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Doctor insights on:
Black Specks Under The Fingernails
What causes black vertical lines under fingernails ? I am asking for a 66 yr. Old male.
Blood clots : Tiny blood clots, usually broken off from heart valves then float to the end arteries of the fingertips and get caught in the capillaries of the nail bed. They are not dangerous in and of themselves, but could be reflective of a heart problem. ...Read more
Fingernails (Definition)
Fingernails are the hard coverings at the end of fingertips. Nails are made out of a protein called keratin. they function to protect the fingertip and to increase sensitivity of touch. Good hand hygiene and nail care is important to prevent bacterial ...Read more
I've noticed small/thin black lines keep appearing under the tips of my fingernails over the past few days. What could this be from?
Splinters: Thin longitudinal black lines under fingernails can be what doctors call "splinters" & can reflect tiny blood clot emboli that get caught there, where there are end arteries & capillaries. Such tiny clots end up there after being generated inside left chambers of heart. Cardiologist exam indicated & urgently if dizzy, feverish, chest pain, irregular heart beats or shortness of breath. ...Read more
Hi, i am scared, my fingernails have changed colour, i did used to have black under my fingernails and i hope it is just fungi, please help me?
Don't be scared: Have you family make you an appointment to see dermatologist to diagnose. Nails can change color for many reasons, and usually nail fungus is yellow and white ...Read more
I have a small black spot under my thumb fingernail, what is it ?
Have it evaluated: Have it evaluated. It is often nothing but it may be a more serious condition such as a melanoma. ...Read more
Should i be concerned about black lines growing under my fingernails? I'm a 51 year old black female, my father had heart disease, no information on my mother, i'm approximately 170 lbs, 5"3, medium build. I work third shift, i don't exercise regularly,
Hello. : Hello. Sometimes black lines can be small splinter hemorrhages. Sometimes black lines can be associated with skin cancer. Do recommend that you see a dermatologist to have this evaluated to ensure that it is not from a worrisome cause. Take care. ...Read more
One of my fingernails is turning black and they all have ridges. ....what could be causing this?
Nail issues: The best thing would be to have it checked out as it could be anything from fungal infection to injury or other disease. If you have ridges it could also be fungal infection but it is difficult to say without looking at it. See your doctor. If it developed acutely it could be an injury but you would have known it since it would be painful to have it bleed and have the blood underneath turn dark. ...Read moreSee 1 more doctor answer
I have a small single black line on the tip of my fingernail. It looks like a small splinter...What could it be?
Splinter hemorrhage: It's called a splinter hemorrhage. If you only have them occasionally, don't worry about it. ...Read more
What are the best places to tell what are black lines in fingernails?
Dermatologist: Your dermatologist is the best source for determining the cause and treatment of black lines in fingernails. ...Read more
I get thin, short, black vertical lines beneath my fingernails that grow out. Months will pass and no lines and then they appear again. What are they?
Nail anomalies : Such discolorations can be caused by intermittent trauma to the nail unit from biting or banging , etc. Other causes could be low-grade infection or inflammation. ...Read moreSee 1 more doctor answer
One of my fingernails is black by the cuticle and on the front. It doesn't wash off. Is it a fungus?
Not necessarily: If it appeared quickly, like over night, then it most probably is trauma. It may also be a mole growing in the area or a fungus. Smokers may get some black in the cuticle and nail. If it lasts for more than two weeks, then go to your dermatologist to have it diagnosed. ...Read more
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- Black lines under fingernail
- Black dots under fingernails
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- Black dot under fingernail
- Black splinter lines under fingernails
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- What are the black spots under my fingernails?
- Talk to a dermatologist online


text: Pro Wrestling Revolution presents this singles contest between "Old School" Oliver John and Go Shiozaki with "The King" Harley Race in his corner. After watching this one, all you're going to say is "WOW!" Oliver John and Go Shiozaki are two of the toughest guys in the business, and they go at it tooth and nail in a back and forth battle. It's hard to see someone win and the other lose when there's a match between two iron wills.

subset: commoncrawl


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(This story first ran at PressConnects.com) BALTIMORE — At 26 years old, UFC light-heavyweight champion Jon Jones admits it is difficult even for him to realize he could soon be considered the best fighter in the history of mixed martial arts. But it's a reality (…)
MANCHESTER, England – If Daniel Omielanczuk was hoping that fighting in the clinch would help him negate Stefan Struve's massive height advantage, he found out relatively quickly how wrong he was.Fil read news >>
Stefan Struve showed off an impressive ground game at UFC 204 read news >>
Struve Dominant On Ground In UFC 204 Win Over OmielanczukEngland continues to be very good toUFC heavyweight Stefan Struve.Fouryears after a TKO victory over UFC heavyweight champion Stipe Miocic, St read news >>
Stefan Struve's height is a weapon in every fight, but it was his often overlooked ground game that ultimately won him his fight with Daniel Omielanczuk.Filed under: News, UFC, Videos read news >>
Check out the UFC 204 fight highlights of Stefan Struve vs. Daniel Omielanczuk from Manchester, England. read news >>
MANCHESTER, England – Although unhappy with how his body performed at Saturday's UFC 204 event, Stefan Struve is ready to address the issues and resume his title walk: "I want to work my way up, back read news >>
Heavyweight Stephan Struve now has three victories in his last four fights, but he doesn't necessarily think he's placed himself in title contention just yet. read news >>
Fresh off a submission victory and now on a solid 3-1 run, Stefan Struve said he's ready for a step up in competition.Filed under: News, UFC read news >>


text:
Development in the city is regulated by the General Plan and by specific zoning ordinances. In addition, the following guidelines may be helpful in planning your project.
- Guide to Residential Design
- North Park Street Design Manual
- Webster Street Design Manual
- Window Replacement Design Guidelines
For other relevant forms, visit our Forms and Handouts page, or contact the Community Development Department directly at (510)747-6850.


text:
Kevin Cowherd of the Baltimore Sun joins the Norris & Davis Show every Tuesday at 7:20 a.m. to discuss the latest in sports – the good, the bad and the idiocy! Great perspective on Baltimore sports & more.
Terps Grant Releases, Randy Moss & Swimsuit ModelsFebruary 14, 2012 2:54 PM
Wide receiver Randy Moss (formerly of the Minnesota Vikings … twice) was caught with marijuana during a traffic arrest in Minneapolis in 2002. He later told Bryant Gumbel he smoked pot "every blue moon."(Credit:Brian Bahr/Getty Images)


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Do you need access to a Commercial Carpet Cleaning service?
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As specialists in Commercial Carpet Cleaning and with years of experience servicing a range of industries, the UK Commercial Cleaning team deliver unrivalled and affordable cleaning solutions for you and your organisation. We have the time, equipment and expertise to care for your carpets, and work with you to achieve excellent results every time.
As the UK's leading Commercial Carpet Cleaners, we understand that first impressions do count and in hotels, offices and other commercial environments, customers often look to your floor covering to indicate the quality of your organisation. Carpet is used in many commercial settings, however, caring for this surface appropriately can be difficult for time poor business owners that understandably do not have the knowledge or equipment to deliver Commercial Carpet Cleaning techniques.
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UK Commercial Cleaning offer a comprehensive carpet cleaning service; we pride ourselves on our professionalism and the outstanding results achieved for both our domestic and commercial clients throughout the UK.


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Not Accepting Guests
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- Last login about 1 month ago
Join Couchsurfing to see Althea's full profile. It's free!
About Me
Discover new things and learn as much as I could
I'm a bit of a dreamer and an idealist. I love discovering new things and coming up with new ideas. I've gone through quite a lot of changes and challenges in my life and they only made me a better person. That is why I love traveling, exploring new things and especially meeting new people. I love exchanging stories and having genuine interactions with people. I enjoy spending time with all types of people, because I believe there is always something we can learn from each other no matter what. :)
I have lived in Hong Kong, United States, and now living in Cologne, Germany, studying and working.
If you want to know more about me, you can go to my website:
or see my performances on my YouTube channel:
visited 7 states (3.11%)Create your own visited map of The World or jurisdische veraling duits?
Enjoy every single moment in life. Appreciate and be grateful for every little thing that happens in life. Step out of your comfort zone once in a while. Never stop exploring.
Why I'm on Couchsurfing
-Meeting couchsurfers in every city I visit.
-Showing people around my own city.
-Go to meetings and events to meet other couchsurfers.
I've met a lot of awesome people in different places through CS!
Music, Art, Books, Photography, Nature, Cooking, Good Food & Wine.
- arts
- books
- photography
- perfumes
- dining
- cooking
- wine
- traveling
- music
One Amazing Thing I've Done
Amazing thing I've done: Probably how I'd grown from the person I was to the person I am right now. It's amazing how much one could change. It has been a long and adventurous journey and I'm expecting more of that.
Teach, Learn, Share
I am a classical pianist. To me, music is a huge part of my life. I have learned so much about myself and life in general through music and I'd love to share this amazing experience with others.
Countries I've Visited
Canada, Czech Republic, Denmark, France, Germany, Italy, Japan, United Kingdom
Countries I've Lived In
China, Germany, United States


text:
UConn, Syracuse share No. 1 in Big East preseason basketball poll
By The Associated Press
October 19, 2011, 2:48PM
The future of the conference - Syracuse is leaving and UConn may follow - was a major subject of discussion. Full story »
UConn center Michael Bradley needs surgery for broken ankle
By The Associated Press
October 18, 2011, 2:57PM
The redshirt freshman will need about 6 weeks of rehabilitation. Full story »
10,000 fans watch as UConn Huskies - men and women - put on 'First Night' basketball show
By The Associated Press
October 14, 2011, 10:16PM
In addition to the upcoming season, the future of the Big East was a major topic of conversation. Full story »
UConn basketball coaches endorse remaining in Big East
By The Associated Press
October 12, 2011, 11:00PM
Jim Calhoun and Geno Auriemma said, however, that the school must do what is best for its programs. Full story »
UConn men's basketball coach Jim Calhoun says he is 'pro Big East'
By The Associated Press
October 12, 2011, 6:13PM
The coach said he believes the conference is stronger in basketball than the ACC, where Syracuse and Pittsburgh are headed. Full story »
UConn basketball kicks off season with annual Husky Run
By The Associated Press
October 12, 2011, 10:47AM
The 3.4-mile run scheduled for Wednesday afternoon precedes the official start of practice on Friday, and gives the coaches a chance to see which players are coming into the year in top physical shape. Full story »
UConn center Michael Bradley sacrifices scholarship to make way for prize recruit Andre Drummond
By The Associated Press
October 12, 2011, 10:37AM
Initially, Drummond had planned to attend Wibraham & Monson Academy as a post-grad. Full story »
UConn men's and women's basketball to kick off seasons at Friday's 'First Night' show
By The Associated Press
October 10, 2011, 10:33AM
Practice opens on Friday with the annual "First Night" show, a free event that will feature an autograph session, a dunk and three-point contest, and other games. Full story »
Big East, Big 12 discuss merger as members bolt for other conferences
By The Associated Press
September 20, 2011, 8:53AM
School and conference officials from the two leagues have been discussing ways to merge what's left of them if Texas and Oklahoma leave the Big 12, a person involved in the discussions told The Associated Press. Full story »
UConn names Karl Hobbs director of men's basketball administration
By The Associated Press
July 20, 2011, 9:56AM
Karl Hobbs was a point guard and team captain for the Huskies in the early 1980s and spent the last decade as head coach at George Washington University. Full story »
UConn president hopes Jim Calhoun remains head basketball coach
By The Associated Press
July 07, 2011, 2:20PM
New president Susan Herbst hopes the 69-year old Hall of Famer remains one of the institution's faces. Full story »


text:
Empty Netter Assists - 07-22-10
-Ray Shero (above) discussed the salary cap with Adam Gretz of AOL's Fanhouse.
-By way of the Penguins' Twitter page, ice has begun to appear at Consol Enery Center:
-Former Wilkes-Barre/Scranton Penguins defenseman Wade Brookbank signed with the Rockford IceHogs, the Blackhawks' AHL affiliate.
-Happy 40th birthday to former Penguins defenseman Sergei Zubov (right). A star with the Rangers, Zubov came to the Penguins in the 1995 offseason along with Petr Nedved in a deal which sent Luc Robitaille and Ulf Samuelsson to New York. Zubov only lasted on season with the Penguins, but he managed to churn out one of the most productive campaigns by a defenseman in franchise history. In 64 games, he was able to produce 66 points. To this day, Zubov is the last Penguins defenseman to produce more than a point per game during a single season. In the postseason, Zubov was once again stellar as he contributed 14 points in 15 playoff games. In the 1996 offseason, he was traded to the Stars in exchange for Kevin Hatcher. Zubov currently plays for SKA St. Petersburg of the KHL.
Atlantic Division
-While Ilya Kovalchuk (right) and the NHLPA can file a grievance in regards to his contract with the Devils the NHL rejected, the Devils do not have the right to pursue the same action.
-Devils overlord Lou Lamoriello still contends the contract complies with the terms of the NHL's collective bargaining agreement.
-The Flyers re-signed restricted free agent Darroll Powe to a one-year contract worth $725,000.
-The Islanders signed unrestricted free agent forward Jeremy Yablonski to a one-year, two-way contract.
-We try to avoid regurgatating rumors here, but this one is too ridiculous to pass up. Apparently someone called up an ESPN radio affiliate in New York and said Islanders goaltender Rick DiPietro was in a car wreck and suffered a broken back and pelvis. The story picked up steam on Twitter and eventually, rumors were running rampant that DiPietro had actually died.
-Katie Strang, the Islanders beat reporter for Newsday, jumped on Twitter and quickly stamped the bogus story out.
Northeast Division
-The Senators re-signed restricted free agent forward Nick Foligno (right) to a two-year contract worth $2.4 million.
-The Sabres avoided arbitration with restricted free agent forward Patrick Kaleta and signed him to a two-year deal worth a total of $1.815 million. He will have a salary cap hit of $907,000.
Southeast Division
-The Thrashers opted not to re-sign restricted free agent forward Clarke MacArthur after he was awarded a $2.4 million salary award by an arbitrator. As a result, he is now an unrestricted free agent.
Central Division
-The Blues re-signed restricted free agent forward David Perron to a two-year contract worth $4.3 million.
-It looks like the Predators are finally washing their hands of jailed investor and would-be Penguins owner William "Boots" Del Biaggio III.
Northwest Division
-The Flames re-signed restricted free agent forward J.D. Watt to a one-year, two-way contract.
Pacific Division
-The Kings haven't shut the door on signing Ilya Kovalchuk (right) just in case things don't work out for him in New Jersey.
Smythe Division
-A Manitoba man is in some hot water after he placed multiple calls to a 911 dispatcher and demanded the Royal Canadian Mounted Police bring back the Jets. No word yet if Bob Essensa was also included in the demands.
-Happy 101st birthday of former Pittsburgh Hornets forward Wilf Starr.
-Happy 64th birthday to former Pittsburgh Hornets forward Dave Rochefort.
(Photos: Shero-Jamie Sabau/Getty Images; Zubov-Penguins Hockey Cards; Kovalchuk-Jim McIsaac/Getty Images; Foligno-Abelimages/Getty Images; Kovalchuk-Alexander Nemenov/AFP/Getty Images)


text:
realmagick.com The shrine of knowledge.
Violence In Sports Prevention
A selection of articles related to violence in sports prevention.
Original articles from our library related to the Violence In Sports Prevention. See Table of Contents for further available material (downloadable resources) on Violence In Sports Prevention.
- Getting Up Again - A Story of Healing with Phosphorus and Anacardium
- Hope for the future gives life color and meaning. Having a body you can rely on is very important. In many cases the condition of the temple of our soul is a major key to happiness. And what makes healing so satisfactory is that the restoration of health...
Body Mysteries >> Homeopathy
- A View on the Wiccan Rede
- I was listening to radio evangelist Bob Larson talk to a witch on his radio show. The witch mentioned the Wiccan Rede "as you harm none, do as you will." He snorted and ridiculed the idea that such a simple idea could be a legitimate basis for...
Paganism & Wicca >> The Wiccan Rede
- The Religious Experience: A Wiccan Viewpoint
- What is religion? Religion is a set of beliefs which allow us to understand and categorize our world and our place in it. A set of beliefs which define our culture, our expectations, our views of people and behaviors we expect. I have found several different...
Religion & Philosophy >> Religions
- King James Bible: Genesis, Chapter 6
- Chapter 6 6:1 And it came to pass, when men began to multiply on the face of the earth, and daughters were born unto them, 6:2 That the sons of God saw the daughters of men that they were fair; and they took them wives of all which they chose. 6:3 And the...
Old Testament >> Genesis
- Tiwaz
- Welcome to Tyr's Aett, the third and final aett (group of eight) of the Elder Futhark. Tiwaz is the name of this aett's first rune in reconstructed Common Germanic. Its name became first Teiws in Gothic, then later Tiw or Tiu in Anglo-Saxon and Tyr in Old...
Divination >> Rune Stones
- Hypnosis References
- Bower, G. (1990). Awareness, the unconscious and repression : An experimental psychologist's perspective . In J.L. Singer (Ed.), Repression and Dissociation: Implications for personality, theory, psychopathology, and health . (Pp, 209-222). Chicago:...
Parapsychology >> Hypnosis
Violence In Sports Prevention is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Violence In Sports Prevention books and related discussion.
Suggested News Resources
- Vigil held for woman killed in front of children
- County Executive Rushern Baker is asking the County Council to approve spending one million dollars for domestic violence prevention and awareness. "We are committed to doing everything we can to stop these tragedies from happening," said Baker.
- Springfield police arrest man for strangling woman in car
- "They all fall under the abuse prevention act which is directed at preventing and holding those accountable during domestic violence situations," said Sgt. Pete Kirkpatrick from SPD.
- HIV cases up in Oneida Co.; domestic violence a risk factor
- "Every hour in the United States, a woman is infected with HIV," said Erin Bortel, director of prevention services for ACR Health, which serves a nine-county region, including an office in Utica.
- Study: Some Gun Control Laws Result in More Deaths
- Convention attendees look at rifles by Troy Defense at the 2016 National Shooting Sports Foundation's Shooting, Hunting, Outdoor Trade Show at the Sands Expo and Convention Center on Jan. ...
- The vicious cycle: Coachella kids cornered by gangs
- The Boys and Girls Club runs a program called Street SMART, a national violence prevention program that counsels members on how to avoid gangs and resolve conflicts respectfully.
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
Violence In Sports Prevention Topics
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Electra's Cruiser 1 is a stylish, great-riding cruiser. It features a classic steel frame, comfy seat, wide bars, easy-rolling 24-inch aluminum wheels, and plush whitewall tires. Plus, its smaller frame and wheel size are perfect for shorter adults and young riders. It also boasts Electra's Flat Foot Technology so you can place both feet flat on the ground anytime you wish for control.
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Love this bike. I use it for exercise.
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I use this bike for recreational riding in my neighborhood . Loosing five lbs in about three weeks with out even knowing it. It's comfortable to ride. I think the big wheels and comfortable seat work together for a smooth ride even on rough streets. The up right ride is great,made me give up my thin wheeled uncomfortable racer. I'm 55 years old and enjoying biking again!
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Here are three keys for Clemson against West Virginia in tonight's Discover Orange Bowl:
1. Pressure quarterback Geno Smith. West Virginia depends on its passing game, and whatever Clemson can do to disrupt that will be a difference in the game. Smith has only thrown seven interceptions this season, so he's not mistake-prone, and he ranks seventh in the nation in passing average (331.5 yards/game) and ninth in total offense (326.58 ypg). Clemson ranks No. 38 in the country in pass defense and No. 64 in sacks.
2. Control the tempo. West Virginia has had 23 drives of 10 plays or more this season, marking the most since 2001. The difference is in the first downs, where the Mountaineers rank No. 30 in the country with 22.5 per game and are averaging 6.4 yards per play. The majority of their touchdowns (22) have come on first downs. They don't need a lot of time to score in the spread offense, and running the ball isn't a strength (3.8 yards per carry), but Clemson needs to control the tempo of the game and get the Mountaineers' offense off the field.
3. Field position. West Virginia is one of the best teams in the country when it comes to punt returns (No. 16) and kickoff returns (No. 26). Clemson must be leery of Tavon Austin, who had two kickoff returns for touchdowns this season, and is No. 2 nationally in all-purpose yards. He has a single-season school record 2,294 yards and averages 191.2 yards per game. He is No. 5 in punt returns (14.1) and No. 18 in kickoff returns (26.5).


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Is your wedding quickly approaching? If you've already started planning then you've probably already realized that chances are that you will be going over budget (or even WAY OVER budget). To help you out, we are tracking all of the latest Black Friday deals coming for 2016 from David's Bridal to help you save on your perfect gown, bridal dress, invitations and everything else! Although it's still too early to have confirmation on the sale details, to get an idea of what may be coming this year, you can scroll down the page to see what was offered last year and the year before. We plan on knowing more a few days before Thanksgiving and of course will post the details as they emerge right here on BlackerFriday.com!
What do you plan on getting from David's Bridal this Black Friday? Let us know in the comments below!
Happy Thanksgiving everyone!
I just wanted to give everyone an update that David's Bridal just extended their Thanksgiving day through the weekend (online only!). You'll be able to save $10.00 on orders of $50-$99.99, save $25.00 on orders of $100-$199.99, or $50.00 on orders of $200.00+. You'll also save 25% off all wedding invitations and and 50% on all save the dates with promo code MYDATE25. Offer ends Sunday, November 29, 2015.
This offer is not valid in store and excludes some of the already discounted $199.00 or less wedding dresses. It's also not valid on select expensive gowns at $800+, regular price bridesmaid dresses currently $20 off, regular price shoes, regular price jewelry, special value, style steals, prior sales, and existing layaways. Other restrictions may also apply.
To shop and for more details, visit davidsbridal.com.
David's Bridal just announced their online Black Friday weekend deals for 2014 and they will run through December 1, 2014 (while supplies last). This year's deal is similar to last year's as you'll save 50% on all markdowns plus get free shipping. You'll also save 30% on invitations with promo code INVITE30.
Updated November 29, 2013: David's Bridal just released all of their Black Friday weeks deals. From now through Cyber Monday (December 2nd, 2013) save up to 50% on all markdown gowns. You'll also get 10% off on all bridesmaid and Jr. bridesmaid dresses. Free shipping applies through the sale with no minimum order amount needed to qualify.
In 2012, DavidsBridal.com was offering $50.00 to $300.00 off on bridal gowns with another 10% off orders below $200 and 20% orders above $200 with coupon code. Several bridal dresses were discounted to $99.99 with even some bridesmaid and mother-of-the-bride dresses listed as low as $29.99.
See below for their advertised deals at last year's Black Friday sale:


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"I'm Not a Hoarder; I'm a Collector!"
Unless you were buried under a stack of Justice League International comics recently, you no doubt caught the interwebs all aflutter around DC Comics' plan to make all new comics available online for day-and-date digital publication. At first, it sounds positive, right? Save trees and free up that spare room used exclusively for storage bins of old DCs. But what about the tactile experience completed only by hiding out under a bed sheet, flashlight in hand, to caress the pages of a pristine copy of that latest comic? It still has its place, like at Saturday's PalmCon 2011 at the American Polish Club (4725 Lake Worth Road, Greenacres). The Palm Beach County Comic Book and Collectibles Show will feature a ton of collectible comics along with a live Ustream of the Pow Wow Show, an indie film lounge, and booths staffed with web creators, graphic artists, and clothing companies, including 501st Legion, Banky, Bob Bowles, and Carasells Collectibles. The show runs from 10 a.m. to 6 p.m. with a $3 admission, $1 for students. Visit cosmictimes.net/palmcon.
Sat., Sept. 17, 10 a.m., 2011
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Step 1: In a large wok or large pan or heavy bottomed casserole, heat the vegetable oil and margarine over medium flame. Fry garlic followed by the turmeric. Add in onions and continue frying. Add the bay leaf and half of the cracked pepper and salt.
Step 2: Add in the chicken pieces and continue sautéing. Cook over medium heat until the chicken renders its own liquid. There is no need to add water. Continue simmering on low heat until the chicken is partially cooked through and liquid is reduced.
Step 3: Add the vinegar and continue simmering uncovered. When it boils, add the rest of the cracked pepper, adjust the salt level and add the sugar, if using.
Step 4: Continue simmering on low heat until the chicken is fully cooked through and liquid is again reduced, has slightly thickened and somewhat oily.
Step 5: Transfer in a serving bowl and serve with lots of steamed rice. This is distinctly delicious and perfect for rice.
I love this more than a girl.....Posted the 16/09/2013, 10:23
Yummy foodPosted the 17/03/2013, 13:15
This recipe is deliciousPosted the 13/01/2013, 09:11
This is very good and hralthyPosted the 15/07/2012, 22:29


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Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment
Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.
- Heart failure
- Diastolic
- Systolic
- Ejection fraction
- Preserved ejection fraction
- Pathophysiology
- Diagnosis
- Treatment
Clinical interest in heart failure (HF) with preserved ejection fraction (HFpEF) emerged from the confluence of two research areas dealing, respectively, with diastolic left ventricular (LV) dysfunction in hypertrophied hearts and with LV remodelling after small myocardial infarctions. In the late seventies, the first studies appeared that showed diastolic LV dysfunction to importantly contribute to HF in hypertrophic cardiomyopathy,1,2 aortic stenosis,2,3 and hypertensive heart disease.4 Shortly after this inroad from the small niche of diastolic LV dysfunction in hypertrophied hearts, HFpEF was also identified and addressed in studies, which were a 'by-product' of the large HF trials investigating the use of angiotensin converting enzyme inhibitors (ACEIs) in HF with reduced EF (HFrEF) and in post-infarct LV remodelling.5–7 The HFpEF populations derived from the latter studies were, however, clearly different, as they consisted of patients with limited myocardial infarction at risk for unfavourable eccentric LV remodelling. This ambiguous origin of HFpEF contributed to the confusion surrounding HFpEF as a distinct diagnosis8–10 and the neutral outcome of many large HFpEF trials.11,12
Cardiac hypertrophy indeed has little in common with limited myocardial infarction, and in both conditions, mechanisms driving LV remodelling are likely to be dissimilar and react differently to pharmacological treatment. Recently, stringent criteria have been proposed for the diagnosis of HFpEF consisting not only of signs or symptoms of fluid overload and a preserved LVEF but also of evidence of diastolic LV dysfunction.13,14 This caused most HFpEF patients to currently present with a concentrically remodelled left ventricle because of arterial hypertension, obesity, and diabetes, without evidence of coronary artery disease. A low prevalence of coronary artery disease has indeed recently been proposed as a measure for correct patient enrolment in HFpEF trials.15
In the past, HFpEF was frequently referred to as 'diastolic' HF (DHF) in opposition to 'systolic' HF (SHF), which corresponded with HFrEF. Because diastolic LV dysfunction was not unique to HFpEF but also observed in patients with HFrEF, the term DHF was abandoned and replaced by HFpEF16,17 or by HF with normal LVEF (HFnEF).17 The terms HFpEF and HFnEF, however, also have their shortcomings. The notion of a preserved LVEF implies knowledge of a pre-existing EF, which is almost always absent, and the exact range of a 'normal' LVEF is hard to define.18,19 It is not established whether HFpEF and HFrEF represent distinct forms of HF or exist as part of one 'HF spectrum',13 although the distinct patterns of chamber and myocellular remodelling observed coupled with disparate responses to medical therapies would all suggest that they are two discrete disease processes. Heart failure with preserved ejection fraction is currently observed in 50% of HF patients, and outcomes are similar to those seen in HFrEF.20 The dismal prognosis is likely a reflection of the complex multisystem involvement characteristic of all HF, regardless of EF—including skeletal muscle and vascular dysfunction, pulmonary hypertension, renal failure, anaemia, and atrial fibrillation.21 The prevalence of HFpEF relative to HFrEF is rising at an alarming rate of ∼1% per year, thereby rapidly turning HFpEF into the most prevalent HF phenotype over the next decennium; yet in contrast to HFrEF, no improvements in outcome have been realized over the past two decades.20 Despite these worrisome epidemiological trends, pathophysiological mechanisms underlying HFpEF and diagnostic or therapeutic strategies remain uncertain21,22 and will therefore be addressed in the current review, which spans transatlantic views on this subject as part of the Frontiers in Cardiovascular Medicine Series of the European Heart Journal.
The seminal studies on HFpEF explained HF in the presence of normal systolic LV performance by diastolic LV dysfunction, which consisted of prolonged isovolumic LV relaxation, slow LV filling, and increased diastolic LV stiffness.1–4 With the advent of Doppler echocardiography, diastolic LV dysfunction could easily be appreciated from mitral or pulmonary vein flow velocity recordings.23 Abnormal mitral flow velocity recordings suggestive of diastolic LV dysfunction were, however, non-specific for HFpEF, as they also occurred in the elderly24 and in patients with HFrEF.25 The importance of diastolic LV dysfunction for HFpEF was recently reappraised by invasive studies, which showed uniform presence at rest of slow LV relaxation and elevated diastolic LV stiffness26 and which demonstrated that elevated diastolic LV stiffness limited cardiac performance during atrial pacing and exercise.27,28 This reappraisal was also evident from the recent issuing of guidelines for the diagnosis of diastolic LV dysfunction by both the European and American Echocardiography Associations.13,14
The reappraisal of diastolic LV dysfunction as an important mechanism underlying HFpEF does not imply that the latter represents the sole contributor to disease pathophysiology. Numerous other mechanisms have indeed recently been identified and play important roles. These include resting and exercise-exacerbated systolic dysfunction,29–35 impaired ventricular–vascular coupling,33,34,36,37 abnormal exercise-induced and flow mediated vasodilation,28,31–33 chronotropic incompetence,31,33,34,38 and pulmonary arterial hypertension.39,40
Diastolic left ventricular dysfunction
In the absence of endocardial or pericardial disease, diastolic LV dysfunction results from increased myocardial stiffness. Two compartments within the myocardium regulate its diastolic stiffness. These compartments are the extracellular matrix and the cardiomyocytes. A stiffness change within one compartment is also transmitted to the other compartment via matricellular proteins (Figure 1).
Extracellular matrix
Stiffness of the extracellular matrix is largely determined by collagen through regulation of its total amount, relative abundance of collagen type I, and degree of collagen cross-linking. In HFpEF patients, all three mechanisms appear to be involved. Excessive collagen type I deposition results from an imbalance between an exaggerated synthesis and a depressed degradation.41 Several steps are involved in the process of the collagen type I synthesis (Figure 2). Of clinical relevance is the observation that pro-collagen type I carboxy-terminal pro-peptide, which is cleaved by PCP from pro-collagen type I, is released into the bloodstream and therefore a potential biomarker of activity of the PCP-PCPE system.42,43 Excessive collagen type I deposition can result not only from an exaggerated synthesis of collagen type I but also from a depressed collagen type I degradation. In hypertensive patients with HFpEF44 and in patients with aortic stenosis,45 there is decreased matrix degradation because of downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of matrix metalloproteinases (TIMPs). Plasma levels of TIMP-1 have recently been proposed as a potential biomarker of HFpEF development in patients with arterial hypertension.46 Conversely, in patients with dilated cardiomyopathy, there is increased matrix degradation because of upregulation of MMPs.47 These distinct expression profiles of MMPs and TIMPs also correspond with unequal patterns of myocardial collagen deposition with mainly interstitial fibrosis in DHF and both replacement and interstitial fibrosis in dilated cardiomyopathy.48 In patients with aortic stenosis, who develop a depressed LVEF, there is reversal of the balance between collagen antiproteolysis and proteolysis.49
In LV endomyocardial biopsies, one-third of the patients presenting with HFpEF have a normal collagen volume fraction.50 Their LVEDP, LV end-systolic wall stress, and LV stiffness modulus were, however, comparable with patients presenting with a raised collagen volume fraction. This finding suggests that in addition to collagen deposition, intrinsic cardiomyocyte stiffness also contributes to diastolic LV dysfunction in HFpEF.50 Intrinsic cardiomyocyte stiffness is indeed elevated in patients with HFpEF48,50,51 and in patients with right or LV hypertrophy because of congenital heart disease.52 This elevation of cardiomyocyte stiffness has been related to the cytoskeletal protein titin.
Titin is a giant elastic protein expressed in cardiomyocytes in two main isoforms, N2B (stiffer spring) and N2BA (more compliant spring).53 Earlier work showed that the N2BA:N2B isoform expression ratio is increased in eccentrically remodelled explanted hearts from dilated cardiomyopathy patients when compared with control donor hearts.54–56 Although titin-isoform switching is a confirmed mechanism for adjusting myocardial passive stiffness, recent studies suggested that the increased passive stiffness of failing myocardium can also arise from alterations in the phosphorylation state of titin57–59 or from the oxidative stress-induced formation of disulfide bridges within the titin molecule.60
A characteristic feature of HFpEF is slow LV relaxation, which may reduce LV stroke volume, especially at high heart rates.61,62 This finding is in contrast to the normal heart, which accelerates LV relaxation at high heart rates. Left ventricular relaxation is dependent on both cross-bridge detachment and sarcoplasmic reticular Ca2+ reuptake.63 Nitric oxide (NO) signalling is involved as well. Its downstream mediator cyclic guanosine monophosphate (cGMP) reduces myofilamentary Ca2+ sensitivity and thereby facilitates cross-bridge detachment.64 This involvement of NO was also recently reappraised because of close correlations between asymmetric dimethylarginine and diastolic LV dysfunction in failing human hearts65,66 and because of uncoupling of NO synthase-1 inducing HFpEF in an animal model.67 As cross-bridge detachment is an energy-consuming process, slow LV relaxation can also result from a myocardial energy deficit. Recent studies using myocardial phosphorus magnetic resonance spectroscopy indeed showed lower myocardial creatine phosphate/adenosine triphosphate ratio in HFpEF patients compared with normal controls,34,68 consistent with reduced myocardial energy reserve.
Matricellular proteins
The mechanosensitive induction of matricellular proteins affects fibroblast function and regulates cardiomyocyte hypertrophy and survival.69 By binding to collagen, cell surface receptors, and MMPs, matricellular proteins improve both matrix quality and cardiomyocyte function.70 Their role in HFpEF remains unexplored.
Systolic dysfunction
Ejection fraction is preserved in HFpEF, but EF is more accurately regarded as a measure of ventricular–arterial coupling than contractility alone.30 In 2002, two seminal studies reported that regional measures of systolic function, assessed by Tissue Doppler imaging, are impaired in HFpEF, despite a normal EF.29,71 Numerous subsequent studies have similarly shown depressed longitudinal72,73 and radial systolic function in HFpEF.74 However, the significance of these abnormalities has been questioned,75 because global measures of systolic function appeared preserved in HFpEF.76 Recently, a large population-based study demonstrated that both the chamber level and myocardial contractility are subtly but significantly depressed in HFpEF, compared with hypertensive and healthy controls.30 Importantly, the extent of myocardial contractile dysfunction in HFpEF was associated with increased mortality, suggesting that it may be a mediator or nominally a marker of more severe disease.30
End-systolic elastance (Ees), defined by the slope and intercept of the end-systolic pressure–volume relationship, is a gold standard measure of chamber contractility that, in contrast to other measures, is elevated in HFpEF,30,36,76,77 suggesting enhanced contractility. The coexistence of elevated Ees and reduced systolic function by other indices has been difficult to reconcile. However, in addition to being sensitive to contractility, Ees is also influenced by chamber geometry—being increased with concentric remodelling and passive ventricular stiffening—processes commonly observed in HFpEF. Ees is elevated in HFpEF despite depressed contractility, measured using other contractile indices, across each pattern of ventricular chamber geometry.30 It is speculated that the same processes that promote diastolic ventricular stiffening in HFpEF also increase systolic stiffening (Ees) and contribute to reduced myocardial contractility and limited systolic reserve. Systolic function is clearly not as impaired in HFpEF as in HFrEF,73 but recent studies have shown that even mild limitations in basal contractility in HFpEF may become more problematic in the setting of exercise stress,31–35 where an inability to enhance contractility may be associated with impaired cardiac output reserve, more severe symptoms of exercise intolerance, and reduced aerobic capacity.
Ventricular-arterial coupling and vascular dysfunction
Ventricular and vascular stiffening increase with ageing, hypertension, and diabetes, and are abnormally elevated in patients with HFpEF.20,77 Reduced aortic distensibility in HFpEF is strongly associated with impaired exercise capacity.78 Kawaguchi et al.36 showed that both arterial elastance (Ea) and Ees are elevated in tandem in HFpEF, explaining the labile blood pressure swings commonly seen in HFpEF.79 Combined ventricular-arterial stiffening leads to greater blood pressure lability, by creating a 'high gain' system—with amplified blood pressure changes for any alteration in preload or afterload (Figure 3).37 Acute afterload elevation in the setting of ventricular–arterial stiffening causes greater increase in blood pressure, which may then feedback to further impair diastolic relaxation80,81—leading to dramatic increases in filling pressures during stress (Figure 4). Recent studies have also highlighted the importance of abnormal ventricular–arterial coupling during exercise in HFpEF33,34 —where blunted increases in contractility and impaired reductions in arterial afterload with stress each contribute to exertional intolerance.82 Therapies targeting combined ventricular–arterial stiffening improve exercise capacity in elderly hypertensive patients,83 suggesting a possible role in HFpEF.
Systemic vasorelaxation with exercise is attenuated in HFpEF,31–33 promoting impaired delivery of blood flow to skeletal muscle. Vascular dysfunction in HFpEF may be due in part to endothelial dysfunction, as a recent study demonstrated impaired flow-mediated vasodilation in HFpEF compared with healthy age-matched controls.33 Symptoms of dyspnoea and fatigue in HF may be related to pathologic ergoreflex activation, which is also related to NO bioavailability.84 Intriguingly, the extent of flow-mediated vasodilation (a biomarker of endothelial function) is related to the severity of symptoms of effort intolerance during low-level exercise in HFpEF,33 emphasizing the complex cross-talk between peripheral processes and perception of symptoms in HF.85 These data provide further rationale for therapies targeting NO in HFpEF.
Vascular dysfunction is not confined to the systemic circulation in HFpEF, as pulmonary hypertension is frequently observed as well.40 Among elderly patients with normal EF and high pulmonary artery pressure, HFpEF may be the most common aetiology.86 Pulmonary pressures increase with ageing and are correlated with systemic vascular stiffening—both common risk factors for HFpEF.87 Pulmonary hypertension in HFpEF appears to be due to both elevated left heart pressures and high pulmonary vascular resistance, which may develop in response to the former.40 In early-stage HFpEF, pulmonary vasodilation with exercise is preserved, and exertional pulmonary hypertension is passive and secondary primarily to high left heart pressures.28 Elevated pulmonary artery pressures predict increased mortality in HFpEF40 and may represent a novel therapeutic target, although unbalanced pulmonary arterial vasodilation in such patients may lead to pathologic elevations in left heart pressures or even frank pulmonary oedema, and further study is required to define the possible role of pulmonary vasodilators in HFpEF.88
Chronotropic incompetence and cardiovascular reserve dysfunction
Most patients with HF do not complain of symptoms at rest, but rather with physical exertion. A number of recent studies have highlighted the importance of abnormalities in cardiovascular reserve function with exercise stress in the pathophysiology of HFpEF.31–35,38 During physical exertion, cardiac output increases through integrated enhancements in venous return, contractility, heart rate, and peripheral vasodilation.89 Abnormalities in each of these components of normal exercise reserve function have been identified in HFpEF and all may contribute to pathophysiology in individual patients (Figure 5).
Normal diastolic reserve with exercise allows the ventricle to fill to a larger preload volume, in a shorter amount of time, with no increase in filling pressures.90 Indeed, the normal aged heart is more reliant upon enhanced preload reserve to compensate for age-related reductions in contractile and chronotropic reserve.91 Just as diastolic function is impaired in HFpEF, diastolic reserve is also reduced—patients display blunted increases in preload volume with exertion, despite marked elevations in filling pressure.28,92 This is likely related to increased chamber stiffness27 and inadequate enhancement of early relaxation,61,62 although pericardial restraint and enhanced ventricular interaction may also contribute.93
Systolic reserve with exercise is also impaired in HFpEF—with blunted increases in EF, contractility, and longitudinal systolic shortening velocities during exercise.31–35 Exercise stress may 'unmask' mild deficits in resting systolic function, and the inability to reduce end-systolic volume, combined with less increase in end-diastolic volume, greatly limits stroke volume responses during exercise. The causes of systolic and diastolic reserve dysfunction in HFpEF remain unclear, but may be related to myocardial ischaemia (epicardial/microvascular coronary disease or vascular rarefaction), impaired β-adrenergic signalling,94 myocardial energetics,34,68 or abnormal calcium handling.95
Chronotropic reserve is depressed in HFpEF,31,33,34,38,96 even compared with older, age-matched controls and independent of rate-slowing medication use. Similar to HFrEF,97 this is likely related to downstream deficits in β-adrenergic stimulation, because the increase in plasma catecholamines with exercise is similar in HFpEF and healthy controls.31 Autonomic dysfunction may contribute to chronotropic incompetence, as baroreflex sensitivity31 is reduced and heart rate recovery impaired in HFpEF.31,96
Patients with HFpEF display attenuated exercise-mediated reductions in mean vascular resistance and arterial elastance, coupled with abnormalities in endothelial function and dynamic ventricular–arterial coupling.31–33 Many of these abnormalities are noted with normal ageing and are simply more markedly abnormal in HFpEF, consistent with the notion that HFpEF develops as a progressive and pathologic form of exaggerated hypertensive ageing.82 Patients with HFpEF are more likely to display a greater number of discrete individual abnormalities in ventricular–vascular reserve, and recent evidence suggests that acquisition of a sufficient number of individual abnormalities in reserve promotes the transition from asymptomatic hypertensive diastolic dysfunction to symptomatic HFpEF.33 In this way, HFpEF may be conceived as a fundamental disorder of cardiovascular reserve function—diastolic, systolic, chronotropic, and vascular. Future research is required to determine how these abnormalities may be effectively treated.
Diagnostic algorithms
In contrast to HFrEF, the diagnosis of HFpEF is cumbersome, especially in patients presenting in an out-patient clinic with exertional dyspnoea and multiple comorbidities but without obvious physical signs of fluid overload. To avoid a low specificity when diagnosing HFpEF, exertional dyspnoea and a normal LVEF need to be coupled with objective measures of diastolic LV dysfunction, LV hypertrophy, left atrial (LA) enlargement, or plasma levels of natriuretic peptides (NP), as recommended by all hitherto published guidelines for the diagnosis of HFpEF.
Four sets of guidelines for the diagnosis of HFpEF have so far been published.13,98–100 They all require the simultaneous and obligatory presence of signs and/or symptoms of HF, evidence of normal systolic LV function, and evidence of diastolic LV dysfunction or of surrogate markers of diastolic LV dysfunction such as LV hypertrophy, LA enlargement, atrial fibrillation, or elevated plasma NP levels. The first set of guidelines was provided by the Working Group on Myocardial Function of the European Society of Cardiology.98 A second set of guidelines was provided by the NHLBI Framingham Heart Study and combined signs and symptoms of HF, normal LVEF (>50%), and invasive evidence of diastolic LV dysfunction.99 A third set of guidelines was proposed by Yturralde and Gaasch from the Lahey Clinic.100 They implement their assessment with a scoring system of major and minor criteria and use LV hypertrophy and LA enlargement as surrogate markers of diastolic LV dysfunction. Finally, the last set of guidelines was provided by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.13 In accordance to this last set of guidelines, the diagnosis of HFpEF required signs or symptoms of HF, a LVEF>50%, a LVEDVI<97 mL/m2, and evidence of diastolic LV dysfunction. LVEDP >16mmHg, PCW >12mmHg and/or E/E′ >15 provided stand-alone evidence of diastolic LV dysfunction, whereas NP always needed to be associated with an E/E′ >8, a mitral flow velocity Doppler signal showing a E/A ratio <0.5 + deceleration time (DT) >280 ms, a pulmonary vein flow velocity signal showing a Ard-Ad>30 ms (Ard: duration of reverse pulmonary vein atrial systole flow; Ad: duration of mitral valve atrial wave flow), a LA size>40 mL/m2, or a LV mass>149 g/m2 (men) or >122 g/m2 (women).
Validation of these diagnostic guidelines for HFpEF is urgently needed.101 Valuable validation efforts of the last set of guidelines provided by the Heart Failure and Echocardiography Associations of the European Society of Cardiology have to some extent been addressed, including: (i) the diagnostic value of E/E′ against a LV stiffness modulus calculated from multiple LV end-diastolic pressure–volume points observed during balloon caval occlusion;102 (ii) the diagnostic value of LA size >40 mL/m2, LV mass >149 g/m2(men) or >122 g/m2 (women), Ard-Ad >30 ms, and E/A ratio <0.5 + DT>280 ms against E/E′;103 (iii) the diagnostic value of NTproBNP >220 pg/mL against E/E′.104 In contrast to recent critiques on the validity of E/E′ as a measure of LV filling pressures in acutely decompensated HFrEF patients,105 a direct comparison of E/E′ against conductance catheter-derived diastolic LV stiffness moduli yielded a 83% sensitivity, a 92% specificity, and an area under the ROC curve of 0.907 for E/E′ >8 as a measure of high-stiffness modulus in HFpEF patients.102 These findings suggested E/E′ >8 may be able to provide stand-alone evidence of diastolic LV dysfunction without further need of serial non-invasive tests in patients presenting with a 8<E/E′<15.106 Early diastolic LV load, which is high in HFrEF but normal in HFpEF, may account for the dissimilar value of E/E′ as a measure of LV filling pressures in HFrEF and HFpEF.107 A direct comparison between the diagnostic values of E/E′ and mitral or pulmonary flow velocity-derived indices showed the latter to be unreliable for the diagnosis of diastolic LV dysfunction.103 In contrast, however, LA size >40 mL/m2 provided both a high sensitivity and a high specificity to detect E/E′>15. Left ventricular mass >149 g/m2 (men) or >122 g/m2 (women) provided a low sensitivity but a high specificity for E/E′>15.103 Finally, the diagnostic value of NTproBNP >220 pg/mL is currently being evaluated against E/E′ in the Aldo-DHF trial.104 In analogy to LV mass indices, it is expected to have a low sensitivity but a high specificity for the TDI diagnosis of HFpEF.
Role of exercise testing
Heart failure with reduced EF is characterized by chamber dilation and reduced EF—both readily detectable by echocardiography. In HFpEF, chamber size and EF are normal, and the principal haemodynamic derangement is an elevation in filling pressures.26 When pressures are high and congestion is present at rest, HFpEF is readily diagnosed based upon history, physical examination, radiography, NP levels, and echocardiography.13 However, many patients with early-stage HFpEF have significant symptoms of exertional intolerance in the absence of apparent volume overload. Invasive assessment in some patients may reveal pathologic elevation in filling pressures that had not been previously suspected,108 and a recent study found that even among patients with normal exam, echocardiography, NP, and normal resting haemodynamics, many patients may still develop pathologic elevations in filling pressures characteristic of HFpEF during the stress of exercise.28 The diagnosis of HFpEF could only be made using exercise haemodynamic evaluation in such patients, although an abnormal increase in left heart pressures with leg raise (a marker of reduced diastolic reserve) was also a strong predictor of HFpEF. Pulmonary artery pressures track very closely with left heart filling pressures in early-stage HFpEF,28 suggesting that if the former could be accurately estimated by echocardiography during exercise, this may serve as a useful non-invasive screen among patients with normal EF and exertional dyspnoea.
The E/E′ ratio is a cornerstone in the non-invasive evaluation of diastolic function at rest,13,14 and some groups have begun to apply TDI-based evaluations during exercise, with early studies showing reasonable correlations with invasive measures.109 However, E/E′ may be less robust in the setting of tachycardia, hyperventilation, and fusion of early and late transmitral filling velocities, as the variability in both numerator and denominator will be summed. The role of non-invasive diastolic stress testing in the evaluation of early HFpEF merits further study and validation, but at this time invasive evaluation provides more reliable diagnostic information. In patients who do not meet established criteria for positive diagnosis of HFpEF13 but in whom there is reasonably strong clinical suspicion, invasive evaluation should be strongly considered, with exercise stress if available and resting measurements are unremarkable.28
Trial data
An extensive overview of all HFpEF trials performed so far was recently published.22 Diverging efficacy of comparable pharmacological agents in HFrEF and HFpEF was evident for ACEIs, angiotensin receptor blockers (ARB), beta-blockers, and statins (Figure 6). The PEP-CHF study was the first major randomized controlled trial on the use of ACEI in HFpEF patients.110 It compared perindopril 4 mg daily to placebo in elderly patients (≥70 years old) with a diagnosis of HF, LVEF >40%, minimal impairment of segmental LV wall motion, echocardiographic evidence of LA dilatation or LV hypertrophy, and abnormal LV filling kinetics on mitral flow velocity Doppler. The results of the PEP-CHF study contrasted sharply with earlier reports on the use of ACEI in HFrEF,111 as it showed no overall difference in mortality and or need for HF hospitalizations. A neutral outcome in HFpEF and a positive outcome in HFrEF were also repeatedly observed for ARBs. The first major trial investigating cardiovascular mortality and HF hospitalizations in HFpEF was the CHARM-preserved trial, which randomized 3023 patients between candesartan and placebo.11 CHARM-preserved failed to demonstrate a significant effect on cardiovascular death but observed fewer HF hospitalizations in the candesartan-treated patients. I-PRESERVE was so far the largest reported trial for HFpEF as it enrolled 4128 patients and randomly assigned them to irbesartan or placebo.12 Mortality or rates of hospitalizations for cardiovascular causes were again not improved by treatment with an ARB. Outcomes of both CHARM-preserved and I-PRESERVE are at odds with the positive results of the CHARM-Alternative trial,112 which assigned ACEI-intolerant HFrEF patients to the ARB candesartan or placebo.
Some information on the outcome of chronic use of beta-blockers is available in the OPTIMIZE-HF registry, which contains both HFrEF and HFpEF patients. In the OPTIMIZE-HF registry,113 discharge use of beta-blockers exerted no effect on 1 year mortality or hospitalization rates of HFpEF patients, but significantly improved both endpoints in HFrEF patients. Finally, the reverse situation with a positive outcome in HFpEF and a neutral outcome in HFrEF has also been observed. A preliminary report suggested statin therapy to be beneficial in HFpEF114 with lower mortality rates. This positive outcome of statin therapy in HFpEF patients contrasted with the recently reported neutral outcome of statin therapy in the HFrEF patients of the CORONA trial.115 A neutral outcome in HFpEF compared with a positive outcome in HFrEF, as occurred with ACEIs, ARBs, and beta-blockers, could be compatible with flawed HFpEF trial design, but a positive outcome in HFpEF compared with a neutral outcome in HFrEF, as occurred with statins, can no longer be attributed to trial conception but supports different signal transduction cascades driving myocardial remodelling in HFpEF and HFrEF.22
Novel therapies
Recent advances in pathophysiologic understanding of HFpEF have suggested roles for novel treatment strategies. Among the most exciting are agents that enhance cellular cGMP signalling.116 Natriuretic peptides and NO both increase cGMP synthesis, activating cGMP-dependent protein kinases (PKG). Several key transcription factors and sarcomeric proteins involved in hypertrophy signalling, diastolic relaxation and stiffness, and vasorelaxation are modified favourably by PKG-dependent phosphorylation, suggesting these agents may be beneficial in HFpEF.57,58,64,116,117
Phosphodiesterase 5 inhibitors (PDE5I) increase cGMP levels by blocking their catabolism. PDE5I attenuate adrenergic stimulation,118 reduce ventricular–vascular stiffening,119 antagonize maladaptive chamber remodelling,117 improve endothelial function,120 reduce pulmonary vascular resistance,121 and may enhance renal responsiveness to NP.122 The PDE5I sildenafil is currently being tested in the ongoing RELAX trial,123 which will evaluate the effects of PDE5I on exercise capacity, functional status, and ventricular form and function.
Uncoupling of nitric oxide synthase (NOS) has emerged as an important contributor to pathologic concentric chamber remodelling and diastolic dysfunction in animal models of HF, in addition to promoting endothelial dysfunction.67,124 Nitric oxide synthase uncoupling is due in part to oxidative depletion of its cofactor, tetrahydrobiopterin (BH4). Pre-clinical studies have shown that administration of BH4 in animal models reduces pressure-overload hypertrophy, fibrosis, NOS uncoupling, and oxidative stress, while improving systolic and diastolic function.67,124 Enhancement of cGMP function with NP125 or nitroglycerin126 also may mitigate pathologic increases in LV filling pressures during exercise.
Aldosterone plays an important role in the pathogenesis of vascular stiffening and endothelial dysfunction.127 A preliminary open label, non-placebo controlled study documented improvements in exercise capacity and the E/E′ ratio in HFpEF patients treated with spironolactone,128 and aldosterone antagonists are currently being actively investigated for HFpEF in the USA and Europe. Rho-kinase inhibitors such as fasudil and Y-27632 have vasorelaxation properties and have demonstrated the ability to blunt progression of hypertrophic remodelling in animal models of HF.129 Intriguingly, 3-hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) also inhibit rho-kinase signalling, and a case series reported that statin use was associated with the improved outcome in HFpEF, whereas other conventional HF therapies such as ACEI or BB were not.114
Negative chronotropic medications have traditionally been recommended in HFpEF to increase the diastolic filling period, but slowing the rate in the absence of tachycardia tends to only prolong diastasis, where transmitral flow is minimal or absent.130 More importantly, recent studies have repeatedly shown that chronotropic incompetence is highly prevalent and associated with exercise disability in HFpEF.31,33,38,96 Indeed, in the setting of reduced systolic and diastolic reserve, chronotropic reserve may represent the only mechanism to augment cardiac output during exercise, although there is concern that inadequate ability to enhance relaxation with tachycardia may limit stroke volume responses.27,61,62 These questions require further study. The effect of rate adaptive atrial pacing in HFpEF was being evaluated in the RESET trial,131 but enrolment was below goal and the study has since been terminated by the sponsor. In contrast, another trial is testing the efficacy of the If channel blocker ivabradine in HFpEF,132 an agent that slows heart rate. The role of beta-blockade remains unresolved. The SENIORS trial suggested benefit in HF regardless of EF,133 but there was not a large number of patients with truly 'normal' EF (>50–55%). Autonomic dysfunction is prevalent in HFpEF,31 and enhancement in parasympathetic tone via carotid sinus stimulation has been proposed as a treatment,134 but data are not available. Dyssynchrony is common in HFpEF,135 but in contrast to HFrEF, electrical conduction delay is not,136,137 and it remains unknown whether resynchronization therapy may play a role in HFpEF.
The macromolecule titin is the principal determinant of passive cardiomyocyte tension.138 As discussed, the stiffness of titin may be modified based upon the expression of alternative isoforms,55,56,139 but recent studies have produced great enthusiasm that acute modification of titin PKG phosphorylation sites may dynamically modulate titin stiffness.57–59 Chamber stiffness is also altered by the extracellular matrix—including both quantitative and qualitative changes in collagen. Alagebrium chloride (ALT-711) is a novel compound that breaks glucose cross-links and improves ventricular and arterial compliance in animals140 and reduces blood pressure and vascular stiffness in human hypertension.141 A small open-label study found that ALT-711 was associated with reduced LV mass and improved diastolic filling.142 Transforming growth factor-beta (TGF-β) is a pro-fibrotic cytokine, and infusion of TGF-β neutralizing antibody in a rat model of pressure overload was found to reduce fibrosis and development of diastolic dysfunction.143 New advances in cardiac MRI now allow visualization and quantification of myocardial fibrosis associated with diastolic dysfunction,144 providing a potential outcome measure in therapeutic trials targeting fibrosis.
Systolic and diastolic reserve dysfunction in HFpEF may be related to abnormalities in cardiomyocyte energy availability or utilization.31,34,92 Smith et al.68 demonstrated abnormal ATP phosphocreatine shuttle kinetics in HFpEF, and similar results were recently reported by Phan et al.34 Novel therapies targeting energy substrate utilization are currently under active investigation.145 The anti-anginal drug ranolazine blocks inward sodium current, thereby reducing intracellular calcium, and it has also been suggested as a potential treatment for HFpEF,146 although human HFpEF data are currently unavailable.
Heart failure with preserved ejection fraction is a major and growing public health problem in Europe and the USA, currently representing half of all patients with HF. Despite improvements in disease understanding, there are no treatments of proven benefit. Advances in diagnostic algorithms, imaging, and invasive assessment will allow for more accurate and earlier diagnosis, so that therapies may be implemented earlier in disease progression, where potential for benefit may be higher. While important advances have been made in our understanding of the haemodynamic and cellular pathophysiology of diastolic and non-diastolic mechanisms of disease, further research is urgently required to determine how to better target these abnormalities to reduce the substantial burden of morbidity and mortality in this form of HF, which is reaching epidemic proportions.
B.A.B. is supported by a grant from the Mayo Clinic Center for Translational Science Activities and the NIH (UL RR024150) and the Marie Ingalls Career Development Award in Cardiovascular Research. W.J.P. is the recipient and coordinator of a European Commission, Research Directorate General, FP7-Health-2010 grant on diastolic heart failure (261409—MEDIA).
Conflict of interest: none declared.
- Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: email@example.com


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Albany Federal Employee Credit Union robbed
Albany police are looking for the masked gunman who robbed a bank early Tuesday morning.
Officers were called out to the Albany Federal Employee Credit Union at about 9:40 a.m. Bank employees say the robber walked in, pointed a gun at a teller and demanded money. They complied and the suspect fled the scene in a white or beige four door sedan. No one was hurt.
The suspect is described as a black male about 5'8 to 6'0. He was wearing a black long sleeve shirt, black pants, and a ski mask. The Albany Police Department released these images from surveillance cameras.
If you have any information on the crime you're asked to call Crime Stoppers at (229) 436-TIPS.
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After a rough series in San Diego, many people (including myself) believed that a little bit of "home cooking" would be the recipe for the Braves to get back on track. Apparently, that recipe will have to wait for another day, as the Braves fell 6-0 to the defending champs on Friday night.
Bumgarner Dominates Braves, 6-0, for 4th Straight Loss
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Ratings and Reviews
How is one supposed to maneuver their underwear with this product? And zipper malfunction??
These look fantastic and I'm dying to give you my money, but I'm a K9 Officer so I need a version that are black cargo pants. Any chance they exist?
I'd joked around for years about designing a pant like this. They've made my shift substantially more convenient. Best product I've used in my entire career.
This is a product that women in Law Enforcement have sought after for years! It makes for quick and easy use of the restroom without shedding an ounce of duty gear! On top of it all the material repels almost anything you could possibly get into in the field. What more could you ask for in a pair of duty pants? The price?....same as a plain Jane pair of BDU pants.
Perfect pant for female officers who wear a duty belt and have to "go" during shift.
This is by far the greatest pant ever for women! I can literally spend 3 minutes in the bathroom versus 10, just because I'm not having to take my duty belt off. It gives me that added reassurance that I can be the back-up needed incase of an emergency call.
This is a must have pant! It is the ONLY pant that I wear now. The design is amazing and it truly makes a work day easier not having to remove my duty belt!
This is a great idea, anyone that has had to wear a duty belt before can understand how much of a pain it can be, and this is a great solution to a everyday problem.
This is a great product that women in Law Enforcement have sought for a long time! Great also for men. The pants are comfortable and provide quick, easy use of the restroom without having to remove your duty gear. What else could you ask for in a pair of pants? Oh yeah, they repel liquid...perfect!


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stacked 6" cakes to make tower. Covered in fondant, with fondant princess, number, flowers and stone path. Royal icing for the grass. Birthday message is printed paper.
CakeCentral.com is the world's largest cake community for cake decorating professionals and enthusiasts.
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Chocolate Chai Snickerdoodles
Total Time
Prep 15 mins
Cook 15 mins
I found these on Slash food and made them over the weekend...addictive little cookies! The dough is very easy to work with and they flatten out beautifully! Don't skip the cardomom and use good quality cocoa.
Ingredients Nutrition
- 2 1⁄4 cups sugar
- 1 teaspoon ground cinnamon
- 1 teaspoon ginger
- 1 teaspoon cardamom
- 1⁄2 teaspoon ground allspice
- 1⁄4 teaspoon white pepper
- 1⁄2 cup cocoa powder
- 1 cup butter, room temperature
- 2 large eggs
- 2 teaspoons vanilla extract
- 2 1⁄4 cups all-purpose flour
- 1 1⁄2 teaspoons baking powder
- Preheat over to 350°F.
- In large mixing bowl, stir together sugar and spices; set 1/2 cup of the mixture aside.
- Add butter to mixing bowl and cream with sugar until light and fluffy.
- Beat in cocoa powder, followed by the eggs and vanilla.
- Stir in flour and baking powder by hand or at low speed.
- Form dough into 1-inch balls and roll in reserved sugar mixture.
- Bake at 350F for 12-15 minutes or until edges are firm.
- Cool on wire rack and store in an airtight container.
Most Helpful
We liked these very much. On the last few trays, I added sparkling white sugar on the tops to add some glitz. We doubled the recipe and I know that they won't last long! Thanks Greysangel!
These cookies are delicious as well as easy! Even my daughter loved them - she's a snickerdoodle lover (original recipe), but she loved these just as much! I didn't have cardamom - tried a little coriander I had on hand. Next time I'll try a better quality cocoa and cardamom. Thanks for sharing!
These cookies are quite easy to assemble and have a lovely, subtle spicy flavor. I baked for the full 15 minutes. They puff up when baking and the resulting cookies are uniformly shaped. My family loves the spicy cinnamon/chocolate combination. I saved the leftover spicy cinnamon sugar mixture to use on breakfast toast.


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Ruth Daniel Residence
A stay at Ruth Daniel Residence places you in the heart of Tel Aviv, minutes from Bloomfield Stadium and close to Jaffa Port. This hotel is close to Hatachana Compound and Carmel Market. Make use of convenient amenities such as complimentary wireless Internet access, wedding services, and a television in the lobby. Featured amenities include a 24-hour business center, dry cleaning/laundry services, and a 24-hour front desk. Free self parking is available onsite. Make yourself at home in one of the 63 air-conditioned rooms featuring kitchenettes. Rooms have private balconies. 32-inch LCD televisions with cable programming provide entertainment, while complimentary wireless Internet access keeps you connected. Conveniences include desks and refrigerators, and housekeeping is provided daily.
Choose your room
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Services and terms: Ruth Daniel Residence
Standard Room Services
- Air Conditioning
- Coffee & Tea Making Facilities
- Safe
- Minibar
- Hairdryer
- Telephone
- Television
Accommodation facilities
- Lift
- Bar/Café
- Business Centre
- Meetings Room
- Garage
- Internet Centre
- Laundry
- People with reduced mobility access
- Non-smoker Rooms
- Parking
- Restaurant
- 24 hr Room Service
- Secretarial Service


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Most Popular "Revenge" Titles
- Movies or TV
- Genres
- Keywords
- IMDb Rating
- Instant Watch Options
- In Theaters
- On TV
- Release Year
1. Jack Reacher: Never Go Back (2016)
PG-13 | 118 min | Action, Adventure, Crime
Jack Reacher must uncover the truth behind a major government conspiracy in order to clear his name. On the run as a fugitive from the law, Reacher uncovers a potential secret from his past that could change his life forever.
Director: Edward Zwick | Stars: Tom Cruise, Cobie Smulders, Aldis Hodge, Robert Knepper
Votes: 9,810
2. Suicide Squad (2016)
PG-13 | 123 min | Action, Adventure, Fantasy
A secret government agency recruits some of the most dangerous incarcerated super-villains to form a defensive task force. Their first mission: save the world from the apocalypse.
Director: David Ayer | Stars: Will Smith, Jared Leto, Margot Robbie, Viola Davis
Votes: 242,808 | Gross: $324.27M
3. Don't Breathe (2016)
R | 88 min | Crime, Horror, Thriller
Hoping to walk away with a massive cash, a trio of thieves break into the house of a sick man who isn't as helpless as he seems.
Director: Fede Alvarez | Stars: Stephen Lang, Jane Levy, Dylan Minnette, Daniel Zovatto
Votes: 49,772 | Gross: $88.58M
4. Arrow (2012– )
TV-14 | 42 min | Action, Adventure, Crime
Spoiled billionaire playboy Oliver Queen is missing and presumed dead when his yacht is lost at sea. He returns five years later a changed man, determined to clean up the city as a hooded vigilante armed with a bow.
Stars: Stephen Amell, Katie Cassidy, David Ramsey, Susanna Thompson
Votes: 309,825
5. Supergirl (2015– )
TV-PG | 43 min | Action, Adventure, Drama
The adventures of Superman's cousin in her own superhero career.
Stars: Melissa Benoist, Mehcad Brooks, Chyler Leigh, Jeremy Jordan
Votes: 50,061
6. Star Trek Beyond (2016)
PG-13 | 122 min | Action, Adventure, Sci-Fi
The USS Enterprise crew explores the furthest reaches of uncharted space, where they encounter a new ruthless enemy who puts them and everything the Federation stands for to the test.
Director: Justin Lin | Stars: Chris Pine, Zachary Quinto, Karl Urban, Zoe Saldana
Votes: 102,796 | Gross: $158.80M
7. The Magnificent Seven (2016)
PG-13 | 133 min | Action, Adventure, Western
Seven gun men in the old west gradually come together to help a poor village against savage thieves.
Director: Antoine Fuqua | Stars: Denzel Washington, Chris Pratt, Ethan Hawke, Vincent D'Onofrio
Votes: 34,163 | Gross: $89.48M
8. X-Men: Apocalypse (2016)
PG-13 | 144 min | Action, Adventure, Sci-Fi
After the re-emergence of the world's first mutant, world-destroyer Apocalypse, the X-Men must unite to defeat his extinction level plan.
Director: Bryan Singer | Stars: James McAvoy, Michael Fassbender, Jennifer Lawrence, Nicholas Hoult
Votes: 205,291 | Gross: $155.33M
9. Independence Day: Resurgence (2016)
PG-13 | 120 min | Action, Adventure, Sci-Fi
Two decades after the first Independence Day invasion, Earth is faced with a new extra-Solar threat. But will mankind's new space defenses be enough?
Director: Roland Emmerich | Stars: Liam Hemsworth, Jeff Goldblum, Bill Pullman, Maika Monroe
Votes: 89,037 | Gross: $103.14M
10. Hocus Pocus (1993)
PG | 96 min | Comedy, Family, Fantasy
After three centuries, three witch sisters are resurrected in Salem, Massachusetts on Halloween night, and it is up to two teenagers, a young girl, and an immortal cat to put an end to their reign of terror once and for all.
Director: Kenny Ortega | Stars: Bette Midler, Sarah Jessica Parker, Kathy Najimy, Omri Katz
Votes: 62,353 | Gross: $39.51M
11. The Legend of Tarzan (2016)
PG-13 | 110 min | Action, Adventure, Drama
Tarzan, having acclimated to life in London, is called back to his former home in the jungle to investigate the activities at a mining encampment.
Director: David Yates | Stars: Alexander Skarsgård, Rory J. Saper, Christian Stevens, Christoph Waltz
Votes: 76,770 | Gross: $126.59M
12. Deadpool (2016)
R | 108 min | Action, Adventure, Comedy
A fast-talking mercenary with a morbid sense of humor is subjected to a rogue experiment that leaves him with accelerated healing powers and a quest for revenge.
Director: Tim Miller | Stars: Ryan Reynolds, Morena Baccarin, T.J. Miller, Ed Skrein
Votes: 528,048 | Gross: $363.02M
13. Zootopia (2016)
PG | 108 min | Animation, Adventure, Comedy
In a city of anthropomorphic animals, a rookie bunny cop and a cynical con artist fox must work together to uncover a conspiracy.
Directors: Byron Howard, Rich Moore, Jared Bush | Stars: Ginnifer Goodwin, Jason Bateman, Idris Elba, Jenny Slate
Votes: 212,468 | Gross: $341.26M
14. Captain America: Civil War (2016)
PG-13 | 147 min | Action, Adventure, Sci-Fi
Political interference in the Avengers' activities causes a rift between former allies Captain America and Iron Man.
Directors: Anthony Russo, Joe Russo | Stars: Chris Evans, Robert Downey Jr., Scarlett Johansson, Sebastian Stan
Votes: 336,050 | Gross: $408.08M
15. Warcraft: The Beginning (2016)
PG-13 | 123 min | Action, Adventure, Fantasy
As an Orc horde invades the planet Azeroth using a magic portal, a few human heroes and dissenting Orcs must attempt to stop the true evil behind this war.
Director: Duncan Jones | Stars: Travis Fimmel, Paula Patton, Ben Foster, Dominic Cooper
Votes: 150,880 | Gross: $47.17M
16. Star Wars: The Force Awakens (2015)
PG-13 | 138 min | Action, Adventure, Fantasy
Three decades after the defeat of the Galactic Empire, a new threat arises. The First Order attempts to rule the galaxy and only a ragtag group of heroes can stop them, along with the help of the Resistance.
Director: J.J. Abrams | Stars: Daisy Ridley, John Boyega, Oscar Isaac, Domhnall Gleeson
Votes: 592,143 | Gross: $936.63M
17. Storks (2016)
PG | 87 min | Animation, Adventure, Comedy
Storks have moved on from delivering babies to packages. But when an order for a baby appears, the best delivery stork must scramble to fix the error by delivering the baby.
Directors: Nicholas Stoller, Doug Sweetland | Stars: Andy Samberg, Katie Crown, Kelsey Grammer, Jennifer Aniston
Votes: 5,151 | Gross: $64.84M
18. Scream: The TV Series (2015– )
TV-14 | 45 min | Crime, Drama, Horror
What starts as a YouTube video going viral soon leads to problems for the teenagers of Lakewood and serves as the catalyst for a murder that opens up a window to the town's troubled past.
Stars: Willa Fitzgerald, Bex Taylor-Klaus, John Karna, Carlson Young
Votes: 20,821
19. Guardians of the Galaxy (2014)
PG-13 | 121 min | Action, Adventure, Sci-Fi
A group of intergalactic criminals are forced to work together to stop a fanatical warrior from taking control of the universe.
Director: James Gunn | Stars: Chris Pratt, Vin Diesel, Bradley Cooper, Zoe Saldana
Votes: 702,478 | Gross: $333.13M
20. Batman v Superman: Dawn of Justice (2016)
PG-13 | 151 min | Action, Adventure, Sci-Fi
Fearing that the actions of Superman are left unchecked, Batman takes on the Man of Steel, while the world wrestles with what kind of a hero it really needs.
Director: Zack Snyder | Stars: Ben Affleck, Henry Cavill, Amy Adams, Jesse Eisenberg
Votes: 411,900 | Gross: $330.25M
21. Teen Wolf (2011– )
TV-14 | 41 min | Action, Comedy, Drama
A somewhat awkward teen is attacked by a werewolf and inherits the curse himself, as well as the enemies that come with it.
Stars: Dylan O'Brien, Tyler Posey, Holland Roden, Linden Ashby
Votes: 91,673
22. The Prestige (2006)
PG-13 | 130 min | Drama, Mystery, Sci-Fi
Two stage magicians engage in competitive one-upmanship in an attempt to create the ultimate stage illusion.
Director: Christopher Nolan | Stars: Christian Bale, Hugh Jackman, Scarlett Johansson, Michael Caine
Votes: 861,730 | Gross: $53.08M
23. The Magnificent Seven (1960)
Approved | 128 min | Action, Adventure, Western
An oppressed Mexican peasant village hires seven gunfighters to help defend their homes.
Director: John Sturges | Stars: Yul Brynner, Steve McQueen, Charles Bronson, Eli Wallach
Votes: 68,114
24. Central Intelligence (2016)
PG-13 | 107 min | Action, Comedy, Crime
After he reconnects with an awkward pal from high school through Facebook, a mild-mannered accountant is lured into the world of international espionage.
Director: Rawson Marshall Thurber | Stars: Dwayne Johnson, Kevin Hart, Danielle Nicolet, Amy Ryan
Votes: 62,872 | Gross: $127.38M
25. The Revenant (2015)
R | 156 min | Adventure, Drama, Thriller
A frontiersman on a fur trading expedition in the 1820s fights for survival after being mauled by a bear and left for dead by members of his own hunting team.
Director: Alejandro G. Iñárritu | Stars: Leonardo DiCaprio, Tom Hardy, Will Poulter, Domhnall Gleeson
Votes: 438,404 | Gross: $183.64M
26. It (1990 TV Mini-Series)
TV-14 | 192 min | Drama, Fantasy, Horror
In 1960, seven outcast kids known as "The Loser Club" fight an evil demon who poses as a child-killing clown. Thirty years later, they reunite to stop the demon once and for all when it returns to their hometown.
Stars: Richard Thomas, Tim Reid, Annette O'Toole, Harry Anderson
Votes: 68,744
27. Jason Bourne (2016)
PG-13 | 123 min | Action, Thriller
The CIA's most dangerous former operative is drawn out of hiding to uncover more explosive truths about his past.
Director: Paul Greengrass | Stars: Matt Damon, Tommy Lee Jones, Alicia Vikander, Vincent Cassel
Votes: 83,244 | Gross: $162.16M
28. Dazed and Confused (1993)
R | 102 min | Comedy
The adventures of high school and junior high students on the last day of school in May 1976.
Director: Richard Linklater | Stars: Jason London, Wiley Wiggins, Matthew McConaughey, Rory Cochrane
Votes: 123,298 | Gross: $7.99M
29. Anthropoid (2016)
R | 120 min | Biography, History, Thriller
Based on the extraordinary true story of Operation Anthropoid, the WWII mission to assassinate SS General Reinhard Heydrich, the main architect behind the Final Solution and the Reich's third in command after Hitler and Himmler.
Director: Sean Ellis | Stars: Jamie Dornan, Cillian Murphy, Brian Caspe, Karel Hermánek Jr.
Votes: 5,501 | Gross: $2.96M
30. Teenage Mutant Ninja Turtles: Out of the Shadows (2016)
PG-13 | 112 min | Action, Adventure, Comedy
After facing Shredder, who has joined forces with mad scientist Baxter Stockman and henchmen Bebop and Rocksteady to take over the world, the Turtles must confront an even greater nemesis: the notorious Krang.
Director: Dave Green | Stars: Megan Fox, Will Arnett, Tyler Perry, Laura Linney
Votes: 43,584 | Gross: $81.99M
31. The Shawshank Redemption (1994)
R | 142 min | Crime, Drama
Two imprisoned men bond over a number of years, finding solace and eventual redemption through acts of common decency.
Director: Frank Darabont | Stars: Tim Robbins, Morgan Freeman, Bob Gunton, William Sadler
Votes: 1,720,709 | Gross: $28.34M
32. The Godfather (1972)
R | 175 min | Crime, Drama
The aging patriarch of an organized crime dynasty transfers control of his clandestine empire to his reluctant son.
Director: Francis Ford Coppola | Stars: Marlon Brando, Al Pacino, James Caan, Diane Keaton
Votes: 1,176,038 | Gross: $134.82M
33. The Dark Knight (2008)
PG-13 | 152 min | Action, Crime, Drama
When the menace known as the Joker wreaks havoc and chaos on the people of Gotham, the caped crusader must come to terms with one of the greatest psychological tests of his ability to fight injustice.
Director: Christopher Nolan | Stars: Christian Bale, Heath Ledger, Aaron Eckhart, Michael Caine
Votes: 1,706,683 | Gross: $533.32M
34. Sicario (2015)
R | 121 min | Action, Crime, Drama
An idealistic FBI agent is enlisted by a government task force to aid in the escalating war against drugs at the border area between the U.S. and Mexico.
Director: Denis Villeneuve | Stars: Emily Blunt, Josh Brolin, Benicio Del Toro, Jon Bernthal
Votes: 211,496 | Gross: $46.88M
35. Pulp Fiction (1994)
R | 154 min | Crime, Drama
The lives of two mob hit men, a boxer, a gangster's wife, and a pair of diner bandits intertwine in four tales of violence and redemption.
Director: Quentin Tarantino | Stars: John Travolta, Uma Thurman, Samuel L. Jackson, Bruce Willis
Votes: 1,348,079 | Gross: $107.93M
36. John Wick (2014)
R | 101 min | Action, Crime, Thriller
An ex-hitman comes out of retirement to track down the gangsters that took everything from him.
Directors: Chad Stahelski, David Leitch | Stars: Keanu Reeves, Michael Nyqvist, Alfie Allen, Willem Dafoe
Votes: 262,091 | Gross: $43.00M
37. The Hateful Eight (2015)
R | 187 min | Crime, Drama, Mystery
In the dead of a Wyoming winter, a bounty hunter and his prisoner find shelter in a cabin currently inhabited by a collection of nefarious characters.
Director: Quentin Tarantino | Stars: Samuel L. Jackson, Kurt Russell, Jennifer Jason Leigh, Walton Goggins
Votes: 293,040 | Gross: $54.12M
38. Angels & Demons (2009)
PG-13 | 138 min | Mystery, Thriller
Harvard symbologist Robert Langdon works to solve a murder and prevent a terrorist act against the Vatican.
Director: Ron Howard | Stars: Tom Hanks, Ewan McGregor, Ayelet Zurer, Stellan Skarsgård
Votes: 213,499 | Gross: $133.38M
39. Gone Girl (2014)
R | 149 min | Crime, Drama, Mystery
With his wife's disappearance having become the focus of an intense media circus, a man sees the spotlight turned on him when it's suspected that he may not be innocent.
Director: David Fincher | Stars: Ben Affleck, Rosamund Pike, Neil Patrick Harris, Tyler Perry
Votes: 587,189 | Gross: $167.74M
40. Titanic (1997)
PG-13 | 194 min | Drama, Romance
A seventeen-year-old aristocrat falls in love with a kind but poor artist aboard the luxurious, ill-fated R.M.S. Titanic.
Director: James Cameron | Stars: Leonardo DiCaprio, Kate Winslet, Billy Zane, Kathy Bates
Votes: 805,750 | Gross: $658.67M
41. In the Heart of the Sea (2015)
PG-13 | 122 min | Action, Adventure, Biography
A recounting of a New England whaling ship's sinking by a giant whale in 1820, an experience that later inspired the great novel Moby-Dick.
Director: Ron Howard | Stars: Chris Hemsworth, Cillian Murphy, Brendan Gleeson, Ben Whishaw
Votes: 78,926 | Gross: $24.99M
42. The Sopranos (1999–2007)
TV-MA | 55 min | Crime, Drama
New Jersey mob boss, Tony Soprano, deals with personal and professional issues in his home and business life.
Stars: James Gandolfini, Lorraine Bracco, Edie Falco, Michael Imperioli
Votes: 195,436
43. Mad Max: Fury Road (2015)
R | 120 min | Action, Adventure, Sci-Fi
A woman rebels against a tyrannical ruler in postapocalyptic Australia in search for her home-land with the help of a group of female prisoners, a psychotic worshipper, and a drifter named Max.
Director: George Miller | Stars: Tom Hardy, Charlize Theron, Nicholas Hoult, Zoë Kravitz
Votes: 575,820 | Gross: $153.63M
44. Spectre (I) (2015)
PG-13 | 148 min | Action, Adventure, Thriller
A cryptic message from Bond's past sends him on a trail to uncover a sinister organization. While M battles political forces to keep the secret service alive, Bond peels back the layers of deceit to reveal the terrible truth behind SPECTRE.
Director: Sam Mendes | Stars: Daniel Craig, Christoph Waltz, Léa Seydoux, Ralph Fiennes
Votes: 286,279 | Gross: $200.07M
45. Harry Potter and the Goblet of Fire (2005)
PG-13 | 157 min | Adventure, Family, Fantasy
Harry finds himself mysteriously selected as an under-aged competitor in a dangerous tournament between three schools of magic.
Director: Mike Newell | Stars: Daniel Radcliffe, Emma Watson, Rupert Grint, Eric Sykes
Votes: 392,745 | Gross: $289.99M
46. Sleepy Hollow (1999)
R | 105 min | Fantasy, Horror, Mystery
Ichabod Crane is sent to Sleepy Hollow to investigate the decapitations of 3 people with the culprit being the legendary apparition, the Headless Horseman.
Director: Tim Burton | Stars: Johnny Depp, Christina Ricci, Miranda Richardson, Michael Gambon
Votes: 270,756 | Gross: $101.07M
47. Now You See Me (I) (2013)
PG-13 | 115 min | Crime, Mystery, Thriller
An FBI agent and an Interpol detective track a team of illusionists who pull off bank heists during their performances and reward their audiences with the money.
Director: Louis Leterrier | Stars: Jesse Eisenberg, Common, Mark Ruffalo, Woody Harrelson
Votes: 465,510 | Gross: $117.70M
48. Allegiant (2016)
PG-13 | 120 min | Action, Adventure, Mystery
After the earth-shattering revelations of Insurgent, Tris must escape with Four beyond the wall that encircles Chicago, to finally discover the shocking truth of the world around them.
Director: Robert Schwentke | Stars: Shailene Woodley, Theo James, Jeff Daniels, Naomi Watts
Votes: 54,587 | Gross: $66.00M
49. Mission: Impossible - Rogue Nation (2015)
PG-13 | 131 min | Action, Adventure, Thriller
Ethan and team take on their most impossible mission yet, eradicating the Syndicate - an International rogue organization as highly skilled as they are, committed to destroying the IMF.
Director: Christopher McQuarrie | Stars: Tom Cruise, Rebecca Ferguson, Jeremy Renner, Simon Pegg
Votes: 240,712 | Gross: $195.00M
50. Avengers: Age of Ultron (2015)
PG-13 | 141 min | Action, Adventure, Sci-Fi
When Tony Stark and Bruce Banner try to jump-start a dormant peacekeeping program called Ultron, things go horribly wrong and it's up to Earth's Mightiest Heroes to stop the villainous Ultron from enacting his terrible plans.
Director: Joss Whedon | Stars: Robert Downey Jr., Chris Evans, Mark Ruffalo, Chris Hemsworth
Votes: 477,829 | Gross: $458.99M


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Whether it's a single piece of furniture or an entire room, pulling together the right look for your home doesn't have to be overwhelming! LuLu Belles has a highly experienced staff ready and willing to help you choose the perfect pillow, drapery, bedding or furniture fabric for your unique project. Our store is stocked with thousands of yards of the most current fabric and trims from top fabric designers and manufacturers. We are sure to find the perfect fit for any of your fabric and decorating needs!
Our showroom inventory is constantly updated with the latest upholstery and drapery fabrics and decorative trims. If you don't find what you're looking for among our extensive inventory of fabrics and trims displayed here, just call and speak with one of our sales consultants. We'll help you find exactly what you need.
Nowhere else will you be able to find such a selection of silks, wovens, chenilles, jaquards, prints, sheers, velvets, mohairs, linens, decorative trims, wallpaper and so much more!
Our professional workrooms are known for their quality and all work is guaranteed. Let us do the work for you!
The Shoppes at Tallbrooke • 11676 Manchester Road • (314) 991-0020
Store hours: Mon. through Fri. 9am-5pm Sat. 10am-4pm
Store hours: Mon. through Fri. 9am-5pm Sat. 10am-4pm


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Normal Unit. Nation: United Sanctuary. Clan: Oracle Think Tank. Race: Noble. Grade 3 / Twin Drive!!. Power: 10000. [CONT](VC):During your turn, if the number of cards in your hand is four or greater, this unit gets [Power] +4000. [AUTO](VC):At the beginning of your main phase, Soul Charge (1), look at the top card of your deck, and put that card on the top or the bottom of your deck. [AUTO](VC/RC):[Soul Blast (8) & Counter Blast (5)] When this unit's attack hits, you may pay the cost. If you do, draw up to five cards.
- eb05single001
- Weight:
- Company:
- BushiRoad
- Series:
- Celestial Valkyries
- Product Type:
- Single Card
- Rarity:
- RRR Rare