NBA playoffs matchup between the Brooklyn Nets and the Miami Heat in Brooklyn, NYC last night. The Nets went down in flames to the Heat 102-96. During the game, NBA superstar LeBron James walked over to ask Jay Z if he was alright.

subset: commoncrawl


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Phil Dodd
The suggested method of using the vinegar solution is to apply it to a cloth, and not directly spray it onto the target.
If the spray nozzle is set to atomize the solution, then the user will be breathing the vinegar into their lungs. If the spray nozzle produces a jet, then it is all to easy for the jet to accidentally get into the eyes. Vinegar is a mild acid and could act as an irritant to the lungs or eyes if applied directly from a spray bottle.
In the workplace in the UK, we were unable to use vinegar as a cleaning agent because we are goverened by the requirement to work from a COSHH sheet in relation to all substances, and we couldn't find one for vinegar !
In a domestic environment, my recommendation is to do as I describe above, and apply the solution to a cloth for application.
( A large part of my job is in cleaning work )
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What do you think? Give us your opinion. Anonymous comments allowed.
Reply+4#15 - rainyeyes (05/22/2013) [-]
**rainyeyes rolled a random image posted in comment #4310467 at My Little Pony fanfiction, backgrounds, songs, lyrics, and GIFs. **
Hey kids, wanna buy some of this? <-
Hey kids, wanna buy some of this? <-
Reply0#20 to #15 - TIIColdKillaIIT (05/22/2013) [-]
haha nice roll


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Your relationship with food is far more complex than most "diets" or conventional nutrition plans acknowledge. Diets fuel mistrust of one's body and will. We practice a holistic approach to nutrition, which means that we look at how all areas of your life are connected and design a unique plan for healthful eating for the busy woman seeking balance.
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Medea Resort
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
- Continental Breakfast
- Suites
- Restaurant
- Room service
- Free High-Speed Internet
- Wheelchair accessibility
Photos of Medea Resort
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TripAdvisor Reviews Medea Resort Bellona
Travel Blogs from Bellona
Sept. 22: Nerano to Naples (Santa Lucia Harbor)
... darkness of the night, and made pretty patterns of light on the white walls of my cabin. Finally I heard Jacques, right on schedule.... Making his rounds..... I rolled over, and was asleep in a matter of moments. Breakfast at 8:00. My normal orange presse, and cappuccino tasted especially good.... Because we had made it safely through the night. I told Jacques that his anchor light went out, and he was very happy that I put on the table orange light ...
... eruption of Vesuvius in 79CE.
Walk to Pontone
... The cool breeze an sound of rushing water was wonderful. 40mins in and about an hour to go, the kids were mounting a mutiny to turn back, but in the end dug deep to do the back half of the big climb. The overgrown ruins looked stunning in the doppled shade and we had some time down near the base of a small waterfall. The view back toward the ocean showed the little town of Amalfi wedged tightly into the green valley the dark blue of the Mediterranean laying in the background. ...
Wow x 1000
... when you travel things get lost in translation and we end up at Agerola, hey it only adds another 2klm to our 10klm walk.
This is memorable experience I'll let the photos do the talking.
The only additions worth mentioning are the 3400 stairs that lead down from Nocelle to Positano, calf smashers and the most expensive but visually stunning taxi ride from Positano to Conca Dei Marina.
Markets in Naples
... fish, clothes, jewelry. Via San Pasquale, Via Carducci, and Via Imbriani, just south of the Piazza Amadeo metro stop. Porta Nolana Fish Market - 7-1:30 every day. Famous fish market in a historic district; just south of Piazza Garibaldi (near the end of the line for the Circumvesuviana). 40°51.02'N 14°16.1'E "Buvero" Market (S. Antonio Abate) - M-Sat 9-7:30. Food (and other household goods) market on Via Sant'Antonio Abate, north of the train station (S. ...


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MTV Greenlights 'Scream' Pilot, Renews 'Snooki & JWOWW'
Three new reality series are joining the cabler's slate, while sister network MTV2 sets debut for Nick Cannon's "Wild 'n Out" return.
MTV is hoping for its next scripted hit in Scream.
Nearly a year after THR reported that the cable network was eyeing a television adaptation of the Kevin Williamson-created franchise, MTV is moving forward with an official pilot order, The Hollywood Reporter has learned.
Produced with Dimension Films, MTV is currently in search of writers for the one-hour project while Scream director Wes Craven is in discussions to direct the pilot. Should Scream receive a series order, it would be slated for a summer 2014 launch and would join current scripted offerings Teen Wolf (also adapted from a film franchise) and Awkward.
STORY: 'Scream' TV Series in Development at MTV
DiGa Vision will produce, with former MTV executives Tony DiSanto and Liz Gateley serving as executive producers.
Additionally, MTV has renewed Jersey Shore offshoot Snooki & JWOWW for a third season. Its sophomore season was the top original series in the time period in MTV's core persons 12-34 demographic. Season three will continue to follow Nicole "Snooki" Polizzi and Jenni "JWOWW" Farley's journey as they navigate radical life changes.
Three new reality series have also been ordered at MTV: Generation Cryo, centered on kids conceived by anonymous sperm donors; Nurse Nation (working title), revolving around nine young travel nurses assigned to work at a new hospital in a new city; and The Hook Up, a dating show hosted by MTV2's Guy Code host Andrew Schulz that will air as an afternoon strip.
STORY: MTV2 Reviving Nick Cannon's 'Wild 'n Out'
Sister network MTV2 has set a premiere date for Nick Cannon's improv comedy series Nick Cannon Presents Wild 'n Out, which originally aired on MTV from 2005 to 2007. Returning at 11 p.m. July 9, Cannon will be joined by Kevin Hart, Guy Code's Lil DuVal, Amar'e Stoudemire, Mac Miller, 2Chainz, Machine Gun Kelly, A$AP Rocky and Joe Budden.
Joining the MTV2 schedule will be new series Guy Court, a half-hour comedic courtroom show launching this fall. Familiar MTV2 personalities will determine the guilt or innocence of a slew of cases in accordance with Guy Code.
MTV2 has also renewed Mac Miller and the Most Dope Family, which wrapped its first season as the network's highest-rated rookie season, for a sophomore run. Mac Miller will begin production later this year, with an early 2014 return.
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British Royal Succession
British Prime Minister David Cameron wants to see the rules governing royal sucession be changed. Specifically his proposal would see the eldest child of William and Kate take the throne.......regardless of whether it's a boy or a girl.
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07 Feb 2013 Accountancy Age
By Rachael Singh
GRANT THORNTON has been succeeded as auditor to specialist IT recruitment group InterQuest.
Deloitte has been brought in as auditors because InterQuest's chairman Gary Ashworth has married a partner at the UK's fifth largest firm, Grant Thornton.
A company statement said: "The board decided that it was necessary to change auditors in order to comply with the APB Ethical Standard on Auditing following the marriage of the executive chairman of InterQuest, Gary Ashworth, to a partner in Grant Thornton's tax practice.
"The board would like to thank Grant Thornton for its years of service."
Correction: We originally wrote that InterQuest executive chairman Gary Ashworth had taken a partner role at Grant Thornton, which was incorrect. We have amended the article to state that he has married a partner in Grant Thornton's tax practice.
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Expedite your search for the April Calhoun you are looking for with our people search tools. PeopleFinders.com has an information database to help you find a person based on age, past residences, relatives, aliases, and more. April Calhoun was born in 1975 and is 39 years old. Known relatives include Teresa M Greiner, Monalisa Calhoun, Michael B Calhoun, Richard Preston Calhoun, Elizabeth M Greiner, Jamie L Dougall, Richard B Calhoun, Micheaql B Calhoun, Brandon B Calhoun.
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Does anyone have a bathwash they use just for the fragrance?
I know we've done perfume recommendations before, but I don't wear perfume everday, so I'd like to know if you have a bathwash you buy just because it smells so darn good.
YES.. but it's been discontinued. I like B&B Juniper Breeze because it is fresh and clean. I used to like their Garden Herb for the same reason. I also use L'occitane cinnamon orange soap and a jasmine soap when in the spicy or floral mood. I dont wear perfume anymore so I often dust on a bit of lavender powder.. or crabtree and eveyln's spring rain powder for a bit of scent.
Graywings, I've tried many of the fancy and organic lavender powders and bath products. Many of them have a sharper scent than I like. I am currently using plain ol' Johnson & Johnson lavender powder.. but I prefer the Yardley in a can (which you is very cheap when I can find it).
Msrose, I know you said you don't wear perfume much, but if you want something that smells fantastic, you should check out the perfume counter at major department stores. Find something you love. Then look for the body wash online.
I don't like ANY cheap (ish) bodywashes much although I do use B. and Bodyworks Sweet Pea shower gel ($) occasionally.
It's not like L'eau D'Isssey bodywash, however ($$$?)
I have a L'Occitane store nearby, but it is also available online. I'll link their web site below. Perhaps there's a store near you where you can test sniff their products.
Here is a link that might be useful: L'Occitane web site
Bath and Body Works Plumaria shower gel and body spray. They discontinued it in the stores, so now I special order it on sale every 6 months. Love it.
Yes! L'Occitane by far-have never grown tired of it. Ever since we stayed at Four Seasons we have bought that and the bar soap-and my DH has to have to Shampoo and Conditioner also. But, the L'Occitane shampoo and conditioner we buy is only sold at Four Seasons. L'Occitane has shampoo and conditioners, but not the formula that the Four Seasons sells.
Well, I checked the L'Occitane website and it said we have one at our mall, so I decided to go up there today. The directory didn't show it, so I walked the whole mall thinking maybe it was new and not on the directory yet, but never could find it. I guess I'll have to order some, but I was really wanting to check them out in person. I definitely want to try the verbena. Has anyone tried the citrus verbena?
msrose, many of the stores have closed, but you can find it on ebay.
When my favorite perfume stopped being made several years ago, I was able to purchase it on ebay, new bottle, never opened(still do!). You'll have to read thru the L'Occitane products to find out if they're unopened. ;o)
Here is a link that might be useful: L'Occitane
Having worked in medicine for many years where perfume is a big no-no, I hardly ever wear mine (Estee Lauder's Tuscany per Donna). But it's soap and most perfumed soaps make me itch. Many give me rashes or hives so I tend to stick to (the pink) Dove soap bars, which I think smell fresh and clean. In Summer months, though, I love the way my Coppertone sunscreen smells and so I use it for it's "beachy" smell as well as for it's sunscreening properties.
I'm a Dove girl. Usually I stick with the white soap but recently bought the pink. While I like it, I don't like pink soap scum in my white shower so I'm going back to white next time. DH has so many allergies and perfume is a nightmare for him. After almost 29 years of marriage, I don't own anything with perfume.
( I love Coppertone Sun screen too!)
Another pink Dove soap user~I first bought it because I thought it smelled like Roses.
Graywings, you have got to try the Thymes. It's the most true fragrance of Lavendar my nose has ever 'sniffed'! They don't offer a dusting powder, just the body wash as well as other products. The home spray is dellllllllightful!
Another great one is the Eucalyptus, nice for men.
Here is a link that might be useful: body wash
Yes, White Linen bath gel. I've tried many others, but always come back to it.
Here is a link that might be useful: Bath gel
Msrose, you have to smell products just for yourself.
Just like no one can predict what is mouthwatering to you or beautiful, we don't know your smells either.
I could not tell you how many times I have been drawn in by someone elses "likes or even loves" by review or recommendation only to hate it. By trial and error, I have discovered the base notes that appeal to me in fragrances and that does help me find new products.
Stinky, for instance, loves the White Linen Fragrance. My mother did also but I HATE it. ( No maternal rebellion here)
It took me years to learn and recognize the key components in fragrance and when I read a perfumes ingredients, I know what to look for. Aldehydes aren't for me, ever (Chanel #5). They give me a headache and the dry down is yucky.
You want to separate bodywash from a perfume but it is basically all the same.
I like using White Linen bath gel during the warmer months. Have never used the fragrance spray! I tend not to use too much perfume in the summer, so the White Linen bath product is "just enough."
My go to bath product for winter used to be Cinnabar bath grains. Was discontinued. Wow, did those bath grains fragrance the entire bathroom for hours. It was heavenly!
Btw, Bumblebeez, dh gave me a set of Chanel no. 5 products and I loved the bath gel. The #5 perfume is just "okay" imo.
I love Shalimar for winter too. (Also love Guerlain's L'Heure Bleue, but it can be hard to find. That's a very complicated fragrance...not for everyone.) Shalimar bath soap, body lotion & perfume, and Tabu bath soap, lotion and perfume are readily available and nice for winter time.
I love fragrance!(See, I really am stinky!) I try to use products sparingly though...don't take a bath in it...(Unless it's bath gel, that is, lol!)
Stinky, I really dislike all the perfumes you mention even though they are famous and beloved! My granny loved Cinnabar.
My preferences are almost always floral/watery and or fruity and in the perfume strength which makes a huge difference: Aqua Di Gio, L'eau d'Issey, Diorissimo, Daisy, Happy, Be Delicious, Il Baccio, and on a rare occasion, Opium.
I have a good friend who dislikes all my favorites and thinks they all smell old lady!
But I still think bodywash is a watered version of the original but doesn't always smell quite the same.
I dislike the eau de toilette of Daisy and L'eau d'Issey
and they smell like something different entirely.
boopadaboo - Is the St Ives one the scrub or is there a different one? I didn't see it at Walmart yesterday, but I found it online. I may check Target today.
leafy02 - I also checked Walmart for the Neutrogena Rainbath and couldn't find it either. Where do you normally get it?


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The Georgia woman who attempted to steal a mother's newborn is back in custody after a judge denied her bond early Thursday morning. Naquelle Ballard, 19, of Morrow, Ga., sneaked into Southern Regional Medical Center on Wednesday in hopes of replacing the baby she had lost in a miscarriage.
Police and hospital officials say that Ballard walked into the hospital Wednesday morning, clad in scrubs. She went into the room of Jas'mere Brown, also 19, where the mother was nursing her newborn daughter, Khloe. Masquerading as a nurse's technician, Ballard told Brown that she would be back after she was done nursing. In a few minutes Ballard returned and told Brown she would be taking the child to the nursery. Brown handed little Khloe to her, and Ballard tucked the newborn into her large purse.
Karletta Woods, Brown's mother, had searing questions for the hospital. "How was she able to just go in my daughter's room, see that she's nursing and come back a second time and nobody noticed her?" Woods told ABC News.
Ballard was noticed by one person though. Woods actually said hello to Ballard in an elevator, not knowing her newborn granddaughter was inches away from her, sleeping and silent. Luckily, the sensor system that the hospital had in place worked. Each newborn has an ankle bracelet with a sensor inside. Hospital officials say that as soon as Ballard rounded a corner as she headed downstairs, the alarms went off. Two eagle-eyed maintenance workers went after Ballard and managed to wrestle the purse from her. She kept on running and managed to get in her car and drive away but not without the two workers taking down her license plate number and the make of her car. Clayton County Police were able to nab her within an hour.
"We're really pleased with the way that the system worked and the employees reacted," said Southern Regional Medical Center spokeswoman Amanda Bartlett. "The workers thought it was a drill but they reacted appropriately and we're thrilled."
Though Woods and Brown are happy to have Khloe back, they still can't rid themselves of the minutes that their "angelic blessing" (as Woods put it) was gone from them. The family had just lost another child a few days ago when Woods' other daughter had a premature baby that died four weeks after birth.
"They were the worst five minutes of my life. To lose another grandbaby just nine days later?" she sobbed. "I don't know what I was going to do."
According to a police affadavit, Ballard told police that she had lost a baby due to a miscarriage and was trying to steal another to present to her boyfriend as her own. The magistrate court set her next hearing for Jan. 17.
Both mother and daughter have no sympathy for the woman who almost stole their child.
"After all the hard work I've done, and I just went through all of this pain to get her here, you don't do that to someone," Brown told ABC affiliate WSB-TV.
"I have no compassion for her," Woods added.


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Dec 17, 2014
Studio Feature - Healthcare Design
Dec 9, 2014
Student Profile - Hannah Sellers
Nov 17, 2014
Student Profile - Hans Koesters
Nov 4, 2014
On May 4, as part of graduation weekend, the College of Design held its Third Annual End of Year Show at the Land of Tomorrow Gallery on Third Street in downtown Lexington. Students, families, faculty, and staff gathered to celebrate another successful academic year. Among the work featured were projects from the following studios:
Please click through the images above to see the work on display during the show.


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green day
Stevie Ray Vaughan, Ringo Starr, Joan Jett + Lou Reed Elected Into Rock and Roll Hall of Fame
Green Day's Jason White Has Tonsil Cancer
Metallica, U2, Green Day to Tour Together?
Green Day-Touring Will Be 'Nerve Wracking'
Green Day – Warnings Before The Meltdown
Green Day's Armstrong Talks Meltdown
Green Day Doc Premieres
What Happened To Green Day?
A lengthy new article at Billboard.com analyzes the disappointing sales of Green Day's recent triple album release, Uno!, Dos! and Tre!. The last two, Dos! and Tre!, each sold less than 100,000 copies in their first weeks of release, which the article says "would have been unimaginable as recently as a few months ago for Green Day."
Soundgarden Makes Billboard Debut
Soundgarden's first album in 16 years, King Animal, debuted at Number Five on the Billboard album chart last Wednesday (November 21st), selling 83,000 copies in its first week of release. The CD arrived in stores on November 13th and followed up the band's 1996 album Down On The Upside, which debuted at Number Two. Soundgarden disbanded in 1997 after touring that record, reuniting in 2010 and releasing a live album and hits compilation before getting to work on King Animal.


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Orenga calls on youth; a call to battle from Lemanis
VALENCIA (Jeff Taylor's Eurovision) - In life, don't stress out over things that you have no control over.
But in life, if you can make a change when change is needed, be bold enough to do it.
Spain boss Juan Antonio Orenga did just that this week.
Sensing that Spain's squad needed some fresh blood, Orenga named 20-year-old Alex Abrines in the national team that will play at the FIBA Basketball World Cup.
Abrines had some ups and downs with Barcelona this season and for some observers did not seem to merit a place in the national team but he's young, talented and has the potential to be great.
"We need to open the door to future talent and to upcoming talent," Orenga said.
We suspected back in 2011 Abrines had a big future, when he was the MVP of the U18 European Championship.
During EuroBasket 2011, Abrines also played at the U18 All-Star Game and took part in a dunking contest that got the crowd in Kaunas, Lithuania, excited.
Daniel Diaz (Real Madrid) and Guillermo Hernangomez (Cajasol Sevilla) were also in Spain's U18 title-wining team in 2011.
Each of them, along with Pau Ribas (Valencia Basket), have been invited to train with Spain's squad before the World Cup.
That should be viewed as an valuable opportunity.
In 2006, Fran Vazquez had to withdraw from the squad because of a back injury so then coach Pepu Hernandez called one of the three invitees, Marc Gasol, into the team and his career has been on the up ever since.
Having watched both Diaz and Hernangomez this season, it's safe to assume that the latter is a lock for the Spain squad in the coming years. He's a beast.
Hernangomez benefitted from the excellent coaching of Aito Garcia Reneses at Cajasol and is sure to make some headlines soon.
As for Abrines' impact on this year's team, Orenga said: "He can help us in many ways.
"Alex has an incredible capacity for penetrations and finishing.
"He also can give us a defensive intensity that will allow us to rest our number three (small forward)."
Abrines was taken early in the second round of last year's NBA Draft by the Oklahoma City Thunder.
He will now play alongside Spain's Thunder star, Serge Ibaka, at the World Cup.
Orenga impressed last summer with his ability to motivate players.
It has to be a real confidence booster for Abrines to know how the national team boss feels about him.
Spain will play in World Cup Group A, in Granada, against France, Serbia, Brazil, Iran and Egypt.
Someone else that we're going to see in Spain this summer who seems a perfect fit for his national team is Australia boss Andre Lemanis.
He has said the right things in the wake of Pat Mills' rotator cuff injury, something that has just knocked the high-scoring guard out of the Boomers' World Cup squad.
"This is a reality in sport and every team/player has their challenges to overcome," Lemanis said.
"It is better to know this now than have a player go down two games into the World Cup."
Lemanis gave an inspirational comment on facing challenges head-on.
"To succeed at anything," he said, "you need to have resilience, belief and an ability to overcome adversity.
"The spirit and mateship of the Boomers environment will continue to serve us well."
Lemanis is going to bring his Australia squad to Europe for a series of friendly games before they travel to Gran Canaria and play in Group D against Lithuania, Slovenia, Angola, Mexico and Korea.
If the Boomers players follow their coach's advice, they're going to be tough to play.
Jeff Taylor
FIBA's columnists write on a wide range of topics relating to basketball that are of interest to them. The opinions they express are their own and in no way reflect those of FIBA.
FIBA takes no responsibility and gives no guarantees, warranties or representations, implied or otherwise, for the content or accuracy of the content and opinion expressed in the above article.


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Warriors edge Central Lakes in division opener
WILLMAR -- Tyler Hoelscher and Corey Paul were rivals in high school. Now they're freshmen teammates at Ridgewater on the opposite ends of the Warriors' pass rush.
On Saturday, they collaborated on a defensive touchdown that clinched a 14-6 over Central Lakes in the Southern Division opener.
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Maria Shriver Files for Divorce
According to multiple reports, there is no prenup.
The news comes six weeks after the former California governor, 63, publicly acknowledged that he fathered a child with a housekeeper. Mildred Baena retired in January after 20 years working for the family.
The power couple allegedly separated when Shriver, 55, moved out of their Brentwood, Calif., mansion upon learning about the paternity of Baena's son, who was born in 1997, days before the birth of Shriver and Schwarzenegger's youngest son, Christopher. In May, Schwarzenegger apologized in a statement: "There are no excuses and I take full responsibility for the hurt I have caused."
Of the couple's four children, two (Katherine and Christina) are now adults. Shriver will likely agree to share custody of Christopher, 13, and Patrick, 17, with her soon-to-be ex.
The Austrian-born movie star and the American broadcast journalist -- who met in 1977 and married in a 1986 Catholic wedding in Massachusetts -- remain on speaking terms, according to TMZ sources, and expect an amicable division of assets.
They allegedly plan to split hundreds of millions of dollars jointly earned during the marriage. TMZ estimates Schwarzenegger's worth at approximately $300 million and Shriver's at $100 million. The divorce will not go to trial if the couple agrees to settle out of court quietly, and details of the final property settlement will likely be confidential.
Shriver, an Emmy and Peabody award winner, was spotted overseas last week in Athens, Greece, greeting Special Olympics athletes with a smile. She flew there to speak at the dedication of a statue of her late mother, Eunice Kennedy Shriver, who founded the Special Olympic Games.
Halle Berry called it quits with her boyfriend, Gabriel Aubry, ending their five-year relationship. The couple has a 2-year-old daughter, Nahla Ariel Aubry.
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- Saturday 02 July
Arnold Schwarzenegger : Twenty five years ago- ONE MAN TWO POLITICAL PARTIES, later on- ONE MAN TWO WOMEN ! Momentarilly he looks like a pure republican !
- Saturday 02 July
Arnold Schwarzenegger : Twenty five years ago- ONE MAN TWO POLITICAL PARTIES, later on- ONE MAN TWO WOMEN ! Momentarily he is back to a REPUBLICAN SHIP!
- Saturday 02 JulyBy Jesse
Man-O-Man...A guy takes his PP outside to play once in a twenty-five year long relationship (OK...maybe 2,3,4,5 times) and she files for divorce? Sheeesh!
- Saturday 02 JulyBy anna
Really who cares about Maria Shriver and AHHnold. Maria is a Kennedy and we know their reputations, and Ahhhnold--just another rino.
- Saturday 02 JulyBy alan562
Arnie, Just one question: Are you going to be back or are you finally terminated?
- Saturday 02 JulyBy the_fool
Would it help Arnold's case if he brought the maid into court and pleaded insanity? Ha ha ha.
- Saturday 02 JulyBy Lori Ann
How very sad for everyone involved.
- Saturday 02 JulyBy Otto
It is too bad Arnold was so stupid. He should know better.
- Sunday 03 JulyBy Sarita Lopez
Mrs. Baena was cleaning a litlle bit more than just the dust, Too bad for Maria that trusted that woman and was so good to her, now the marriage is ended thanks to that cleaning lady that did not care to hurt Maria in the worse way.
- Saturday 02 JulyBy hello kitty
She was losing her masculinity.
- Saturday 02 JulyBy John
Hey, the man made a mistake, apologized and accepted full responsibility, can you just give him a break now, it happened, he's sorry, time to move on. If he wasn't the Governator, would we be making such a big deal here ?
Maria has to save her dignity and divorce him, it it what it is
- Saturday 02 JulyBy FREE ARNOLD
dammit Arnie...didn't you know enough to pull out?
- Sunday 03 JulyBy Eli S.
10k/5k/1krun and walk FUNDRAISER....in Shiprock New Mexico...july 30th...for victims of Contamination from urainium mine tailinf on the navajo reservation....Contamination of livestock and drinking water..."LET ZO FLY" ur invited "Maria"
- Sunday 03 JulyBy Chris
- Sunday 03 JulyBy letmay8
Those who hate Maria are the Guatemalan ho side - they can speak english if they want to. Arnold and his guatemalan ho can go to hell.
- Sunday 03 JulyBy tokyo joe
He may be a very lucky man...tell me you haven't noticed that she gets uglier by the year...she's scary looking...what does she look like first thing in the morning without makeup aaaaaaaaaah
- Sunday 03 JulyBy Angela
Oh Arnie..fooling around with the housekeeper and not even bothering to use contraception? That is so tacky. Nice way to humiliate your whole family you fool.
- Friday 08 JulyBy gandii
SOME IDIOT THAT THINKS ANYTHING COULD BE A DISCRACE TO CATHOLICS.."Shriver is a disgrace to Catholicism OMG...if you live in LA look at that multi billion dollar monument by the Music Center they built for Mahoney...what a SIN... 4 blocks down the street on skid row pepple are dying... killing...raping...starving...families in cardboard boxes...the good the CATHOLICS could have done for the NEEDY...its sick...instead they honor themselves...that is plain discusting...even my Martyr Catholic Mother from Ireland was appalled....sick...sick sick...Catholicism is sickening...
Maria...you rock...forget those thieves at the Vatican....Pedophiles....
Jennifer Aniston
Is it Brad(ley) and Jen take 2? Jen was spotted out on the town with dreamboat ...
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After Fairly Legal actress, Sarah Shahi, laid into Paris via Twitter for almost...
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According to Denise, she's not sure that her estranged ex is completely sober....
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Lack of devotion of Dpreview.com?
Where is the proper review of 1Dx since it is launched 3 years ago?
It is not only the missing of this flagship camera but huge collapse of review system.
Photographers who need a comparison to chose and have to decide their next camera are confused that they can not put the 1Dx at the top.


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CHOKING HAZARD -- Small parts. Not for children under 3 yrs.
The favorite family game filled with wacky activities.
The newest version boasts 600 new playing cards and a Family Pack! View larger.
Though the game features new playing cards, gameplay is still the same--roll the 10-sided, colorful die, pick the matching colored card, and complete the activity listed to advance to the next Planet Cranium. Once you get to Cranium Central, successfully complete the final task and lead your team to victory! The bright, fun colors and cartoonish characters only add to the overall silliness and goofiness of the game, encouraging those playing to let their guard down and have a good time.
Build It, Sing It, Perform It, Draw It
Cranium is great for large groups or events--whether it's a party, a reunion, or just even a family game night. The game constantly challenges players in trivia and creativity, creating a fun and spontaneous atmosphere.
However, keep in mind this particular version of Cranium is designed for ages 16 and up, so if you have younger children, you may want to play one of the other versions. There is also a warning listed about the clay containing wheat--just a thoughtful heads-up for anyone with wheat allergies.
What's in the Box
Game board, 600 cards, 10-sided die, two tubs of clay, timer, pencils and paper pads, four play pieces, and a 60-card bonus Family Pack.
Product Details
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It looks like some cards were missing and the box was falling apart. Other than that everything was good.Published 2 months ago by Kim Colgrove
would be nice to have a reset button that takes it back to 0Published 2 months ago by Pat and Duke Monson
My kids were 9 when we bought this. They were really too young for many of the tasks, but they love playing so much that when we come to a card that has a song or movie they... Read morePublished 4 months ago by William C Phelps
I really enjoy this game! It's great when playing with casual gamers. Keeps things interesting because there's a different thing to do every round.Published 6 months ago by Kit
Love Cranium, such a fun game! There's something for everyone and if you are stuck in one category, you can get something completely different next time. Read morePublished 7 months ago by Sara
Such a fun game. And definitely can be played for family fun (although younger kids might not get all the references).Published 8 months ago by Amazon Customer
This is my favorite game! Came quickly and exactly as described! Perfect for family game night or a night with friends.Published 12 months ago by AJ Creps
This is not the product advertised. This is not the older more comprehensive version of cranium. This is the "new for this year" abbreviated version with a smaller board no... Read morePublished 13 months ago by J1070


text:
Jazz point guard Deron Williams still holds out hope for playing in the team's 2008-09 NBA regular-season opener, which comes next Wednesday night vs. the Denver Nuggets.
Reality, however, prompts him to suspect the likelihood is slim at best.
"I'm not going to rule it out," Williams said. "But Doc (Jazz team physician Dr. Lyle Mason) says it's not looking too good for opening night, just the way it looks right now."
A Jazz-released timetable for Williams' anticipated absence "a minimum of two weeks," dating to last Monday also suggests he will miss the opener.
Williams has a sprained left ankle, sustained when he landed on foot of Chicago guard Derrick Rose after attempting a 3-point shot in the first quarter of last Saturday night's preseason road game against the Bulls.
The Jazz are calling it a second-degree inversion sprain, which by definition involves a partial ligament.
Williams said he initially feared he would be out for the entire season.
"I heard something pop, so I thought first thing I had dislocated my ankle," said Williams, who today was speaking publicly about the sprain for the first time. "I don't know anything about injuries. But that was the first thing I was worried about. That was the first thought: I was going to miss the whole season."
Williams, who is wearing a walking boot, said the ankle remains swollen and discolored, and his foot is swollen as well.
He is receiving treatment for the injury twice daily, and is icing the ankle around the clock, but he still can't put pressure on his foot making the chance of playing a week from now seem that much less likely.
"I'm never happy to be out. I don't like missing games," said Williams, who played all 82 regular-season games last season. "So, I'm just going to try to get back as soon as possible. They put that timetable, but if I can get back before that, then I'm definitely going to do everything in my power to try."Williams also fully exonerated Rose, the No. 1 overall selection in last June's NBA Draft, from having any responsibility for the injury.
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Comprehensive DescriptionRead full entry
BiologyFound in coastal waters. Enters estuaries (Ref. 4833). Diet depend on size; small fish (7.0 cm) have a generalized diet of amphipods, polychaetes and detritus (Ref. 31455).
Nuchequula gerreoides Trusted
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Senior Member
Mid. I'm a mid main. I like the freedom to control the map when I'm doing well.
Jimmie Rustled
Well yea sure alot of players are willing to play support but how many of them are actually decent at it?
Most of those players are so proficient in their other roles that their skill in those outweighs their skill in support. Why? because they dont play support often. And even if they did or were forced the pick support, guess who they would pick? Nunu, zil, fiddlesticks, teemo... But why would the pick those champions for support? because theyre obviously trolling and refuse to play anything else.
Even in champion select, once you ban thresh you ban about 40% of most support players because they cant support with anything else.
Turtle vs Beaver
Marksman for me. The only thing maining three roles at once is because I can't stand supports that are only supporting because they're stuck with it. Get me a support who wants to support then I can do full damage.
© 2015 Riot Games, Inc. All rights reserved. Riot Games, League of Legends and PvP.net are trademarks, services marks, or registered trademarks of Riot Games, Inc.


text:
that if there was peace between Israel and Palestine, then they Israeli people might start asking difficult questions about how their country is being managed, with so few benefiting from perpetual war, while the majority struggle to make ends meet. Perpetual war covers over the cracks in society.
If selected for publication, it will appear as soon as possible on Haaretz.com.


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Item: 803371 Model: 2954MC-03
See the completeBush Enterprise Collection
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Smooth Operating Drawers
With two large filing drawers that can hold both your legal- and letter-size files, this Bush Enterprise lateral file features full-extension ball-bearing sides that allow the drawers to open and close easily even when there's weight inside the drawers. This gives you easy access to the files in the very back of the cabinet, and the top drawer can also be locked to protect sensitive documents when you need to step away from your work area.
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Privileged's Will and Gilmore Girls's Logan: A Theory
Privileged's Will and Gilmore Girls's Logan: A Theory
I recently received a message from Team member syako in which she put forth a theory about a connection between Privileged (which, sadly, ends tonight!) and Gilmore Girls. The theory is this: Viewers of both shows who like the character of Will on Privileged (Megan's hunky but perhaps a little spoiled neighbor) were probably also fans of Logan on Gilmore Girls. So far we are proving this theory correct: She likes both Will and Logan, and I don't care very much for either of them!
Where do you fall? Did you like Logan during the Gilmore Girls days? Do you care for the handsome Will, despite his occasional whining?
Privileged has, in some ways, filled the hole that was left when Gilmore Girls ended — I just find it so refreshing to see a TV show about teens and an early 20-something girl that isn't, well, trashy. Tonight's season finale is titled "All About a Brand New You!" and features Kathy Griffin as the wedding planner for Marco and Keith's wedding. There's a ton of other drama, including (but not limited to) issues with Megan's dad, a Spring break-related tiff between Rose and Sage, and Luis's refusal to attend a gay wedding.
Tune in tonight and then come back tomorrow and chat with me about the finale! To watch a clip from tonight's episode, read more.
Privileged photo courtesy of the CW and Gilmore Girls photo courtesy of Warner Bros.
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- This Marvel character will not be appearing in the new Avengers movie — Hitfix
- That time Sarah Jessica Parker forgot Sex and the City existed — Moviefone
- The 6 most unintentionally creepy sitcom characters — Cracked
- If you love Downton Abbey, you need to watch Call the Midwife — BuddyTV
- 25 valuable lessons you learn while watching TVD — The Vampire Diaries
- Watch the trailer for Blunt Talk, starring Patrick Stewart — Splitsider
- Inside Vin Diesel's emotional interview about Paul Walker — POPSUGAR Celebrity & News


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PHILIPPINES: San Mig beer boosts profits
The Philippine food and drinks conglomerate San Miguel has seen its net income rise 32% to 2.42 billion pesos (US$43.3m) in the first four months of the year, compared to the same period last year.
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VIEWS: 1 PAGES: 10 CATEGORY: Biology POSTED ON: 6/3/2010
We evaluated the effects of exercise on the vascular constrictor responses to α-adrenergic stimulation in the db/db mice. Twenty male db/db and their age-matched wild-type (WT) mice were exercised (1 hour/day, five days a week). Mice were anesthetized 7 weeks later, thoracic aortae were mounted in wire myograph and constrictor responses to phenylephrine (PE, 1 nM-10 M) were obtained. Citrate synthase activity measured in the thigh adductor muscle was significantly increased in db/db mice that were exercise trained. Maximal force generated by PE was markedly greater in db/db aortae and exercise did not attenuate this augmented contractile response. Vessels were incubated with inhibitors of nitric oxide synthase (L-NAME, 200 M), endothelin receptors (bosentan, 10 M), protein kinase C (PKC) (calphostin C, 5 M), cyclooxygenase (indomethacin, 10 M) or Rho-kinase (Y-27632, 0.1 M). Only calphostin-C normalized the augmented PE-induced constriction in db/db and db/db-exercised mice to that observed in WT (p0.05). Cumulative additions of indolactam, a PKC activator, induced significantly greater constrictor responses in aortic rings of db/db mice compared to WT and exercise did not affect this response. Our data suggest that the augmented vasoconstriction observed in the aorta of db/db mice is likely due to increased PKC activity and that exercise do not ameliorate this increased PKC-mediated vasoconstriction. [PUBLICATION ABSTRACT]
Effect of Exercise on Augmented Aortic Vasoconstriction in the db/db Mouse Mo... M Khazaei; F Moien-Afshari; T J Kieffer; I
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Pelizaeus-Merzbacher Disease Karen Woodward Brian Harding ADL adreno leukodystrophy fect in the PLP1 gene mainly have point BAEP brainstem auditory evoked potential mutations, there have been only 2 female patients with PLP1 gene duplications de- CT computer tomography scribed to date. CSF cerebrospinal fluid EEG electro encephalogram GENETICS ER endoplasmic reticulum PMD/SPG2 represents a spectrum of ERG electro retinogram CNS myelin disorder caused by dosage MAG myelin associated glycoprotein effects and mutations of the proteolipid MAPH multiplex amplifiable probe protein (PLP1) gene (Figure 1). Increased Figure 1. Genetic mechanisms for disease hybridization dosage of PLP1 is the major cause of in patients with PMD/SPG2. The majority of MBP myelin basic protein PMD with approximately 60% to 70% of patients, approximately 60% to 70%, have a PLP1 MLD metachromatic leukodystrophy patients having a submicroscopic duplica- gene duplication, approximately 15% to 20% tion of chromosome Xq22 including the have a mutation in the PLP1 gene, a minority MLPA multiplex ligation-dependent probe have a loss of PLP1 caused by a deletion or a amplification entire PLP1 gene (38, 49). A few patients null allele and approximately 10% to 20% have a OMIM online Mendelian inheritance in Man. have a deletion of PLP1 (44) or a null molecular defect that is currently unknown. http: //www.ncbi.nlm.nih.gov/omim mutation that gives rise to loss of protein (Figure 2). An up-to-date list of the muta- PLP1 proteolipid protein gene (12, 52). Approximately 15% to 20% of tion spectrum can be obtained from http: PMD Pelizaeus-Merzbacher disease cases have PLP1 sequence changes that //www.med.wayne.edu/Neurology/plp.html. SPG spastic paraplegia produce abnormal PLP1/DM20 pro- Splice-site (55) or non-coding region mu- UPR unfolded protein response teins. ese are mainly missense point tations (21) have also been described that VEP visual evoked potential mutations within the gene but may also cause abnormal expression of PLP1. e include nonsense or small deletions and remaining 10% to 20% of patients have insertions that cause frameshifts (24) DEFINITION clinical features of PMD but do not have Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder of the CNS caused by mutations in the proteolipid protein gene (PLP1) gene located at Xq22. e milder disorder X- linked spastic paraplegia type 2 (SPG2) is allelic, though PMD and SPG2 are listed separately as OMIM31208 and OMIM312920 respectively. HISTORICAL ANNOTATION Pelizaeus gave the first clinical descrip- tion of PMD in 1855 (43), to which Merzbacher added further clinical details from the same family and a neuropatho- logical report in 1910 (37). Post-mortem examination also confirmed the disorder in an affected sister (35). EPIDEMIOLOGY, SEX DISTRIBUTION PMD is rare; in Germany amounting to only 6.5% of all leukodystrophy (20). It principally affects hemizygous males, while females are generally asymptomatic carriers. However, the rate of occurrence in females exceeds Duchenne muscular dystrophy, and is more common in fami- Figure 2. PLP1 topology showing 4 putative transmembrane domains, 2 extracellular loops and lies with milder forms of PMD or SPG2. one cytoplasmic loop. The alternatively spliced region present in PLP1 and absent in DM20 and the known mutations are shown. See http://www.med.wayne.edu/neurology/plp.html for a current list of Manifesting females with a molecular de- the mutation spectrum. Figure kindly provided by Dr James Garbern. Chapter 34. Pelizaeus-Merzbacher Disease 311 in spermatogenesis is that the mothers are carriers. ree atypical cases with non- contiguous duplication are of particular note as the additional copy of the PLP1 gene integrated into different regions of the X chromosome (Xp22, Xp11.4 and Xq26) in an apparent transposition event occurring at a sub-microscopic level (25) (Figure 3). ese unusual duplication events have been termed submicroscopic transposon cases. e advantage to using FISH for molecular genetic diagnosis of PMD is that it is a visual technique and these unusual cases where the PLP1 gene has duplicated and then moved to another site in the genome can easily be identified. e disadvantage is that small duplications, less than 50 kb, could be missed and consequently a combination of FISH and another higher resolution dosage technique is ideal. Figure 3. Representation of PLP1 gene duplications on chromosome X. Xp is shown with green shading and the PLP1 gene is shown in red. The typical tandem duplications are detected as a doublet CLINICAL FEATURES by interphase nuclei FISH using a genomic probe containing the PLP1 gene. Atypical cases where the ere is considerable variation, but additional copy of PLP1 is transposed to another site can be detected by metaphase FISH as the extra common characteristics include nys- copies have been reported within Xp22, Xq26 or Xp11.4 (associated with an inversion). Adapted from Woodward et al (61). tagmus, stridor, ataxia, psychomotor developmental delay, spasticity and onset a detectable abnormality suggesting that cells within the PNS and heart, spleen, within the first year of life (7, 12, 24, 48). mutations in regulatory regions or other thymus and lymph nodes. Disease severity ranges from severe conna- gene loci can cause PMD. tal PMD through an intermediate classi- Detection and characterisation of cal form with a slowly progressive course, e PLP1 gene. PLP1 is localized to PLP1 duplications. Since duplications are to mild PMD/SPG2. Symptoms of con- Xq22 (36) and encodes the proteolipid the most frequent cause of PMD, dupli- natal PMD develop shortly after birth, protein (PLP1) and its smaller alterna- cation analysis should be performed prior motor and intellectual development is se- tively spliced isoform DM20 (17). PLP1 to mutation screening. Dosage detection verely delayed with patients often having is the major myelin component in the techniques such as interphase fluorescence seizures and no head control. Small head CNS, constituting approximately 50% in situ hybridization (FISH) (58, 60) circumference and optic atrophy are also of total protein. PLP1 and DM20 are hy- (Figure 3), quantitative multiplex PCR common. Death occurs in early child- drophobic proteins of 276 and 241 amino (26, 46) and Southern blotting (11) have hood to the third decade of life. Classical acids respectively and they are highly been successfully used for diagnosis in the PMD is the most common form of the conserved across species being identical patient, the female carrier and in some disease with symptoms usually present- in man, mouse and rat. Predicted pro- cases prenatal detection. e techniques ing in the first year of life and patients tein structures include 4 transmembrane of multiplex amplifiable probe hybridiza- often surviving into their sixth decade. domains with cytoplasmic amino and tion (MAPH) (2) and multiplex ligation- SPG2 manifests as progressive weakness carboxyl terminals (57) (Figure 2). PLP1 dependent probe amplification (MLPA) and spasticity of the lower extremities is composed of 7 exons extending over (49) are currently being evaluated. with or without CNS involvement. SPG2 approximately 17 kilobase (kb). Exon 3 Molecular analysis of the duplications has a later onset of one to 5 years and a contains an internal splice donor site that in PMD patients has revealed great varia- milder phenotype with patients often able creates an alternatively spliced transcript tion in size (<300 kb to >4.6 megabase to walk, talk and have a normal lifespan DM20 (40) and leads to an internal [Mb]) and position of the breakpoints (29, 47). deletion of 35 amino acids. e expres- on either side of PLP1 (27, 58). Most sion of PLP1 and DM20 is spatially and duplications are arranged in a tandem ori- Imaging. CT shows non-specific chang- temporally regulated during development entation and have an intrachromosomal es, but MR demonstrates failure to my- (9) with expression mainly within oligo- origin suggesting that they probably arise elinate in comparison with age-matched dendrocytes, the myelinating cells of the during male meiosis (27, 38, 58). e controls (3). T1-weighted images lack the CNS but also at a lower level in Schwann consequence of a grand paternal origin high signal observed in myelinating white 312 Chapter 34. Pelizaeus-Merzbacher Disease Figure 4. Coronal section through the basal ganglia in a 15-year-old male with slowly progressive disease. matter, while high intensity persists in T2-weighted images due to lack of my- elination and high water content. MRS has given conflicting results (56). Figure 6. In demyelinated areas (A, luxol fast blue-cresyl violet) there is relative preservation Laboratory findings. CSF findings of axons (B, Glees silver method). and routine biochemical examination are normal. EEG changes (48) will assist in the differential diagnosis of PMD related seizures. Abnormalities in BAEP, abnor- mal waveform or prolonged latency, are useful in early diagnosis if the only other indication is eye movement disorder or an affected sibling. VEP may be abnormal in the face of a normal ERG indicating mal- function of the visual pathways. Nerve conduction studies are usually normal, as the PNS is mostly spared. Exceptions include some patients with loss of PLP1 Figure 7. Myelin staining is completely absent from the spinal cord but well preserved in spinal function that have a mild demyelinating roots. peripheral neuropathy and slower nerve conduction velocities that are not uni- connatal cases with death in infancy there formly distributed along the nerve (13). is almost complete lack of myelin, while in patients with a slower tempo of disease MACROSCOPY Figure 5. Little stainable myelin remains (A) one encounters the classical tigroid or In connatal cases with early death the Loyez, (B, C) luxol fast blue-cresyl violet. At discontinuous pattern with preservation higher magnification (C) residual perivascular of myelin islets around blood vessels brain is normal in size and the white myelin islets can be seen. matter is unremarkable on coronal slic- (Figure 5). Oligodendrocytes are mark- ing. In the classic form, with prolonged nerves are normal. e cerebellar white edly reduced or absent especially where survival, the brain is usually two-thirds matter, brainstem and spinal cord tracts myelin is completely lacking. Axons are the expected weight. On sectioning the are shrunken and gray, in striking contrast preserved (Figure 6). ere is astrocytosis, gray matter appears unremarkable, while to the normal plump, white cranial and and fibrillary gliosis. In unmyelinated ar- ventricular dilatation depends of the spinal nerve roots. eas microglia are not increased, and there degree of white matter loss (Figure 4). is usually very sparse sudanophilic lipid e central and subcortical white matter HISTOPATHOLOGY in perivascular macrophages.Cranial and along with the commissures and fornix e cerebral cortex is usually not af- spinal nerve roots which have a differ- are gray and sunken with a gelatinous or fected, but there are rare reports of poly- ent myelin structural protein (PMP-22) firm consistency. U-fibers may be patchily microgyria (42). ere is often cerebellar are normally myelinated (Figure 7) and spared, and the centrum semi-ovale can cortical degeneration with either predom- it may be possible to follow individual show white streaks. e optic nerves and inant granule or Purkinje cell degen- CNS unmyelinated axons in continuity chiasm are thin and grey, but other cranial eration. With conventional myelin stains, through the root transition zone into the the hemispheric white matter varies: in Chapter 34. Pelizaeus-Merzbacher Disease 313 with specific features such as globoid even within families (27) suggesting the cells (Krabbe), metachromasia (MLD), influence of modifier genes and/or genetic systemic involvement and trilamellar in- background. Understanding how the dif- clusions (ADL), spongiosis and abnormal ferent mutational mechanisms underlie mitochondria (Canavan), massive cavita- pathogenesis is becoming clearer by com- tion (CACH), or pigmented macrophages paring the patients with animal models. (van Bogaert and Nissen). Extensive min- eralization is not a feature of PMD, as Distinct cellular defects underlie the it is in Aicardi-Goutières leukoencepha- pathogenesis in each form of PMD. PLP1 lopathy where there is also diffuse lack mutations. Splice-site or non-coding Figure 8. Generalized association between of myelin staining or fragmentation of PLP1 mutations can cause abnormal ex- PMD/SPG2 disease severity and dosage effects myelin fibres. Discontinuous demyelin- pression and a reduction in message and and mutations of the PLP1 gene. Patients with ation and calcification are also prominent protein that has been recently reported to PLP1 gene duplications mostly have a classical PMD phenotype but symptoms at the severe findings in Cockayne syndrome, which affect myelin stability and axonal integrity connatal and mild/SPG2 end of the spectrum are is autosomal recessive and demonstrates (22). More commonly, the mutations are also possible. Patients with a point mutation in striking dysmorphology, microcephaly, missense and the clinical phenotype may the PLP1 gene have a wide range of phenotypes and atrophy of the cortex brainstem and depend on the position of the altered but are often more severely affected than duplication patients. Patients with loss of PLP1 cerebellum. amino acid. Mutations within the PLP1 function caused by a deletion or a null mutation specific region (exon 3B) that affect trans- have mild PMD/SPG2 and peripheral nervous EXPERIMENTAL MODELS port of PLP1 but not DM20 give rise to a system involvement. Many spontaneous point mutations less severe phenotype and do not usually PNS where they appear normally myelin- have been described (62). In mouse they cause oligodendrocyte death (16, 47). Ab- ated. include jimpy (Plpjp), myelin synthesis-defi- errant or truncated proteins generated by One report of the neuropathology of cient jp mouse (Plpjp-msd), jimpy-4J mouse PLP1 mutations are predicted to result in SPG2 demonstrated mild myelin loss (Plpjp-4j), and rumpshaker (Plpjp-rsh). ere misfolded PLP1 that accumulates in the in the centrum semi-ovale compared to is also the myelin deficient rat (Plpmd), the rough endoplasmic reticulum (ER) and severe loss in the spinal cord (6). shaking pup (Plpsh), and the rabbit with fails to be transported to the oligodendro- paralytic tremor (Plppt). e jimpy mouse cyte cell membrane (15). e misfolded IMMUNOHISTOCHEMICAL AND has a point mutation, while the others proteins are often associated with pre- ULTRASTRUCTURAL FINDINGS have missense mutations causing single mature oligodendrocyte death and may Lack of PLP1 in PMD was first dem- amino-acid substitutions of the Plp gene. gain a novel function that is deleterious to onstrated immunohistochemically by Ko- Several mirror the genetic defects found the cell (16). Activation of the unfolded eppen et al (33). Other myelin proteins, in clinical human disease. Transgenic protein response (UPR) has recently been MBP, MAG, CNP are variably reduced mice models having additional copies of reported to modulate disease severity in (12, 33). Ultrastructural data in humans the Plp gene have been generated and oligodendrocytes expressing the mutant is limited and predates discovery of the show myelination defects, astrogliosis and protein through a signaling cascade that gene defect. Of 2 case reports from the seizures, indicating that precise regulation coordinates the accumulation of mutant same laboratory, one showed no compact of Plp is required and modeling the com- PLP1 in the ER with changes in gene ex- myelin, the other regular myelin periodic- mon human mutation of duplications pression, protein synthesis, and possibly ity and a normal intra-period line (PLP). (45). apoptosis (54). is was confirmed in a personally exam- PLP1 deletion. Patients with a deletion ined biopsy (19) where among many na- PATHOGENESIS of PLP1 (44) or a loss of function muta- ked axons there was some preservation of e molecular basis for the phenotype tion (12, 52) have mild disease and wide- thin but compact myelin discontinuously variability is not completely understood spread demyelination in the CNS and between internodes, a feature which has but probably reflects the distinct cellular PNS that is not associated with the other been described in some animal models effects of the different genetic mecha- mechanisms of disease. ese patients (4). nisms involved. ere is some general demonstrate that although PLP1 is ex- association with disease severity in that pressed at low levels in the PNS compared BIOCHEMISTRY loss of PLP1/DM20 gives rise to mild dis- to the CNS, PLP1 or DM20 are required ere is loss of galactolipids specific to ease(12, 44, 52). Severe connatal PMD is for peripheral myelin function. Length- the myelin sheath (32). Loss of cerebro- mainly caused by missense point muta- dependent axonal degeneration has been side is variable and non-specific as a func- tions in highly conserved regions of PLP1 found in humans and knockout mice tion of deficient myelination. (8) and duplications are most often found with a functionally null Plp gene (14). in patients with classical PMD having a e degeneration is not associated with DIFFERENTIAL DIAGNOSIS moderate phenotype (8, 51) (Figure 8). significant demyelination and is similar to PMD is readily distinguishable mor- However, heterogeneity in severity exists that observed in the PNS in Charcot-Ma- phologically from those leukodystophies 314 Chapter 34. Pelizaeus-Merzbacher Disease rie-Tooth disease type I patients that have cumulate in the late endosome/lysosome FUTURE DIRECTION AND THERAPY an inherited demyelinating neuropathy. with cholesterol and to be involved in Although there is currently no specific e disruption in PLP1-mediated axon- aberrant trafficking and assembly of my- treatment available for PMD/SPG2 pa- oligodendrocyte interactions is probably elin components (50). Such accumulation tients the wide range of animal models responsible for this axon degeneration is suggested to interfere with myelination analogous to the different molecular (14). e Plp mutant mice (5, 31) do and reduce the viability of the oligoden- mechanisms of disease will facilitate the not develop classic signs of PLP1 related drocyte (50). In contrast the mice with potential for therapy. Possible options for disease and have a normal number of oli- lower transgene copy number have nor- restoring myelin function include either godendrocytes (63). e mice have only mal development with no clinical signs gene therapy or somatic cell transplanta- ultrastructural abnormalities that include until later in life. ese include late onset tion. However, there are great problems swellings in small diameter axons (6-8 demyelination and axonal swelling and with gene therapy due to the sensitiv- weeks) and late onset axonal degenera- degeneration suggesting that the oligo- ity of PLP1 gene dosage and the gain of tion (17). ey demonstrate that neither dendrocytes are unable to maintain their function mutations. Gene delivery may PLP1 nor DM20 are necessary for myelin myelin sheaths. e pathology is similar be difficult but it will be an even greater assembly but that they are required for to that of the Plp knockout mouse indi- challenge to obtain PLP1 expression at myelin and axon maintenance probably cating that changes in gene dosage either the correct level for normal myelination being needed for axon-glial interaction. increased or decreased may be causing the and maintenance. A reduction of PLP1 PLP1 duplication. Patients with in- axonal changes. expression maybe more successful, for creased dosage of PLP1 have a variable example by antisense gene therapy, as phenotype that can range from severe Expression of the disease in females. loss of PLP1 gives a less severe phenotype connatal (18) to mild PMD/SPG2 but As PMD is a recessive X-linked disorder as shown by PMD patients with a PLP1 typically have a classical form (45, 51). it almost exclusively affects males. Small deletion or null mutation. Alternatively, At least one severe case is probably due numbers of manifesting females have somatic cell therapy may be an easier to the patient having a further additional been described with PLP1 point muta- option and transplantation of oligoden- copy of PLP1 as dosage analysis suggests a tions and these have been associated with drocyte precursors into the CNS has triplication rather than a duplication (18, milder disease in males (23). is obser- shown potential for animal models (10, 58). e range in clinical severities within vation has been described by patterns of 34). e sustained clinical improvement the group of PMD patients with increased X-inactivation. Female carriers with a of 2 female PLP1 duplication carriers dosage of PLP1 may also be explained by duplication have heavily skewed X-inac- also supports this approach demonstrat- the different duplication structures. is tivation with the X chromosome bearing ing that certain oligodendrocyte lineages may cause the juxtaposition of different the duplication being preferentially inac- may proliferate and compensate for dys- regulatory sequences, which could influ- tivated. Consequently these female carri- myelination even years after birth (28). ence the expression of the PLP1 gene. ers are mainly asymptomatic.In contrast, Other therapies aimed at maintaining the e effect of modifier genes either within point mutation carriers show a random axon integrity may also be helpful. the duplicated region or elsewhere in the pattern of X-inactivation (59). erefore genome may also affect PLP1 expression half of the cells in point mutation carri- REFERENCES 1. 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