text:
Some Light
Friday, 23 November 2012
Gracia, Louise and I have been working on a bookend zine for It's the Dusty Hour, called The Glimmer of Armour. The title of this light-themed zine comes from one of the lines of the poem I wrote for the zine called 'Daytime Party'. When I was writing it, I was thinking about my previous poem, written for the Dusty Hour zine, which was all about the close of day, and feeling protected by being alone. 'Daytime Party' acts as an opposite counterpart: being exposed in the day, surrounded by people. I also wanted to write something that wasn't too cliché about light – something more personal and unexpected. The zine will be ready for sale in my shop soon, so this is a little peek (thanks to Gracia and Louise for sending me these images of their collages from the zine). Gracia also wrote this post about it.
The timing of working on this zine this week has not gone unnoticed by me. Collaborating on a zine called 'The Glimmer of Armour' on a week when I've felt, and many of my family and friends have felt, worried and hopeless, has been strange. Yet, it was a welcome distraction. I've said this many times, and I know it's a comment that probably results in people rolling their eyes at me, but I think words and narrative are one of our 'defences' in life. After all, one of the functions of sitting down to write or sitting down to read is to create a dialogue. It's one of the things I cling to when things feel a bit hopeless.
I also found out that a personal essay I wrote about Israel was accepted for publication this week in the literary journal, Meanjin. On any other week, I would have been just happy to have my work accepted in a journal I love. On this week however, it means so much more. All the things I can't say now are expressed in this essay I wrote a few months ago. Strange thing this is, timing.
I should also mention that I wrote this article on nostalgia, period dramas and blogs a few weeks ago, and it was published this week: The Ethics of Nostalgia. I would honestly love some feedback on it.
I'm hoping for a peaceful weekend, for everyone.
5 comments:
- Mariella said...
I would love to read your essay on Israel. It's been a though week for me too, but I could not agree more the function of writing or reading is to create a dialogue, a dialogue that unfortunately too often is missing. Big hugs Hila!
- Friday, November 23, 2012
- Rambling Tart said...
I can only imagine how gutting this week has been for you. I have a friend from Tel Aviv and I'm so glad that she is safe, and her friends and family. I hope so much that your beloveds are safe too. I'm so glad you have a defense in your words, may they continue to comfort, strengthen, and ease your pain. XO
- Friday, November 23, 2012
- Desmond Webster said...
I like your formulation of nostalgia in your article. From the first introduction of the television and film, large swaths of people were influenced by what they saw. You note this in the Merchant Ivory films, but it probably started much earlier in the twentieth century.
It's also interesting that you cite the show Mad Men, because the advertising executives in that show overtly acknowledge that they are attempting to artificially manufacture nostalgia in their potential customers.
But there something else that this made me question. Isn't nostalgia simply a complicated human emotion? What I mean is the two most complicated human emotions to unpack and comprehend are nostalgia and melancholy. So the triggers that shift those emotions in one direction or the other in people is also going to be complicated.
Anyway, I enjoyed reading your article, Hila. And I hope that all is well with you and your family.
- Friday, November 23, 2012
- Jane Flanagan said...
No eye rolling here. Words definitely are my bulwark against the world as well as my way of connecting with it on terms I'm comfortable with. It's an interesting move to me that a tool of communication can become a fortress of solitude and selectiveness.
I've been thinking about you all week and praying in my own non-praying way. We need a word for that.
And I'm so glad you worked on another zine. It looks already beautiful.
Congrats on the publications too! I look forward to reading it all!
- Saturday, November 24, 2012
- Hila said...
Mariella: It'll be published next year, I think in June. But I'll keep you posted on it. Oh yes, the concept and spirit of dialogue is completely missing here - people seem to like viewing things in black and white when it comes to this topic. An easy thing to do when you're completely distanced from it, and not affected by it personally and emotionally. Sometimes people's lack of empathy astounds me.
Krista: Thank you so much. It's gotten to the point where even voicing real concern for family and friends in Israel is taken as as 'attack'. Sigh. I hope your friend is okay.
Desmond: Thank you for this response about my article, it's much appreciated. I definitely agree that there is an individual and personal mode of nostalgia - how much of that we can neatly separate from collective nostalgia is debatable, but for me, it is, as you said, a complex thing that perhaps is not always open to categorisation, or open to be unpacked. I guess my article was mainly about collective nostalgia, and how that is often used culturally and politically - sometimes, this can be a dangerous thing. Thanks for such a thoughtful response again.
Jane: yes, that's what reading and writing are for me: communication, but also, a retreat and a defence. All these functions are important. I'm glad you're not eye-rolling at me - I got told the other day that I'm 'overly-earnest', hmm, wtf?
Oh yes, we definitely need to invent a word for non-praying praying. I know I can count on your support, so thank you.
- Monday, November 26, 2012


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The rings have been distributed and the 27th title flag raised.
And judging by the first dozen games, the New York Yankees have put the 2009 season in the rear view mirror.
However, at 9-3 and rolling, they continue to play like champions.
The Bombers have played four series -- and won them all.
And not against the bottom feeders.
The Yanks took two out of three from the Red Sox, Rays and Angels.
Yesterday, behind Andy Pettitte, the Bombers completed a sweep of the Texas Rangers, grinding out a 5-2 victory. Mark Teixeira's two stellar defensive plays and first home run kept Andy from an early exit.
Pettitte, who notched win No. 231 in what I believe is a Hall of Fame career, threw 107 pitches over eight innings, surrendering two runs on four hits.
Andy struggled early, but, as usual, he battled. In the end, it wasn't pretty, but Pettitte got the job done.
Texas came into the Yankee series with the best ERA in baseball, but the Bombers tortured C.J. Wilson, Scott Feldman and Rich Harden.
The Yanks hit home runs.
On Saturday alone, they had six infield hits.
Nick Johnson sometimes frustrates Yankee fans with his patience -- but he always frustrates opposing pitchers. During three combined at-bats Saturday, he and Nick Swisher -- despite his struggles -- saw 24 pitches against Feldman.
Translation: Feldman was gone with one out in the third inning Saturday. The hard-throwing Harden was history yesterday after just 3 2/3 innings.
The Yanks whitewashed Texas -- a good team -- by scores of 5-1, 7-3 and 5-2.
That's a combined score of 17-6.
The big three: Sabathia, Burnett and Pettitte, are 6-0.
Mariano Rivera is 5-5 in save opportunities.
Derek Jeter's out with a head cold yesterday. No problem. His shortstop stand-in, Ramiro Pena, gets what proves to be the game-winning hit, driving in two.
It feels like every time Pena or Francisco Cervelli play, they contribute.
Curtis Granderson looks very comfortable as a Yankee. Robinson Cano is on fire, honoring his talent, both at the bat and in the field.
The only pitchers who have lost this season were not members of last year's championship team: Chan Ho Park on opening night and J@vi@$ Va@q$e# ( I refuse to say or spell his name), his first two starts.
Who know if Park will be on this team down the road. The other gentleman better step it up before he falls into Ed Whitson-Carl Pavano-Kevin Brown territory.
The bottom line: The Yanks, notorious slow starters, head to the West Coast playing great baseball.
Yes, they are a 1/2 game behind Tampa Bay, who smacked around John Lackey and the Red Sox in today's annual Patriots Day game.
But the defending champs have sent an early message that they are still the team to beat.
Meanwhile, the Red Sox are 4-9 after today's defeat, and they look old and slow.
I like their pitching, but their position players don't scare me.
I picked the Sox to finish second this year only because Theo Epstein will not stand for mediocrity and he will make moves.
The end could be near for Red Sox heroes Mike Lowell, Jason Varitek and David "Big Papi" Ortiz.
Stick a fork in all of 'em because they're done.
And don't think Theo will lose sleep or think twice about shipping out these broken down valises.
How fast the tide has turned.
The Yankees are defending champs and looking to do it again in 2010.
For the Red Sox, who haven't looked this ordinary in a long time, this season could be their version of the Yankees' 2008.
And that was a season to forget.
The Yankees nine-game road trip starts with three in Oakland, followed by three versus the Angels and wraps up with three in Baltimore against the dreadful 2-11 Orioles.
The Bombers are off today. Tomorrow's 10 p.m. opener in Oakland pits that J.V. pitcher (0-2, 9.82 ERA) vs. the A's Gio Gonzalez (1-0. 3.38 ERA). Oakland is off to a 9-5 start, which is good for first place in the A.L. West.

subset: commoncrawl


text:
This Is 40 (Two-Disc Combo Pack: Blu-ray + DVD + Digital Copy + UltraViolet) Comedy
- Summary
- Reviews / Ratings
- Photos
- Videos
- Events
From the director of Knocked Up and The 40-Year-Old Virgin comes an unfiltered, comedic look inside the life of an American family.
After years of marriage, Pete (Paul Rudd) and Debbie (Leslie Mann) are approaching a milestone meltdown. As they try to balance romance, careers, parents and children in their own hilarious ways, they must also figure out how to enjoy the rest of their lives. Featuring Melissa McCarthy, Jason Segel, Megan Fox, John Lithgow and Albert Brooks, This Is 40 is a candid and heartwarming comedy about the challenges and rewards of marriage and parenthood in the modern age.
Jul 17, 2015
Dec 19, 2012
Dec 13, 2012
Dec 07, 2012
More Details
Released - Friday, March 22 , 2013
- Starring - Paul Rudd, Leslie Mann, John Lithgow, Megan Fox, Maude Apatow
- Directed by - Judd Apatow
- Distributed by - Universal Studios
- MPAA Rating - NR


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We would fly back to Italy just to return to Adler Thermae Spa Resort near the medieval hamlet of Bagno Vignoni, in the heart of Tuscany.
P.E.I. measures just 225 kilometres from tip to tip - little more than the distance of Ottawa to Montreal. But the island, which is home to 140,000 people, contains 30 golf courses.


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DOR Jam
By nearly any standard, 80-year-old Vivian Martin is a model citizen.
She has never--ever--missed an opportunity to vote. Her modest west Phoenix home is immaculate, from the green lawn to the autumn-themed pumpkin centerpiece in the dining room. She's genteel and alert, although osteoporosis sometimes limits her mobility.
And for the past 39 years, Martin had never been late in filing her state and federal tax forms--until April 17 of this year, that is.
That's when Vivian Martin's model-citizen status changed.
She filed a routine property-tax-credit form two days late.
Despite pleas for assistance from Martin and from two state legislators, the Arizona Department of Revenue hasn't budged, refusing even to grant her a hearing on the matter.
Martin's refund only comes to about $400, and she wants the money so that she can pay her 1996 property taxes, which were due October 1.
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Department of Revenue officials did not return repeated telephone calls from New Times.
Martin, who subsists on Social Security checks, has driven downtown to file her property-tax-credit claim form at the Department of Revenue for the past eight years, since her husband died. She's always received a refund on her property taxes.
The property-tax credit, called the 140 PTC, is offered under state law to low-income, elderly Arizona residents. If you meet the criteria, the only other requirement is to file the claim form by April 15.
But Martin was suffering from a bout of high blood pressure last April when her claim form was due. She was afraid to drive, and didn't recall that the form was due until the deadline had passed.
She recalls, "When I went to fill out my papers, I said, 'Oh, shoot. I'm one day late.'"
Martin told her grandson, who advised her, "'Just go ahead and mail it. They'll probably knock you a little bit.'
"But they took it all away," she says. "I thought that was very uncaring."
So did state Senator Mary Hartley and Representative Kathi Foster, who represent District 20, where Martin lives. Hartley wrote and called Department of Revenue officials, asking that Martin be allowed to appeal. But Hartley's requests were met with a firm "no."
Bea Casey, a special assistant to DOR's acting director Paul Waddell, wrote to Hartley, explaining that state law required that the 140 PTC be filed on April 15, unless an extension has been previously requested.
Martin observes that if she'd had the chance to file for an extension, she would have just gone ahead and filed the 140 PTC itself.
Casey wrote, "The department recognizes that the filers of 140 PTCs are persons over 65 years of age and that the granting of such a refund is an important part of their income; however, this can only take place within the authorities granted by law which clearly requires that a timely filing take place."
"Give me a break!" Foster says, shuffling through the correspondence between the legislators and DOR. "This is not a person who is trying to shaft anyone."
DOR reports that 22,111 filers were granted refunds totaling nearly $6.4 million during the past fiscal year.
Martin wants to know how many filers weren't granted their refunds, because they were a day or two late.
"I'm sure that there's other people my age that have had this kind of thing happen to them," she says.
"I call it cheating.
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text:
Baby Penguins Everywhere!
By Melissa Guion
(Philomel Books, $16.99)
With books for the youngest readers, art is incredibly important. It needs to enchant children, and ideally captivate adults as well.
If the art brings them in, the children will want to look at the book while hearing our words. And while we can't expect every book to have the lasting power of "The Cat in the Hat," or its poetry, it is rewarding when a storybook has a sweet message.
In "Baby Penguins Everywhere!" Melissa Guion brings us into an enchanting frozen world of a penguin, who is a little lonely as she waddles about ice floes.
One day, she sees something floating in the water … a hat. And from that hat popped a little penguin!"
Maybe there is something magical about hats in stories for kids. Many penguins alight from the hat and they are playful, with colorful balls and a rope.
And like any mom, minding a bunch of playful toddlers, it becomes exhausting and she needs "just a minute to herself."
It's a lovely concept, and most important, doesn't make parents want to puke on a fourth read. As any parent will attest, if you give a child a book that grates on you, that is the book the child will want to read. Every night. Maybe during the day, too.
So go with one parents will relate to, enjoy and appreciate the beautiful art.


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Since Walden took over the subcommittee chairmanship just over two years ago, he's been complaining that the FCC is an overly burdensome regulator stifling innovation and job growth.
Judging by the text of a speech that Walden delivered Monday to the National Association of Broadcasters in Las Vegas, the Oregon Republican still has a host of problems with what he jokingly called the "Friendly Candy Company" (which is one of the agency's old nicknames).
Said Walden:
I have spent a fair amount of time dealing with the FCC as a former licensee, current amateur radio operator, and chairman of the subcommittee of jurisdiction. In each of these capacities. I have reached the same conclusion: that the FCC has been more concerned lately with expanding its authority than working with us to embed better processes.
Walden in 2012 helped push a bill through the House that would, among other things, establish time limits for proceedings and put new limits on the review of mergers. Democratic critics complained the bill would weaken the agency and it died in the Senate.
At the broadcaster's convention, Walden described some of the roots of his problems with the commission. He explained how he filed an application with the FCC in 2003 to license some translators for his Oregon stations -- and he had to wait until this year to get approval (which happened to be long after he sold the stations in 2007).
Added Walden:
If the FCC is able to set shot clocks for licensees, surely it can set shot clocks for itself and report to Congress how well it is meeting them.
Beyond shot clocks, the FCC should be required to find a market failure before intervening. To conduct cost-benefit analyses before imposing regulations. And to adhere to the radical notion that any conditions on a transaction should be limited to transaction-specific harms otherwise within the agency's jurisdiction, rather than seen as a means for a shakedown.
-- Jeff Mapes


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Check out all of our upcoming events at The Half Moon
We hold many supplier evenings and masterclass events so check out below to see what's on in the pub. To see all of our music & comedy shows and to buy tickets please go to the Live Music page.
We're only a small venue and many of our shows sell out so please buy in advance to avoid disappointment.


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The Clinical and Laboratory Characteristics of Recurrent Drug- Related Hyponatremia (0597-10-HMO)
This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2012 by Hadassah Medical Organization
Hadassah Medical Organization
Information provided by (Responsible Party):
Hadassah Medical Organization
ClinicalTrials.gov Identifier:
First received: January 10, 2012
Last updated: NA
Last verified: January 2012
History: No changes posted
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
No Study Results Posted on ClinicalTrials.gov for this Study
|Study Status:
|This study is not yet open for participant recruitment.
|Estimated Study Completion Date:
|January 2017
|Estimated Primary Completion Date:
|January 2015 (Final data collection date for primary outcome measure)


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If Oregon's new higher education board gets its way, about 36,000 Oregonians will get state financial aid to attend college beginning in 2016. And instead of a relatively puny $2,000 grant, 26,000 of them would get as much as they need to complete a full financial aid package, an average of more than $4,000.
Thursday marked the first time that a public board in Oregon weighed budget requests from across higher education -- community colleges, universities and student financial aid -- to recommend to the governor which should be the highest priorities.
> $66 million for increased college financial aid
Told by Gov. John Kitzhaber it could make about $150 million worth of requests, the Higher Education Coordinating Commission decided Thursday that $66 million should be put into the hands of students in the form of need-based scholarships.
If the governor were to agree, it would represent a 60 percent increase in state financial aid for 2015-17 compared with the current two-year budget. By contrast, the commission recommended that funding for community colleges and universities be increased 7 percent above the costs of continuing current level of state-funded operation. (The state only pays a fraction of the costs to run universities and community colleges; tuition, plus local property taxes for community colleges, covers most of the costs.)
The governor and Legislature will weigh a lot of competing requests for state money, and a final decision is not expected until June, said higher ed chief Ben Cannon. But if the higher education commission's plan were enacted, every recent high school graduate entering a public university or community college starting in fall 2016 could count on enough financial aid to bridge the gap between what they and their family can afford and the roughly $20,000-a-year cost of tuition, fees, room and board.
"To create this pledge for our high school students, that if they get the Oregon diploma and go to a community college or public university, their (financial) needs will be met -- that's pretty exciting," Cannon said.
The grants, which would average more than $4,000, would be guaranteed to all who are eligible -- but only for the first two years of college. Students who return for more years of college would be offered the same Oregon Opportunity Grant they can get now -- up to $2,000 limited to those who submit complete applications by Feb. 1.
Commission members said they understand that universities and community colleges need more than a 7 percent funding bump in order to offer robust and effective academic programs and student services after a decade of deep state funding cuts.
If Oregon is to reach its 40-40-20 goal of having 40 percent of its young people earn four year degrees, another 40 percent get two-year degrees or industry certification and the rest at least a high school diploma, it needs to "step up" funding for universities and community colleges, said commission member David Rives, a community college instructor.
But colleges and universities report the $34 million and $39 million infusion they would receive, if the commission gets its way, would leave them treading water after years of cuts, Cannon said.
A disappointed Rives agreed: "This is pretty flat."
A 60 percent hike in need-based aid for students, on the other hand, would make a large difference and would likely cause a dramatic change in the mindset of Oregon high school students about whether going to college is really possible, commission member Duncan Wyse said.
-- Betsy Hammond


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Family Gras provides economic bling for Jefferson Parish carnival season
The orange plastic fencing meant to defend the landscaping was up, the portable toilets were out and organizers whispered silent prayers that the scattered showers forecast for the evening would spare the event, which was set to begin at 5 p.m. with music from Tony Orlando and parades featuring the Krewes of Exalibur and Atlas.
Jefferson Parish officials are hoping the third annual Family Gras festival - billed by the parish as a family-friendly Mardi Gras alternative - will surpass last year's in terms of attendance and economic impact.
The parish's overall Carnival season generated a total of $24 million in 2008 and attracted 800,000 people, according to a recently released study by the University of New Orleans Hospitality Research Center and the Jefferson Convention and Visitors Bureau.
Family Gras 2008 was a big part of that total, with a concert line-up featuring Billy Ray Cyrus, Taylor Swift and the Bangles that drummed up about $3 million of that cash, according to Violet Peters, president and CEO of the convention and visitor's bureau.
That's quite a come-up for the festival, which generated about $500,000 in its first year.
"We're very enthusiastic because it can only go up from here," said Peters Friday afternoon, dressed in Mardi Gras purple, green and gold as she zipped around the concert site checking last-minute details.
The visitor's bureau isn't making any predictions for this year, but Peters' said they've gotten great feedback from their advertising campaigns. The bureau targeted communities within a 200-mile radius of the parish hoping to attract out-of-town guests.
Indeed, Family Gras has expanded to include a second stage featuring Louisiana musicians on North Hullen Street behind Chevy's restaurant, as well as an art market in the Whole Foods parking lot on Veterans.
This year's concert line-up boasts national favorites such as Sheena Easton, Davy Jones of The Monkees, Jesse McCartney and Sara Bareilles, whose hit "Love Song" dominated radio airwaves in 2007 and 2008.
Much-beloved local acts include Bobby Cure & The Summertime Blues Band, Benny Grunch and The Topcats.
Despite the ominous forecast all Jefferson Parish parades are expected to roll this weekend, according to Karen Kraak Wood, director of Carnival for Jefferson Parish.
"I think there's no indication there will be any (thunder) storms," Wood said about noon Friday, indicating that local meterologists have assured her there will be no parade-canceling lightning. said.
But if the skies open up over Family Gras, organizers are ready. Last year, downpours turned the plaza area into a lumpy, muddy mess. Now, attendees will dance on a layer of limestone.
Over near the food booths opposite the main stage,David Brewster and Chris LaBonty of New Orleans Cookery unloaded equipment and ingredients Friday afternoon for their tasty wares: Louisiana crab cakes, alligator-on-a-stick, Swannie's blackened bourbon chicken and Cajun stew. Both remember last year's soggy weather, which Brewster said kept some folks away. But he remained positive, citing that the forecast calls for scattered showers.
"That means it's gonna rain around us," Brewster said.
Michelle Hunter can be reached at email@example.com or 504.883.7054.


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In Antigonish Saturday to face X-Men
SACKVILLE, N.B. ŌĆō The Mount Allison Mounties will face their biggest game of the season Saturday when they travel to Antigonish to face the St. Francis Xavier X-Men in AUS Football action.
With three teams tied for second place with identical 2-4 records and two weeks remaining in the regular season, SaturdayŌĆÖs games will have all kinds of playoff implications.
The Mounties are coming off a huge 25-12 win last Saturday in Sackville against the Saint MaryŌĆÖs Huskies, a team that blitzed them 43-7 the previous week in Halifax.
ŌĆ£I think the same message holds true from last weekend,ŌĆØ Mount Allison coach Kelly Jeffrey said. ŌĆ£We have to improve and get better. WeŌĆÖre not looking ahead to anything other than winning this game this weekend.ŌĆØ
While SaturdayŌĆÖs game could be a pivotal tie-breaker heading into the final weekend, Jeffrey said he doesnŌĆÖt want his players looking ahead to Acadia on the final day of the season.
The Mounties have yet to win on the road this season, with both wins coming in the friendly confines of MacAulay Field.
ŌĆ£We have to start fast and play well early so we can get into the game before the crowd does,ŌĆØ Jeffrey said. ŌĆ£It seems to be when we play at home itŌĆÖs after weŌĆÖve played a team on the road. I donŌĆÖt know if itŌĆÖs a home and away thing or if weŌĆÖre just more familiar with our opponent.ŌĆØ
Heading into the game, Jeffrey is hoping to see his clubŌĆÖs potent running attack continue. At the same time, he wants his players to win the turnover battle ŌĆō something they did against Saint MaryŌĆÖs last Saturday.
ŌĆ£The things weŌĆÖve done well recently are the things we believe are going to be key,ŌĆØ he said. ŌĆ£The biggest thing is hanging onto the football and doing well in the turnover battle.ŌĆØ
Jeffrey said St. F.X. has a lot of explosive players on offence. He said itŌĆÖs going to be important to avoid the big play ŌĆō something that haunted them in the season opener in September, a 51-5 loss at home.
The MountiesŌĆÖ final home game is next Saturday against Acadia.


text:
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3-4 Defensive Coordinators
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Signal transduction of ischemic preconditioning
- Ischemia
- Preconditioning
- Signal transduction
Time for primary review 20 days.
1 Ischemic preconditioning and its endpoints
Brief episodes of ischemia/reperfusion protect the myocardium from the damage induced by subsequent more prolonged ischemia. When first described by Murry et al. [1] such ischemic preconditioning was elicited by brief coronary occlusion, and the endpoint was reduced infarct size. Soon, however, a variety of preconditioning stimuli were uncovered including hypoxia [2], rapid cardiac pacing [3,4], thermal stress [5], stretch [6,7] and various pharmacological agents (for review, see Refs. [8,9]). Also, various endpoints of ischemic preconditioning have been used: ischemic preconditioning protects against infarction in all species tested so far (for review, see Ref. [8]), and there is also evidence that it might be operative in man (for review, see Ref. [10]). Ischemic preconditioning also reduces the extent of apoptosis [11–13]. Other studies have used recovery of contractile function as an end-point of ischemic preconditioning. Although it appears logical that less infarcted myocardium in preconditioned hearts should result in improved regional and subsequently global function, ischemic preconditioning does not improve regional myocardial function within the first hours of reperfusion (thus it does not attenuate stunning) in rabbits, dogs and pigs in vivo [14–18] (for discussion, see Ref. [19]). However, with longer reperfusion ischemic preconditioning diminishes adverse left ventricular remodeling following infarction and improves long-term functional recovery in chronically instrumented rabbits [20]. Therefore, lack of functional recovery during short periods of reperfusion can not be used to refute preconditioning's morphological protection, while on the other hand caution should be used when extrapolating findings from short-term recovery of contractile function to reduction of infarct size.
Ischemic preconditioning protects against arrhythmias in mice [21], rats [22–24], rabbits [25] and dogs [26]. In pigs, however [27–30], ischemic preconditioning not only fails to reduce the incidence of ventricular fibrillation during ischemia/reperfusion, but even accelerates the onset of ventricular fibrillation during sustained ischemia and decreases the ventricular fibrillation threshold [27]. These pro-arrhythmic effects cannot be blocked by glibenclamide, indicating that the acceleration of ventricular fibrillation by preconditioning is not a consequence of KATP channel activation [29]. Therefore, the present review will mainly concentrate on the signal transduction of the infarct-reducing effect of ischemic preconditioning.
2 Temporal limits of ischemic preconditioning
Not all combinations and durations of ischemia and reperfusion will trigger the preconditioning phenomenon and protect ischemic myocardium. There appears to be a critical threshold. A preconditioning regime of only 1 or 2 min of ischemia with subsequent reperfusion prior to the index ischemia has no protective effect in rabbits [31], pigs [32] and humans [33]. Above this threshold, a controversy exists on whether or not the protection conferred by ischemic preconditioning is a graded phenomenon that depends on the intensity of the preconditioning stimulus. While in one study in rabbits [34], increasing the intensity of the preconditioning stimulus by increasing the number of preconditioning cycles of ischemia/reperfusion resulted in greater infarct size reduction, this was not confirmed in dogs [35]. On the other hand, increasing the intensity of the preconditioning stimulus by increasing the duration of the preconditioning ischemia from a single cycle of 3 min low-flow ischemia and subsequent 15 min reperfusion to a single cycle of 10 min low-flow ischemia followed by 15 min reperfusion results in a greater infarct size reduction in anesthetized pigs [32].
Apart from the number of preconditioning cycles and the duration of ischemia, the duration of the intermittent reperfusion determines the protection achieved by ischemic preconditioning. In rats, protection is still evident when the reperfusion period is shortened to 1 min, although there is no protection if reperfusion is only 30 s in duration [38]. Typically, a 5-min period of ischemia followed by up to 60 min of reperfusion before the index ischemia results in salvage. However, if the reperfusion interval is prolonged beyond 1 h in anesthetized pigs [39], 1–2 h in anesthetized rabbits [31] or dogs [40], or 2–4 h in conscious rabbits [41] protection is no longer evident. While protection can be reinstituted with a second cycle of preconditioning ischemia/reperfusion in rabbits [42] and dogs [43], this is not the case in pigs [39]. Full reperfusion is not mandatory for ischemic preconditioning's protection [36,37].
Thus there is a definite and fairly rigid time frame for ischemic preconditioning. Somehow the myocardium 'remembers' that it has been preconditioned by a brief ischemic period which has occurred up to several hours before the index ischemia. The exact nature and location of this memory is one of the great unsolved mysteries of ischemic preconditioning.
3 Signal transduction in the early phase of ischemic preconditioning
3.1 Receptor-dependent endogenous triggers
3.1.1 Adenosine
The first signal transduction element identified as part of preconditioning's mechanism (Fig. 1) was the adenosine receptor [44]. An increase in interstitial adenosine concentration during the preconditioning ischemia occurs in rats [45], rabbits [46–48], dogs [49] and pigs [32,50–52]. Attenuation of the increase in interstitial adenosine concentration in pigs [50] or blockade of adenosine A1- and A3-, but not A2-receptors [44,53–56] almost completely blocks the infarct size reduction achieved by ischemic preconditioning in rabbits. Conversely, an increase in the interstitial adenosine concentration with uptake inhibition by dipyridamole lowers the threshold for ischemic preconditioning in anesthetized dogs [57] and rabbits [58].
3.1.2 Bradykinin
Bradykinin also contributes to infarct size reduction by ischemic preconditioning [32,59,60]. The increase in the interstitial bradykinin concentration occurs earlier than the increase in the interstitial adenosine concentration in pigs [32], and its interstitial release during the index ischemia is enhanced by ischemic preconditioning [61]. Bradykinin is a necessary trigger only during a less intense preconditioning stimulus, i.e., a shorter duration of preconditioning ischemia in pigs [32] or a single cycle of ischemia/reperfusion in rabbits [60], while during a more intense preconditioning stimulus, i.e., a more prolonged period of preconditioning ischemia [32] or repeated cycles of ischemia/reperfusion [60], adenosine is more important. From their experiments in rabbits, Goto et al. [60] have proposed a model of additive interaction of triggers that contribute to the initiation of ischemic preconditioning. Also, in pigs only blockade of the bradykinin B2-receptor combined with increased breakdown of endogenous adenosine by adenosine deaminase completely abolishes the infarct size reduction achieved by an intense preconditioning stimulus [32].
3.1.3 Opioids
Blockade of opioid receptors with naloxone abolishes the infarct size reduction achieved by ischemic preconditioning in rats [62–64], rabbits [65,66] and pigs [67]. The important opioid receptor for such cardioprotection has been identified as the δ-receptor [68,69], while the importance of activation of the κ-opioid receptor is still controversial [24,69]. In one study in isolated rat hearts, blockade of κ-opioid receptor abolished ischemic preconditioning [24], suggesting a beneficial role of κ-receptor activation in ischemia/reperfusion. In contrast, in another study using the same animal model, activation of the κ-opioid receptor increased infarct size [69] with the possibility of putting the heart into an 'anti-preconditioning' state [70].
Both adenosine and opioids appear to trigger ischemic preconditioning in an interactive fashion in several species [62–64,67]. Whether both signals are oriented in parallel or back-to-back remains to be established. The latter explanation has recently been suggested by studies in isolated rat hearts in which the fentanyl-induced increase in contractile function following ischemia/reperfusion was abolished by pretreatment with an adenosine-receptor antagonist [71].
Of course, the importance of different triggers varies among different species; for example, in the rat opioid receptors appear to be the principal ones involved in ischemic preconditioning [68], and it is difficult to show a role for adenosine [72], while in rabbits and pigs adenosine, bradykinin and opioids each are of major importance.
3.1.4 Prostaglandins, norepinephrine, angiotensin and endothelin
Blockade of cyclooxygenase by aspirin in rats [73] or rabbits [74] did not interfere with the infarct size reduction achieved by ischemic preconditioning, suggesting that endogenous prostaglandins are not involved in preconditioning's cardioprotection. However, there is evidence that lipoxygenase products may be involved. The improvement in postischemic contractile function in preconditioned hearts was completely abolished by a 12-lipoxygenase inhibitor in rats [75] as well as in 12-lipoxygenase-deficient mice [76].
There are other neurohumoral agonists which can precondition the heart when administered exogenously but which are not released in sufficient quantity by ischemic myocardium to trigger protection endogenously, such as norepinephrine, endothelin and angiotensin. Therefore, administration of antagonists to α-adrenergic [77–80], angiotensin [80,81], or endothelin [82] receptors has no effect on the ability of brief ischemia to precondition the heart.
3.2 Receptor-independent endogenous triggers
3.2.1 Free radicals
Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled during hypoxia or ischemia/reperfusion ([83,84]; for review, see Ref. [85]). An immediate consequence of such gradual impairment of respiratory function is the increase in the production of reactive oxygen species and free radicals in the mitochondria [84]. Also, activated neutrophils can produce large quantities of free radicals [86]. At high concentrations, the highly reactive free radicals can induce lipid peroxidation of membranes, altering their integrity and increasing their fluidity and permeability. A second important site of free radical attack are the membrane proteins involved in the transport of ions and the maintenance of cellular ionic homeostasis. This is especially true for proteins containing sulfhydryl groups (for review, see Ref. [87]). The myocardium, however, has a series of defense mechanisms including the enzymes superoxide dismutase, catalase, and glutathione peroxidase in addition to endogenous antioxidants such as vitamin E, ascorbic acid, and cysteine to protect the cell against cytotoxic oxygen metabolites.
Free radicals, however, not only damage cardiac myocytes but also act as triggers of ischemic preconditioning. Infusion of N-2-mercaptopropionyl glycine, a diffusible antioxidant [88,89], or dimethylthiourea, a radical scavenger [90], blocks the protection of ischemic preconditioning. The mechanism by which oxygen radicals precondition the myocardium is less clear, but free radicals can activate G-proteins [91], protein kinases [90] and ATP-dependent potassium channels [92–94].
3.2.2 Nitric oxide (NO)
The role of endogenous NO in ischemic preconditioning is currently unclear. Blockade of nitric oxide synthase attenuates the increased functional recovery following ischemia/reperfusion induced by ischemic preconditioning in rats [95]. In contrast, NO is not a trigger or mediator of the early phase of ischemic preconditioning against infarction in either rabbits [96] or pigs [97].
3.2.3 Calcium
The flux of calcium through L-type calcium channels has been discussed as a trigger of ischemic preconditioning, since atrial muscle taken from patients with chronic blockade of L-type calcium channels could not be preconditioned by ischemia [98]. However, the calcium antagonist nisoldipine does not attenuate ischemic preconditioning in an in situ model of regional ischemia in anesthetized pigs, thereby challenging a major role of endogenous calcium as a trigger of ischemic preconditioning in vivo [99].
3.3 Exogenous triggers
All of the above substances can put the heart into a preconditioned state when given exogenously by infusion. This includes the endogenous substances that act through receptor activation (adenosine, bradykinin, opioids).
Exposure of rabbit hearts to a low flux of oxygen radicals generated by purine/xanthine oxidase for 5 min, followed by a 15-min washout, puts the heart into a preconditioned state [89,100]. Exogenous NO donors decrease infarct size [96,101], potentially by acting through free radicals [96] or by activating ATP-dependent potassium channels [102] (for review, see Ref. [103]). Also, activation of the prostaglandin EP3 receptor [104–106], the α1-adrenoceptor [77–80], the endothelin receptor [82] or the angiotensin receptor [80,81], by exogenous administration of the respective agonists can put the heart into a preconditioned state. Similarly, repeated intracoronary calcium infusions in anesthetized dogs mimic ischemic preconditioning [107–109].
3.4 G proteins and phospholipases
Adenosine [110–112] and opioid receptors [113] are coupled to inhibitory G proteins. Therefore, chronic treatment with pertussis toxin which blocks inhibitory G proteins abolishes preconditioning's protection in the rabbit [112]. The adenosine receptor is coupled through Gi to, among others, phospholipases C (PLC) and D (PLD). PLC catalyzes the hydrolysis of membrane inositol-containing phospholipids into inositol trisphosphate and diacylglycerol (DAG). PLD degrades other membrane phospholipids, including phosphatidylcholine. The immediate degradation products are choline and phosphatidic acid. The latter is metabolized further by a phosphohydrolase to DAG [114]. DAG stimulates the translocation and activation of protein kinase C (PKC). The onset of the PLC reaction is typically very rapid, and DAG production is short-lived, peaking at 30 s, whereas the PLD reaction is delayed but accounts for a more prolonged production of DAG, associated with prolonged activation of PKC [115]. Indeed increased PLD activity accompanies preconditioning and PLD blockade with high-dose propranolol attenuates its protection [116].Thus both pathways are thought to be critical components of PKC activation.
3.5 Protein kinases
3.5.1 Protein kinase C
Activation of PKC is physiologically mediated by liberation of DAG from membrane lipids by phospholipases. DAG binds to the regulatory subunit of PKC resulting in a conformational change which causes the molecule to attach to its RACK binding sites (see below) and also uncovers the ATP binding site. Activation of PKC first requires a transphosphorylation of a threonine residue at its activation loop which is followed by dual autophosphorylation at serine and threonine residues at its C-terminus [117,118]. The initial transphosphorylation depends on a phosphoinositide (PI)-dependent kinase (PDK) 1 [119,120]. Whether phosphorylation of PKC is also involved in ischemic preconditioning is unknown. PI3 kinase is activated during ischemia, and the prevention of its activation by wortmannin or LY294002 abolishes the improvement in functional recovery by ischemic preconditioning following 20 min of global ischemia in isolated rat hearts [121]; wortmannin also attenuates the reduction of infarct size by ischemic preconditioning in isolated rabbit hearts [122].
PKC isozymes are not randomly distributed within the cell, but are associated with specific compartments or structures. A peculiar trait of PKC isozymes is that they physically move within the cell when activated. Mochly-Rosen [123,124] demonstrated with immunofluorescent techniques that inactive PKC isozymes are found in the nucleus and perinuclear region, and that they translocate to cross-striated structures (possibly the contractile elements) and cell–cell contact regions following activation. RACKs (receptors for activated C kinase) are located on various intracellular structures and form docking sites for the activated isozymes [124,125]. The RACKs were previously thought to be highly isozyme-specific so that the activated isozyme would bind only to its RACK and to no other; for PKCε it was thought to be RACK 2. However, using PKCε transgenic mice Pass et al. recently demonstrated that at high levels of expression PKCε can interact with both RACK 2 and RACK 1, arguing against the complete selectivity of PKC–RACK interactions [126]. Nevertheless a peptide antagonist for RACK 2 [127] blocked preconditioning's ability to protect both rat [125] and rabbit [128] cardiomyocytes, suggesting that PKCε is the isoform involved in preconditioning [129].
Ping et al. [130] identified 11 PKC isozymes in the rabbit heart. Using specific antibodies to each isozyme they demonstrated that a series of four cycles of 4 min of coronary occlusion/6 min of reperfusion caused translocation of only two novel isozymes, ε and η, suggesting that it was one of these two isozymes translocated during brief ischemia that contributed to cardioprotection. Studies in rat hearts confirmed that specific isozyme translocation occurs in preconditioned hearts, although the important isoforms appeared to be α, δ, and ε [131]. Finally in dogs, only PKCα was translocated in response to ischemic preconditioning [132]. Using isozyme-specific peptide antagonists [127], it was suggested that only PKCε is capable of putting rat [125] or rabbit [128] cardiomyocytes into a preconditioned state.
In vivo experimental data strongly support the notion that PKC plays an important role in eliciting preconditioning's protection. In rabbits, blockade of PKC alone completely abolishes the infarct size reduction triggered by ischemic preconditioning [133–135]. However, in the hearts of rats [131,136,137] and dogs [138,139] the results of pharmacological blockade of PKC are controversial. In pigs [140] blockade of PKC with staurosporine alone does not interfere with the infarct size reduction achieved by ischemic preconditioning; this is in part because of an alternate signaling pathway utilizing activation of a protein tyrosine kinase rather than PKC (see below).
3.5.2 Tyrosine kinases
Ischemic preconditioning's protection in the rabbit can also be aborted by administration of either genistein, a relatively selective tyrosine kinase antagonist by virtue of competitive inhibition of the enzyme's ATP binding site, or the more selective antagonist lavendustin A, a noncompetitive inhibitor at the ATP binding site as well as a noncompetitive inhibitor at the substrate binding site [141]. Because both genistein and lavendustin A can block the protection induced by PMA, a direct activator of PKC, the involved tyrosine kinase is unlikely to be part of a surface receptor, but rather appears to be downstream of PKC [141].
In the rabbit, PKC and tyrosine kinases appear indeed to be in series. In other species, however, tyrosine kinases may also be present in a second pathway that bypasses PKC. In the pig heart [140,142] antagonists of PKC or tyrosine kinase alone could not block protection from ischemic preconditioning. Yet if they were combined, protection was completely eliminated [142], suggesting the existence of a second signal transduction pathway which parallels PKC and contains at least one tyrosine kinase. The rat heart may act similarly [80,137], since multiple cycles of preconditioning can overcome the abrogation of protection by PKC blockers, suggesting the presence of a similar bypass pathway in that species [137]. Also in dog hearts, blockade of tyrosine kinase alone failed to abolish infarct size reduction by ischemic preconditioning [143]; however, recalling the observations in pigs, this finding does not exclude the involvement of tyrosine kinase in ischemic preconditioning in dogs.
3.5.3 Mitogen-activated protein (MAP) kinases
Potential downstream targets of PKC and tyrosine kinases are the mitogen-activated protein kinases (MAPK). Each subfamily of the MAPK family, ERK, JNK and p38, has been suggested to play a role in the cardioprotection achieved by ischemic preconditioning (for review, see Refs. [144,145]). All of the MAP kinases are activated by dual phosphorylation of a serine and a threonine residue by a MAP kinase kinase. Upon activation, MAP kinases — like PKC — physically move within the cell, and for example translocate into the nucleus (p38, ERK) (for review, see Ref. [145]). The MAP kinase kinase is a tyrosine kinase and at least that for p38 MAPK can be blocked by genistein [146]. Thus MAP kinase kinase has been proposed to be the tyrosine kinase in preconditioning's signaling pathway [147].
In isolated rabbit hearts ERK1 activity increases only in ischemically preconditioned myocardium [148], but no difference in ERK1 and ERK2 phosphorylation between non-preconditioned and preconditioned myocardium is detectable in pigs in vivo [149]. Like p38 (see below), ERK can activate MAPKAP kinase 2 α and β, leading to phosphorylation of the small heat shock protein 27 [150].
A causal role of ERK activation in the cardioprotection achieved by ischemic preconditioning is controversial; while an inhibitor of ERK (PD 98059) fails to block the infarct size reduction seen after ischemic preconditioning in isolated rabbit hearts [148], its intramyocardial infusion abolishes ischemic preconditioning's protection in pigs in vivo [151].
Both JNK46 and JNK54 are present in the heart [152] and are strongly activated during reperfusion following ischemia. Their activation/phosphorylation during ischemia has been suggested by some studies [149] (for review, see Ref. [145]), but in one report a reduction in JNK phosphorylation during ischemia has been measured [146]. JNK46 activation during no-flow ischemia is most likely mediated by PKC, since activation of JNK46 is completely blocked by chelerythrine, a PKC inhibitor [153].
Intramyocardial infusion of anisomycin reduces infarct size in rabbits [154] and pigs [155] and is associated with activation of JNK. In isolated rat hearts, blockade of JNK46 with curcumin blocks the infarct size reduction of ischemic preconditioning to a similar extent as blockade of p38 using SB203580 [156].
22.214.171.124 p38
Most attention has focused on the p38 MAPK cascade. At least five isoforms of p38 MAPK have been identified, although only p38 α and β are expressed to any degree within the heart [157]. Different isoforms of p38 appear to mediate different biological functions (for review, see Ref. [145]). In neonatal rat cardiomyocytes, p38α mediates apoptosis whereas p38β is anti-apoptotic [158]. p38 MAPK, like all of the MAP kinases, has two activation sites which must be phosphorylated for activation: a threonine residue at amino acid 180 and a tyrosine residue at site 182. This kinase is activated by a MAP kinase kinase (MEK 3 or MEK 6) [145] which itself is activated by a MAP kinase kinase kinase. p38 is phosphorylated within minutes during global or regional no-flow ischemia in isolated rat hearts [159–164] as well as in rat [162,165], dog [166] and pig hearts in vivo [149,167].
With prolongation of ischemia, however, the phosphorylation of p38 may be reduced towards preischemic values, whereas phosphorylation is once again increased upon reperfusion [162,165]. The transient p38 activation during prolonged ischemia might be related to decreased phosphorylation or increased dephosphorylation by phosphatases (for review, see Ref. [168]). In contrast to the above studies, no activation of p38 by ischemia per se is seen in isolated rabbit hearts [146–148,169].
Following ischemic preconditioning, phosphorylation of p38 during the index ischemia is increased in isolated rat and rabbit hearts [146,147,160,161,170], unaltered in pig hearts in vivo [149], or even decreased in isolated rat hearts [164] and dog hearts in vivo [166]. In vitro, ischemic preconditioning primarily prevents the ischemia-induced activation of p38α in p38α-transfected rat cardiomyocytes, while p38β is downregulated during ischemia in control and preconditioned cells [157].
The importance of p38 activation for cardioprotection thus remains controversial. Protection in isolated cell models is determined from reduced trypan blue uptake and/or enzyme release (lactate dehydrogenase, creatine kinase), while in isolated hearts or hearts in vivo the extent of necrosis (TTC staining, histology) and/or apoptosis is quantified. Rat cardiomyocytes transfected with a dominant negative p38α isoform, which prevents ischemia-induced p38 activation, are more resistant to lethal simulated ischemia [157]. Similarly, in isolated rat hearts [171] and pig hearts in vivo [167], blockade of p38 with SB 203580 does not affect the infarct size reduction achieved by ischemic preconditioning, and even reduces infarct size per se. In contrast, SB 203580 effectively blocks protection in other cell models of ischemic preconditioning [147,172,173], and abolishes the infarct size reduction of ischemic preconditioning in isolated rat hearts [160,174], rabbit hearts [175] and dog hearts in vivo [166].
Explanations for the controversial findings might relate to the relative balance between different isoforms of p38 in different species and experimental models as well as the selectivity of different inhibitors in a given dose range. SB 203580, for example, not only inhibits p38 MAP kinase [176], but also dose-dependently inhibits JNK [177], tyrosine kinases such as p56 lck and c-src [178] and cyclooxygenase [179], and it activates c-raf [180].
3.5.4 Timing of protein kinase activation
The signal transduction cascade of ischemic preconditioning can be divided into triggers and mediators. Triggers are important during the episode of preconditioning ischemia and reperfusion, and blockade of a trigger's action during this preconditioning phase will abolish its cardioprotective effects. Mediators are important during the prolonged index ischemia, and blockade of a mediator's action during the sustained ischemia will abolish preconditioning's protection.
The timing of protein kinase activation appears to be critical for the cardioprotection achieved by ischemic preconditioning. The rabbit heart can still be ischemically preconditioned in the presence of staurosporine, a PKC antagonist which blocks PKC's ability to phosphorylate substrates, as long as staurosporine is washed out prior to the index ischemia. However, introduction of staurosporine just prior to the index ischemia is sufficient to completely abort preconditioning's protection against infarction [135]. Thus it would appear that phosphorylation by PKC is required only during the index ischemia. That finding would eliminate phosphorylation of a PKC substrate as the memory step in preconditioning.
A similar behavior is seen for tyrosine kinase activation in rabbit hearts. Neither of the tyrosine kinase inhibitors genistein or lavendustin A alone had any effect on infarct size in rabbits, and when infused to bracket the preconditioning ischemia each failed to block protection. However, when present at the onset of the index ischemia both genistein and lavendustin A completely aborted preconditioning's protection [141]. Thus both PKC and protein tyrosine kinase can be defined as mediators and not triggers of cardioprotection.
The time for activation of p38 is not clear. Timing studies in isolated rat hearts indicate that the index ischemia rather than the preconditioning ischemia is the critical time for SB203580 to block protection [174]. Studies in isolated myocytes also suggest that PKC activation precedes p38 activation [172]. However, Maulik et al. [160] noted that pretreatment of rat hearts with SB 203580 before the preconditioning ischemia effectively blocked protection. A recent study in dogs concluded that activation of p38 is important only during the preconditioning ischemic period. In that study blockade of p38 with SB 203580 abolished cardioprotection only when given prior to the preconditioning, but not when given prior to the index ischemia [166]. According to these results, activation of p38 during ischemic preconditioning would act as a trigger rather than mediator, and would be expected to be located upstream of PKC.
4 Potential end-effectors of ischemic preconditioning
4.1 Energetic and substrate metabolism
Apart from infarct size reduction, ischemic preconditioning reduces energy demand during the index ischemia in dogs [181]. Slowing of ATP consumption in preconditioned hearts was confirmed by NMR studies in pig hearts [15,182]. Studies in rat hearts, however, yielded diverse results, with preconditioning either slowing [183–186], accelerating [187–190] or having no effect [191,192] on the rate of ATP consumption during the index ischemia. The differences between these studies in rats relate to the preconditioning procedure. In studies with one or two cycles of preconditioning ischemia, ATP consumption is slowed [183–186], while more than two preconditioning cycles abolish the effect on ATP consumption during the index ischemia. Regardless of changes in the rate of ATP consumption during the index ischemia, left ventricular developed pressure recovered faster in preconditioned than control hearts. These data suggest that preservation of high energy stores during the index ischemia is not a prerequisite for the cardioprotection achieved by ischemic preconditioning.
Also, a slower accumulation of ischemic catabolites, such as lactate, has been demonstrated in preconditioned hearts ([181,185,193,194]; for review, see Ref. [195]). Most importantly, glycogen depletion by the preconditioning ischemia has been proposed to be involved in cardioprotection [196,197]. However, other reports have cautioned that glycogen depletion alone did not protect the heart against ischemic injury [189,198]. Furthermore, pharmacological preconditioning of the heart gives full protection with no glycogen depletion [198].
Apart from the alterations in energy and substrate metabolism, ischemic preconditioning reduces intracellular acidification during the index ischemia. This reduced intracellular acidification most likely reflects decreased anaerobic glycolysis, since blockade of the increased proton efflux by a sodium–proton exchange inhibitor did not alter ischemic acidification [199]. Also, ischemic preconditioning delays the detrimental rise in intracellular sodium [200] and free calcium [200–203] caused by subsequent index ischemia. Both reduced acidification and the slower rise in intracellular sodium and calcium could contribute to the protection achieved by ischemic preconditioning, insofar as activation of potentially detrimental enzymes depends on the intracellular pH and calcium concentration [204,205]. Also, the resolution of ionic disturbances during the reperfusion period following the index ischemia was accelerated in pharmacologically preconditoned rat hearts [206].
4.2 Protein synthesis
Whether or not protein synthesis is required to mediate ischemic preconditioning's protection is controversial. In the first description in anesthetized rabbits, protein synthesis, either at the translational level (mRNA–protein) or at the transcriptional level (DNA–mRNA), was blocked with cycloheximide and actinomycin D, respectively. Neither substance given intravenously 30 min prior to the preconditioning ischemia altered infarct size reduction triggered by ischemic preconditioning [207]. Subsequent studies in isolated rat [208] and rabbit hearts [209] also failed to demonstrate an effect of transcriptional blockade with actinomycin D on preconditioning's protection, but clearly demonstrated that blockade at the translational level with cycloheximide abolished ischemic preconditioning's salutary effect on infarct size reduction. The only striking difference between the two latter studies and the initial report is the 10-fold lower concentration of cycloheximide used in the two later investigations.
4.3 KATP channels
Two distinct populations of KATP channels exist in cardiomyocytes. The sarcolemmal and mitochondrial channels have different reactivities and different properties. Whereas pinacidil opens and glibenclamide closes both channels at the concentrations generally employed, nicorandil [210] and diazoxide [211,212] are believed to primarily open mitochondrial channels. 5-hydroxydecanoate (5HD) is a potent closer of mitochondrial channels ([213]; for review, see Ref. [214]), while HMR 1098 or 1883 closes only surface channels [215–217]. These drugs have been used as tools to explore the role of KATP channels, specifically mitochondrial channels, in preconditioning, and conclusions are necessarily dependent on the avowed specificity of the agents.
It is still a matter of debate which channel is important for the cardioprotection achieved by ischemic preconditioning (for review, see Refs. [214,218–221]). In some studies in rat and rabbit hearts [213,222], pretreatment with diazoxide protected the myocardium from ischemia, while in another study in rabbits diazoxide failed to reduce infarct size [223]. 5HD [213,224] but not HMR 1883 [225] blocks protection by ischemic preconditioning in rats and rabbits, suggesting that the mitochondrial but not sarcolemmal KATP channel is responsible for preconditioning's protection. In dogs, blockade of both channels is required to completely abolish the infarct size reduction of ischemic preconditioning [226].
Some of the controversy may be the result of incorrect assumptions about the specificity of the channel openers and closers. In fact, recent data indicate that both diazoxide and 5HD may not be as selective as previously thought. Diazoxide, the alleged mitochondrial channel opener at the concentrations employed in most studies, can open sarcolemmal KATP channels in the presence of elevated ADP [227], and diazoxide-mediated protection can be prevented by either HMR 1098 [218] or HMR 1883 [228], putative sarcolemmal channel closers. Furthermore, 5HD, a drug heretofore felt to close only mitochondrial KATP channels, prevented the ischemia-induced shortening of action potential duration which is associated with opening of sarcolemmal KATP channels [229].
Another ongoing debate relates to the question of whether activation of the mitochondrial KATP channel is a trigger rather than an end-effector of preconditioning's protection [222,230]. In rabbit hearts, 5HD blocks protection induced by either ischemia or diazoxide only when it is present during the preconditioning ischemic period or the diazoxide infusion. When 5HD is present only during the index ischemia, protection persists. Both genistein and an antioxidant block protection from diazoxide, suggesting that mitochondrial KATP channel opening might be acting as a signal transduction element rather than serving as end-effector [222]. In support of this hypothesis, diazoxide-induced opening of KATP channels increased the formation of reactive oxygen species in isolated adult rat cardiomyocytes [231]. Again in support of this hypothesis, PKC antagonists reportedly block diazoxide's protection in the isolated rat heart [232]. Although these data would support the role of the mitochondrial KATP channel as trigger of preconditioning, other compelling data do not support this hypothesis: the protection induced by the PKC activator PMA in isolated rabbit hearts was abolished by 5HD [233]. Also, 5HD blocked the protective effect of the MAPK activator anisomycin in isolated rabbit hearts [154]. Finally, the KATP channel blocker glibenclamide infused after preconditioning but before the index ischemia eliminated protection in the dog heart [234]. More recently, Fryer and coworkers found attenuated infarct size reduction by ischemic preconditioning in anesthetized rats, when 5HD was given during the index ischemia only, but also when given only during the preconditioning stimulus, suggesting that KATP channels serve both a trigger and effector function [235].
Finally, the preeminent question of how opening of either the sarcolemmal or the mitochondrial KATP channel could directly protect the heart remains. Opening of sarcolemmal KATP channels increases the outward potassium current, resulting in a decrease in the duration of the action potential [236,237] which, in turn, might decrease the inward calcium current through the voltage-dependent calcium channels [238]. Decreased intracellular calcium overload then would reduce ischemic injury [239]. However, when changes in action potential duration were blocked with dofetilide, an antagonist of yet another potassium channel, preconditioning's protection was not affected [240].
Two hypotheses have been proposed to explain how the opening of mitochondrial KATP channels could be potentially cardioprotective. The first hypothesis refers to mitochondrial calcium handling, insofar as opening of the mitochondrial KATP channels would decrease mitochondrial calcium overload, by reducing calcium uptake and increasing calcium release, thereby preserving the integrity of mitochondria (for review, see Ref. [220]). The second hypothesis relates to changes in mitochondrial volume [241], which is regulated by opening of mitochondrial KATP channels. These volume changes are important, insofar as they affect energy flow through the electron transport system and the architecture of the intermembrane space, thereby influencing efficient energy transfer between mitochondria and cellular ATPases [241,242]. Because the mitochondrial KATP channel may well not be the end-effector at all but rather a signal transduction element (see above), one must be receptive to other suggestions.
4.4 Sodium–proton exchanger
Xaio and Allen [243] have suggested that the sodium–proton exchanger might be the end-effector of ischemic preconditioning, and that its inhibition might lead to protection of the ischemic heart. They noted that the sodium–proton exchanger appeared to be blocked at reperfusion only when rat hearts had been preconditioned. Addition of HOE 642, a highly selective blocker of the sodium–proton exchanger, shortly before reperfusion to a non-preconditioned heart preserved postischemic function by an amount equal to that achieved by ischemic preconditioning. HOE 642 had no additive effect when combined with ischemic preconditioning, further suggesting a common mechanism. Similarly, 5-(N-ethyl-N-isopropyl)amiloride, another blocker of the sodium–proton exchanger, limited infarct size in rabbits by an amount equal to that of preconditioning [244], and amiloride could not augment preconditioning's anti-infarct effect [245]. Neither kinase inhibitors nor 5HD could abolish amiloride's protection, suggesting that the sodium–proton exchanger must be operative at a very distal point in the signaling pathway. Adenosine is reported to block the exchanger [246], and this is consistent with the previously demonstrated ability of adenosine to pharmacologically precondition the heart (see above). Finally in dogs, blockade of the sodium–proton exchanger limits infarct size [247], and this reduction in infarct size is not attenuated by either blockade of KATP channels or an adenosine receptor antagonist [248].
In dogs, ischemic preconditioning and blockade of the sodium–proton exchanger are equally effective in reducing infarct size following an index ischemia of 60 min duration, while with prolongation of the index ischemia to 90 min, blockade of the sodium–proton exchanger reduces infarct size to a greater extent than ischemic preconditioning [249]. Also, activation of PKC, which is involved in preconditioning (see above), activates rather than blocks the sodium–proton exchanger [250]. These data do not support a role of the sodium–proton exchanger as the end-effector of ischemic preconditioning's protection, but rather suggest distinct pathways and mechanisms (for review, see Ref. [251]).
4.5 Cytoskeleton
MAPKAP kinase 2 phosphorylates the small heat shock protein HSP27 [252–254], which appears to be regulated by its phosphorylation state. HSP27 acts as a molecular chaperone and binds unfolded proteins, preventing nonspecific aggregation of proteins [255]. HSP27 also regulates actin filament organization. In HSP27-transfected cells heat shock-induced disassembly of actin filaments is prevented [256]. Furthermore, HSP27 stabilizes actin filaments during oxidative stress [257].
Prolonged ischemia is known to cause cytoskeletal disruption [258]. Overexpression of HSP27 confers protection against ischemia in isolated rat cardiac myocytes [256]. In Langendorff-perfused rat hearts, ischemic preconditioning induces redistribution of HSP27 from the cytosol to the sarcomere, and the recovery of global contractile function following 40 min of global ischemia is significantly enhanced [259]. Similarly, ischemic preconditioning induces redistribution of HSP27 from the cytosol to the sarcomere in dog hearts in vivo [166]. This redistribution of HSP27 is abolished by pretreatment with SB 203580, supporting involvement of p38 activation [260]. Furthermore, in isolated cardiomyocytes subjected to osmotic stress and hypoxia, cytochalasin D, a drug known to disrupt the cytoskeleton, blocks the protective effect of ischemic preconditioning or diazoxide against increasing osmotic fragility [154].
Therefore, redistribution of heat shock proteins from the cytosol to the sarcomere and the subsequent alteration in the stability of the cytoskeleton appear to be important for ischemic preconditioning's cardioprotection, although further studies in vivo using more specific drugs than cytochalasin D are required to corroborate this concept.
4.6 Volume regulation
The osmolarity of body fluids is strictly controlled so that cells do not experience changes in osmotic pressure under normal conditions. Osmotic balance is maintained by matching the osmotic pull of proteins and nucleotides within the cell by sodium outside the cell. Because the conductance of the sarcolemma to sodium is very low extracellular sodium is an efficient osmolyte. During ischemia ATP is broken down to AMP and two inorganic phosphates thus tripling the osmotic pull. Similarly, failure of the sodium/potassium pumps leads to buildup of intracellular sodium and thus a collapse of the sodium gradient. Each increase in osmolyte concentration of 1 mM above the baseline intracellular osmotic pressure of 5430 mmHg exerts an additional pull of 19 mmHg [261]. After 30 min of ischemia myocardial cells of an isolated rat heart accumulate about 20 mM of sodium [262]. That translates to an increase in transmembrane osmotic pressure from the sodium alone of 380 mmHg. Breakdown of ATP and creatine phosphate also would contribute. This osmotic imbalance results in swelling of the ischemic cells. This swelling may be exacerbated further on reperfusion when the hyperosmotic extracellular milieu is replaced by isoosmotic perfusate. In the end the cell bursts from osmotic forces. Preconditioning makes cardiomyocytes very resistant to membrane failure when they are challenged with hypotonic media [263]. In ischemically preconditoned rat [264] and pig [265] hearts, the extent of myocardial edema formation — along with infarct size — is reduced. Alterations in channels involved in cell volume regulation therefore might be involved in the cardioprotection achieved by ischemic preconditioning. Chloride channels are involved in moment to moment volume regulation, and Diaz et al. [266] hypothesized from experiments in rabbit cardiomyocytes and isolated hearts that opening of swelling-induced chloride channels was responsible for the protection achieved by ischemic preconditioning. However, their electrophysiological and infarct size data could not be confirmed [267]. There are also organic osmolytes, such as taurine or sorbitol, which are involved in ischemia/reperfusion damage. In anesthetized rats, taurine depletion indeed reduces infarct size following ischemia/reperfusion, with the relationship between myocardial taurine content and infarct size being almost linear [268]. Similarly, depletion of myocardial sorbitol content by inhibition of aldose reductase attenuates infarct size in isolated rabbit hearts [269]. Whether ischemic preconditioning alters myocardial taurine or sorbitol contents is unclear at present.
The sodium–hydrogen exchanger may also provide an avenue for sodium entry into the ischemic cell. Although most theories suggest that calcium entry might be the ultimate consequence of sodium entry (via the Na+/Ca2+ exchanger) the osmotic effects of sodium entry should not be overlooked. If the sodium–hydrogen exchanger turns out to be the end-effector of preconditioning and its inhibition the final step in the cascade leading to protection, then the principal effect of its inhibition may be prevention of swelling rather than calcium entry.
Connexins are distributed throughout the heart [270], and connexin 43 forms channels which are involved in volume regulation during changes in the intra/extracellular milieu [271]. During acute [272] and chronic [273] myocardial ischemia, as well as during inflammation [274], heterogeneous loss of connexin 43 occurs, thereby potentially affecting cell volume regulation during osmotic stress. However, whether ischemic preconditioning alters myocardial connexin concentration or its distribution is unknown at present. Taken together, an alteration in the osmotic load might be one potential way of reducing myocardial ischemia/reperfusion injury. The importance of osmotic load for ischemic preconditioning, however, remains to be established.
4.7 Tumor necrosis factor (TNF) α
TNFα concentrations are increased during hypoxia [275] and ischemia [276,277]. In patients, monoclonal antibodies against TNFα reduce the extent of irreversible tissue damage during acute myocardial infarction, suggesting a deleterious role of TNFα in the scenario of ischemia/reperfusion [278]. Ischemic preconditioning attenuates infarct size and the ischemia-induced increases in the serum and myocardial TNFα-concentration in rabbits in vitro [276] and in vivo [277]. Therefore, cardioprotection by ischemic preconditioning might involve downregulation of TNFα, although a cause–effect relationship remains to be established in future experiments.
5 Differences between the early and the late phase of ischemic preconditioning
While the first window or early phase of protection is short-lived, a second window or late phase of protection appears about 24 h after ischemic preconditioning [8,279,280], and this latter anti-infarct effect is believed to last for up to 3 days [281]. In contrast to the early phase of ischemic preconditioning, the late phase of protection includes a strong anti-stunning effect [279]. Although the signal transduction pathway leading to protection in the late phase shares many of the steps identified for early phase protection, there are certain differences between both phenomena (for review, see Refs. [279,280]). For example, endogenous nitric oxide is a key trigger and mediator of the late phase of ischemic preconditioning [282], and the late phase of protection clearly results from altered expression of protective proteins.
6 Potential reasons for current controversies
The issue of endpoints was already discussed in Section 1.
6.1 Species
Ischemic preconditioning protects against infarction in all species tested so far (for review, see Ref. [8]); however, the signal transduction — as clarified so far — varies among different species. For example the functional role for PKC isozymes differs among species, with PKCε being most important in rabbits, PKCδ in rats and PKCα in dogs (see above). The question of which species is the closest to humans can obviously not be answered, although it appears that large mammals may have an advantage.
6.2 Models
A variety of different models has been used to study preconditioning's effect, such as neonatal and adult cardiomyocytes, in vitro isolated, buffer- or blood-perfused hearts or in vivo anesthetized or conscious animals. The signaling system is inherently different among those models due to the specific conditions of the preparations. For example, free radicals are certainly less important in blood-perfused in situ systems than in oxygenated buffer-perfused preparations.
Also, age appears to be an important issue. During postnatal development the expression of protein kinase C declines [283], MAP kinases remain unaltered [284], and free radical production is increased [285]. Therefore, the sensitivity towards a certain signaling cascade will change during development. Indeed, rat hearts become more vulnerable to ischemia with advancing age and the beneficial effect of ischemic preconditioning, which was seen in hearts of young rats, appears to be reversed in middle-aged rat hearts; i.e., creatine kinase release increased rather then decreased in aged preconditioned hearts [286].
6.3 Protocols
A variety of protocols has been used to precondition the heart, including single vs. multiple cycles of ischemia/reperfusion, short vs. long durations of the preconditioning ischemia, low-flow vs. no-flow ischemia and regional vs. global ischemia. Thus, the intensity of the preconditioning stimulus varies among most experimental studies, which in itself will lead to differences in the triggers involved (e.g., bradykinin vs. adenosine, see above). We now know that there is a large degree of redundancy in the preconditioning system. For example, at least three receptors are involved as preconditioning triggers. Antagonists to a single receptor do not abolish protection, but rather raise the threshold for a protective effect. Thus one investigator preconditioning hearts with multiple cycles might report that a given receptor blocker fails to abolish protection, while another using a single cycle of ischemia to precondition might see abolition of protection with the same drug. Both observations are valid, and confusion is unavoidable. The same seems to occur with the kinases. Activation of kinases appears to be very protocol-dependent. With multiple cycles of ischemia/reperfusion PKC is further upregulated, while p38 MAP kinase is decreased [287], and the relative importance of tyrosine kinases is increased (see above).
None of the studies so far has completely analyzed all identified targets of preconditioning's signal transduction cascade within a given experimental protocol.
6.4 Inhibitors and activators
Pharmacological agents are valuable tools in delineating the mechanism(s) of ischemic preconditioning. However, the results obtained are influenced by the effectiveness and specificity of the drugs for a given target at a given concentration. As outlined above, most pharmacological agents lack such specificity (e.g., diazoxide, SB203580), especially when given at high enough concentrations to be effective. Furthermore, most kinase inhibitors lack specificity for a certain isoform which may have opposing functional roles (e.g., apoptotic effect of p38α and p38β, see above).
6.5 Transgenic and transfection approaches
With transgenic and transfection approaches, intra-species differences must be considered. For example, infarct size following 30 min of ischemia and 24 h of reperfusion is highly strain-dependent in mice [288] and rats [289]. Therefore, transgenic and transfected mice must always be compared to controls from the respective wild-type strain.
Apart from the problems of quantifying the rate of transfection, overexpression of a certain protein might cause loss of its selectivity. For example, the RACK for PKCε was thought to be RACK 2. However, at high levels of expression PKCε interacts with both RACK 2 and RACK 1 [126].
Another emerging facet of signaling systems is the crosstalk between different pathways [290], suggesting that myocardial signaling systems, rather than following the linear signaling paradigm postulated for ischemic preconditioning, are instead highly interactive. This is especially of importance in transgenic animals, as the knockout of one gene might up-regulate another gene, or overexpression of one protein (by transfection) might downregulate others.
7 Summary
Following 15 years of research, parts of the signal transduction cascade of ischemic preconditioning have been identified, and there is good agreement on the major endogenous triggers (adenosine, bradykinin, opioids, free radicals) involved in ischemic preconditioning, although, of course, the importance of different triggers varies among different species. Agreement exists also on the involvement of certain protein kinases, such as protein kinase C or protein tyrosine kinases, although the sequence of their activation (in series or parallel) appears to be once more species- and model-dependent. However, the importance of other elements of the downstream signal cascade, such as the MAP kinases and the ATP-dependent potassium channels, is still incompletely understood and the end-effector of preconditioning's protection is still unknown. Potential candidates of interest already exist (cytoskeleton or volume control), and the importance of novel proteins [291], such as desmin and villin, or kinases, such as Akt [291], in cardioprotection needs to be defined. A better understanding of the different elements within the signal transduction cascade and their hierarchic order is of utmost importance to potentially utilize the phenomenon of preconditioning in the clinical setting in the future.
- Copyright © 2001, European Society of Cardiology
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text:
September 2008
Post-Show Blog for 9/22/08 (OF Rankings)
2008 2009
Matt Holliday Grady Sizemore
Grady Sizemore Matt Holliday
Carl Crawford Carlos Beltran
Carlos Beltran Alfonso Soriano
Bobby Abreu Ryan Braun
Curtis Granderson Matt Kemp
Ichiro Suzuki Alex Rios
Magglio Ordonez Carl Crawford
Vladimir Guerrero B.J. Upton
Eric Byrnes Nick Markakis
Carlos Lee Carlos Lee
Alfonso Soriano Ichiro Suzuki
B.J. Upton Josh Hamilton
Alex Rios Jason Bay
Lance Berkman Carlos Quentin
Adam Dunn Manny Ramirez
Chris Young Nate McLouth
Torii Hunter Bobby Abreu
Gary Sheffield Curtis Granderson
Nick Markakis Corey Hart
POD for Sunday-Monday
Pitch: Lewis, Dice-K, Liriano, Danks, Lackey, Morrow, Gallagher, Sabathia, Arroyo, Pelfrey, Oswalt, Od. Perez, Dempster, Haren, Volstad, Cain, Lowe
Pitch: Beckett, Meche, Miner (gamble), Garza, Weaver, Nolasco, Harang (he's baack!), Webb
Post-Show Blog for 9/19/08 (Closer Rankings)
Closers, closers, closers. Aside from the elite guys, there's a significant amount of turnover here. This is why I'll always target a Papelbon/Rivera/Nathan/K-Rod and after that, not worry about the position too much. Make sure you draft at least two of them with solid job security, but your second one doesn't have to be a big name. Soria's a perfect example. Sure the Royals don't win a lot of games, but his peripherals last season were outstanding. Save opportunities tend to vary quite a bit from year to year, so I'm not at all surprised that he's emerged as a top tier option. Don't panic if you can't draft a third closer. Plenty emerge during the season. As long as you constantly monitor all these developments, being competitive in the saves category shouldn't be all that difficult.
2008 2009
Francisco Rodriguez Jonathan Papelbon Joe Nathan Mariano Rivera
Takashi Saito Joe Nathan
J.J. Putz Francisco Rodriguez
Billy Wagner Joakim Soria
Mariano Rivera Brad Lidge
Jonathan Papelbon Jose Valverde
Bobby Jenks Kerry Wood
Francisco Cordero Brian Fuentes
Jose Valverde Francisco Cordero
Post-Show Blog for 9/18/08 (3B Rankings)
I 'm in full agreement with what was said on today's show. Third base is loaded. If you can't get A-Rod, Wright, or Ramirez, definitely wait as long as possible to take a third baseman. As much as I like Longoria, who I own in a long-term keeper league, he'll almost certainly be selected very early, maybe even within the top three rounds. Now can Longoria perform at a third round level in 2009? Absolutely. But it's also possible he disappoints relative to where he's drafted. In a single season league, I'd much rather snag Adrian Beltre in the 10th round and use my third round pick on someone at another position with a proven track record of elite production. You could even take this a step further and pick an Eddie Encarnacion or Ryan Zimmerman, young players with upside who could easily crack the top 10 next year.
Feel free to chime in on this subject or any other.
2008 2009
Alex Rodriguez Alex Rodriguez
David Wright David Wright
Ryan Braun Aramis Ramirez
Miguel Cabrera Chipper Jones
Garrett Atkins Evan Longoria
Aramis Ramirez Garrett Atkins
Adrian Beltre Mark Reynolds
Ryan Zimmerman Adrian Beltre
Chone Figgins Chone Figgins
Chipper Jones Troy Glaus
Post-Show Blog for 9/17/08 (SS Rankings)
On to the shortstops.
Despite his place on these lists (7th on both), Furcal's the
obvious pick here as a guy who could hang around longer than he should in
drafts. Unfortunately, not everyone
watches the 411! Hitting atop that emerging
Dodgers lineup, especially if Manny stays, Furcal will score a ton of runs
while swiping 35+ bags. I always like to
get speed out of the shortstop and second base positions so I can focus on power
outfielders. Furcal's been a longtime favorite
of mine, as outside of the elite names you see below (H-Ram, Reyes, Rollins), he's the only one who
fits that profile.
Agree? Disagree? Have any questions completely unrelated to
this? Let's hear it!
2008 2009
Hanley Ramirez Hanley
Jose Reyes Jose
Jimmy Rollins Jimmy Rollins
Derek Jeter Derek
Carlos Guillen Jhonny
Troy Tulowitzki Michael Young
Rafael Furcal Rafael
Edgar Renteria Troy Tulowitzki
Miguel Tejada J.J. Hardy
Michael Young Stephen Drew
Updated Feud Standings
Two weeks to go…Can anyone catch Siano? And could Stats Sr. actually finish in last place? Stay tuned!
Post-Show Blog for 9/16/08 (2B Rankings)
With all due respect to our outstanding trio of S's, I don't really understand why Rickie Weeks is so high on this year's list. The guy's having a worse season than last year and wasn't even among the 2008 top 10. I guess it's based on potential more than anything else, along with Upton's loss of second base eligibility and Kent's pedestrian year. I'm gonna go out on a limb and say that no Weeks owner is leading their league in average. I'm one of them, and sit dead last in that category.
Zach Steinhorn
2008 2009
Chase Utley Chase Utley
Brandon Phillips Ian Kinsler
B.J. Upton Brian Roberts
Brian Roberts Brandon Phillips
Dan Uggla Dustin Pedroia
Robinson Cano Dan Uggla
Ian Kinsler Rickie Weeks
Jeff Kent Howie Kendrick
Howie Kendrick Robinson Cano
Freddy Sanchez Alexei Ramirez
***Also a reminder that the final 411 chat of the season will take place on FRIDAY, SEPTEMBER 26th at 11:30 AM ET (after the show) and will run for about 90 minutes.
Post-Show Blog for 9/15/08 (1B Rankings)
Here's the first base rankings comparison. Fairly similar lists with M-Cab and Youkilis replacing Pena and Konerko. Pena hasn't been the total bust many (including myself) predicted, but we all knew he was overvalued, and that .244 AVG is ugly. Konerko, assuming he plays every day, could be a sleeper heading into '09, someone who will slip quite a bit in drafts. Despite his impressive numbers, I won't be targeting Youkilis. Look for all those Red Sox fans to take him too early, and focus on someone else!
Let us know what you think, and keep those questions coming.
2008 2009
Albert Pujols Albert Pujols
Prince Fielder Lance Berkman
Ryan Howard Ryan Howard
Lance Berkman Miguel Cabrera
Justin Morneau Mark Teixeira
Mark Teixeira Prince Fielder
Carlos Pena Justin Morneau
Adrian Gonzalez Kevin Youkilis
Paul Konerko Adrian Gonzalez
Derrek Lee Derrek Lee
POD for Sunday-Monday
Post-Show Blog for 9/12/08 + Catcher Rankings
On today's show, we kicked off our series of 2009 positional rankings, starting with the catchers. From now through September 23rd, I'll be posting the 2009 rankings along with our rankings from last year so we can see just how much things have changed. Feel free to post your own rankings, comments, and of course, general questions.
2008 2009
Russell Martin Russell Martin
Victor Martinez Brian McCann
Brian McCann Geovany Soto
Jorge Posada Joe Mauer
Joe Mauer Victor Martinez
Bengie Molina Chris Iannetta
Kenji Johjima Ryan Doumit
Jason Varitek Kelly Shoppach
A.J. Pierzynski Jorge Posada
Jarrod Saltalamacchia Matt Wieters


text:
BIRMINGHAM, Alabama - Jeff Aiken got more out of his first trip to Maebashi, Japan, than the memory of running a marathon.
The home inspector from Alabaster ultimately returned with a bride.
Aiken and a fellow runner from Birmingham remained after taking part in the marathon in Maebashi. He was on a tour and needed someone who could speak "American English."
Choko Kimura
filled the bill. Now the two are a married couple, back in Japan as he competes in a running event tonight Birmingham time.


text:
"I now pronounce you husband and wife," my father said.
Daniel and Amanda beamed and swayed toward each other.
"You may kiss your bride."
Article Video
It all began years earlier with Amanda and I conspiring on a swing to marry her off to one of my brothers (since her brother was clearly too young for me). It became hopeful when she started dating Daniel and ended tragically on Valentine's Day 2007. In fact, it was only with the random influence of a friend that Amanda and Daniel got back together; but regardless of the trials they experienced, Daniel and Amanda Martin were married Friday, Aug. 5, 2011.
There are three major events in our lives: Birth, marriage and death. These are three events that cannot be ignored - they are three of the greatest events in our very, very short lives. Birth we're going to address second and this from the perspective of parents (because who actually remembers their own birth, and of those who do, how many of them aren't traumatized?) and death we will leave for last.
Marriage is an event that takes place less and less in today's culture. Instead of husband and wife the world has shifted toward "partners" and "cohabitation." It is no longer considered a prerequisite to a shared life. In fact, marriage in some cases is frowned upon because getting out of it is not as easy as getting away from a "partner." Parting ways with a spouse is often more expensive than moving out of "cohabitation."
So the question is raised, why should I get married? What do married people have that cohabitants don't?
"When you stand in front of God and everybody, and say I will be with you forever, you can trust in that," Margie McConnell said. "You said it in front of the whole world."
Diana Price said marriage provides a level of security.
"I feel incredible peace," she said. "He's my best friend and I understand people who live together say that's true, but they have a back door. That doesn't mean (marriage is) perfect, but you have a knowledge that you're in it for the long haul."
My dad, who has married more people than Elizabeth Taylor (but in a different way), said, "Trust is the foundation of all great relationships. The deeper the trust, the stronger the relationship can grow. Cohabitation is based on distrust and stymies a relationship from the start."
On Aug. 4 I practiced my Maid of Honor speech. I paced across the stage and imagined the wedding party sitting at their table after the fateful "I do's."
"From what I have observed of love," I said. "It is a gift from God, a gift given in portions depending on how hard you want it, how hard you seek it, and how hard you hold on."
McConnell described marriage as being comprised of trust and a deeper commitment.
"When you make a commitment you have a deeper level of intimacy," Price said. "It's your soulmate - your confidant."
On Friday, Aug. 5, 2011, I stared at the bride and groom seated at their wedding table.
"The love God is going to give you is dangerously beautiful," I said. "It's a love you don't want to lose and you don't want to give up on."
Marriage is not the same as having a "partner" or "cohabiting." No matter how you look at it, legally, socially, or emotionally - marriage is completely different. Research it, learn the facts, observe reality. Because, the truth will show you the better choice, and if truth tells you that marriage is the better deal then don't let society, strangers or even family dissuade your reality.
Don't just take it from me. Take it from people who know, from people who agreed to be filmed so they could share these truths with you.


text: Thanks for all the great advices I appreciate all off them I thought about it and came to the solution that I'll just go a more relaxed way of eating - like more diary/ sometimes rice or potatoes , if there's no other option etc. More over I try to stick closely as possible to the paleo lifestyle ( like try to avoid bread, coke and other proccessed foods). Furthermore it's interesting that I'm not the only one like you Turnstone and thanks for the tip with Gadsie. :-)


text:
DETROIT — A year after presenting their business idea to bring kayaking to Detroit's Belle Isle, Detroit River Sports has made it a reality.
This weekend the company began renting kayaks from a pop-up location on Belle Isle near the Detroit Yacht Club and hopes to eventually have a permanent home.
Available from 10 a.m. to 7 p.m., rental costs are $15 per hour or $50 per day for a single-person kayak; the cost is $20 per hour or $65 per day for a two-person kayak.
Longtime friends Howbert,
Brian Ellison and Andy Dold started the company, a 2012 Hatch entrepreneur grand finalist.
The operation plans to expand its hours as needed based on demand. Kite boarding, wind surfing and possibly cross-country skiing in the winter are offerings Detroit River Sports is considering in the future.Related: Detroit River Sports paddles toward June opening
MLive Detroit plans to check out the rental operation Sunday. Check back for more.


text:
About 30,000 families whose kids are covered by Pennsylvania's health insurance program for children will now have until 2015 to switch them to Medicaid.
Gov. Tom Corbett's office said Wednesday the extra time to switch from the Children's Health Insurance Program is being allowed by the federal government.
The U.S. Health and Human Services Department said the switch is required by the 2010 federal health care law that expands Medicaid to more low-income adults.
The deadline to switch had been 2014, but Secretary Kathleen Sebelius offered in September to cooperate in a phased-in transition.
The switch affects children whose family income is between 100 percent and 133 percent of the federal poverty level. The state Insurance Department said notices will be mailed from CHIP insurance carriers this month.