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The Donkey's Nutz (Foxwoods WPT Finals Preview Edition)
Tonight on The Donkey's Nutz we have an action packed show! We rebound from the disaster that was Sunday Night's program by giving you a full preview of the just started Foxwoods WPT Finals! Donkey Dodgers Poker (DonkeysDodgers.com) is giving away a $300 SEAT to an event at the WPT Finals Wednesday, 7pm @ Blackie's Bulldog Tavern (181 George Washington Highway Smithfield, RI)! We'll discuss the upcming WPT Events, speak to some local players that are gonna be playing in the WPT Finals, some that already have and we welcome you calls if you're gonna be playing too!
Rules have come up a lot recently in my conversations with people and we'll open up the forum to discuss some "stupid rules" in pub poker, some good ones and possibly some you think need changing. Of course mainly we'll discuss Donkey Dodgers rules but we're willing discuss rules across the board at Foxwoods, Mohegan, or your favorite pub poker tour!
We also have the results of the not so epic heads up showdown between host Jay Messier & "Jumpsuit" Jimmy Higgins!
As always, who knows where else the show will go...
Donkey's Nutz (WPT SPECIAL: Mike Sexton, Vince Van Patten)
An EPIC Donkey's Nutz Radio Show is coming up TONIGHT, (Midnight-2am)! Here's what we have in store straight from the WPT Finals earlier this week:
-Hall of Famer Mike Sexton along with his WPT Co-Host, the man of a million catch phrases Vince Van Patten join us! -Former Voice of Poker After Park Ali Nejad joins us for a great interview discussing the future of poker post "Black Friday"! -We discuss the Media Only Event Jay Messier played in, side by side with WSOP Bracelet winner & WPT Champion Hoyt Corkins & how he may have ruined the game for everyone involved! -WPT President Adam Pliska speaks with the DZ program!
-We discuss some of the inner workings of filming a WPT Event! -3rd Place finisher Bob Carbone gets some in game advice from Jay Messier! -Why eating Fuddrukkers isn't such a good idea after sitting through a 9 hour poker event!
Debra Jay - Author - "Aging and Addiction"
in Health
Debra Jay appeared frequently on The Oprah Winfrey Show. She is a noted author, lecturer and interventionist. She has been seen most recently on The Dr. Oz Show.
Debra is author of No More Letting Go: The Spirituality of Taking Action Against Alcoholism and Drug Addiction (Bantam). She is coauthor of the books Love First and Aging and Addiction (Hazelden).
Debra worked for the Hazelden Foundation as an inpatient addiction therapist on both men's and women's units in primary care. She facilitated the family program, coordinated the older adult program, and worked in the extended care, aftercare and outpatient programs. She designed an outpatient family program. She also supervised the women's unit. She has worked as a clinical interventionist since 1996.
She is a guest lecturer at Wayne State University for graduate-level studies on substance abuse. She is a trustee of the Care Continuum Board of St. John Providence Health System and is a member of the Clinical Care Team.
Debra Jay is a nationally recognized public speaker and writes a newspaper column on alcohol and drug addiction. She is a graduate of The Ohio State University and the Hazelden School of Addiction Studies. She is also a graduate of the Dale Carnegie Course on Public Speaking.
The Scotty Clark Poker Show #26
in Blogs
Amanda Musumeci and Claudia Crawford are our guests. Amanda won her first piece of WSOP jewelry in Hammond, and we wlll talk about her new blog among other things.
Claudia finished 10th in the Hammond Main for a good score, and we are going to try and get her on the air after a big night in New Orleans for Halloween and a Madonna concert. We will also be trying to get Melanie Weisner on the air, live from South Africa where she just won a $1K WPT preliminary event.
We will also be following up on Will's trip to Hammond, announce a petition to "Free The Poker Monkey", talk about the WSOP Main Event and give away prizes...
Follow this show on Twitter at @scottclarkpoker Listen LIVE every Sunday at 3:00 PM (CST) on Blog Talk Radio and OnTiltRadio.com. You can listen to archived shows atThe Poker Monkey's blog or at scottyclarkpoker.com
You can also catch us on ITunes, Stitcher, or at the PokerFuse.com directory.
This show seeks additional sponsors at this time. Lock Poker is the exclusive online poker site sponsor of this show, no other sites may apply. You can be a sponsor on this show for as little as $200 per month, a great value for your advertising dollar.
Please contact me at firstname.lastname@example.com for more information.
Casino City Gang -- Is this a fantasy edition
in Football
Casino City's Vin Narayanan and Aaron Todd discuss their reaction to the PokerNews interview of former Full Tilt Poker honcho Howard Lederer, Cantor Gaming's big push into real-money betting on Fantasy Sports and whether the WSOP Main Event, the WPT and other high profile poker events are still appointment television for poker fans. They also pick every NFL game for Week 3.
Casino City Gang: WSOP fantasy edition
in Sports
With the World Series of Poker set to begin next week, Casino City's Vin Narayanan and Aaron Todd draft their fantasy poker team and also discuss the recent attempted robbery at the Bellagio, the plummeting numbers in the World Poker Tour's marquee event and make their best bets
The Donkey's Nutz (BONUS Sunday Night Edition)
The Donkey's Nutz Radio is bringing you a very special BONUS Show between 9-11pm TONIGHT! Jay is preparing for two days @ Foxwoods where he'll be hangin' out with Mike Sexton, Vince Van Patten & The rest of The WPT Crew as he covers the Final Table of The WPT $10,000 Event! Call in with your questions that you want him to ask!
The Scotty Clark Poker Show #7
in Blogs
Jared Hubbbard, Mark Rose, Nick Brancato, and Gabe Fajuri from Potter & Potter Auctions are our guests. The Poker Monkey co-hosts.
Jared is a Lock ProElite. We will be focusing on his blog at www.jaredhubbard.com and his series "How to Become a Successful Professional Poker Player" among many Lock Poker related subjects. Monkey's buddy, Mark Rose will be our second guest and our third guest, WPT Boot Camp instructor "Nicky Numbers" Brancato will be giving us live cash game tips.
Gabe Fajuri will be closing out the show, and we will learn more about Potter & Potter Auctions and their Second Annual Gaming Auction being held online live June 23rd.
Follow this show on Twitter at @scottclarkpoker Listen LIVE every Sunday at 3:00 PM (CST) You can listen to archived shows here or at www.scottyclarkpoker.com You can also catch us on ITunes, at the PokerFuse directory and re-broadcasted at OnlinePokerTour on Wednesdays at 5PM and 10PM (EST).
This show seeks additional sponsors at this time. Lock Poker is the exclusive online poker site sponsor of this show, no other sites may apply.
You can be a sponsor on this show for as little as $200 per month, a great value for your advertising dollar.
Please contact me at email@example.com for more information.
The Donkey's Nutz (Dealing w/ A-Holes at The Poker Table!)
With the Foxwoods WPT Ladies Only Event only 4 days away, is Jay Messier backing off his stance to be a hero for mens rights?! With one of his bext friends weddings taking place later the same afternoon he's debating his priorities! There will be plenty of talk about the Ladies Only Event and YOUR CALLS telling Jay whether he should go to his friends wedding or stand up for the Y Chromosome!
The Scotty Clark Poker Show #4
in Blogs
Sunday May 27 Frank Kassela, Dwyte Pilgrim, Aaron Massey and David Plastik are our guests. Poker Monkey makes his debut as co-host!
Follow this show on Twitter at @scottclarkpoker and you can listen LIVE every Sunday at 3:00 PM (CST) You can listen to archived shows at this page or at SCOTTYS BLOG.
Frank Kassela is a two-time WSOP Bracelet winner and was the 2010 WSOP Player of the Year. Dwyte Pilgrim was the 2010 WPT-Borgata Champion and is a three-time WSOP Circuit winner. Chicago's Aaron Massey is a WSOP Circuit standout, who has qualified for the 2012 WSOP Circuit National Championship. Long-time professional David Plastik will be coming on the show to talk about the 1980s, when he was a free-lance rock photographer, and his works were published in Guitar, Rolling Stone, Cream and Hit Parader,
This show seeks additional sponsors at this time. Lock Poker is the exclusive online poker site sponsor of this show, no other sites may apply.
You can be a sponsor on this show for as little as $100 per month, a great value for your advertising dollar. Please contact me at firstname.lastname@example.com for more information.
FLPR Season 2 Ep. 5
in Hobbies
Tonight on the Poker Podcast we are joined by special guest co-host Bootsy Collins. We will discuss the new insurance website that will pay you if your all in hand gets cracked. We discuss the upcoming Parx Casino WPT schedule, Full Tilt hiring again and Johnny Sep discusses a few things he needs to get off of his chest. Join us in the live chat and on Black Chip Poker for our live radio freeroll!
Donkey's Nutz (BACK After 2 Weeks Off!)
We have two weeks of poker talk to catch up on tonight! Including lost of great interviews with some of Pub Pokers BIGGEST STARS last week @ our Seasonal Points Championship! We talked to John Cascione, The Rev, Big Daddy Moon, Jeremy Hart, Herman Ho, John Murray, Pat O' Donnel, Alfredo Perez, Jim Higgins, our eventual Champion Gene Babcock & more!
Also I have a few things that PISS ME OFF I gotta get off my chest!
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In a port tasting, tasting Graham's is almost like tasting a big, rich, succulent Merlot after a group of blockbuster, tannic Cabernets. Sweeter and more obvious than many ports, the opaque purple-colored 1994 is fruity, powerful, and rich, with an addictive hedonistic quality. It will be ready to drink in 8-10 years and keep for up to 30. As always, this is a showy, flamboyant port that has the advantage of being slightly sweeter than other 1994s. A great Graham's. Anticipated maturity: 2002-2035.
(10/ 1996)
A big, tough, young vintage Port that's closed and difficult to taste. Emits lovely aromas of chocolate, berry and plum, and is full-bodied with lots of sweet, fruit flavors and masses of velvety tannins. Long, sweet finish. Best after 2010.
(4/ 1997)
Deep garnet. Amazing nose: complex and rich, cigar box and fig, violets and sweet baking spice, muscovado sugar, ripe baked plums. Huge depth and richness, grippy but fully rounded tannins. Depth and yet no heaviness. Slight nuttiness. After all that intensity, still has freshness on the finish. Baked potato skins. Lovely sweetness. Drink 2020-2035. (18.5/20 points)
(10/ 2010)
93 points Neal Martin: "The Grahams 94 is still very tight and youthful on the nose, quite strict and conservative with smoky black fruit with hints of Chinese 5-spice, singed leather and bay leaf. Very well defined. The palate is full-bodied, creamy in texture on the entry, very spicy with a thwack of lemongrass and ginger on the black palate, superb length, a Grahams straining at the leash. This has impressive length: muscular and compelling. Excellent. Drink now-2035. Tasted April 2010." (Wine Journal, eRobertParker.com, 11/2010)
Below is a listing of the wine review scores we frequently reference in our notes. While these sources remain an excellent source of information, we always recommend that you trust your own palate. Scores in these publications often represent the personal taste of an individual critic, which may not always coincide with your own. We have a huge team of excellent wine professionals that can match wines you've had in the past with new arrivals that meet your flavor profile.
The item you have chosen is not in stock in our retail stores or within our main
1997 Fonseca Vintage Port
1965 Taylor Fladgate "Very Old Single Harvest" Tawny Port
1995 Poças Vintage Port (375ml)
1977 Fonseca Vintage Port
1991 Dow's Vintage Port

subset: commoncrawl


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Thank you so much Victoria for nominated my page..........very much appreciated!
Credits: Four Season Siggies by Dagi's Temp-tations and Fresh Fields by Mandy King, kidish {font}
Proudly CT for Pixelily Designs, Luv Ewe Designs, B2N2 Scraps, Wimpychompers, Blue Heart Scraps and more.
I got picked!! I'm gobsmacked! Thanks for picking my layout, Lydia!


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Lizs Wares on Etsy.com
Planning a wedding this year? Looking for a gift? Or just want to reward yourself? Then come visit Lizs Wares for bridal, prom, and casual jewelry all designed by me, Liz! My favorite materials to use vary from faux pearls, turquoise, and other gemstones such as Abalone/paua shell, Cat eyes beads, and other various glass beads. So come check out my shop!
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Holiday Inn Portsmouth Downtown
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
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Bluegrass Country
... areas. Sheets were soaked from condensation so I came in to use dryer. Woman already in there and she was territorial. I just gave her my best overly nice sarcastic attitude. I think it worked well.
-Cars up and down gravel path during night and early morning. We didn't realize that there was another RV city just below our tent site.
I Thought These Jackets Were Waterproof
... of starting. We traveled some of our route in our Budget truck yesterday, not too bad.
We returned our Budget truck to a dealer this morning and got our loaded bikes out. Wow, another learning curve. The front of the bikes seem so heavy, we wobbled and wobbled and wobbled down the road. The cars are terrified of us for a change. We had to relearn balance with heavy packs. We had to relearn shifting. I went 5 miles before I remembered I had three front sprockets on ...
We are still in Wheelersburg, Ohio. We are so tired from travel and preparation to get here that we overslept and missed breakfast. Scott has a terrible cold and his eyes are blood red. He does not feel well at all. I can't tell if I am sick or just mean and mad that I am on this bike again. We checked out, headed to get the local maps needed, and to Scott's wits end, and my joy, we had to spend the night again. I slept like a log, and ...
The Buckeye States Rainy Welcome
... home where we were needed. Amazing how all things fell into place for us to get home at the exact time we were needed.
But now I know too much. I know how hard these endless days can be. I know about the road traffic. I know I do not want to be here. I say to Scott, "do not expect the happy Chris of the first journey to show up this time". Hee Hee, Poor guy. He has such patience with me. I am ornery and scared. I do not want to be here. The white-hot memory of the trap ...
Bits and Bobs
A quiet morning enjoying the pool, hummingbirds and deer. The heat of over 90 F was almost unbearable until a series of thunderstorms broke its spell. Early lunch and off to cover three states. Along the interstate highway to leave Kentucky for West Virginia and then into Ohio. Sams Superstore ...


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Discover what to do, where to stay and what to see in New York City with our planning tool.
NYC is the place for inquisitive minds looking for new things to see, hear, taste and learn.
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Get tips, maps and everything else you'll need during your stay.
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NYC Comedy Week – 2-for-1 Tickets to New York Comedy Shows
March 23–29, celebrate the show's final season with a two-course lunch or two cocktails for $19.69.
Stay in New York City and save with these offers.
New York City is made up of five boroughs: the Bronx, Brooklyn, Manhattan, Queens and Staten Island. Each one has enough attractions—and enough personality—to be a city all its own. Learn more about them with this guide.
The Brooklyn Table Tennis Club is a go-to outpost for Ping-Pong aficionados in Kings County and beyond. The place boasts niceties both hi-tech (a Newgy Robo-Pong robot) and hygienic (an on-site shower), and its resident coaches include Nison Aronov, a decorated professional player in both the former Soviet Union and the United States. If you're feeling competitive, ask about the Thursday and Sunday tournaments, which feature a low entry fee and prizes for the top players.


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They are on their way! Three of the world's most famous ships are heading for Southampton for the tenth anniversary of the Cunard flagship, Queen Mary 2 in the port on Friday.
The world's grandest ocean liner, QM2 and her sister ships, Queen Elizabeth and Queen Victoria, are sailing in formation from Lisbon, Portugal to Southampton ahead of a visit by the Duke of Edinburgh to celebrate QM2's tenth anniversary as Cunard's flagship.
QM2 is on the final leg of her annual world cruise and her sister ships were on hand to escort her home to Southampton in style. For the first time ever, the three Queens were photographed side-by-side at sea as part of a shoot which took months of meticulous planning.
Centrepiece of the shoot was QM2 herself, the only ocean liner in service today and still the fastest passenger ship afloat ten years after she was named by the Queen in Southampton back in 2004.
It took the three ships around an hour to sail out of Lisbon to the site of the shoot.
All shipping in the area had to be totally cleared for the three Queens to ensure absolute safety for the technical manoeuvre. Cunard director, Angus Struthers said: "This is the first time all three Queens of the Cunard fleet have been seen together anywhere outside Southampton or New York, and the first time these magnificent ships have been seen together at sea."
More Shipping Stories
- Take a look at the new Red Osprey ferry after its £2.2m refit
- PICTURES & VIDEO: Ferry back in service after £2.2m refit
- Shipbuilding to return to Southampton - creating 250 new jobs
- PICTURES: USS Theodore Roosevelt - the facts and figures behind huge aircraft carrier
- Thousands of US sailors arrive as massive aircraft carrier drops anchor in Solent
- VIDEO: Gigantic 1,100ft long US aircraft carrier carrying 5,000 men anchored off Hampshire coast from today
- Massive aircraft carrier to anchor off Hampshire coast - because it's too big to fit into port
- Royal Navy unveils new uniforms with Southampton seaman


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3/27/2015Kansas Credit Unions Called to Action on State Issues
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Overview:Credit Unions are one of the most highly regulated sectors in the economy. Does a visit from your examiner cause you to get heartburn? Relief may be at hand! Learn how to prepare for a productive examination process and what to do when you don't agree with the results.
Speaker: David Reed is an author, consultant and nationally recognized speaker. He received his undergraduate degree from Virginia Tech in 1986 and his Juris Doctorate from George Mason University School of Law in 1989. Formally, Mr. Reed was Vice President and General Counsel for Apple Federal Credit Union in Fairfax, Virginia. In his role as chief legal officer he established institutional legal policy, provided legal advice to the Credit Union concerning a variety of matters including the establishment and revision of Credit Union policies and procedures, organization compliance with federal regulations, contractual agreements, regulatory matters, and corporate governance. David has been selected to train NCUA Field Examination and Audit staff on Bankruptcy matters.
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'I'm not going to rape you' - as a chat up line(32 Posts)
Wahtawah Fri 26-Oct-12 23:27:52
EduCated Tue 06-Nov-12 13:03:43
Trekkie Mon 05-Nov-12 19:56:16
babylann Mon 05-Nov-12 17:24:05
KRITIQ Mon 29-Oct-12 12:33:27
YerMaw1989 Mon 29-Oct-12 12:30:24
deleted203 Mon 29-Oct-12 01:22:44
FastLoris Mon 29-Oct-12 01:13:23
YerMaw1989 Sat 27-Oct-12 19:34:05
Anniegetyourgun Sat 27-Oct-12 15:04:37
Alameda Sat 27-Oct-12 13:44:50
OldLadyKnowsNothing Sat 27-Oct-12 02:13:01
BeingBooyhoo Sat 27-Oct-12 01:40:53
BeingBooyhoo Sat 27-Oct-12 01:38:10
lisaro Sat 27-Oct-12 01:24:30
OldLadyKnowsNothing Sat 27-Oct-12 01:13:02
OldLadyKnowsNothing Sat 27-Oct-12 01:05:27
OldLadyKnowsNothing Sat 27-Oct-12 00:58:04
NewNames Sat 27-Oct-12 00:40:59
NewNames Sat 27-Oct-12 00:40:51
Wahtawah Sat 27-Oct-12 00:38:19
OldLadyKnowsNothing Sat 27-Oct-12 00:30:55
Wahtawah Sat 27-Oct-12 00:24:26
BeingBooyhoo Sat 27-Oct-12 00:11:21
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President Obama got it two-thirds right when he said that the delayed confirmation of his attorney general nominee, Loretta Lynch, is owing to Senate dysfunction and Republican stubbornness.
He left out the part about Democratic intransigence and at least one incident of "wacko-birdness" from the left.
Introducing her husband on Super Tuesday night, Ann Romney said women this election season are interested in jobs, the economy and the debt.
Translation: So could we shut up already about contraception?
Republicans might wish nothing more than to stuff birth control pills back into the bottle, but Democrats aren't about to let them. The narrative already has a title: "The Republican War on Women." Cue theme from "Psycho."
Who'd have thought that Rush Limbaugh would become the great uniter in this divisive political season?
Indeed, he has united decent people of all stripes and persuasions with his vile remarks about a Georgetown Law student.
Let me be blunt: If Republicans nominate Rick Santorum, they will lose.
The prospect of four more years of Barack Obama holds some appeal for many Americans, but probably not for most Republicans. It may give doubters among them some comfort, however, to know that Obama and Santorum share the same prayer: that Santorum be the Republican nominee.
Can civility be saved?
This has become the question du jour among scholars, journalists and others who fret about such things at dozens of programs popping up around the country. As a nation, we seem to want to be a more civil society, which is laudable if, quite possibly, unlikely.
Inevitably, discussions about the current state of civility begin with disclaimers and acknowledgement that Americans have always been a bunch of rowdies and rascals. Previous eras have made current incivility look like a (real) tea party that erupts into a food fight of crumpets and scones.
Mitt Romney's recent losses to Rick Santorum in Colorado, Missouri and Minnesota revealed a truism that Romney might want to study — but not too much!
Parting with one's dreams isn't only sweet sorrow, it also can be liberating. Beneath the sorrow and alongside the liberation, one finds not only peace, but often oneself.
Put another way, it's hell to be a front-runner.
Two of the top news stories this past week have revolved around reproductive rights, though both raise far more troubling issues than a woman's right to contraception or abortion.
The more compelling questions concern a person's or an institution's freedom of conscience and the right to act upon one's moral beliefs without fear of intimidation and/or government coercion.
When it comes to Newt Gingrich's post-speaker activities on the Hill, it all depends on what your definition of "lobbying" is.
In Monday's debate, Mitt Romney charged Gingrich with "influence peddling." But Gingrich insists that he was merely working as a historian when he collected $1.6 million from Freddie Mac over a six-year period. Which in some version of reality could be true. Broadly speaking, a historian who is hired to dig ditches is still a historian.
One thing we've learned since the Republican primary season began: There's an awful lot of pious baloney out there.
The vast majority of it is on the plate of the man who coined the phrase — Newt Gingrich. Not that he's dining alone. Gingrich first tossed the holy lunchmeat on the counter during one of the New Hampshire debates after Mitt Romney tried to aver that he never set out to be a career politician. He was a businessman first, he said, who found his way to politics.
It is axiomatic in these political times that The Candidate must submit to comedic humiliation — with grace, humor and the skin of an armadillo. In this upside-down universe, the court jester is the monarch and the would-be king must submit to the jester's pranks.
Callista Gingrich has done something she might come to regret — succumbed to the Twitter fairy and opened the door to unwelcome scrutiny.
St. Augustine Record ©2015. All Rights Reserved.


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The administration of ribose raises the hypoxic threshold of mammals experiencing a hypoxic condition. The presence of an effective amount of ribose in the tissue of a mammal increases the tolerance to hypoxia and decreases the symptoms of hypoxia in mammals experiencing chronic hypoxia due to cardiovascular disease or peripheral vascular disease. Such mammals are additionally benefited by administration of ribose and a vasodilator or an isotropic agent. Mammals experiencing transient hypoxia from high altitude, anesthesia or exercise are also benefited.
1. A therapeutic method comprising administering ribose to a mammal in an effective amount to increase the tolerance of the mammal to hypoxia so that ribose is present in the tissue of the mammal during the hypoxic event.
2. The method according to claim 1 wherein the mammal is a human.
3. The method according to claim 2 wherein ribose is administered in a dosage of about one to 60 grams.
4. The method according to claim 1 wherein ribose is administered at least five minutes prior to the occurrence of the hypoxic event.
5. A therapeutic method comprising administering ribose and a vasodilator to a mammal in an effective amount to increase the tolerance of the mammal to hypoxia so that ribose is present in the tissue of the mammal having reduced tissue circulation during the hypoxic event.
6. The method according to claim 5 wherein the mammal is a human.
7. A therapeutic method comprising administering ribose and an inotropic agents to a mammal in an effective amount to increase the tolerance of the mammal to hypoxia so that ribose is present in the tissue of the mammal having reduced tissue circulation during the hypoxic event.
8. The method according to claim 7 wherein the mammal is a human.
9. The method of claims 1, 5 or 7 wherein ribose is administered orally, intravenously or intraperitoneally.
10. The method of claims 1, 5 or 7 wherein the hypoxia is due to cardiovascular disease, myocardial stunning, anaesthesia, surgical procedures, peripheral vascular disease, intermittent claudication, pulmonary dysfunction, physical exertion, pharmaceutical treatment, tachycardia or poisoning.
This application is a Continuation-in-part of application Ser. No. 09/290,789, filed on Apr. 12, 1999, which is a continuation of provisional application No. 60/090,001, filed Jun. 19, 1998 which issued as U.S. Pat. No. 6,159,942, on Dec. 12, 2000.
The present invention relates to compositions and methods for raising the hypoxic threshold in mammals experiencing a hypoxic condition. Such mammals include humans with cardiovascular or peripheral vascular disease, or humans undergoing chronic or transient hypoxia.
It is well known that the energy coinage of the cell is adenosine triphosphate (ATP). During anabolism, the energy derived from the metabolism of nutrients is transferred to high energy phosphate bonds of ATP. The energy in these bonds is expended during the energy consumption phase. An important and ōcostlyö expenditure, in which ATP is rapidly cycled, is that required for muscular contraction.
The energy buildup steps occur within the muscle cell during two basic processes. Oxidative phosphorylation replenishes ATP by the breakdown of circulating fatty acids, glucose and intramuscular glycogen and triglycerides. Anaerobic phosphorylation provides ATP from creatine phosphate, circulating glucose and intramuscular glycogen via kinase reactions such as the myokinase reaction.
In the synthesis of ATP via the nucleotide salvage pathway, the nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP. Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. Ribose is found in the normal diet only in very low amounts, and is synthesized within the body by the pentose phosphate pathway. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate adenosine monophosphate (AMP.) AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP. During energy consumption, ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine, hypoxanthine and inosine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway.
In U.S. Pat. No. 4,719,201, it is disclosed that when ATP is hydrolyzed to AMP in cardiac muscle during ischemia, the AMP is further metabolized to adenosine, inosine and hypoxanthine, which are lost from the cell upon reperfusion. In the absence of AMP, rephosphorylation to ADP and ATP cannot take place. Since the precursors were washed from the cell, the nucleotide salvage pathway is not available to replenish ATP levels. It is disclosed that when ribose is administered via intravenous perfusion into a heart recovering from ischemia, recovery of ATP levels is enhanced.
The availability of PRPP appears to control the activity of both the salvage and de novo pathways, as well as the direct conversion of adenine to ATP. Production of PRPP from glucose via the pentose phosphate pathway appears to be limited by the enzyme glucose-6-phosphate dehydrogenase (G6PDH). Glucose is converted by enzymes such as G6PDH to ribose-5-phosphate and further phosphorylated to PRPP, which augments the de novo and salvage pathways, as well as the utilization of adenine. The addition of ribose bypasses this rate limiting enzymatic step.
Many conditions produce hypoxia. Such conditions include acute or chronic ischemia when blood flow to the tissue is reduced due to coronary artery disease or peripheral vascular disease where the artery is partially blocked by atherosclerotic plaques. Transient hypoxia frequently occurs in individuals undergoing anesthesia and/or surgical procedures in which blood flow to a tissue is temporarily interrupted. Peripheral vascular disease can be mimicked in intermittent claudication where temporary arterial spasm causes similar symptoms. Finally, persons encountering high altitudes may become hypoxic.
Thus, a continuing need exists for methods to raise the hypoxic threshold of cardiac and skeletal muscle.
The present invention provides compositions for, and methods to raise the hypoxic threshold in a mammal. It is believed that the present compositions and methods allow mammals to tolerate situations in which, absent the present compositions and methods, the mammal would experience the onset of symptoms and consequences of hypoxia. The preferrred compositions include D-Ribose alone or, optionally, in combination with vasodilators and/or inotropic agents in pharmaceutically acceptable carriers. Hypoxia may be chronic, as in mammals with congestive heart failure, coronary artery disease or peripheral vascular disease. Hypoxia may also be transient, as in mammals undergoing anesthesia and surgical procedures, experiencing high altitudes, or exposed to toxic substances that interfere with oxygen utilization.
It is here shown that the administration of ribose will raise the hypoxic threshold of a mammal such as a human or domestic animal, thereby enabling such mammals to better tolerate the situation causing hypoxia. It is further disclosed that in mammals in which the hypoxia is caused by reduced blood flow due to arterial occlusion or spasm, the administration of ribose plus a vasodilator will enhance the raising of the hypoxic threshold.
FIG. 1 shows the dose response of the adenine salvage pathway in normal adult rats to the administration of ribose.
FIG. 2 shows the mean power output per sprint session of normal adult humans, following administration of ribose or placebo, as measured on an exercycle.
FIG. 3 shows the peak power output per sprint session of normal adult humans, following administration of ribose or placebo, as measured on an exercycle.
The present invention provides a method of raising the hypoxic threshold of a mammal such as a human or domestic animal, by the administration, i.e., oral, intravenous or peritoneal administration of and effective amount of ribose to said mammal. The invention also provides provides ribose-containing compositions that enhance the delivery of ribose to target tissue and are therefore especially beneficial to mammals experiencing hypoxia.
For the purpose of describing this invention, the following terms have the following meanings:
1. ōRiboseö means a monosaccharide, including but not limited to, ribose, and any 5-carbon precursor of ribose, D-ribose, ribulose, xylitol and xylulose.
2. ōVasodilatorö includes any substance that causes dilation of blood vessels, including but not limited to, adenine, hydralazine, arginine, nitroglycerine or analogs thereof, administered alone or in combination, transdermally or orally, or physical agents such as hot compresses, heating pads or ultrasound administration.
3. ōInotropic agentö includes any substance which increases the stroke volume and cardiac output of the heart, including but not limited to, dobutamine, arbutamine, dopamine, amrinone and milrinone, and anlaogs thereof, alone or in combinaton.
4. ōHypoxiaö means any state in which the tissue oxygen saturation is reduced to a less than optimal level. Hypoxia includes anoxia, ischemia and poisoning with toxic agents such as carbon monoxide and cyanide which interfere with oxygen utilization. Hypoxia may be chronic as in congestive heart failure, coronary artery disease, peripheral vascular disease or pulmonary dysfunction, or transient as in anesthesia, surgical procedures or exposure to high altitudes.
5. ōHypoxic thresholdö is that basal level where oxygen saturation of tissues less than optimal. A raised hypoxic threshold increases tolerance to situations which would otherwise result in hypoxia.
6. ōIschemiaö is that state of hypoxia caused by reduced circulation of blood to tissue.
In patients with ischemic heart disease, regions of the heart may be poorly perfused, dysfunctional, but still viable. Myocardial ischemia limits blood flow and therefore the available supply of oxygen. This limited availability of oxygen affects oxidative metabolism, which ultimately negatively affects the production of adenosine triphosphate (ATP), essential for maintenance of contractility and cellular integrity. Varied states of ischemia exist. However, either transient or chronic ischemia may result in partial reduction of myocardial ATP with subsequent impairment of contractile function, which can lead to heart failure but not cell death.
Therapeutic intervention is variable and must be tailored to each patient. Non-surgical therapies may offer a primary mode of treatment. The first line of action includes angiotensin-converting inhibitors, digoxin and diuretics. So-called inotropic agents such as dobutamine, arbutamine, dopamine, amrinone and milronine, which increase stroke volume and cardiac output, have been universally used for treatment of cardiac dysfunction, which can be manifested by edema, dyspnea, pulmonary congestion and organ hypoperfusion. Many previous studies have investigated the use of ribose in healthy animals such as dogs, rats and swine that have been subjected to ischemic insult. While such studies maysuggest therapies for humans with cardiovascular disease, subsequent human clinical studies often fail to support these suggestions.
Many patients suffering from ōsilentö cardiovascular disease, that is, such patients are unaware of their condition of chronic hypoxia. The treadmill test has been extensively used to raise the oxygen demand of the heart and uncover the low hypoxic threshold. However, treadmill testing may not be the test of choice in all situations. Dobutamine has been found particularly useful for simulating exercise in patients with coronary artery disease. The infusion of dobutamine produces a stressful myocardial condition similar to that produced by exercise, while the patient is in a controlled hospital setting, with intravenous infusion, in which intervention is readily available. It is theorized that dobutamine increases myocardial stroke volume and cardiac output while reducing ventricular volume and mitral regurgitation due to its vasodilating effects. Because of these multiple effects, dobutamine has been investigated extensively as an agent to increase sensitivity in identifying segmental wall motion activity by echocardiography.
In co-pending patent application Ser. No. 09/290,789 (the ō'789 Applicationö), the teaching of which is hereby incorporated by reference, it is disclosed that administration of D-ribose increases the energy level of mammals by stimulating the synthesis of ATP. Examples therein show that ATP levels in the skeletal muscle of healthy mammals under normal conditions of oxygen availability increase upon ribose administration and that the increase is correlated with an increase in performance and activity levels. It is also shown that administration of D-Ribose provides some benefit even to patients with coronary artery disease.
The present invention is based on the discovery that administration of ribose can also increase the tolerance of tissue to low oxygen availability, that is, to hypoxia. Energy and oxygen availability can each independently influence tissue integrity and function. Although ribose has been shown to enhance energy levels under conditions of normal oxygen availability, the present invention surprisingly shows that when ribose is present, tissue can endure low oxygen availability while still maintaining normal function, without being subjected to the deleterious effects due to low oxygen. Even if energy is available in sufficient quantities, but oxygen is low, adverse effects may still occur in the hypoxic tissue. These effects include pH changes, imbalance in intermediate metabolites and the like. In other words, ribose ameliorates the effects of hypoxia, that is, it raises the hypoxic threshold.
The advantages of ribose in raising the hypoxic threshold may not be readily available to mammals with poor circulation and that therefore the benefits shown in the '789 Application may fall far short of optimal. The present method also contemplates the use of vasodilators and/or inotropic agents (ōinotropsö) to increase the delivery of ribose to tissue in order that mammals may experience the maximum benefit from ribose administration.
It has been investigated and is here disclosed that the beneficial effects of D-ribose, in the presence of a vasodilator, provides overall stabilization and/or improvement in myocardial function in patients with severe cardiovascular disease. The effect of D-Ribose on heart wall motion seen on echocardiographic examination was studied in various populations suspected of having stunned or hibernating myocardium, as is more fully disclosed in co-pending patent application, Ser. No. 09/405,462 entitled EFFECT OF RIBOSE ON THE ISOTROPIC RESPONSE TO DOBUTAMINE, which was filed on the same day as this application. Upon infusion of high levels of dobutamine, at a dosage sufficient to simulates exercise stress, ribose was shown to raise the hypoxic threshold and enabled patients to tolerate high levels of dobutamine. It is believed that co-administration of D-ribose and a vasodilator will enhance myocardial energy levels in cardiovascular patients and will raise their hypoxic threshold. This, in turn, will improve their clinical status before, during and after revascularization or heart transplant, and enhance the treatment of cardiovascular disease or end-stage heart disease or failure. It is further believed that perfusion of a donor heart with D-Ribose before removal from the donor and during transport, will prolong the period during which the heart is suitable for transplant.
Even persons free of disease occasionally experience transient situations of hypoxia. Such situations include exposure to high altitudes, anaesthesia, tachycardia, surgical procedures that temporarily interrupt blood flow, and poisoning with agents such as iron carbonyl, carbon monoxide and cyanide that interfere with oxygen utilization. Such persons would benefit by the raising of the hypoxic threshold.
The present method comprises the administration of an effective amount of D-Ribose for an adequate period of time to raise the hypoxic threshold in mammals. This method also comprises the administration of D-Ribose in combination with a vasodilator to patients subject to acute or chronic hypoxia, accompanied by poor circulation, in adequate amounts for a period of time to raise the hypoxic threshold. This method provides the combined effects of D-Ribose and mid- or high-dose dobutamine admionistration so as to reduce or eliminate the deleterious effects of hypoxia. This invention provides D-ribose to patients already receiving dobutamine as part of their post-operative management following a revascularization procedure, in order to improve their clinical outcome.
Myocardial hibernation and stunning define conditions in which tissue viability may be present but is hindered in the presence of reduced regional or global blood flow. The phenomenon of hibernating and stunned myocardium has been the subject of increasing interest with recognition that function may improve in these regions after restoration of adequate blood supply or treatment with newly available therapies such as the Batista procedure, in which the diastolic volume of the ventricle is surgically reduced by removal of non-viable or poorly viable tissue. The resulting ejection efficiency of the ventricle is improved with the patient usually experiencing a clinical benefit.
Among the techniques used to distinguish non-viable from viable myocardium, echocardiography is commonly used because of its direct measurement of contractile function, which is thought to be a better predictive indicium than blood-flow tracing with radionuclides. Myocardial stress induced by dobutamine infusion increases the sensitivity of echocardiography. However, the sensitivity of this technique for detection of viable myocardium may be limited in the presence of severe coronary artery disease. Although sensitivity is correlated to mid- or high doses of dobutamine, that is, 10 to 40 μg/kg/min, high doses cause ischemia and distress in these vascularly compromised patients. It is herein disclosed that when ischemia is induced with mid- or high-dose dobutamine, D-Ribose raises the hypoxic threshold. From these results, it can be predicted that the hypoxic threshold of mammals in other situations that result in the symptoms of ischemia, will likewise be raised by the administration of ribose. In this example, ribose was administered intravenously. However, it is well known that ribose is readily absorbed from the gastrointestinal tract and the peritoneal lining. Therefore, the route of administration may be determined by convenience. Ideally, oral administration of ribose is the preferred route. If the patient is attached to an intravenous line, it may be more convenient to add ribose to the infusate. If the patient is unable, unwilling, or uncooperative enough to tolerate oral or intravenous administration, peritoneal infusion can be used quickly and effectively.
Coronary artery bypass grafting (CABG) has become a routine procedure. During this procedure, blood flow is restored to regions of the heart served by stenotic coronary arteries. Identification of those areas that are hibernating or stunned and identifying the non-viable segments aids the surgeon in revascularizing those regions that are most capable of being revived and improved with reperfusion.
Peripheral vascular disease (PVD) is caused by stenoses of the peripheral arteries, leading to hypoxia of the skeletal muscles, especially during exercise. Patients suffering from PVD are frequently unable to walk for a distance before experiencing severe pain and fatigue. Raising the hypoxic threshold by the administration of ribose, preferably with a vasodilator, can reduce or eliminate these symptoms.
Various methods of revascularization may be considered by the medical personnel and subsequently offered to the patient. Ischemia may be viewed in the disease state as either acute or chronic, and decisions made accordingly. Table I summarizes the decision grid.
Each treatment carries its own risks and benefits. For example, angioplasty has a lower rate of long-term success than CABG due to the tendency of the vessel to re-occlude (ōrestenosisö), but because it is a simpler procedure with lower risks, it will be often indicated as a first course of action, when the patient has an amenable lesion. However, not all patients carry the same preoperative risk for each procedure. If the heart contains large areas of non-viable tissue with severely decreased myocardial performance, a heart transplant rather than CABG may be the patient's only alternative. Regardless of the surgical therapy chosen, preconditioning with oral and/or IV D-Ribose, preferably in conjunction with vasodilator administration, decreases the risk to the patient by raising the hypoxic threshold. Preoperative, operative and postoperative risks, which include death, infarction and myocardial dysfunction are lessened.
Just as the recipient patient benefits from the administration of D-Ribose, the donor heart used in transplantation can benefit from the use of D-Ribose. By administration of D-Ribose, the donor heart will show higher maintenance of energy levels and function during preservation and following revascularization. It is expected that this extended maintenance of viability will allow the ischemic period of preservation to be extended, so that more donor hearts will be available and optimal matching of donor and recipient may occur across a wider geographic area.
In the '789 Application, it is disclosed that healthy mammals show an increase in ATP following administration of D-Ribose and that humans with CAD show improvement in clinical condition on oral administration of D-Ribose. The use of dobutamine for echocardiographic diagnosis of stunned or hibernating myocardium clearly indicates that concomitant administration of a vasodilator with D-Ribose further enhances the ribose effect, enabling the patient to tolerate stress of a degree that would, in the absence of either ribose or vasodilator, cause symptoms of hypoxia. Without being bound by theory, it would seem that ribose alone is sufficient to raise the hypoxic threshold, but that in CAD patients, arterial stenosis (es) may impede the delivery of ribose to the muscle tissue. Therefore, it is apparent that the administration of a vasodilator with D-Ribose will improve the tolerance to hypoxia in a CAD patient.
The references identified in the specification are incorporated herein by reference to the extent that they supplement, explain, provide background for, or teach the methodology, techniques and/or compositions employed herein.
The following examples are included to demonstrate preferred embodiments of the invention. In each example, D-Ribose is disclosed as the preferred embodiment. However, it is known in the art that certain pentoses such as xylitol and ribulose are readily converted to D-Ribose in vivo. Therefore, the term ōD-Riboseö is intended to include such precursors of D-Ribose. It should be appreciated by those skilled in the art that the techniques and dosages disclosed in the examples that follow represent techniques and dosages discovered by the inventors to function well in the practice of this invention, and thus can be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the concept and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Effect of D-ribose on Nucleotide Salvage in Resting Rat Muscle
It has been theorized but not objectively shown that ribose, via PRPP synthesis, increases the rate of ATP synthesis via the nucleotide salvage pathway. However, nothing is known about the total adenine nucleotide (TAN) or ribose levels in the resting muscle and therefore, it is possible that the synthetic enzyme pathway is already saturated and that administration of ribose does not increase ATP levels in normal, non-ischemic skeletal muscle. In order to demonstrate the effect of ribose on the pathway, plantaris complex muscles of healthy adult male Sprague-Dawley rats were surgically exposed and perfused with reconstituted blood perfusion medium containing amino acids, mM glucose and 100 μU of bovine insulin/ml. The muscle was perfused with reconstituted blood medium at ś40 ml/min, providing tissue perfusion of approximately 0.65 ml/min. Varying concentrations of D-ribose were added to the perfusate to bring the concentration to 0.156 mM, 0.5 mM, 1.58 mM, 5.0 mM and 15.0 mM. The muscle was perfused for 30 minutes. A minimum of two rats was used for analysis at each dose of ribose tested.
Following perfusion, muscle sections were quickly dissected from the limb and freeze-clamped with aluminum tongs chilled in liquid nitrogen. Muscle sections were lyophilized and reconstituted in distilled water for subsequent separation of adenine nucleotides by reverse-phase high pressure liquid chromatography. Results are expressed as salvage of adenine (i.e., formation of ATP) in nanomoles salvaged per gram wet weight of muscle per hour (nM/gm/hr).
As is shown in FIG. 1 and Table II, adenine salvage at zero millimolar (mM) ribose is less than 50 nM/gm/hr and doubles with administration of 0.158 mM ribose. At 5 mM ribose, the rate of ATP synthesis reaches 250 nM/gm/hr. These results show that normal, healthy muscle has low baseline levels of ribose and nucleotide salvage capability, which can be increased by the administration of ribose.
Increased Exercise Capacity in Normal Subjects
Four healthy, fit subjects in the age range 24 to 26 years of age were tested. The group was selected to be homogeneous regarding fitness level, gender and mean age with no known metabolic, neuronal, endocrine or cardiopulmonary disorders. All were capable of or had experience with cycling. The study protocol included four phases: (1) an initial baseline phase consisting of no exercise session; (2) a loading phase including three days of administration of either D-ribose or placebo (glucose) three times per day; (3) a training phase of three days employing exercise sessions characterized by serial (N=6) bouts of short (10 second) high-intensity cycle sprints at 7% body mass resistance with 50 second rest periods between sprints twice per day (morning and afternoon), and (4) a recovery phase for a period of 48 hours after the final training session. FIG. 1 is a diagram of a single cycle sprint bout.
Muscle biopsies (MB) were performed on the vastis lateralis muscle using both legs in order to evenly distribute and minimize sampling and possible muscle soreness per leg due to the biopsy itself. The first MB was collected at rest at the beginning of the study to establish a baseline and immediately after the first training session of day 0 or the first phase. During the loading phase, no MB was taken. Muscle Biposies were taken following the final training session and after 48 hours of recovery.
Two subjects were randomly selected for inclusion into the placebo or ribose group. Ribose or glucose was administered orally in a 250 ml iso-osmotic solution containing 10.0 grams of either ribose or placebo three times per day for three days preceding training (loading phase) and for three days during training (training phase). One-half liter isotonic electrolyte solution was given immediately post exercise and again 30 minutes later to avoid dehydration.
The concentration of the following analytes was determined in the MB samples: ATP, ADP, AMP, IMP (inosine monophosphate), TAN (total adenine nucleotides), creatine phosphate and creatine.
As can be seen from Tables III to V and FIGS. 2 and 3, administration of ribose increased performance by 9%.
The improvement in performance is reflected in the ATP levels in the muscle biopsies. As shown in Table VI, the subjects preloading with ribose for three days began the training phase with higher levels of ATP, which declined significantly more than that of the placebo group after the sprint bouts, indicating that ATP was being utilized more efficiently. Recovery of the ribose group at 48 hours was 82% of the initial level, compared to 78% in the placebo group.
Use of D-Ribose Plus Dobutamine
A. Echocardiography
A single-center, randomized, double-blind placebo-controlled clinical trial was carried out to evaluate the safety and efficacy of D-Ribose on myocardial wall motion during echocardiographic examination in patients suspected of having stunned or hibernating myocardium.
Patients Included:
ages 18 or older, male or female
stable resting wall motion abnormalities noted on baseline echocardiography, defined as at least two segments with abnormal function.
at least five days from a major cardiac event such as myocardial infarction or unstable angina
no known allergies or contraindications to D-Ribose or dobutamine
stable medical regimen of vasoactive medications
known coronary artery disease (CAD) discovered by cardiac catheterization, myocardial infarction or positive stress test
patients with high index of suspicion for CAD provided they have a resting wall abnormality on ECHO
for females of child-bearing potential, a negative pregnancy test
signed informed consent approved by an Institutional Review Board
Patients excluded:
diabetes mellitus requiring insulin or an oral hypoglycemic agent
inability to sign consent form
history of non-ischemic cardiomyopathy
clinically significant liver or renal disease in the judgment of the investigator
advanced valvular heart disease in the judgment of the investigator
Patients were randomized into placebo and ribose groups according to a computer generated randomization schedule. The identity of the contents was blinded to the investigator. Patients were identified by initials. The selected study population was comprised of 25 patients (22 men and 3 women) with a mean age of 57+/−11 years. All had reduced left ventricular systolic function (mean ejection fraction 30+/−8%, range 18 to 48%). Twenty-two patients (88%) had prior myocardial infarction and only one subject was evaluated after recent (<4 weeks) infarction. Nineteen patients (76%) had stable angina pectoris and 21 (84%) were receiving one or more medications to treat ischemia (nitrates (21), beta-antagonists (9), calcium channel antagonists (9)). Coronary artery disease (>=50% diameter stenosis) was documented by angiography in 22 patients. Of the 21 who had recent studies, 12 had three-vessel, 8 had two-vessel and one had single vessel disease. Subjects were admitted to the hospital on the morning of study day 1 after an 8 hour fast. After a limited physical examination, a baseline (AM) echocardiogram was obtained. Following the imaging study, continuous monitoring of the heart rhythm was initiated.
After completion of the baseline echocardiography, intravenous infusion of test agent (D-Ribose or placebo) at a set infusion, along with an infusion of 5% glucose in water (D5W) at 100 ml/hour as a maintenance fluid was initiated. D-Ribose, 10% in water at 180 mg/kg/hour, or placebo D5W at 1.8 mg/kg/hour, were given as sterile, pyrogen-free solutions. After the test agent had been administered for one, two, three or four hours, a resting echocardiogram was obtained. At completion of this rest period, dobutamine was infused. Dobutamine hydrochloride (Dobutrex« solution, Eli Lilly, Indianapolis) was mixed in D5W (5% dextrose in water), giving a concentration of 1.0 mg/ml. During echocardiography, dobutamine was administered at an initial dose of 5 μg/kg/minute for three minutes. The dose of dobutamine was then increased to 10 μg/kg/min and infused for three minutes. Echocardiograms were obtained at the low dose stages and at peak stage. Every three minutes the concentration of dobutamine was increased by 10 μg/kg/minute increments until the standard endpoint was reached. The standard endpoint was set to be ≧2 mm ST-segment depression on ECG; significant side effects or arrhythmias; achievement of 85% of the age-predicted maximal heart rate; a systolic blood pressure >250 mm Hg, a significant fall in systolic blood pressure or a maximal dose of 50 μg/kg/minute.
Post-infusion images were recorded approximately eight minutes after discontinuation of dobutamine. Upon completion of imaging, the test article infusion was terminated. Subjects were observed overnight and on Day 2 were crossed over to the alternate test article. Study protocols on Day 2 were identical to those of Day 1.
B. Echocardiographic Analysis
Baseline (AM) and PM two-dimensional echocardiograms and any post-revascularization studies were performed using an Advanced Technology Laboratories UM9 HDI (Bothell, Wash.) with a 3.0 MHZ phased array transducer and a Hewlett Packard Sonos 1500 (Andover, Mass.) with a 2.5 MHZ phased array transducer. Parasternal long and short-axis and apical two and four-chamber images were recorded on 0.5 inch videotape and digitally stored on floppy discs using a Nova MicroSonics DCR or Colorvue system (Mahwah, N.J.). End-diastolic and systolic images were acquired on line at 67 msec intervals.
The Day 1 and Day 2 AM and PM echocardiograms for each subject were transferred from floppy disk to a customized image network where each subject's images were archived only by hospital number. The images were retrieved from the network and analyzed using the Indiana University Off-line Revue System. Once retrieved, the images were rearranged in computer memory to display AM and PM images side by side for each echocardiogram view. Two blinded investigators rendered a consensus interpretation of regional wall motion in 16 left ventricular segments. Wall motion was graded as: (1) normal; (2) mildly hypokinetic with <5 mm inward systolic motion; (2.5) severely hypokinetic with minimal inward systolic motion and wall thickening; (3) akinetic with an absence of inward motion and wall thickening; (4) dyskinetic with paradoxical outward motion. A global wall motion score was derived for each echocardiogram (sum of individual segment scores per number of segments scored.)
The Day 1 and Day 2 dobutamine echocardiograms comprised of resting, 5, 10 μg/kg/minute, and peak dose images were stored and reviewed using the procedures and equipment previously described for the AM and PM images, except that side by side comparison was not performed. Using the previously described scoring system, regional wall motion was graded by consensus by two blinded investigators. Hyperdynamic wall motion during dobutamine infusion was scored as one normal wall motion. A one grade improvement of wall motion during dobutamine infusion was considered significant. Global wall motion scores were derived for each stage of the dobutamine echocardiogram.
During low-dose dobutamine, wall motion improved in more segments on D-Ribose than placebo (65 segments v. 48 segments ). Stress-induced ischemic abnormalities occurred in more segments on placebo than on ribose (43 segments v. 31). Stress-induced abnormalities occurred in more patients on placebo than on ribose (71% v. 46%).
Eleven patients subsequently underwent CABG after completion of Study Day 2. At least one echocardiogram was obtained postoperatively in each of these subjects. Regional wall motion was compared between the follow-up echocardiogram and the Day 1 AM study by two blinded investigators. A single, blinded investigator made determinations of ejection fraction on the AM, PM, dobutamine and any post-revascularization echocardiograms using the four-chamber view and the Simpson's method. As shown in Table VII, the accuracy of dobutamine plus D-Ribose in identifying patients with increase in ejection fraction (EF) after surgery greater than or equal to 5% was 82% compared to 45% of placebo controls.
Relief of Exercise Induced Angina in Patients with CAD
A sixty-eight year old male patient with a history of coronary artery disease, status post triple coronary artery bypass, experienced exercise induced angina. His present medications are: enalapril (an angiotensin converting enzyme inhibitor), carvedilol (a β blocking agent), nitroglycerine patch and nitroglycerine tablets sublingual as needed. The most recent coronary angiogram revealed advancement of his coronary artery disease with total occlusion of one of the bypass grafts. The patient performed poorly on two stress tests. His exercise regimen consisted of a daily walk.
Due to the development of angina caused by hypoxia, the patient was able to walk less than one mile per day, at which point he took sublingual nitroglycerine. The patient was given oral D-ribose dissolved in about 250 cc. of water. Over a six-month period, the patient received intermittent doses of 5-10 grams per day of D-ribose. Post ribose administration, the patient was able to increase his exercise tolerance to two miles per day without any supplementation of oral nitroglycerine. When the ribose was discontinued, his pre-ribose, anginal-inducing exercise state recurred, which necessitated the use of supplemental oral nitroglycerine. Resumption of oral ribose allowed the patient to walk two miles per day, without angina or the need for nitroglycerine. His subjective evaluation of the ribose treatment is there is ōmuch less angina pain. I feel better, have more energy and can be more active without pain or pills [nitrogycerine].ö
The patient will be placed on a regimen of ribose ingestion followed by low-dose nitroglycerine within 30 minutes, at least one hour before exercise, in order to obtain the increased benefits of preloading with ribose, as is seen in Example 3.
Improved Treadmill Test Performance
A sixty-year old male patient with stable coronary artery disease was observed to show a greater than fifty percent occlusion of more than one epicardial coronary artery and stable angina. The patient was tested for treadmill performance. After two baseline treadmill tests, following the Bruce protocol, he received orally administered D-ribose (40 gm in three divided doses daily) for three days and completed a third treadmill test. At each time, the test was to be stopped when a) the patient exhibited ST segment depression of 1 mm or more in the ECG tracing; b) when the patient complained of angina or c) when the patient stopped due to dyspnea or fatigue. In each test, this patient concluded the test due to shortness of breath, but experienced no angina.
As can be seen from Table VIII, the administration of D-ribose for three days before the final treadmill test increased energy and heart function as measured by decrease in rate-pressure product at each stage of testing, including rest (zero time). It is generally accepted that the product of heart rate and systemic pressure is a measure of myocardial function and energy level, with lower numbers indicating better myocardial function. As a result of the administration of ribose, average tolerated time on the treadmill increased. In addition to the objective measure of efficacy, the patient subjectively reported feeling more energetic during ribose administration.
In the Bruce protocol, the treadmill speed in increased in three minute increments from 1.7 to 6.0 miles per hour, while the slope is increased from 10 to 22%.
It is expected that these results will be further improved if the patient also uses a vasodilator as per example 4.
D-Ribose and Vasodilating Agents
Results reported by Angello show that ribose unmasked ischemic myocardial tissue in the healthy swine heart. (U.S. Pat. No. 4,824,660) It should be pointed out that most of the prior studies on the effect of ribose were performed on healthy animals such as dogs and swine. For example, Foker (U.S. Pat. No. 4,719,201) found that when healthy dogs were made globally ischemic by cross-clamping the ascending aorta for 20 minutes, the infusion of 5% ribose allowed faster recovery of ATP levels. Likewise, Angello found that ribose, in the absence of a vasodilating agent, improved blood flow in the stunned heart of healthy swine, while Sawada found slight beneficial effect of ribose before the co-administration of dobutamine. The difference between the results of Angello's swine study and those found here may be be due to the poor circulation in the patients in this study which impedes the delivery of ribose to the tissue.
Therefore, ribose given with any of the known vasodilators, such as nitroglycerin, nitrates, nitrites, papaverine, isoproterenol, nylidrin, isoxsuprine, L-arginine, nitroprusside, adenosine, dobutamine, xanthines, ethyl alcohol, dipyridamide, hydralazine, minoxidil and diazoxide and analogs thereof may be expected to benefit heart patients. In addition to these agents, endogenous vasodilators such as nitric oxide and prostaglandins can be induced by known pharmaceutical agents. Non-pharmaceutical vasodilation, such as by the simple application of heat or hyperthermia-inducing medications will provide a substantial benefit in enhancing the perfusion of D-Ribose into tissue. For example, the patient having peripheral vascular disease may obtain the benefits of this method by applying a heating pad or warm compress to the area of stenosis, while self-administering D-Ribose.
Preoperative Conditioning with Ribose
Thirty study patients are selected from those scheduled for the therapies listed in Table I, excluding those patients in the excluded group of Example 1. The patients are divided into three groups: twenty are preloaded with D-Ribose and ten with D-Glucose as a control. Ribose may be administered in any convenient manner for any effective time. The dobutamine studies of Example 3 showed that three hours of pre-loading showed beneficial effect, while the normal healthy males of Example 2 were preloaded for three days. However, it is thought that for raising the hypoxic threshold, any length of time, even five minutes preoperative, will reduce or eliminate those effects of hypoxia, such as free-radical formation, that are not due to depressed energy levels. These free-radicals and other metabolites that accumulate during hypoxia are thought to be a possible cause of reperfusion injury, which delays recovery of the patient.
It is desirable to combine the benefits of longer term preloading to enhance energy, as is disclosed in the '789 Application, with the benefits of the presence of ribose during the hypoxic event. Therefore, when surgery is scheduled on a non-emergency basis, at least two weeks before scheduled surgery, the patient will take one to 60, preferably 10 to 30 grams, of D-Ribose or D-Glucose orally, preferably within 30 minutes prior to the administration of a vasodilator. NitroDur« nitroglycerin patches (Key Pharmaceuticals, Miami) are an especially convenient means of administration of a vasodilator, but any vasodilator may be administered. Once the patients are admitted to the hospital for surgery, it may be most convenient to administer the solutions intravenously. Ten of the ribose group are given 5% D-Ribose in 5% D-Glucose. Ten of the ribose group are given 5% D-Ribose in 5% Glucose plus a vasodilating agent. The preferred vasodilator is dobutamine at one to 10 μg/kg/minute. The control group of patients is given 10% D-Glucose. The administration of the test solutions is continued before, during and after the surgical procedure.
It is believed that the group given ribose will show better surgical outcome, faster recovery time, maintenance or improvement of myocardial function compared to the preoperative state and a decreased need for pharmaceutical or additional support following surgery than the control group given glucose.
Stress Induced Ischemia
From the results of the clinical tests of Example 3, it is apparent that D-Ribose protected the heart from the stress-induced ischemia seen with dobutamine at higher doses. In patients given dobutamine alone, the frequency of inducible ischemia was seen to be 71% of the segments analyzed. D-Ribose decreased the number of segments showing inducible ischemia to 46%. It is to be expected, therefore, that administration of D-Ribose will have a beneficial effect whenever high doses of therapeutic agents are used that lead to stress-induced hypoxia.
Peripheral Vascular Disease
In peripheral vascular disease, poor circulation may be limited to the area of stenosis or vascular lesion. Therefore, such patients can obtain the benefits of ribose in raising the hypoxic level of the skeletal muscle with or without co-administration of a vasodilator. Following ingestion of three to ten grams of ribose, warm compresses or a heating pad are applied for at least 30 minutes to the area of the leg or legs having poor circulation. This method may be applied before exercise, but maximal benefit will occur if the method is applied daily.
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and methods described herein without departing from the concept and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same of similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope and concept of the invention as defined by the appended claims.
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Short Cuts
Irish virgin who went to live in Galloway, Scotland. She may be the same as St. Midnat.
Generations of Catholics have admired this young saint, called her the "Little Flower", and found in her short life more inspiration for own lives than in volumes by theologians. Yet ... continue reading | shop
According to his legend, Sebastian was born at Narbonne, Gaul. He became a soldier in the Roman army at Rome in about 283, and encouraged Marcellian and Marcus, under sentence of death, to ... continue reading | shop
Lucy's name means "light", with the same root as "lucid" which means "clear, radiant, understandable." Unfortunately for us, Lucy's history does not match her ... continue reading | shop
Bishop and missionary, also listed as Robert of Hrodbert. A member of a noble Frankish family, he was appointed bishop of Worms, Germany, and then dedicated himself to spreading the faith among the ... continue readingMore Saint of the Day
Generations of Catholics have admired this young saint, called her the "Little Flower", and found in her short life more inspiration for own lives than in volumes by theologians. Yet Therese died when she was 24, after having lived as cloistered Carmelite for ... continue readingMore Female Saints
St. Michael the Archangel - Feast day - September 29th The name Michael signifies "Who is like to God?" and was the warcry of the good angels in the battle fought in heaven against satan and his followers. Holy Scripture describes St. Michael as "one of the chief ... continue reading
The name Gabriel means "man of God," or "God has shown himself mighty." It appears first in the prophesies of Daniel in the Old Testament. The angel announced to Daniel the prophecy of the seventy weeks. His name also occurs in the apocryphal book of Henoch. He was the ... continue reading
Artaldus (also called Arthaud) was born in the castle of Sothonod in Savoy. At the age of eighteen, he went to the court of Duke Amadeus III, but a year or two after, he became a Carthusian at ... continue reading
Lorenzo Ruiz is the first Filipino saint. He is also the first Filipino martyred for the Christian Faith. Lorenzo Ruiz was a layman, married, and had two sons and a daughter. Born in Binondo, Manila, ... continue reading
By Alex Basile
Every carpenter must practice patience. We can learn important lessons from the wood shop in Nazareth from the humble Saint Joseph. I have always been a "do it yourself" type of guy thanks to my father. My dad is always a steady presence during my home-improvement ... continue readingMore Christian Saints & Heroes


text:
Red Poppy in Brookline, MA May 25, 2009
The following keywords apply to this work;
beauty, botany, bright, brilliant,close, closeup, colorful, color, countryside, environment, flora, flower,natural, nature, one, orange, outdoor, outdoors, plant, poppies, poppy, poppy's, seasons, spring, springtime,Nayvelt, Luda Nayvelt, Ludmila Nayvelt, LudaNayvelt
Nikon D60, 200 mm lenses
raw photography, converted with photomatic
Views: 5905 as of October 20, 2014
12 Jan 2011
Red Poppy was featured in the group The World As We See It , or as we missed it.
"Red Poppy" was featured in All About Flowers on May 27, 2009
see also wild poppies from California
Great sharp macro. Good detail. Nice DOF. Congrats.
thank you Margaret
– LudaNayvelt
Gorgeous, Luda. I love the bright red against that yellow background. Wonderful !
thank you Sue
– LudaNayvelt
Just gorgeous, Luda, what a brilliant red!
thank you Barbara
– LudaNayvelt
– LudaNayvelt
Wonderful capture!
– LudaNayvelt
Amazing work, my friend!
thank you Bela
– LudaNayvelt
Incredible colors and detail~ absolutely Gorgeous!!!!!!!!!!!
thank you Cheryl
– LudaNayvelt
gorgeous, everything : the angle, the crop, the colours….
thank you Sonia, this is actual 1 to 1 shot, no crop
– LudaNayvelt
thank you Lilian
– LudaNayvelt
Wow! Talk about vivid and beautiful!
thank you Wayne
– LudaNayvelt


text:
That's Phucked
That's Phucked
Crazy phucked up blog and articles about anything and everything. Articles include Vagina a how to guide, Why do we love the drunken girl, Prostitutes and bullets, Scrotum Self Repair and much more.
NASCAR Tony Stewart Runs Over Driver Killing Him
2014-08-10 10:00:00
NASCAR driver Tony Stewart runs over driver 20-year-old Kevin Ward Jr.During a confrontation at a sprint car race on Saturday night at Canandaigua Motorsports Park in New York. Ward was killed.Here are some of the eye witness reports from the scene:Tyler Graves, a sprint-car racer and friend of Ward's, told Sporting News in a phone interview that he was sitting in the Turn 1 grandstands and saw everything that happened."Tony pinched him into the frontstretch wall, a racing thing," Graves said. "The right rear tire went down, he spun on the exit of (Turn) 2. They threw the caution and everything was toned down. Kevin got out of his car. … He was throwing his arms up all over the place at Tony for most of the corner."I know Tony could see him. I know how you can see out of these cars. When Tony got close to him, he hit the throttle. When you hit a throttle on a sprint car, the car sets sideways. It set sideways, the right rear tire hit Kevin, Kevin was sucked underneath and wa...
Do You Have An Advil? I Have a Splitting Headache
2014-08-05 01:00:00
Buddy, no amount of Advil is going to help you out here! Thanks to phantasm for uploading the picture
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2014-08-02 04:40:00
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South African Farm Murder With Machete
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No more penis abuse. Back to good old gore.Here is a picture of a victim of a series of farm murders in south Africa. Head was cut open with machete.Since the country's first fully democratic elections in 1994, more than 3,000 white, mainly Afrikaans, farmers have been killed in their homes.The so-called "farm attacks" are part of the wave of criminality that has engulfed the country in recent years, something criminologist blame of a number of factors, including inept policing and widening social inequality. Thanks to maxnormal for uploading the picture to ThatsPhucked
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In response to one of our regulars on the I Hate My Penis Part 2 who asked. Why is there not a I hate my pussy article?Here you go vucko27. Leave it to the crazy Japanese again to pour hot Sauce on a pussy and then, well watch and see!
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Hello ThatsPhucked Readers!Want more hilarious and strange porn? Blood and gore got you down with the world?Take a walk into the strange world of Phucked Porn .NOTE: If you already had an account at ThatsPhucked.com. Your same login exists on PhuckedPorn.comGo on, you can't help but touch yourself...Visit PhuckedPorn.com
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22, Female, Single, FWB Needed
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Anyone want to apply? I hear she is capable of positions even yoga professionals would be envious of!
Blue Balls Kill
2014-06-25 04:20:00
GF not putting out? Told her about blue balls and still no action?Show her this pic of what can happen without a release. Maybe, just maybe...Urban Dictionary definition of blue balls :"the excrutiating[sic] pain a man receives when his balls swell to the size of coconuts because of lack of sex, unfinished bjs, and just not cummin[sic] when he knows he should. "
1 Stake 2 Girls
2014-06-20 07:52:00
What does 1 Stake 2 Girls get you? Well, this! Maybe related to Ghetto Baseball?
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Really, WTH happened here? Not even sure this is real... Picture Uploaded by ELCOMANDODELWEST
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He may have lost a leg and an arm, but still have his penis!
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The great thing about stick shift, is you also get a manual hand brake.Why do I care? In the case of this slut, she fucks the hand brake and the stick shift!
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Every man has "3 legs" but this poor bastard is down to just one. Or is it really just 0.5?
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Seems to me that phucked up porn is niche that everyone here would like.This is based on the videos and comments on that particular topic.So I have decided to create another site that specializes on Phucked Up Porn of videos and pics. Of course lots of sexy stuff on there too.If anyone has any features you'd like to see, let me know in the comments!Mr. Phucked
Stapled Flappy Pussy Sex
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Ladies with big flappy pussy lips now know what to do with them. You can attach them together with metal and let your guy phuck your pussy lips.Readers, there is always a solution to every problem. I have to give her kudos for working with what she has got.
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Skank Of The Week May 6th
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The strange thing about this slut. She is cute, but phuck that pussy is ugly.Taking her home from the bar you think you're in luck. Then you take her pants off. What do you do...?Click to zoom
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Who is she? Poor victim of a crime? Dead hooker?We may never know. Either way, waste!
Got Butter?
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Pole DancerMore articles from this author:
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Men can be pole dancers too. Just a little more dangerous...
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new avatar! something weird happened with the size though. I guess that's what I get for not bothering to check if it was within size limits. lol
as for tv shows (I subject I could talk about endlessly), the stuff on now that I'm currently keeping up with is Parks and Recreation, Parenthood (people make fun of me for that one, but it's actually REALLY good. lol), and I think that's about it... next month Community comes back though. w00t. and then eventually Mad Men and Game of Thrones and Doctor Who. and Breaking Bad this summer.
I used to watch Walking Dead but I thought it sucked last year so I haven't gotten back into it. I heard this season has been much better so I'll get around to it eventually. :P