text:
- 74 years old
- Date of birth: Feb 21, 1932
- Date of passing: Aug 25, 2006
To a wounderful mum and best friend. I hope that you are in a better place and that dad, dusty and cassie are not giving you too much of a hard time.I miss you mum very much. There is not a day or time that i dont think about you, and all the happy times and laughs we had. Mum you are in my heart and soul, you will never be forgotten. xxxxxxxxxxxxx
"Happy birthday to my loverly mum who is gone but never forgotten. Xxxxxxxx"
""There is an appointed time for everything, A time for every activity under the heavens: A time for birth and a time to die; A time to plant and a time to uproot what was planted; A time to kill and a time to heal; A time to tear down and a time to build up; A time to weep and a time to laugh; A time to wail and a time to dance; A time to throw stones away and a time to gather stones together; A time to embrace and a time to refrain from embracing; A time to search and a time to give up as lost; A time to keep and a time to throw away; A time to rip apart and a time to sew together; A time to be silent and a time to speak A time to love and a time to hate; A time for war and a time for peace."
Losing a loved one often throws us into a gamut of emotions as described by the inspired writer of Ecclesiates. As each year passes since the death of your loved one, I pray that times of "healing", "laughing", "dancing", and "loving" have overtaken their counterparts of weeping and wailing, and that fond memories keep Ms. Vera forever alive in your heart.
One day very soon, you will experience a time of perfect happiness and everlasting peace as you welcome her back to life! ......"When he had said these things, he cried out with a loud voice: "Lazʹa·rus, come out!" The man who had been dead came out…...John 11: 43, 44"
"Happy birthday to my most beautiful mum. Love you so much xxxx ❤"
"Love and miss you. Another year, where does the time go, I hope your behaving yourself, i know what a character you can be. I do miss our laughs and banters. Love you Mum xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Death is rarely welcomed even when one has lived beyond "three score and ten" (Psalm 90: 10) as had Ms. Vera. As you reflect on her birth and passing, may you find comfort and peace in God's assurance of the resurrection hope. (Isaiah 25:8 & John 5:28, 29). In the meantime may you cherish the memories of her life, love and laughter and may those memories keep her alive in your hearts, until God's promises are fulfilled. I am deeply sorry for your loss. "
"Happy Birthday to a wonderful mum who is always in my heart. Love and miss you so much. xxxxxxxxxxxxx"
"God bless to a wonderful mum who is always in my heart. Love and miss you so much. xxxxxxxxxxxxxxxxxx"
"Happy Mother's day. Love and miss you so much xxxxxxxxxxxxxxxxxxx"
"Happy Birthday mum. Love and miss you loads xxx"
"Happy Xmas. You never guess what, im only cooking Xmas dinner, that's why im sending you this today. Love and miss you, wish you were here to share Xmas with me and Sam. Say hi to Jake, Cassie, dusty and dad. Xxxx"
"Where has the time gone. Another year, another Xmas. I love and miss u so much. I miss my best friend. Love you mum xxx"
"7 years already, where has the time gone. It seemed only yesterday we were going to L.A eating fish and chips. I miss you so much. Love and hugs xxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Happy Birthday, 81 today. Love and miss you so much xxxxxxxxxxxx"
"Hi mum just want to wish you and the family a very Merry Xmas. love and miss you so much xxxxxxxxxxxxxxxxxxxxxxxx"
"Hi mum, six years today. Cant wait to see you as i miss you sooo much.
Love and hugs xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Happy Birthday , 80 today, hope you had a good day with dad and the kids. love and miss you so much. xxxxxxxx"
"Hi Mum, Dad, Cassie, Dusty and of course our little man. Just want to tell you guys sam and i got engaged, sorry jake i no you wanted her all to yourself. I miss and love you guys soooooooo much. all my love and hugs. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Hi mum hope the kids are behaving themselves. Miss you all so much. So hard for me this time of year, i remember all the fun we use to have and the presents we bought one another even the presents for Dusty, Cassie and little man (jake). LOVE you and MISS you all. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"5 years have gone by, but it only seems like yesterday we were laughing and joking. MISS u mum, say hi to jake, cassie & dusty. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Thinking of you. Happy Birthday for tomorow.
Love you and miss you sooooo much. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Hi mum, nearly your birthday, you would of been 79 this year. Jake is still with us, dont now for how long but everyday is a blessing, with him here i feel as though you are still very close to me, i no you are in my heart but it feels different with jake. love you mum very very much, xxxxxxxxxxxxxxx"
"Happy New Year Mum. Sorry didnt send you xmas wish, i was still thinking about you. Looking into putting your ashes down to snell hatch so i have some where to go and talk to you, i know i talk to you everyday but i would like you to go somewhere nice and peaceful so you can lay to rest properly. love and miss you so much. Your loving daughter Sue xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx"
"Hi Mum, i no im a day early.There are so many things i want to say to you, i wish you was here, i miss our chats and laughter. Love you sooo much."
"Hi mum, Happy Birthday for the 21st. Hope Cassie is behaving herself, i bet she was pleased to see you. miss u love u xx"
"Cassie and Jake are still behaving themselves, but you already no that. Love you mum and miss you. xxxxxxxxxxxxxxxxxxxxxxx"
"i love you and miss you soooo much. my heart sometimes aches because i miss you and our happy times we had. xxxxxxxxxxxxxxxxxxxxxxx"
"Love Samantha xxxxxxxxxxxxxxxx"
"Hi mum, 3 years already, where has the time gone. It only seems like yesterday that we were on our way to L.A. love you mum and miss you so much.xxxxx"
"Even though i never got to meet you,i have heard so much about you from Sue.Reunited with the love of your life Harry.God bless Vera.Love Samantha,Cassie and Jake xxx"
"forever in my heart and soul. you will never be forgotten"
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text:
Average, not as good as other NCL cruises
Sail Date: June 16, 2014
Reviewed: 2 years ago
Traveled As: Singles/Friends
Room Type: Balcony
Cabin: GTY
If I was to use one word to describe the ship, I would say "dated". As this ship used to be the Pride of Aloha, there are numerous murals and decorations depicting Hawaiian life. No, I wouldn't say this was a bad thing, but it left service in Hawaii in 2008 - 6 years ago.
When comparing this ship to Pride of America, which we cruised on last December, I can only say that NCL did a magnificent job of creating a Hawaiian experience on that ship. We would have liked to see a bit more Bahamian culture on board (some of us actually like "learning" something on these cruises).
Other items to mention:
The ship needs work. It appears that on a previous cruise, our bathroom door was pried open forcefully, as there were marks on the door and it always stuck while opening/closing.
Also, this might seem like a small item, but when nature calls, nature calls. The public restroom signs are tiny and they are the same size (and look the same) as the firefighters closets, hose connections, crew passageways, laundry drops, etc. They need to be bigger and easily identified.
Other than that, Cagney's was wonderfully delicious, the shows were good, the cabin stewards friendly and overall a good experience. We have been cruising many times, but was the first cruise for my brother-in-law.
Oh- yea...... He HATED the disembarkation - the lines, the customs wait, the "gathering of the baggage", the confusion (and he's a retired police officer). But that's the situation nowadays and it WAS in Miami.
Category Ratings
Click table then swipe to view all columns.
Click table then swipe to view all columns.
|Ship Quality
|Dated, needs sprucing up. Also, the ship needs to put out fishing lines or barriers to prevent those pesky seagulls from helping themselves to someone else's breakfast (in Freeport and Nassau). The are dirty animals and can spread diseases if they are not noticed by the passenger who went back to get some coffee. There are ways to keep them away - NCL needs to find a way. Mysteriously, there were none in Miami when we pulled in the last day - How'd that happen???
|Food and Dining
|Cagneys was great. Anytime a specialty restaurant is booked up solid, there's a reason..
|Service and Staff
|Onboard Activities
|Destinations and Excursions
|Cabin / Stateroom
|The A/c blows right down on you. Gets cold, but very comfortable comforter.
Port Ratings
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|Miami, Florida
|Busy, hectic, confusing (but it's Miami)
|Freeport, Grand Bahama Island
|Nassau, Bahamas
|Great Stirrup Cay (Cruiseline Private Island), Bahamas
Everyone take note. Even though you just want to get in the buffet line at the cafe, THERE really is a second buffet on the same deck outside. The cruise staff tells you about it, but nobody listens !! Go back there and enjoy the easy access to the food !!

subset: commoncrawl


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{image-kps gill_28042008.jpg news.oneindia.in}New Delhi, April 28: The Indian Olympic association on Monday suspended the Indian Hockey Federation and appointed a five member ad-hoc panel that will replace the sports body.
IOA's decision comes after a sting operation by a news channel exposed corruption in the Indian Hockey Federation. Earlier on Sunday, expressing dismay at the state of Indian hockey, FIH chief Els van Breda Vriesman said the world body can't work with a federation whose top official was under investigation following a TV sting operation. It (the sting operation) is never heard of in the world of field hockey. I wish the Indian hockey gets positive publicity and not this kind. We are in touch with both International Olympic committee and the Indian Olympic Association (IOA) how to proceed in such situation," she said.
"Now the IOA has to manage Indian Hockey Confederation because I don't think we can work with a half-suspended Secretary General (K Jothikumaran) and a president probably linked because he protects his secretary in this case," she added.
OneIndia News


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N.L.'s 34th man vote takes a happy twist with Chipper's surprise early selection
MLB scored by naming Chipper Jones to the N.L. All-Star team, leaving four others, including phenom Bryce Harper, to battle for the final roster spot.
The decision to add Braves great Chipper Jones to the National League All-Star team makes everyone chipper. Even a prime opponent in the 34th man vote, 19-year-old phenom Bryce Harper, was supporting Jones' candidacy over his own.
And so was Harper's manager, Davey Johnson, who sniffed that no one should be going to Kansas City after just 200 at-bats. And just about everybody else was, as well.
Sure, the retiring Jones may not have the numbers of teammate Michael Bourn, another of the 34th man candidates, but Jones deserved a nice All-Star sendoff. And Kauffman Stadium is as good a spot as any to do it considering it's the only stadium he's never played in (fact courtesy of Royals p.r. man extraordinaire Mike Swanson).
After Harper told the Washington media, "If I had a vote, Chipper's going,'' Jones, whose selection came courtesy of injured outfielder Matt Kemp's inability to play, said he texted Harper to tell him how much he appreciated it, saying to Harper, "That's a very classy thing for a 19-year-old kid to say.''
(Side note: Harper has turned out to be a lot nicer kid than he was portrayed on his quick run through high school, junior college and the minors. That's great for baseball because, as Chipper pointed out, he's going to be making a lot of All-Star Games in the future.)
Actually, this whole 34th man episode has been a wonderful display of class all around in a year with some crazy All-Star controversies. I agreed with Harper that Jones already should have been named to the team based on his wonderful career, and he had a much greater right to complain than the biggest complainer out there (I won't mention the guy again, but it's the fellow who was threatening to file a grievance over his nonselection).
Anyway, the 34th man vote can carry on now without this Larry Legend, and could be a fairer fight among the classy kid, World Series MVP David Freese, Jones' deserving teammate Michael Bourn and the Diamondbacks' surprise cycle king Aaron Hill.
I've got a hunch that not one in this group of nice young men will complain regardless the result, helping to make the National League's 34th man story one of the nicest All-Star tales of the year.


text:
Build Guide by PschedelicPorn
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Ezreal Build
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
Hey, guys !
That´s my first guide and it will help you to pown.
I´m german but i will di my best to write english.
But don´t think ez ais a bad char cause he was neved !
Sheen: great for ez, it´s make mana and the passive is great for the skill bashing
wriggles latern: you have distance liefesteal and can farm creeps !!!
manamune: mana, mana regenaration and attack damage, **** up it´s very nice
madreds bloodrazor: dmg, attack speed and the passive are perfect to pown
the black cleaver: reduce the armor and the damg great, awesome with exhaust and his cripple
trinity force: it makes all, and has the same effect as sheen, it´s really awesome
berserker greaves: you have a better attck speed and can pown you distance lifesteal and your armor penetration with the black cleaver
Skill Sequence
Standard sequence:
arcane shift-> exhaust-> essence flux-> mystic shot bashen
Allone fights:
do mystic shot and go out the others range, if they have low life attack they with her standard skill sequence
Team fights:
standard sequence is all you need :D
jungle fights:
you can attck through the wall and do your arcane shift to teleport you throug the walls
Important !!!
If a rival have low life and is going away use your trueshot barrage


text:
[intransitive] + adv./prep. to move quickly through the air in a way that makes a sound Cars and trucks swooshed past. Word Originmid 19th cent.: imitative.verbjump to other results
BrE BrE//swuːʃ//; NAmE NAmE//swuːʃ//Verb Forms present simple I / you / we / they swoosh
BrE BrE//swuːʃ//; NAmE NAmE//swuːʃ//he / she / it swooshes
BrE BrE//ˈswuːʃɪz//; NAmE NAmE//ˈswuːʃɪz//past simple swooshed
BrE BrE//swuːʃt//; NAmE NAmE//swuːʃt//past participle swooshed
BrE BrE//swuːʃt//; NAmE NAmE//swuːʃt//-ing form swooshing
BrE BrE//ˈswuːʃɪŋ//; NAmE NAmE//ˈswuːʃɪŋ//
Check pronunciation: swoosh


text:
House of HOPE RESale
Helping local families in crisis through Project Hope
There is always something new to discover at House of Hope Resale!
Welcome to the largest treasure hunt of its kind!
House of Hope Resale offers furniture, antiques, collectibles, clothing, decor, housewares, art, toys, books, jewelry and more.
New arrivals every week!
Enjoy guilt-free shopping ‐ all proceeds benefit local families through Project Hope.
Wednesdays thru Saturdays
10 AM to 4 PM
Mondays thru Saturdays
10 AM to 4 PM
Cash and checks only. All sales final
We appreciate and accept donations during hours of operation. All contributions are tax-deductible and a receipt is provided. Pick up service is available for larger items. Call 847-381-5721 for arrangements.
Don't miss upcoming events and sales ‐ email us to join our VIP list and be first to know!
HOUSE of HOPE RESALE
DeerPath Commons
955 South Rand Road -- Near Binny's Beverage Depot
Lake Zurich, IL
Phone: 847-550-2000
Email: email@example.com


text:
Health insurer Humana has created two companies intended to help providers make the transition to new forms of contracts as reimbursement models shift away from fee for service.
The companies are Transcend and Transcend Insights. The parent organization said it was making the move with the goal of providing resources and information technology to support providers in making the transition to population health models.
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text:
Our mission is to provide quality and everything we do is dedicated to the satisfaction of our clients.
To achieve the production of PVC products of superior quality that is fully tailored to individual needs.
The work lead us care, quality and professionalism.
The satisfaction of our clients is our biggest success.
Contact us and we will be happy to answer your request.
Follow us on Facebook


text:
A number of books, magasines and websites feature and discuss some marketing strategies for big and small businesses such as jewellery making. Here are 10 selected practical, workable and helpful marketing tips:
1. Create varied quality designs that your audience can quickly and easily choose from, this would save them time from mall hopping just to find one that appeal to them and suit their taste.
2. Come up with unique jewellery designs that can be given an appropriate catchy name that excites and intrigues. Specialised designs can have specific theme created to attract a specific age group. i.e. "my-only-love" jewellery design can become popular to single and married couples. An added explanation of the meaning behind the design could make it a gift item intended to send a specific message or to symbolise a personal feeling. With this, you will create a specific receptive market of your merchandise.
3. Display your jewellery designs in as many local events as possible, i.e. tradeshows, bazaars and festivals so that it will gain local exposure. But be selective; choose an event that would be an appropriate market


text:
Tanzanian Methodia Mathias, 21, claims that Rebecca Balira, 47, an HIV expert with links to the London School of Hygiene and Tropical Medicine, forced her to work unpaid daily from dawn to midnight. Southwark crown court has heard how Ms Mathias was slapped and punched by Balira after her employer flew into a rage over a money box.
The young woman told the court she was forced to share a bed with Balira's 12-year-old son, deprived of her passport and banned from contacting her family or friends.
Her six-month ordeal only ended when Ms Mathias told the "one friend she had in this country" about her mistreatment and the police were called in.
Ms Mathias was allegedly held as a slave at Balira's cramped two-bedroom flat in Thamesmead for seven months. Giving evidence today she told jurors she was beaten and spoken to "horribly" by Balira within weeks of her arrival in London.
Ms Mathias said: "She said that I was stupid and useless and that she had paid for me to come here and it was a waste of her money."
She claimed she was regularly beaten by Balira: "Sometimes she used shoes, sometimes she slapped me and sometimes she used a wooden spoon."
She said she had no time off between February and September last year and the only money she received, £20, came from a lodger.
Balira arranged for Ms Mathias's visa and paid for her flights from Dar es Salaam to London.
Balira, of Thamesmead, denies trafficking a person into the UK for exploitation, knowingly holding another in servitude and two counts of common assault. The trial continues.
- More about:
- Hygiene
- Passports
- Southwark Crown Court
- Tanzania


text:
Journalism and Training Resources
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text:
Tijs Michiel Verwest is a Dutch born musician popularly known as Tiesto. He is popularly known as a DJ, musician and producer of a music genre referred to as electronic dance. Tiesto has used several aliases in the past with his most recent being DJ. Tiesto. He has however dropped the DJ tag to his name and his most recent works simply bear Tiesto. Tijs Michial Verwest is originally from Netherlands. He was born on the 17th of January 1969 in Breda, Noord-Brabant, Netherlands. Tiesto's love for music began quite early from about age 12. At age 14, he was already serving as a DJ in school parties and small gigs. By 1985 he was already a resident DJ and continued up until 1994, working at several Netherlands clubs. He began releasing music in 1994, when he released some material under Chemo and Coolman labels (subsidiaries of Noculan Records). At this time he mainly produced gabber and hardcore tracks under aliases like DJ Limited and DJ Joker. He kept busy releasing several materials along with various people under various labels. In 1997, he established Black Hole Recordings with his friend, Arny Bink. He met Dennis Waakop Reijers, a producer, composer, writer and arranger and they have been working together since then. He also worked with Ferry Corsten in 1999 and 2000 to release Gouryella. His first major claim to widespread fame was his 2000 remix of "Silence" that featured Sarah McLachlan. His first solo album came in 2001 and it was titled In My Memory. The album contained several great hits and music video that helped to springboard his career. The DJ Magazine has named him as the World's number 1 DJ 3 (2002 through 2004) consecutive times.
Tiësto tour dates 2017 United Kingdom
|26 Aug 2017
|Boucher Road Playing Fields
Tiësto does not currently have any concerts scheduled in United Kingdom in 2017. The last time Tiësto played a show in United Kingdom was 2013, in Glasgow. Overall, Tiësto have played a total of 22 gigs in the country. If you're ready for a road trip, Tiësto, currently has 3 gigs booked in cities like Eugene (United States), Pointe-Calumet (Canada).
Other Tiësto concerts
|23 Jun 2017
|Gorge Amphitheatre
|George, US
|24 Jun 2017
|Wet Republic
|Las Vegas, US
|02 Jul 2017
|Wet Republic
|Las Vegas, US
|04 Jul 2017
|Governors Island
|New York, US
|29 Jul 2017
|Wet Republic
|Las Vegas, US
|05 Aug 2017
|Downsview Park
|Toronto, CA
|05 Aug 2017
|Max Bell Theatre
|Calgary, CA
|05 Aug 2017
|Wet Republic
|Las Vegas, US
|13 Aug 2017
|Wet Republic
|Las Vegas, US
|01 Sep 2017
|Exodus Festival
|Las Vegas, US
|02 Sep 2017
|Randall's Island
|New York, US
|08 Sep 2017
|Berkley Riverfront Park
|Kansas City, US
|16 Sep 2017
|Wet Republic
|Las Vegas, US
Past Tiësto gigs
|17 Jun 2017
|Wet Republic
|Las Vegas
|04 Jun 2017
|Wet Republic
|Las Vegas
|28 May 2017
|Wet Republic
|Las Vegas
|21 May 2017
|Wet Republic
|Las Vegas
|18 May 2017
|TAO Beach
|Las Vegas
|22 Apr 2017
|Wet Republic
|Las Vegas
|08 Apr 2017
|Bar Smith
|24 Mar 2017
|LIV Night Club
|Miami Beach
|11 Mar 2017
|10 Mar 2017
|24 Feb 2017
|Tribeca Grand Hotel Screening Room
|New York
|27 Jan 2017
|Los Angeles
|21 Jan 2017
|Park City Live
|Park City
|02 Dec 2016
|Dubai World Trade Centre
|17 Sep 2016
|Mall Of Asia Concert Grounds
Tiësto's latest news
Tiësto latest news, rumours and lineup confirmations.
01 Jun 2015
America's TomorrowLand Sister Festival, TomorrowWorld, Confirms First Wave of Artists. Tickets on Sale.
Once again TomorrowWorld (the amazing festival that stemmed from its massive mother festival TomorrowLand in Belgium) will delight audiences with its magic in the beautiful forests of Chattahoochee Hills right outside Atlanta, Georgia.TomorrowWorld has just released the entire Phase 1 ...
05 Feb 2015
BIG-NAME Artists Added to Tomorrowland 2015 Including Tiesto, Carl Cox, Axwell Λ Ingrosso, Armin Van Buuren, More. Worldwide Tickets On Sale Saturday.
Tickets went on sale to residents of Belgium last Saturday, but this Saturday is the big one the worldwide on sale! The allotted tickets to the Belgium on sale sold out, and this Saturday the entire festival will certainly do the same.Saturday at 17:00h Central European Time will se...
29 Jan 2015
Dates Confirmed for Electric Daisy Carnivals in New York and Las Vegas.
The dance party continues, as Insomniac have confirmed dates for the 2015 Electric Daisy Carnival in both New York and Las Vegas.The first of the two massive events to take place is the NYC edition, which will bring bouncing EDM beats to Metlife Stadium over Memorial Day Weekend Sat...
27 Jan 2015
Tickets to Belgium's Tomorrowland Electronic Music Festival Go On Sale to the World February 7th.
Another July, another massive Tomorrowland electronic music festival - at least that has been the case over the last ten years, since the world-famous festival's 2005 debut.Widely known as the largest and gathering of DJs, producers, and live electronic acts in the world, the aptly...
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text:
LG Wine II Cases
Get the right kind of protection with LG Wine II cell phone cases and LG Wine II cell phone covers! Accessory Geeks has various LG Wine II cases and LG Wine II covers to match with your style, needs and personality. Whether you are looking for the ideal stylish LG Wine II cases or the perfect LG Wine II case to protect your phone, you can trust in Accessory Geeks to have the trendiest LG Wine II cases and LG Wine II covers. Our large selections are all set at the lowest prices which will have you saving more money than you ever expected from a store. Get in style with LG Wine II cases or maybe something a little more rugged like LG Wine II covers. Whichever cell phone case you are look for the LG Wine II, Accessory Geeks is here to help. Watch this video to decide which types of Cell Phone Case fits youLG Wine II CasesAccessory Geeks is proud to offer the largest selection of LG Wine II cases on the web. Search through our large inventory of LG Wine II cases and LG Wine II covers with various styles that are made to suit your personality and your lifestyle. You'll find low prices and free shipping on all LG Wine II cases or LG Wine II covers sold in the U. S. The quality of our LG Wine II cases and our LG Wine II covers are second to none and coupled with our low prices, it's hard to not know why Accessory Geeks is your one stop show for your cell phone accessories.
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text:
Randomized trials
Preeclampsia (PE) is an important cause of maternal and perinatal mortality and morbidity. The risk of adverse outcome is much higher when the disease is severe and of early onset requiring delivery before 37 weeks' gestation (preterm PE) than at term. A major challenge in modern obstetrics is early identification of pregnancies at high-risk of preterm PE and undertaking of the necessary measures to improve placentation and reduce the prevalence of the disease.
Prediction of preterm preeclampsia
Extensive research in the last 20 years has identified a series of early biophysical and biochemical markers of impaired placentation Akolekar et al, 2011). A combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and maternal serum pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11-13 weeks' gestation can identify a high proportion of pregnancies at high-risk for preterm PE (Akolekar et al, 2011 (2012).
Prevention of preterm preeclampsia
The prophylactic use of low-dose aspirin for prevention of PE has been an important research question in obstetrics for the last three decades. More than 50 trials have been carried out throughout the world and a meta-analysis of these studies reported that the administration of low-dose aspirin in high-risk pregnancies is associated with a decrease in the rate of PE by approximately 10% (Askie et al, 2007).
Recent meta-analysis of randomized studies reported that low-dose aspirin started at or before 16 weeks was associated with a 50% reduction in the overall risk for PE and an 80% reduction in preterm PE (Bujold et al 2010, Roberge et al, 2012). However, the small number and small size of individual trials preclude definitive conclusions to be drawn and the results need to be examined in a prospective major randomised trial. In such trial the dose of aspirin to be used should be 150mg because with lower dosage a high proportion of the population are non responders (Caron et al, 2009, Rey and Rivard, 2011).
Safety of low-dose aspirin
First-trimester use of low-dose aspirin is not associated with increase in risk for fetal abnormalities (Slone et al, 1976; Klebanoff and Berendes, 1988; Werler et al, 1989; Norgard et al, 2005). Although approximately 10% of women receiving Aspirin develop gastro-intestinal symptoms there is no evidence of increase in any type of maternal bleeding or placental abruption (Sibai et al, 1993; Caritis et al., 1998; Rotchell et al, 1998, Bujold et al, 2010). Similarly, there is no association between daily consumption of low-dose Aspirin during the third-trimester and antenatal closure of the ductus arteriosus, intraventricular hemorrhage or neonatal bleeding (Di Sessa et al, 1994; Schiessl et al, 2005; Wyatt-Ashmead, 2011,Duley et al, 2007).
Proposed study
This will be a multicentre trial in the UK and other countries in the European Union. There will be screening for preterm PE at 11-13 weeks' gestation by a combination of maternal medical history and characteristics, maternal serum PAPP-A, and PlGF, MAP and uterine artery PI.Women who are deemed to be at high-risk for preterm PE (about 10% of the population) will be offered the opportunity to participate in the aspirin vs. placebo trial. Participants will be randomized to one tablet per night of either aspirin 150 mg or matching placebo tablet and treatment will continue until 36-37 weeks.
Objectives: To examine if the prophylactic use of low-dose aspirin from the first-trimester of pregnancy in women at increased risk for preterm preeclampsia can reduce the incidence of the disease. Secondary objectives include the effect of aspirin on the incidence of early PE (delivery <34 weeks) and total PE, birthweight below the 3rd, 5th and 10th percentile, stillbirth or neonatal death, neonatal intensive care unit admission, composite measure of neonatal mortality and morbidity, placental abruption, spontaneous preterm delivery <34 weeks and <37 weeks.
Sample size: We need to recruit 33,680 pregnancies to the screening study to identify 3,368 high-risk pregnancies. If 50% (1,684) of these agree to participate in the randomized study and aspirin reduces the rate of preterm PE by 50%, this will be significant with a power of 90%.
Governance: The trial will be conducted in compliance with the protocol, the Declaration of Helsinki (1996), the principles of Good Clinical Practice and applicable regulatory requirements. The study will be reviewed and approved by the National Research Ethics Committee, Medicine and Healthcare products Regulatory Agency and applicable Hospital Trusts. The University College London Clinical Trials Unit will manage the sponsors' responsibilities and Quality Assurance to ensure compliance with the Clinical Trial Regulations.
- Clinical sites: UK, Spain, Belgium, Italy
- Partners: Fetal Medicine Foundation (UK registered charity), UCL Clinical Trial Unit,Hy Laboratories Ltd. (Hylabs), Astraia, Hananja, PerkinElmer
- Support: GE Viewpoint
- Downloadable content please click here


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Member since 11/23/2012
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Reviews & Stories
Amazing Job - Manchester, UK
Mr Marando was recommended by a family friend. I could not thank him enough for the work he has done (Breast Augmentation) from the first consultation, the procedure, through to the aftercare, everything was done to make me feel at ease. Though I am only 11 days post-op I can tell that the end results are going to be perfect. He is a lovely man and the work done by him and the staff and the... READ MORE


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This headphone pack gives you two Shure SRH440 studio headphone sets and an ART HeadAMP 4 stereo headphone amp at a great price.
Shure SRH440 Studio Headphones
The Shure... Click To Read More About This Product
This headphone pack gives you two Shure SRH440 studio headphone sets and an ART HeadAMP 4 stereo headphone amp at a great price.
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ART HeadAMP 4 Stereo Headphone Amp
Most home recordings involve from one to four people, any or all of whom are going to need headphone monitoring. The monitor amp would be connected to the tape deck's headphone output or a mixer output so that the performers can hear themselves and each other. Of course the same application can apply to band rehearsals and even home entertainment. HeadAMP provides amplification and individual volume control for up to 4 headsets. It can be driven by either line-level or headphone amplifier signals (mono or stereo).
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Our product catalog varies by country due to manufacturer restrictions. If you change the Ship-To country, some or all of the items in your cart may not ship to the new destination.


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In 2011, a Mexican newspaper editor named Maria Elizabeth Macías Castro was decapitated for using social media to spread news about the activities of the country's criminal groups.
So starts a new animated explainer created by I Shot Him, a San Francisco-based design studio, which used Castro's death and other anecdotes to explain the years-long Mexican drug war:
The video takes a bit of an advocacy bend, arguing that the United States plays a major role in the violence, both because our high levels of drug use fuel the narcotics trade and because our loose gun controls make it easy for cartels south of the border to arm themselves.
You can agree or disagree with that thesis, but the video is at least a refreshingly original way to learn about a conflict that can be hard to comprehend.


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The exchanges occurred at Cwmbran where South Wales Argus reporter Mark Choueke asked the deputy prime minister about the case of Peter Law, a long-serving Labour politician in Wales and Welsh Assembly member, who has announced he is leaving the party and standing as an Independent in the Blaenau Gwent constituency.
Mr Prescott "blew his top", according to Choueke, when the reporter asked how he and his Cabinet colleagues had reacted to Mr Law's decision.
He said that Mr Prescott told him: "It didn't even register with us."
When Choueke pressed him further, Mr Prescott, he said, retorted: "Why are you asking me about this? I don't care. It's a Welsh situation. I'm a national politician."
Choueke again pressed him and Prescott replied: "Where do they get these amateurs from? You're an amateur, mate. Go get on your bus, go home."
Choueke asked: "Are you too big for the regional press now, John?"
Prescott replied: "Bugger off. Get on your bus, you amateur."
A spokeswoman for Mr Prescott said that he had already answered questions about Mr Law earlier.
She said: "In this particular situation the approach was quite unreasonable and quite unprofessional. There was just one question and the reporter kept going back and back on it."
Referring to Mr Prescott's "I don't care" remark, the spokeswoman said that had to be put in context.
She said: "Mr Prescott is not indifferent to this matter at all. He had answered questions quite repeatedly. The journalist was being quite arrogant and unreasonable about it."
Mark Templeton, news editor of the South Wales Argus, commented: "That is just absolute nonsense."
- More about:
- South Wales
- Wales


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Defensive lineman Vance Walker is the newest member of the Denver Broncos, after reportedly signing a two-year deal worth $4M today. Walker flew to Denver to meet with John Elway and the team today and there was enough mutual interest and respect to consummate a deal.
#Broncos have agreed to 2-year, $4 million deal with Vance Walker.— Jeff Legwold (@Jeff_Legwold) March 12, 2015
Walker played for the Kansas City Chiefs in 2014, serving mostly as a backup defensive end in their 3-4 scheme. He saw 238 defensive snaps, notching 12 stops and 3 sacks, according to Pro Football Focus. This earned him a +6.8 cumulative grade from the leading analytics site, which is very impressive, considering the amount of snaps he saw.
In Wade Phillips' 3-4 defense, Walker will be a valuable part of the rotation. Able to play either defensive end spot, MHH Analyst Erick Trickel believes that Walker is versatile enough to play the nose tackle position, as well. At 6-foot-2. 305 pounds, Walker isn't a behemoth, but he does possess the power and requisite quickness that Phillips like to see in his nose tackles.
Walker, a 2009 seventh round pick by Atlanta, might not be a premier free agent, but he represents the kind of second-tier value that Elway is obviously looking for in this year's class. That's the operative word—value.
The Broncos also have visits scheduled with safety Darian Stewart and offensive guard Shelley Smith, today and tomorrow, respectively. We'll keep you apprised of those meetings posthaste.
Chad Jensen is the Publisher and Lead Analyst for MileHighHuddle. You can find him on Twitter @ChadNJensen and on Google+.
Follow MileHighHuddle on Twitter @MileHighHuddle and become a subscriber to receive access to premium content and discounted Broncos tickets.
Join the Conversation On The MHH Forums and Discuss This Article With Broncos Fans
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Mile High Mailbag: Pre-Free Agency Edition
OFFENSE: Quarterback | Running back | Tight end |
Offensive tackle | Offensive guard | Center
DEFENSE: Defensive tackle | Defensive end | Outside linebacker |
Inside linebacker | Safety | Cornerback
Position: QB RB FB WR TE OT OG C DT DE OLB MLB S CB K P LS


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Kostoski Photographer
KeyshlaModel Female Orlando, Florida, US
My MM URL: http://www.modelmayhem.com/KeyshlaR
Mayhem # 1222398
About MeHi! Thanks for stopping by. :-)
I hope you enjoy my Photos!!
Just so you know a little about me im 20 years old. Im a full time student and part time worker. I would like to get more involved with modeling. I love taking photographes and enjoy the rush you get at a fashion show. Im truely not comfortable doing nude so please dont ask. Hope you enjoy the site and don't hesitate to write.
If you want to get in contact me please write to me threw this website Thank You.
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Dani Accessories
Kaufmann's Large Open Tote with Logo
Ships from USA , delivers within 14-21 DaysAdd to wishlist
- Dimensions: 16.5" x 13" x 5"
- Vinyl
- Made in USA
- Web ID: 89312817
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No questions asked return or exchange*: items may be returned or exchanged for a full refund in the original form of payment or a Vogily Credit within 14 days after shipping. Your satisfaction is our biggest prize, so we do everything to ensure that you are happy with your purchase. All products are 100% authentic, procured from brands directly and are backed by our purchase protection with 10 times money back guarantee. *Please refer to the detailed return policy on the site for exceptions
Ships from USA , delivers within 14-21 Days


text: Can anyone please tell me why libraries and homegroup are useful in W7? I understand it is "easier" to setup, but is there anything else? I already have my files organized in folders (Audio, Documents, Programs, Pictures, Videos). Is there any difference if i set that folder as a library? Is Homegroup any different than normal file sharing (when everything is setup). The only difference i noticed is that there are no write permissions (at all, except public folder, but that is not even the same folder) when using homegroup.


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Belladonna Lily, White
SHOP ALL belladonna lilies
White Belladonna Lily White Bulbs | Cape Belladonna | White Naked Lady Bulbs
More than 15 years ago a well-known southern California plant breeder set out to develop some new belladonna varieties, ones that were extra drought resistant and super easy care. Sadly, the man, Fred Meyers, died before this project was completed and the unnamed varieties were left to fend for themselves in a field in the California desert. Hearing of this, we arranged with the Meyers family to harvest some of these belladonna bulbs and offer them for sale for the first time ever. Like somewhat reluctant heroes an Indiana Jones adventure, we braved jeep rides along skinny cliff trails (pleeeease don't let that wheel slip), hillsides thick with thorny cactus, rattlesnakes (yes, we're serious) and baking heat to reach the field where these grow. For 5 years nobody has tended these at all - no water, no weeding, no removal of spent foliage and no dividing - nothing. So if you're looking for tough, beautiful and exclusive blooming plants, you've found them. Large 2 1/2" diameter bulbs are ready to grow and bloom profusely. It is with great pleasure that we offer these.
Planting Guide
tip of bulb just at the soil line
light - quite drought tolerant once established
Full sun
Additional Details
Common Name:
Belladonna lily, Cape belladonna, Naked ladiesBotanical Name:
Amaryllis belladonna pink hybridsExposure:
Full sunHardiness:
Zones 7-11Height:
Crisp white blossoms in scented clusters of 6-12 bloomsBloom Season:
Late summerBulb/Plant Size:
2 -1/2" + - very large bulbNumber:
1 large belladonna lily bulbs


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California Healthcare
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Hospital Payment Arrangements with Laboratories Could Pose Contractual, State Law and Compliance Risks
By Richard S. Cooper, Esq.
McDonald Hopkins LLC
Increasingly we are having hospital clients approach us about proposed arrangements that are designed to let third party laboratories "bill" and be paid under the hospital's payer contracts. Most often, this arrangement is designed to permit laboratories which are unable to obtain contracts with key payers to "piggyback" on the hospital's contracts. Many payers are limiting the number of laboratories they will contract with so more laboratories are finding themselves out of network with payers.
Read article
It's Time to Get Serious About Cyber Security
By Sarah Krizanic
Practice Manager, Medic Management Group, LLC
Although the most recent ransomware attacks took place outside of America it should not be ignored. The infamous, and appropriately named, WannaCry crypto-virus wreaked havoc in more than 60 countries and infected over 200,000 computers. A wide variety of industries were affected, many of which came to a screeching halt, including transportation, communications, and healthcare.
Read article
The Equal Pay Pendulum
By Matt Lynch
Shareholder, Sebris Busto James
Equal pay has been in the news of late, with marches and other efforts by advocates to raise public awareness of pay inequity between men and women in the workplace. These efforts have focused on strengthening the 1963 Equal Pay Act, which requires employers to pay men and women the same for equal work. Recent developments on the judicial and legislative fronts have addressed pay practices that can impact pay inequality, and these developments may prompt employers to change the way they pay their employees.
Read article
Attracting Physicians In A Shallow Market
Mary Campbell
Vice President and Account Executive, Parker, Smith & Feek
One important part of any compensation structure is the benefits and perks a company offers to employees. Overall compensation becomes especially important when considering those occupations facing major shortages and enhanced standards.
Read article
California Healthcare News Feed
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We try to keep things fresh and new...and avoid repeating vintage pieces.
But sometimes we find another example of something fantastic (usually something that sold super fast) and we can't resist...
This is the third variation of a Mexican Mother of Pearl pitcher we've handled.
The first, we acquired in a fantastic flea market in Mexico City. The second at a market in Toronto...
And now the third, found by a favorite client of Caviar20's in Northern Ontario,
This pitcher is a variation of its siblings with its brass body and a thick wood handle.
A unique pitcher is an essential and versatile vessel for the home that entertains.
Perfect for group cocktails and all-season entertaining, a unique pitcher can easily adapt to be an original and charming vase for flowers.
This pleasing vase is embellished with dynamic mother of pearl tile. The combination of iridescent blue with touches of grey, tobacco brown and magenta and will work well in any interior.
Questions about this piece? Contact us or call +1.416.704.1720
Additional images available on request.
Mother of pearl and brass
Hallmarks on bottom
Mexico, 20th century
Very good vintage condition


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Surprise your backpacker husband by showcasing his first love over your walls. It may not stop him from going on a night ride with his wild hogs but will surely be an overwhelming gesture that you appreciate his hobbies. After all that's how we rise in love.
Height: 50 cm
Width: 70 cm
Shape: Rectangular


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Contact us 24/7: +44 330 022 5700
Burberry Beauty
Lip & Cheek Bloom - Poppy No.09
Zoom In
- Instructions for use:
- - Use your finger to dab color onto lips or cheeks, then blend for a seamless finish
- - Apply additional layers to build intensity
- - 3.5g/ 0.12oz.
For use on both your cheeks and lips, Burberry Beauty's 'Bloom' shades are inspired by the vibrant colors seen in an English garden. The innovative blend of Silicone, jellifiers and emollients creates a bouncy mousse-like texture, while organic pigments and Mica ensure a velvety finish that blurs away imperfections. Effortless to apply, blend and build, this fool-proof 'Poppy' tint will brighten and lift your makeup look.
- Luminous satin finish - Buildable formula - Also available in: Rose, Hydrangea, Orange Blossom
As seen in THE EDIT magazine
Product Code: 597846
Find out the shipping options available for your destination
Arrange your return for an exchange or refund within 28 days using our free collection service
Help & Advice
Product Code: 597846


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News » Politics
Female Legislators Rise Up Against Closed Door AHCA
Prompted to anger by the closed-door negotiations of Republican men on the secretive Senate version American Health Care Act, female legislators are speaking out about the right to universal health care, and the need to protect women and girls.
HRC Blasts Pence for Endorsing Focus on the Family's Anti-LGBT Agenda
The scheduled Pence appearance is being viewed by HRC as a clear indication of the Trump Administration's hostility and opposition to LGBT equality during Pride Month.
Happy Pride! Pence to Help Anti-LGBT Group Celebrate 40th Anniversary on Friday
Vice President Mike Pence's visit Friday to Colorado to celebrate the anniversary of Focus on the Family comes at a time of change for the religious right during the age of President Donald Trump.
Trump Admits There Are No Comey Tapes
President Donald Trump declared he never made and doesn't have recordings of his private conversations with ousted former FBI Director James Comey,
McConnell Faces Hunt for GOP Votes for Senate 'Favor the Rich' Health Bill
The bill would cut and redesign the Medicaid program for low-income and disabled people, and erase taxes on higher earners and the medical industry that helped pay for the roughly 20 million Americans covered by Obama's law.
Senate Obamacare Repeal Bill Condemned by LGBT Advocates
If passed, the bill would take away health insurance from millions of people, including lesbian, gay, bisexual, transgender, and queer (LGBTQ) people.
Senate Republicans Release Bill to Cut Benefits to Poor, Alter Obamacare
"We live in the wealthiest country on earth. Surely we can do better than what the Republican health care bill promises," said Senate Minority Leader Chuck Schumer, D-N.Y.
Joe Biden to LGBT Gala: 'Hold President Trump Accountable'
Former Vice President Joe Biden, warning of transgender Americans "under attack" in Republican-led states, on Wednesday challenged the nation's LGBT community to push back against President Donald Trump's administration.
AP Sources: Senate Health Bill Would Reshape Obama Law
Senate Republicans would cut Medicaid, end penalties for people not buying insurance and erase a raft of tax increases as part of their long-awaited plan to scuttle President Barack Obama's health care law, congressional aides and lobbyists say.
Strangest Stats Ever Show People Would Rather Watch Sessions, Comey Than Porn
This can't be right.


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|"Shapira, Yoav" <Yoav.Shap...@mpi.com>
|RE: Help! First Web App does not work
|Tue, 30 Sep 2003 12:38:13 GMT
Howdy, You probably haven't customized build.xml correctly, so it's trying to connect to a dummy host that doesn't exist on your network. Yoav Shapira Millennium ChemInformatics >-----Original Message----- >From: Thomas Chen [mailto:email@example.com] >Sent: Monday, September 29, 2003 7:22 PM >To: email@example.com >Subject: Help! First Web App does not work > >Hi, > >I installed the Tomcat, JDK and Ant on my NT box, and followed instructions >on install the first web app, everything goes well except when I ran > >ant install > >I get follow error messages: > >BUILD FAILED: >file:/e:/testApp/build.xml: 364 java.net.UnknownHostException: E > >Can someone tell me what is going on? >Thanks in advance... > >Thomas > > > >--------------------------------------------------------------------- >To unsubscribe, e-mail: email@example.com >For additional commands, e-mail: email@example.com This e-mail, including any attachments, is a confidential business communication, and may contain information that is confidential, proprietary and/or privileged. This e-mail is intended only for the individual(s) to whom it is addressed, and may not be saved, copied, printed, disclosed or used by anyone else. If you are not the(an) intended recipient, please immediately delete this e-mail from your computer system and notify the sender. Thank you.
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Bypassing the short-season circuit entirely last year, the right-handed batter was thrown into Class-A Charleston. The prospect was drained, and it showed when he hit just .241 in 46 games.
After the offseason Refsnyder went back to the Riverdogs in 2013 with force. He batted .370 in 13 games, which earned him a quick promotion to the Florida State league and the Class-A Advanced Tampa Yankees were happy to have him.
Refsnyder stormed Tampa in April with a phenomenal .404 average in his first 12 games. He was hitting at a high rate and he was excited to be there.
"The promotion was a little surprising because Angelo [Gumbs] was already in Tampa," Refsnyder said. "I originally thought that Angelo and I would be separated the whole year.
"I was excited, but at first it did come as a surprise. I wasn't really sure what would happen when Angelo came back. We both play second base, but [we had] been switching off. It's been good."
In May Refsnyder's numbers dropped. He was hitting .212 and already acquired 99 at-bats in 26 games. Clearly, it was a month of struggles and Refsnyder was having trouble finding his previous success.
"Hitting is tough," Refsnyder remarked. "I wasn't finding holes. Marcus [Thames] and Slate [Tommy Slater], our head roaming hitting coordinator, came in and they helped me to quiet it down and get back to the basics.
"Right now I'm focusing on a little bit more power. Marcus and I have been working on some back hips stuff so I'm kind of trying to learn from that stretch.
"I've been hitting really well lately. It's a long season and there will be some ups and downs, but hopefully I can limit my struggles next time."
Baseball is an unpredictable sport and at this level it's about gaining experience, making the changes that are necessary, and keeping the game simple.
"I'm calming things down and trying to swing at better pitches," Refsnyder reassured. "Usually when guys start struggling they want to start hitting again. They start straining the zone and my game is to take a lot of walks, get on base, and things like that.
"I went out of my comfort zone as far as my strengths so right now the biggest adjustment I'm making is to swing at better pitches."
In order to drive the ball young players need to sharpen their pitch recognition. Marcus Thames, the Tampa Yankees hitting coach, attributes Refsnyder's slump to just that pitch recognition. For Refsnyder it's a work in progress.
"Pitch recognition," Thames said. "He was swinging at bad pitches there for a little bit. His mechanics, his hands got away from him and he started chasing pitches. You know, he was just trying to do a little too much instead of trusting his work and hitting better pitches.
"He can really hit, but he just got into a bad habit. If you swing at bad pitches your swing is going to start mess up and your mechanics are going to break down. He started tinkering with the leg kick and the toe tap, but all of that stuff wasn't the problem.
"The problem was that he was swinging at bad pitches and when you do that your swinging is going to break down. He's getting back to getting the pitch he can drive and once he's done that he'll be really good."
So far the month of June has been good for Refsnyder. His stats are back up and he's showing improvement with an average of .354 in 20 games, and after striking out 24 times in 26 May games he has struck out just seven times in June thus far.
What has changed? Refsnyder attributes his recent success to the luck of the game, but Thames believes the prospect has managed to get his head out of the game.
"He's not thinking as much. He's going out playing the game and keeping it simple," Thames reports. "If you start thinking about my hands are here and my fingers are here and I have to hit here, when you're in the box things are going to go badly. He's just got to eliminate all of that and just compete."
Defensively, Refsynder is pleased with his progress. He struggled for a spell, carrying errors from Charleston to Tampa, but has been working diligently and the errors are starting to decrease.
"I'm making some hard plays and trying to benefit with how hard the pitchers are working," Refsnyder said. "Overall it's going really well. I'm not surprised, but enthusiastic about how it's going so far. In the past dozen games I feel more comfortable on second base."
Going forward Refsnyder would like to work on hitting consistently and driving the ball to all parts of the ball park.
"I'm really excited at how far I've come from the beginning of the year to now," Refsnyder said.
Refsnyder is working to improve his swing on the sinkerball in and if he can keep the ball out over the plate his hit ability will increase.
"He's been swinging at the sinkerball and it's a ball, it's off the plate. With a sinkerball I'd like to see him keep the ball out over the plate, which would give him a better shot driving the ball out over the diamond," Thames concluded.
"Lately he's been making good plays defensively. He's been going to his backhand, throwing back across the field, and across his body. He's a true professional. He's been working hard and eventually he's going to get it."
Refsnyder Back To Basics
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December 17th, 2013
Welcome to this EXTRA SPECIAL edition of SILENCE! Get ready to swivel your mind with delight as you are guaranteed 100% Gary Lactus and 0% The Beast Must Die in the following narrowcast. Christmas really has come early! Pinch yourself! HARDER! USE TOOLS! DO IT ON A MORE SENSITIVE PART OF YOUR BODY! NOT THERE! THERE! That's right, this is not a dream! Stop crying and listen to Gary EXCLUSIVELY reveal his latest work as sci fi writer M. Gary M. Lactus! Then THRILL as he interviews Gareth Brookes about his truly unique graphic novel, The Black Project. Then listen to it over and over again, louder and louder until next time! Keep it cosmic!
Contact us:
This edition of SILENCE! is proudly sponsored by the greatest comics shop on the planet, DAVE'S COMICS of Brighton.
It's also sponsored the greatest comics shop on the planet GOSH! Comics of London.
Doctor Who: Fifty Stories For Fifty Years — 2012… and the next fifty years
November 23rd, 2013
Before the last of these essays, a little bit of other stuff…
This post is going to go live at precisely midnight — at which point it will be the fiftieth anniversary of Doctor Who, and so this is the last of the fifty stories essays.
Enough people said they would want a book of this that I've put one together, and that is also available from midnight tonight. You can buy it as a paperback, hardback, Kindle ebook (US) (UK), or non-Kindle ebook (with no DRM on the ebooks). And for those of you who visit us at Thought Bubble, you can buy a paperback copy off me personally.
But don't worry if you're too poor to buy one, or you just don't like me and don't want me to have money — the essays are essentially the same as they were when published here, but without the dodgy screencaps, and with quite a bit of copy-editing and fact-checking. You can still read the original versions here for free.
But anyway, here's the last essay


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I love thick pile microfiber blankets. Only wool is warmer, and this doesn't itch! I got this throw for my living room sofa. It's great for napping under or bundling up when I don't want to crank the heater. It's warm, but won't leave me roasting. I got the red one, and I adore the color, but it had already bled through to the sherpa side when I got it. While I haven't seen any further bleeding through yet, I do expect it to get worse when I wash it. Luckily thusfar it's not rubbing off on anything else, so I'm not going to return it, but it makes it a little less presentable for guests.Read More
Like I said, the throw was very nice. Well made and a lovely color.It just wasnt what I needed at the time.Im sure most people would love it. It is luxurious, and a very nice warm color.Read More
A little smaller than I expected, but very warm and soft. The sherpa side can shed a bit if against the right kind of fabric, but generally I haven't had a problem.Read More
I bought two of these as a gift for Christmas. The throw was nice looking and very soft. I had them monogrammed and it looked great. The people I bought them for seemed to really like it!Read More
I ordered this for my boyfriend for Christmas and he loves it. It is a really good-looking blanket that will work with most living rooms due to the neutral colors. It is super soft and very warm! I just wish I had ordered one for myself....Read More
Micro Mink Sherpa Throw
Today: $31.49


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The best part about eating Chinese food is the confidence that comes when more than one billion people tacitly support your culinary decision. Eat with the in crowd with this Groupon.
Choose from Three Options
- $13 for $23.95 worth of halal Chinese and Indo-Pak food for two or more
- $26 for $46.95 worth of halal Chinese and Indo-Pak food for four
- $15 for $25 worth of halal Chinese and Indo-Pak food for delivery or take-out
- See the full menu
China 3
At China 3, chefs use Zabiha hand-cut meats to build a menu of halal Chinese and Indo-Pak dishes. Szechuan style shrimp, broccoli simmered in garlic sauce, and sweet and sour chicken showcase the culinary flavors of the far east. Meanwhile, South Asian classics include goat biryani and kabobs galore, all served with naan cooked in a traditional clay oven.
Customer Reviews
11981 S Apopka Vineland Rd
Orlando, FL 32836
+14074650788Get Directions


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Casey Foundation Fights Md. Over Land Seized for Highway
Friday, November 23, 2007
Maryland highway officials and the philanthropic Eugene B. Casey Foundation are battling in court over the state's decision to seize 405 acres of the foundation's land for the intercounty connector, even though the land is seven miles from the highway's planned route.
The state has taken the wooded, rolling hills in Boyds, and has offered to pay the foundation $3.44 million, to replace some of the parkland and mature forests that will be bulldozed to build the six-lane toll highway between Gaithersburg and Laurel. The Montgomery County parcel is part of the Maryland State Highway Administration's "environmental mitigation" plan, which received federal approval.
Environmentalists say the Casey land is too far away to help the wildlife in the more than 900 acres of forests, wetlands and parkland that the 18.8-mile highway will destroy. The bigger issue: The foundation, its attorney said, doesn't want to sell and thinks the state has no right to the property.
Bethesda lawyer Robert Park said the foundation wants to keep the property along Schaeffer Road, west of the South Germantown Recreational Park, as one of its many real estate investments. The state's powers of eminent domain, which allow it to seize private land for public use, he said, don't extend to taking property to mitigate a highway's environmental harm.
"They don't want to sell the property," Park said of Betty B. Casey and other trustees. "The state doesn't have the right to take this property."
The Casey Foundation is one of the Washington area's largest philanthropic organizations, with a net worth of $166 million, according to its 2005 federal tax filing. Eugene B. Casey, who died in 1986, was a developer and one of upper Montgomery's largest land owners. Betty B. Casey, 80, his widow, lives in Potomac, according to voter records.
The state took ownership of the foundation's property in May, after the trustees declined to negotiate a fair market price, said Melinda Peters, the intercounty connector's project director. Upon seizing the land, the state deposited its purchase offer of $3.44 million with the Montgomery Circuit Court and filed a condemnation case against Betty Casey and other trustees. A judge is expected to rule in spring on whether the state has the right to seize the land.
County Council President Marilyn Praisner (D-Eastern County), who opposes the connector, said the Casey property didn't need to be protected. Because of its rural zoning, she said, it was never at risk of being densely developed.
"What sticks in my craw is it's nowhere near the neighborhoods or forests being impacted by the intercounty connector," Praisner said. "To pick a parcel just because it's a big forested area so far away may meet the letter of the requirement, but it sure as heck doesn't meet the spirit of it."
Peters said the state condemned the Casey property at the suggestion of 13 agencies, including the National Park Service, the Maryland Department of Natural Resources and the Maryland-National Capital Park and Planning Commission. It's part of the state's plan to provide 777 acres of parkland to replace the 88 acres that the connector will destroy.
In court filings, the Maryland attorney general's office says the Casey property qualifies as necessary for "public use" because buying forested parkland is required under that federally approved plan.
Dominic Quattrocchi, a senior planner for the Montgomery Department of Parks, said planners couldn't find such a large piece of privately owned forest closer to the connector route. Because it's surrounded by parkland, he said, the Casey parcel will contribute to an even larger swath of mature, protected forest that some birds, such as wild turkeys and warblers, need to breed and raise their young.


text:
Drs Wan and Hollins were joint first authors on this manuscript.
FUNDING/SUPPORT: The following funding bodies were involved in this study: Wellcome Trust Senior Clinical Fellowship (C. E. B.), Airway Disease Predicting Outcomes through Patient Specific Computational Modelling (AirPROM) project (funded through FP7 EU grant), MAARA, NC3R, and the European Regional Development Fund (ERDF 05567) part funded the research laboratories. This article presents independent research funded by the Leicester Respiratory National Institute for Health Research Biomedical Research Unit. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
∗CORRESPONDENCE TO: Christopher E. Brightling, PhD, FCCP, University of Leicester, Glenfield General Hospital, Groby Rd, Leicester, LE3 9QP UK
Copyright 2016, The Authors. All Rights Reserved.
Bronchial epithelial ciliary dysfunction is an important feature of asthma. We sought to determine the role in asthma of neutrophilic inflammation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in ciliary dysfunction.
Bronchial epithelial ciliary function was assessed by using video microscopy in fresh ex vivo epithelial strips from patients with asthma stratified according to their sputum cell differentials and in culture specimens from healthy control subjects and patients with asthma. Bronchial epithelial oxidative damage was determined by 8-oxo-dG expression. Nicotinamide adenine dinucleotide phosphate oxidase (NOX)/dual oxidase (DUOX) expression was assessed in bronchial epithelial cells by using microarrays, with NOX4 and DUOX1/2 expression assessed in bronchial biopsy specimens. Ciliary dysfunction following NADPH oxidase inhibition, using GKT137831, was evaluated in fresh epithelial strips from patients with asthma and a murine model of ovalbumin sensitization and challenge.
Ciliary beat frequency was impaired in patients with asthma with sputum neutrophilia (n = 11) vs those without (n = 10) (5.8 [0.6] Hz vs 8.8 [0.5] Hz; P = .003) and was correlated with sputum neutrophil count (r = –0.70; P < .001). Primary bronchial epithelial cells expressed DUOX1/2 and NOX4. Levels of 8-oxo-dG and NOX4 were elevated in patients with neutrophilic vs nonneutrophilic asthma, DUOX1 was elevated in both, and DUOX2 was elevated in nonneutrophilic asthma in vivo. In primary epithelial cultures, ciliary dysfunction did not persist, although NOX4 expression and reactive oxygen species generation was increased from patients with neutrophilic asthma. GKT137831 both improved ciliary function in ex vivo epithelial strips (n = 13), relative to the intensity of neutrophilic inflammation, and abolished ciliary dysfunction in the murine asthma model with no reduction in inflammation.
Ciliary dysfunction is increased in neutrophilic asthma associated with increased NOX4 expression and is attenuated by NADPH oxidase inhibition.
Normal mucociliary clearance is essential in pulmonary defense. Abnormal mucociliary clearance is a feature of asthma, particularly in severe disease, as a consequence of ciliary dysfunction. This ciliary dysfunction might contribute to the persistent inflammation and susceptibility to infection in the asthmatic airway, as evidenced by higher bacterial DNA level, and fungal colonization, in particular Aspergillus fumigatus.
Importantly, asthma is a heterogeneous disease and in addition to the Th2-mediated eosinophilic paradigm, neutrophilic-predominant inflammation is a feature of one third of patients with asthma.,,, Although the cause of neutrophilic asthma is unclear, it is associated with increased presence of proinflammatory and Th1 cytokines in sputum and bacterial colonization. Pathogens can exert direct toxic effects on ciliary function or indirectly via oxidative stress, and stimuli such as infection, pollutants and proinflammatory mediators can induce production of reactive oxygen species (ROS). The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)/dual oxidase (DUOX) family plays an important role in the generation of ROS and contains seven members: NOX1-5 and DUOX1/2. DUOX expression in the bronchial epithelium has been reported,,, and DUOXs have been shown to be important for neutrophil recruitment to the airways. In addition, we have previously reported that NOX4 expression was increased in airway smooth muscle in asthma, leading to increased ROS production and intrinsic airway smooth muscle hypercontractility. Whether NOX/DUOX expression is altered in the bronchial epithelium and possibly contributes to an increased susceptibility to ciliary dysfunction in asthma is unknown.
We hypothesized that ciliary dysfunction in asthma is due to a combination of an intrinsic abnormality in ciliary function and airway inflammation. To test our hypothesis, we assessed: (1) the ciliary beat frequency (CBF) in fresh ex vivo epithelial cells from patients with asthma with and without sputum neutrophilia, (2) the role of NADPH oxidases in ciliary function and their specificity to the neutrophilic asthma phenotype, and (3) the effects of NADPH oxidase inhibition on ciliary function in a murine in vivo ovalbumin (OVA) sensitization and challenge model.
A more detailed description of the methods is available in e-Appendix 1.
Patients with asthma and healthy control subjects were recruited from a single center (Glenfield Hospital). Asthma severity was defined by using the Global Initiative for Asthma (GINA) treatment steps (mild to moderate asthma, GINA steps 1-3; severe asthma, GINA steps 4-5). The study was approved by the Leicestershire Ethics Committee (UHL 10613), and patients gave their written informed consent.
Primary epithelial cells were isolated from bronchial brushes during bronchoscopy. Experiments were undertaken by using epithelial human bronchial epithelial cells, characterized by cytokeratin 5 and 14 (Abcam) expression. Ciliary function was assessed in ciliated air-liquid interface (ALI) cultures or fresh epithelial strips by using video microscopy as previously described.,
Human bronchial biopsy specimens were embedded in glycomethacrylate. Sections were stained by using an 8-oxo-dG monoclonal antibody, anti-NADPH oxidase 4 antibody (Abcam), anti-DUOX1 (Abcam), and anti-DUOX2 (Millipore) or corresponding isotype control (DAKO and ImmunoStep). Staining intensity above isotype control for 8-oxo-dG expression was assessed by using a semiquantitative scoring ranging from none to low, moderate, or high staining (0-3). For NOX4 and DUOX1/2, staining intensity was measured in all areas of epithelium by thresholding using CellˆF software (Olympus). All assessments were made by an observer blinded to the subjects' clinical characteristics. Cytospins of human bronchial epithelial cells were labeled with polyclonal rabbit antibodies to NOX1 and NOX4 (4 μg/mL, Insight Biotechnology; 4 μg/mL, Abcam, respectively) or the corresponding isotype control (BD Bioscience). They were indirectly labeled with an R-Phycoerythrin-conjugated secondary antibody (AbD Serotec). Cells were counterstained with 4′,6′-diamidino-2 phenylindole (1 μg/mL; Sigma-Aldrich).
Total RNA was extracted from epithelial ALI cultures by using an RNeasy Mini Kit with DNase I treatment (Qiagen). Complementary DNA synthesis and quantitative polymerase chain reaction were performed with a two-step real-time quantitative polymerase chain reaction kit (Invitrogen) by using the Chromo4 Real-Time Detector and Opticon Monitor 3 (Bio-Rad Laboratories). The internal normalizer gene was 18S RNA amplified with 18S primer forward (h18SRNA.891F:GTTGGTTTTCGGAACTGAGG) and 18S reverse primer (h18SRNA.1090R:GCATCGTTTATGGTCGGAAC); amplification of NOX4 was with primers forward (hNox4.598F:TGGCTGCCCATCTGGTGAATG) and reverse (hNox4.878R:CAGCAGCCCTCCTGAAACATGC). Primers (Operon MWG Biotech) and reaction mix (Invitrogen) were used as described previously. Relative quantification of NOX4 messenger RNA (mRNA) was performed by using the comparative 2−ΔΔCt method and expressed as fold-change. The internal normalizer gene was 18S RNA.
RNA expression levels from basal epithelial cells were examined by using the Human Genome U133A probe array (GeneChip; Affymetrix). Hybridized biotinylated complementary RNA was stained with streptavidin phycoerythrin (Molecular Probes), scanned with a HP GeneArray Scanner (Hewlett-Packard). Image data from each microarray were individually scaled to an intensity of 200 by using GeneChip Operating Software (Affymetrix). Scaled average differences and absolute call data were exported to text files for further analysis.
Intracellular ROS generation in human bronchial epithelial cells was quantified by using 5-(and-6)-carboxy-2′, 7′-dichlorofluorescein diacetate oxidation.
In a standard murine model of OVA sensitization and challenge protocol that was adapted from Caceres et al, airway inflammation, remodeling, and ciliary function were assessed. The University of Leicester Ethics Committee and the UK Home Office approved the experimental protocols.
To investigate the effects of NADPH oxidase inhibition in asthmatic epithelial cells and a murine model, we used GKT137831 (Genkyotex), a NADPH oxidase inhibitor that is selective for NOX1 and NOX4 vs NOX2, NOX3, and NOX5. GKT137831 has greater selectivity and potency for NOX4 than for NOX1. Its potential inhibitory effects on DUOX1/2 have not been fully explored.
Statistical analyses were performed by using PRISM version 6 (GraphPad Software). Parametric data were described as mean ± SEM; geometric mean ± 95% confidence intervals (CIs) were used for log normally distributed data, and nonparametric data are presented as median ± interquartile range. Comparisons between groups were assessed by using t tests (Mann-Whitney U test for nonparametric data). Comparisons across ≥ 3 groups were analyzed by using an analysis of variance (ANOVA) model (Kruskal-Wallis test for nonparametric data) with post hoc pairwise comparisons with the Tukey test (the Dunn test for nonparametric analyses). Sputum eosinophil (> 3%) and neutrophil (> 61%) counts were used as cutoffs to define inflammatory asthma phenotypes. Statistical analyses were performed as indicated in the figure legends, and P < .05 was taken as the level of statistical significance.
Clinical characteristics of the subjects who provided bronchial biopsy specimens for immunohistochemistry or epithelial brushings for ex vivo bronchial epithelial strips are shown Table 1.
Data are presented as mean ± SD unless otherwise indicated. GINA = Global Initiative for Asthma; IgE = immunoglobulin E; NA = not applicable.
CBF was reduced in patients with neutrophilic vs nonneutrophilic asthma (mean difference ± 95% CIs, –2.97 ± 0.87; P = .003) (Fig 1A) and was correlated with the percent sputum neutrophil count (r = –0.70; P < .001) (Fig 1B). Compared with our previously published CBF in healthy control subjects (10.7 ± 0.4 Hz), CBF was reduced in those patients with asthma with sputum neutrophilia (5.8 ± 0.6 Hz; P < .0001) but not in those without sputum neutrophilia (8.8 ± 0.5 Hz; P = .089). There was no relationship between sputum eosinophil count and CBF (r = 0.19; P = .40) (Fig 1C).
Oxidative stress-induced DNA damage, represented by semiquantitative assessment of 8-oxo-dG expression, was increased in the bronchial epithelium in patients with neutrophilic asthma (Kruskal-Wallis test, P = .005) (Figs 2A, 2B) and in those with severe disease vs mild to moderate disease and healthy control subjects (Kruskal-Wallis test, P = .036; data not shown). The intensity of bronchial epithelial 8-oxo-dG expression was also correlated to airflow obstruction (rs = –0.68; P < .001) (Fig 2C) and the percentage of sputum neutrophils (rs = 0.48; P = .02) (Fig 2D).
Gene array analysis revealed the presence of NOX4 and DUOX1 and DUOX2 expression, but not the other NOX family members, in primary basal epithelial cells from ≥ 3 of the six donors with asthma. There was no significant difference in the proportion of healthy vs asthmatic donors who expressed NOX4, DUOX1, or DUOX 2, and their relative expression was not significantly different between cells from patients with asthma vs healthy control subjects (NOX4, 1.6-fold [0.79-3.1]; DUOX1, 0.87-fold [0.46-1.63]; and DUOX2, 1.12-fold [0.38-3.3]). The geometric mean (95% CI) percent β-actin expression was 0.07% (0.05-0.12) for NOX4, 0.69% (0.56-0.95) for DUOX1, and 0.45% (0.06-1.3) for DUOX2. We therefore focused our immunohistochemical analysis of bronchial biopsy specimens on NOX4 and DUOX1/2.
NOX4 protein expression in epithelial cells of tissue bronchial biopsy specimens was significantly increased in patients with neutrophilic asthma (29.5% ± 3.7%) compared with patients with nonneutrophilic asthma (18.5% ± 3.2%; P = .041) and with healthy control subjects (18.6% ± 2.9%; P = .032) (ANOVA, P = .040) (Figs 3A, 3C), and it was significantly correlated with sputum neutrophil count (r = 0.52; P =.042) but not with lung function. DUOX1 protein expression was increased in the epithelium in patients with nonneutrophilic (29.0% ± 7.4%) and neutrophilic (22.3% ± 4.7%) asthma vs healthy control subjects (9.8% ± 3.2%; P = .026 and P = .041, respectively); it was not differentially expressed in neutrophilic vs nonneutrophilic phenotypes (P = .465) (ANOVA, P = .048) (Figs 3B, 3D) and did not correlate with sputum neutrophil count (r = –0.06; P = .832). Although DUOX2 was expressed in a much lower percentage of epithelium, a significant increase was seen in patients with nonneutrophilic asthma (0.97% ± 0.29%; P = .026) but not neutrophilic asthma (0.58% ± 0.15%; P = .072) compared with healthy control subjects (0.27% ± 0.07%), and expression was not differentially expressed in neutrophilic vs nonneutrophilic phenotypes (P = .258) (ANOVA, P = .045) (e-Fig 1).
NOX4 mRNA in epithelial ALI cultures was significantly increased in neutrophilic asthma samples compared with healthy control samples (P = .009) and nonneutrophilic asthma samples (P = .0061) (ANOVA, P = .004) (Fig 3E). NOX4 mRNA expression, as with DNA damage, was correlated to airflow obstruction (r = –0.54; P = .039) (Fig 3F). In basal epithelial cells, NOX4 mRNA expression was similarly elevated, although not significantly, in the neutrophilic subtype compared with the health and the nonneutrophilic subtype (data not shown). At the protein level, basal epithelial cells expressed NOX4 by immunofluorescence (Fig 3G) but not NOX1 (data not shown).
Baseline ROS production did not differ between health and nonneutrophilic or neutrophilic asthma. However, ROS-induced ROS production in response to H202 stimulation increased in neutrophilic asthma compared with health and nonneutrophilic asthma as the concentration of H202 increased. Indeed, the maximal H2O2-induced intracellular ROS generation in basal epithelial cells was significantly increased in patients with neutrophilic asthma (mean ± SEM optical density, OD arbitrary units) (3,380 ± 270) compared with health (2,371 ± 252; P = .02) but not significantly increased compared with patients with nonneutrophilic asthma (2,542 ± 398; P = .11) (ANOVA, P = .037) (Figs 4A, 4B). The response to this maximum dose demonstrated a trend to a correlation in the percentage of sputum neutrophils (r = 0.4; P = .052). GKT137831 at 20 μM (Genkyotex) significantly reduced H2O2-induced (10 mM) intracellular ROS generation, in health from 1,849 ± 281 to 826 ± 194 (mean difference [95% CI], 1022 [–1407 to –638]; P = .001), and in asthma from 2,356 ± 246 to 1,247 ± 134 (–1,130 [–1,429 to –830]; P = .0002) (Fig 4C). GKT137831 similarly attenuated 1 mM H2O2-induced ROS generation. In patients with asthma, this reduction by GKT137831 (–1,362 ± 105) was greater than with N-acetylcysteine (5 mM) (–1,044 ± 90) (mean difference [95% CI], –318 [–626 to –10]; P = .04) (Fig 4D). The reduction in H2O2-induced (10 mM or 1 mM) ROS generation in response to GKT137831 or N-acetylcysteine was not significantly different between health and asthma.
CBF and pattern were assessed in primary ALI cultured epithelial cells from subjects with and without asthma by using high-speed video microscopy (Videos 1A-1D). In contrast to our ex vivo observations, there was no significant difference in the mean ± SEM CBF between health and disease according to the scraping method (difference between means, 0.12 ± 1.4 Hz; P = .93) (Fig 5A) or the overhead viewing method (difference between means, 0.80 ± 1.40; P = .57 [five healthy control subjects and 20 patients with asthma]; data not shown). There were no relationships with asthma severity (data not shown) or sputum neutrophil count (rs = –0.32; P = .34). Beat patterns were similar in the healthy control and asthmatic groups, including percentage of normal cilia (50 ± 7% vs 40% ± 5%; P = .28) (Fig 5B), dyskinetic cilia (41% ± 7% vs 53% ± 4%; P = .15) (Fig 5C), and static cilia (9% ± 3% vs 7% ± 2%; P = .58) (Fig 5D). These findings, together with similar levels of ciliogenesis in culture between asthma and health (60% ± 6% vs 63% ± 4%; P = .72) and surface morphology index (1.6 ± 0.14 vs 1.7 ± 0.12; P = .54), suggest the bronchial epithelial cells from patients with asthma do not have a primary deficiency in differentiation.
To further establish the role of NADPH oxidase in ciliary dysfunction in asthma, we investigated the effect of GKT137831 on ciliary function of fresh bronchial epithelial strips studied within 1.5 h of bronchoscopy. These experiments were performed without any additional stimuli in contrast to the in vitro experiments described earlier. Using these fresh samples from patients with asthma, GKT137831 (5 μM and 20 μM) significantly increased CBF from baseline over the 1 h of incubation. GKT137831 20 μM at 1 h resulted in elevated CBF (10.9 ± 0.6 Hz), significantly different from baseline (6.4 ± 0.5 Hz) (mean difference [95% CI], 4.5 [3.5-5.5]; P < .0001) and from the diluent controls (8.9 ± 0.9 Hz, 2.0 [0.6-3.4]; P = .01) (Fig 6A). With GKT137831 20 μM, the percentage of normal cilia increased from 32% ± 5% to 48% ± 6% (mean difference [95% CI], 16% [10-22]; P < .0001) at 0.5 h and from 28% ± 5% to 45% ± 5% (mean difference [95% CI], 17% [6-27]; P = .01) at 1 h vs diluent (Fig 6B). The percentage of dyskinetic cilia was reduced from 57% ± 4% to 50 ± 5% (mean difference [95% CI], –7% [–14 to 0.3]; P = .04) at 0.5 h (Fig 6C) vs diluent. This improvement in CBF in response to NADPH oxidase inhibition was in fact due to cilia motility. NADPH oxidase inhibition lowered the proportion of static cilia compared with diluent, from 11% ± 4% to 2% ± 1% at 0.5 h (mean difference [95% CI], –9% [–16 to –2]; P = .01) and from 17% ± 7% to 2% ± 1% at 1 h (mean difference [95% CI], –15% [–29 to –0.6]; P = .04) (Fig 6D). Sputum neutrophil count was correlated to the GKT137831-induced reduction in the percentage of static cilia (r = 0.61; P = .03) (Fig 6E). It was also correlated to the percentage of normal cilia (r = 0.55; P = 0.05 [data not shown]). These improvements were significantly different in patients with neutrophilic vs nonneutrophilic asthma (Fig 6F).
In a murine model of OVA sensitization and challenge with the use of a standard protocol (Fig 7A), there was evidence of inflammation in the bronchoalveolar lavage, which was predominantly neutrophilic (Fig 7B) as well as ciliary dysfunction (Figs 7C, 7D). Administration of GKT137831 following OVA sensitization resulted in no significant change in bronchoalveolar lavage total inflammatory cell count (OVA sensitization alone vs GKT137831 alone, 303 [243-660] cells vs 240 [14-413] cells; P = .33) or cell differential. Following sensitization and challenge with OVA, the CBF was markedly impaired (P < .001 compared with baseline), and the addition of GKT137831 improved this finding almost back to baseline (P = .003). Similarly, the percentage of ciliated cells was reduced following sensitization and challenge with OVA compared with baseline (P = .007) and was restored following the addition of GKT137831 (P = .024).
To our knowledge, we report here for the first time that bronchial epithelial ciliary dysfunction in asthma is related to neutrophilic inflammation. This ciliary dysfunction, evident in vivo, does not persist in vitro, suggesting that the asthmatic airway environment is essential in the development and maintenance of ciliary dysfunction. In contrast to DUOX1, which was increased in asthma independent of inflammatory phenotype, and DUOX2, which was only increased in nonneutrophilic asthma, NOX4 expression was upregulated only in the bronchial epithelium from patients with asthma with neutrophilic inflammation in vivo. This increased NOX4 expression was also present in vitro with NADPH oxidase-dependent increased ROS generation in primary epithelial cells from patients with asthma with neutrophilic inflammation. Critically, NADPH oxidase inhibition completely abrogated ciliary dysfunction in ex vivo epithelial strips, as evidenced by restoration of CBF to the frequency we previously described in epithelial strips from healthy subjects and in an in vivo murine model of asthma with evidence of neutrophilic lung inflammation, but it did not significantly reduce this inflammation. Taken together, these findings support the view that ciliary dysfunction in asthma is both NADPH oxidase-dependent (in particular NOX4) and inflammation-dependent, with both necessary but neither sufficient, as persistent ciliary dysfunction was not observed in vitro despite increased NOX4 expression, and NADPH oxidase inhibition abolished ciliary dysfunction without affecting airway inflammation.
Noneosinophilic, and specifically neutrophilic, asthma is common but responds poorly to corticosteroid therapy. Neither the mechanisms nor the clinical management of neutrophilic asthma are fully understood. Oxidative stress and neutrophilia are often associated, and, consistent with this view, we found that neutrophilic asthma and airflow obstruction were associated with oxidative DNA damage, as evidenced by increased bronchial epithelial 8-oxo-dG expression assessed semiquantitatively. Critically, we extended our earlier observation that ciliary dysfunction is impaired in asthma and associated with increasing severity to demonstrate that this ciliary dysfunction is a particular feature of neutrophilic asthma. Normal ciliary function is a key component of innate immunity, and its impairment is likely to promote persistence of inflammation and increase risk of airway infection and colonization by pathogens.,, Indeed, macrolide antibiotics have demonstrated efficacy in noneosinophilic asthma, but concerns related to antibiotic resistance as a consequence of long-term widespread antibiotic use highlight the need for new therapies to treat neutrophilic asthma. The biologic relevance of the magnitude of CBF changes we observed in fresh bronchial strips following GKT137831 treatment must be addressed in future studies. However, following exposure to GKT137831, the CBF in the patients with asthma improved to a level we have reported previously in health and the improvement above diluent (2 Hz) was similar to the differences observed between health and COPD.
NADPH oxidases play a critical role in ROS generation. NOX4 and DUOX1/2 expression in the epithelium was evident in asthma. DUOX1 was increased in asthma independent of inflammatory phenotype, and DUOX2 was only increased in nonneutrophilic asthma. In contrast, NOX4 was only increased in neutrophilic asthma. NOX4 plays a crucial role in regulating altered oxidative pathways in idiopathic pulmonary fibrosis,, and several nonrespiratory diseases,,, and its expression is upregulated by oxidative stress itself and inflammation. We found that increased ROS in the bronchial epithelium was a feature of neutrophilic asthma that persisted in vitro in association with increased NOX4 expression. Although NOX4 might be upregulated by neutrophilic inflammation, its overexpression can occur independently of the asthmatic environment. Importantly, ciliary dysfunction did not persist in vitro, suggesting this NOX4 upregulation was not itself sufficient to drive ciliary dysfunction but also required the presence of airway inflammation.
Beyond asthma, bronchial epithelial ciliary dysfunction is a fundamental abnormality in bronchiectasis, as well as in COPD. Antioxidant therapy, such as N-acetylcysteine, has been considered in these conditions; however, studies are inconsistent with benefits demonstrated in some studies but not in others., The magnitude of benefit is also relatively small, possibly due to poor tolerance of high concentrations of the therapeutic agent, questionable bioavailability, and use of nonspecific antioxidant therapies that enhance the clearance of ROS rather than targeting ROS generation. Our findings suggest that NAPDH oxidase inhibition, which reduces intracellular ROS generation, improves ciliary dysfunction and thus extends the potential role of NADPH oxidases (and particularly NOX4) in asthma beyond the described impact of upregulated NOX4 on airway smooth muscle hypercontractility.
A major limitation of our study is that although GKT137831 has good specificity and potency for NOX4, it also has effects on NOX1 and is likely to exert effects on DUOX, as has been observed with similar inhibitors in this class (eg, GKT136901). Our findings support a key role for NOX4; the expression of this NOX family member was increased in neutrophilic asthma and associated with ciliary dysfunction. However, we cannot fully exclude possible contributions from other mechanisms, including other members of the NOX family (particularly DUOX1/2). In addition, due to the considerable homology in the amino acid sequence of DUOX1 and DUOX2, the DUOX2 antibody may cross-react with DUOX1. However the amount of staining seen with the DUOX2 antibody is considerably less than that with the DUOX1 antibody. Thus, we are confident that DUOX2 is not highly expressed in the bronchial epithelium. One further potential limitation of our study is the lack of direct in vivo human data demonstrating that NADPH oxidase inhibition modifies ciliary function and inflammation. However, we have confirmed the importance of NADPH oxidase in ciliary dysfunction in fresh ex vivo primary cells studied immediately after obtaining the cells at bronchoscopy, and we supported the observations by using an in vivo murine model of asthma with neutrophilic lung inflammation. This asthma model clearly showed that NADPH oxidase inhibition markedly improved ciliary function but did not significantly attenuate lung inflammation. These findings suggest that although the presence of inflammation might be important for NOX4 activation, it is the consequent ROS generation rather than the inflammation per se that is critical in ciliary dysfunction.
Bronchial epithelial cells from patients with asthma with neutrophilic airway inflammation exhibit heightened NOX4 expression and ROS generation. NADPH oxidase inhibition in an in vivo murine model of asthma improved ciliary function, which was also confirmed in ex vivo bronchial epithelial cells from patients with neutrophilic asthma. These findings support the view that NADPH oxidase inhibition (and in particular NOX4) might present a new stratified approach for the treatment of neutrophilic asthma.
Author contributions: C. E. B. is the guarantor for the manuscript. C. S., A. W., C. O., P. W. A., and C. E. B. conceived the study. W-Y. H. W., F. H., L. H., L. W., and R. A. H. collected the data. W-Y. H. W., F. H., L. H., L. W., R. A. H., E. G., V. M., and A. S. performed the assays. W-Y. H. W., F. H., L. H., L. W., R. A. H., S. B., R. S., D. D., L. C., and C. E. B. analyzed the data. W-Y. H. W., F. H., R. S., and C. E. B. wrote the manuscript. All authors provided critical review of the manuscript and approved of its contents and submission.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. D. has received speakers fees from AstraZeneca, Boehringer Ingelheim, and Chiesi Pharmaceuticals. C. S. is a paid employee and owns shares of Genkyotex SA. A. W. serves on advisory boards for GlaxoSmithKline and receives research support from GlaxoSmithKline, Pfizer, and AstraZeneca. C. E. B. serves on advisory boards for GlaxoSmithKline, AstraZeneca, MedImmune, Roche, and Aerovance; receives honoraria from Novartis; and receives research support from GlaxoSmithKline, AstraZeneca, and MedImmune. None declared (W.-Y.H.W., F.H., L.H., L.W., R.A.H., S.B., E.G., A.S., L.C., V.M., A.W., R.S., C.O., P.W.A.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors thank Genkyotex for donating compound GKT137831. The authors also thank all the clinical staff for helping with collecting samples and patient details, Myriam Bahri, BSc, for her help with immunohistochemistry, and the patients for their participation in this study.
Additional information: The e-Appendix, e-Figure, and Videos can be found in the Supplemental Materials and Multimedia sections of the online article.
e-Online Data
Video 1A
Video 1B
Video 1C
Video 1D
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Blip.fm is internet radio made social. It's easy to search for, play, and discover free music recommended by real people. Join today to create your own free station and start listening to @Triptonic.
What other DJs are saying about Electric Moon-Mental Record
PennyDreadfulsNightmareJuice Time to crawl off to bed before the sun rises. :*
lalunajade Electric Moon ~ Mental Record


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