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Can the Saudis save the economy?
We're depending on the House of Saud to replace lost Libyan oil. We also need the Saudis to quiet political unrest in the Persian Gulf. The future of the economy depends on it.
Related topics: oil, OPEC, politics, economy, Anthony Mirhaydari
A great horde of disaffected youth stretching from the Moroccan coast to the banks of the Caspian Sea, frustrated by a lack of opportunity and a rising cost of living, has created a wave of political bloodlust. Uprisings already have removed two North African tyrants from power, and one now challenges Libya's Moammar Gadhafi as Western powers deploy air and sea assets in support of the opposition.
Protests that started with a desperate Tunisian fruit vendor have washed over the Middle East, stirring disaffection in such places as Iraq, Iran, Algeria, Oman, Yemen, Kuwait, Syria, Jordan and Bahrain.
The loss of more than 1 million barrels per day of Libyan sweet crude oil production and fears of additional supply disruptions have pushed crude oil prices up more than 40% from last August. Omani and Bahraini oil refinery workers have staged protest strikes over the past week. And Saudi Arabian Shiites have taken to the streets in Qatif, near the heart of the kingdom's oil infrastructure.
Meanwhile, the horrific Japanese earthquake, tsunami and nuclear tragedy is pushing crude even higher as traders anticipate that lost nuclear production of electricity will be replaced by oil and gas.
Where do we find salvation? Because, heaven knows, we need to be saved: Oil has traded near $104 recently and gas prices have pushed toward $4 a gallon -- a price some economists say would tip the economy over.
Do high oil prices mean recession?
A spike in fuel prices driven by political unrest is economic kryptonite, and it's the worst possible problem we could have right now. Rising prices are forcing central bankers around the world to start policy-tightening cycles and move up interest rates. At the same time, higher energy costs tax consumers, reducing spending power.
Anthony Mirhaydari
Keep in mind that every single recession from 1973 on has been preceded by or coincided with a sharp rise in oil prices.
Hapless investors are glued to their trading monitors, subject to daily headline risks and the fortunes of rebel fighters and protesters half a world away. Consumer and business confidence, which had become cautiously optimistic, is sinking again. Wall Street economists are busily marking down their first-quarter and full-year growth estimates.
Since all of this is driven by political unrest and armed rebellion, policymakers in the West are helpless. If the Federal Reserve tries to loosen policy further, it risks making the problem worse by pushing hot, speculative cash into the commodity market and forcing food and fuel prices even higher. Remember that increases in the prices of these necessities are what catalyzed the protests in the first place.
Unlike with the financial crises of the past few years, more cheap money isn't the solution, and the Fed can't be our savior.
Nor can we just, to borrow a phrase, "drill baby, drill": Offshore production in the Gulf of Mexico is as difficult as anything humans have ever done, and opening new fields in, say, Alaska would take years even if it were politically possible. Time is our enemy here. Before higher prices could encourage new production, the damage to the economy would already have been done.
Salvation from the House of Saud
Instead, the future depends on the ability of King Abdullah and the House of Saud to quickly fill the gaps in global crude supplies while also tamping down protests throughout the region. OPEC controls the world's supply of spare oil. And Saudi Arabia is overwhelmingly the largest contributor to that supply.
Moreover, the kingdom sits at the political center of the Persian Gulf. Riyadh is the seat of power for Sunni Muslims. It plays a key role in the struggle to control Iranian ambitions. It is also on the front lines of the fight against al-Qaida's ambitions on the Arabian Peninsula.
Saudi Arabia already has committed itself to filling any oil supply deficits and has worked with European importers to replace lost shipments of Libyan sweet crude.
On the unrest front, more than 1,000 Saudi troops have crossed the King Fahd Causeway to bolster Bahrain's royal family. And now the Saudis are poised to play a role in the future of Yemen as that country's military leadership abandons its president.
While President Barack Obama has been outspoken in his support of rebels in Libya, Egypt and Tunisia, his administration has been less forceful in supporting protests in Saudi Arabia's sphere of influence. The Saudis had previously expressed disapproval of America's abandonment of Egypt's Hosni Mubarak. This is realpolitik at work. Only so much newfound freedom can be tolerated when oil is at stake.
Saudi Arabia is our bulwark, against both an oil supply crunch and an uncontrollable political contagion sweeping across the world's key energy production and transit hub. Whether its leaders are up to the task will determine the course of the economy and stock prices in the months to come.
Supply constraints
The most important metric is the balance of crude oil supply and demand. And it's more tenuous than most realize.
Right now, a 1.1 million barrel per day (mmb/d) loss of Libyan production has dropped global spare production capacity to 3.6 mmb/d, according to Credit Suisse. That loss represents 4% of the total global supply. All of the excess capacity comes from OPEC, since non-OPEC production is falling. And more than 75% of OPEC's oil comes from Saudi Arabia.
But this estimate hinges on the belief that Saudi Armaco had around 3.5 mmb/d of extra capacity before the Libyan shutdowns. Some experts aren't so sure. Goldman Sachs suggests that OPEC has less than 2 mmb/d of spare capacity, based on anecdotal evidence that the Saudis have been pumping upward of 1 mmb/d more than the official production numbers since November.
There are other factors at work which effectively weaken the cushion as well. Incremental Saudi production is of a lower grade than the lost Libyan oil. And Morgan Stanley analysts say they believe that only 1.5 mmb/d worth of additional Saudi supply can be put into service within six weeks. Increasing Saudi Arabia's total production capacity would "require close to three months and is likely to prove very costly and challenging logistically," according to Morgan's Hussein Allidina.
The Arab League of Nations asked for a "No Fly Zone" they got it as well as Billions of foreign aid from American. Well it's time to repay the piper. My opinion. I would suggest a fixed price on oil for the next twenty-five years. Bringing down the price at our pumps would help. America would have some time to develop a workable oil alternative which the oil producers fear.
I've worked with these exploitive sand farmers and all they want is to exploit people. Especially American businesses.
Don't hold your breath on anything fantastic happening.
'Do High Oil Prices Mean Recession?'...
If your hands and feet are bound, have a concrete block chained around your neck, and then you were cast into the sea, does that mean you're going to drown? Get real! Either you've been trying to break Rumplestilskin's record, or you've traded the mantra of journalist for government lackey. The informed are well aware that we've been in a depression for some time now, and the manipulation of oil prices is only one item on a long list of causes.
The idea is to extract the wealth of the nation, and subjugate its people. The players are few, but powerful. The majority know this. Some agency recently released a report that the American people have been able to put about 5% of their money into savings. As I read the article I could imagine corporate America and their front-line political allies salivating. The final squeeze is on, and we're the lemons.
Too bad the underpaid remains of our rapidly dwindling workforce still need to use gasoline in those foreign made cars.
The peaks and valleys for future oil prices has already been charted by the elite in the two-headed serpent that controls our government, and their global cohorts. What can be done? Nothing! Add our country to the list beneath the Roman Empire, Egyptian Empire, Persian Empire, etc.. .
You've GOT to be kidding!!! What a rediculous article!!! KILL the SPECULATORS and we'd all be FINE!!!
As early as 2003 the Saudis had a press conference WARNING us that we have to do something about SPECULATORS. They said they had been selling oil to us in the USA at $24/bbl since RAYGUN but because of the SPECULATORS there was no way it would go below $$38/bbl! It was selling at THAT time at $46/bbl!
They said they have stock in companies and could NOT AFFORD to have the economy wrecked! They didn't want the world wrecked.
Well GUESS THE HECK WHAT??? The speculators ruined the economy. Then we gave them $700 BILLION dollars to steal and re-speculate.
I do NOT want to give MY HARD EARNED MONEY to worthless people looking to do NOTHING for the world than to make unearned money for their bank account at my my country or even the SAUDI"S expense! Kill the speculators one way or the other and I MIGHT believe what you say.
Meanwhile, back at 1600 Pennsylvania Avenue, its just another day of planning the next vacation or golf outing.
1: Congress is also out of session
2: Obama is overseas, in South America, one of the fastest growing economic regions in the world. Brazil in particular is a VERY good business oppertunity...
Anyway, world-wide supply of Oil has been falling for three years now, so its clear we've hit peak oil. The cheap stuff is GONE, and continuing to rely on it is pure idiocy. Its time to finally start to push hydro-fuels, and if that means forcing every gas station to have a fill-up station, so be it.
Either government forces the oil-co's to start moving away from oil, or we live with $5/gal. Your choice.
This isn't about our oil, it's about world markets. "Drill, baby, drill" is stupid. We don't need to drill; we're already the third largest producer of oil in the world. What we need is some sort of market mechanism that keeps that oil at home instead of selling it on the open market We can drill until there's a pump in every back yard, it won't lower the price of oil.
Perhaps an export tariff on our oil producers? Sell it here for $50 a barrel, or sell it overseas and we'll tack on a $50 tax for taking it out of the country. We could call it a national resource that would put our security at risk if we lost it, like we do now with limiting missile technology to other countries.
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[BRIEFING.COM] The major averages posted solid gains ahead of tomorrow's policy directive from the Federal Open Market Committee. The S&P 500 rallied 0.8%, while the Russell 2000 (+0.3%) could not keep pace with the benchmark index.
Equity indices hovered near their flat lines during the first two hours of action, but surged in reaction to reports from the Wall Street Journal concerning tomorrow's FOMC statement. Specifically, Fed watcher Jon Hilsenrath indicated that the statement ... More
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Steamed Fish with Spicy Ginger Sauce
Mild-flavored fish works best in this easy recipe. Mirin is a sweet, low-alcohol rice wine that's found in the Asian food sections of most large supermarkets; sweet sherry is an acceptable substitute.
Yield: 4 servings (serving size: 1 fillet, about 3 tablespoons leek mixture, and about 3 tablespoons sauce)
More From Cooking Light
Nutritional Information
Amount per serving
- Calories: 279
- Calories from fat: 25%
- Fat: 7.6g
- Saturated fat: 1.1g
- Monounsaturated fat: 2.7g
- Polyunsaturated fat: 2.7g
- Protein: 36.7g
- Carbohydrate: 12.2g
- Fiber: 2g
- Cholesterol: 54mg
- Iron: 2.3mg
- Sodium: 537mg
- Calcium: 104mg
- Sauce:
- 1/4 cup fresh orange juice
- 1 tablespoon grated peeled fresh ginger
- 2 tablespoons mirin (sweet rice wine)
- 2 tablespoons low-sodium soy sauce
- 1 tablespoon dark sesame oil
- 1/2 to 1 teaspoon crushed red pepper
- Fish:
- 4 (6-ounce) halibut or trout fillets
- 1/2 cup chopped green onions
- 1 tablespoon grated peeled fresh ginger
- 1/4 teaspoon salt
- 1/4 teaspoon freshly ground black pepper
- 1 cup thinly sliced leek (about 1 large)
- 1/2 cup (1-inch) julienne-cut carrot
- 1/2 cup (1-inch) julienne-cut red bell pepper
- 4 cups water
- 4 cilantro sprigs (optional)
- To prepare sauce, combine first 6 ingredients, stirring with a whisk.
- To prepare fish, lightly score each fish fillet by making 3 (1/4-inch-deep) crosswise cuts with a sharp knife. Combine onions and 1 tablespoon ginger, tossing well. Rub about 2 tablespoons onion mixture evenly into slits of each fillet. Sprinkle fillets with salt and black pepper. Combine leek, carrot, and bell pepper; arrange half of leek mixture in a 10-inch pie plate. Pour half of sauce over leek mixture; arrange fillets in a single layer over leek mixture. Top fillets with remaining leek mixture; drizzle with remaining sauce.
- Open a small metal vegetable steamer; place steamer upside down in a large, deep wok. Add water; bring to a simmer. Wearing oven mitts, carefully place pie plate on top of inverted steamer. Cover and cook 12 minutes or until fish flakes easily when tested with a fork. Wearing oven mitts, carefully remove pie plate from wok. Garnish with cilantro sprigs, if desired.
- Wine note: The delicacy of the fish, the citrusy flavors, and the lightly exotic touch of ginger all demand a wine that is itself light, delicate, dry, and fruity: riesling. It's also a boon that riesling is high in acidity--always a great counterpoint to the oils in fish (that's why we squeeze lemon on fish). Of all rieslings, German wines are the most delicate and fruity. There are many great German rieslings available in wineshops; be sure to buy one labeled "Kabinett" or "Spätlese." A kabinett riesling is the lightest; spätlese is more full-bodied. Selbach-Oster, Dr. F. Weins-Prüm, and Dr. Loosen are all terrific producers. Prices start at $13. -Karen MacNeil
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Abrolhos Islanders relive the past in new photo exhibition.
This [series episode segment] has
Jeff Carter is hardly a household name. But some people say he deserves to be.
December ushers in a season for big, blockbuster exhibitions but there's an exhibition at the National Archives in Canberra that deals with issues closer to home.
Old shop interiors in country towns might be considered an eyesore by locals, who believe a lick of paint and a basic renovation wouldn't go astray, but they are the focus of a search by a writer and photographer who wants to document these places before they disappear.
When one of this countrie's most renowned landscape photographers, Olegas Truchanas died, he left a lot more than a collection of beautiful images.
Lake Hindmarsh has been attracting people and animals because the rains have returned.
John Thorn was the composer on the Lake Hindmarsh project
Altitude Art members, Mitch McAuley, Martin King and Dagmar Cyrulla discuss their work.
For Mitch McAuley, the story of Sisyphus resonates at Lake Hindmarsh.
Peter Gebert takes Michael Cathcart on a tour of Lake Hindmarsh.
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ABC Rural online is a digital space to tap the national debate about food, fibre and minerals production.
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Bush Telegraph is following the life of Wilbur 101—a free range pig—from birth to slaughter. Read about the animal welfare issues faced by Wilbur 101's owners, and give your point of view in our online polls. Wilbur 101 is not a pet, and his owners plan to slaughter and sell him at Christmas.


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If you have recently received your intake approval from the Ambulance Service of NSW, you will have also been notified that you will be required to upgrade your drivers licence to an unrestricted Light Rigid (LR) licence.
ABC Driving School has been conducting these upgrades for candidates of the Ambulance Service of NSW, for several years and will be happy to assist you with a one-on-one course, at the Parramatta, Penrith, Campbelltown, and Central Coast Heavy Vehicle Training Centres.
The course is conducted in one day, over seven and a half hours normally commencing at 08.00am and concluding at 3.30pm, with a compulsory 30-minute lunch break. The vehicle used for the course is a Toyota Commuter minibus.
The cost of this course is $750 (Arndell Park), $820 (Central Coast) and $850 (Parramatta, Penrith or Campbelltown), there are no other additional or hidden charges, we currently have over a 90% pass rate within the scheduled seven and a half hour timeframe, however if you do require any additional lessons, these hours will be charged at $100.00 per hour. Current manual car driving experience is essential to increase your chances of a successful outcome.
Alternatively you can also upgrade your licence to a class MR, this will also satisfy the entry conditions to the Ambulance Service, however you will be required to undergo tuition in a Class MR truck and there may be some additional charges involved. If you do decide to upgrade to a Class MR, tuition can be conducted at our Heavy Vehicle Training Centres at Parramatta, Penrith, Campbelltown, Kogarah Central Coast or Wollongong.
Visit the Ambulance employment page


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After a best actor award at this year's Cannes Film Festival, there's no stopping Bruce Dern. As Woody in Alexander Payne's masterpiece "Nebraska," fe...
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I can still vividly recall the night in 1967 when I attended the opening night screening of the film version of Wait Until Dark in New York. Like all red-blooded American guys, I was enchanted with actress Audrey Hepburn (unfortunately, not reciprocated).
I love St. Patrick's Day. It's so inclusive. By that I mean that though it's a bona fide religious holiday, you don't need to be particularly pious to enjoy it. Wishing everyone a safe and (reasonably) responsible holiday, I present my own candidates for the top drinking movies of all time.
The late, great Jack Lemmon's birthday is February 8th which led me back to one of his finest performances -- Days of Wine and Roses. Watch it for the first time or watch it again. Rest in Peace, Jack Lemmon.
As the mother of a demonized child in "The Omen," Lee Remick was used to playing the damsel in distress role. In this 1969 photo, however, she looks c...
For most people, the holiday season is over and done with. Christmas decorations have been put back into storage and the tree has been disposed of. But for arts entrepreneurs the situation is quite different.
We all know that rare thing called good character is no prerequisite for a great actress, but Patricia Neal had this quality, in spades. We will not see her like again.
In song-writing, where success is ideally a matter of fifty percent lyrics and fifty percent music, Stephen Sondheim almost always achieves the delicate balance.
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My father used to make Russian tea (Tang + instant tea + cinnamon stick) when I was a child. This is a better, more adult version. I think the tea bags need to soak longer than 5 minutes to give it a strong tea flavor. Otherwise, we've followed this recipe twice with great success, and I'm making it again tomorrow for another holiday party.
Spiked Spiced Russian Tea
EmRem24 Posted: 12/12/08
pajnron Posted: 01/03/09
Excellent beverage. I served it at my annual Christmas party with rave reviews, even though I cheated and used store bought (no pulp) orange juice.
skspillman Posted: 02/02/09
I made this for a Super Bowl party and everyone loved it! I brewed the tea for about 15 minutes instead of 5. I used store-bought orange juice, and, since I was out of cinnamon sticks, I just sprinkled in some Saigon cinnamon. I will definitely make this again!
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Certificate of Manumission by Richard Jones
|I Richard Jones of Gorham in Ontario County & State of New York do hereby certify that I manumit and discharge from my service my negro woman named Jane and this writing is to be a perpetual bar from my heirs or representatives holding said Jane as a slave. Canandaigua 8th August 1811
Richard Jones
In the presence of Henry Fellows Daniel D. Barnard}State of New York ss: On the eighth day of August one thousand eight hundred and eleven Daniel D. Bernard to me personally known appeared before me and being by me duly sworn deposed that he saw Richard Jones to him personally known execute the above certificate wherefore let it be recorded. John C. Spencer master in chancery
A true copy of the original Recorded 8th August 1811 at 2 o'clock p.m.and examined.


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Mini Ghost Cupcakes(12)
Photo: Mark Thomas
Decorate mini chocolate cupcakes for Halloween treats by topping them with whipped topping ghosts and chocolate chips,
- Yield: 3 dozen cupcakes
- How To:
- Read Reviews
- Write a Review
- Save Recipe
- 1 (12 oz.) container Cool Whip
- 3 doz. mini chocolate cupcakes
- 72 mini chocolate chips
- 36 regular chocolate chips
- Fit a pastry bag with a plain round tip (or use a plastic bag with a corner snipped off). Fill bag with Cool Whip. Pipe cream into peaks on each cupcake.
- Position two mini chocolate chips as eyes and one regular chocolate chip as a mouth on each ghost, flat ends facing out. (Cupcakes may be refrigerated for up to 3 hours. Bring to room temperature before decorating.)
October 2006
Nutritional Information
- Calories: 86
- Fat: 4g
- Saturated fat: 3g
- Protein: 1g
- Carbohydrate: 12g
- Fiber: 1g
- Cholesterol: 6mg
- Sodium: 52mg


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Flex EZ Button
This is not your average button Stacks addon.
Create smart buttons of any width and use RapidWeaver's Add Link feature to easily set your links.
Use them to create fancy buttons, attractive e-commerce buttons, and even colorful charts...
Completely coordinated with the Flex EZ Menu stack for greater flexibility and variety.


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Thursday December 25, 2008 5:25 pm
Christmas Tree Cluster
Posted by Sheila Franklin Categories: Science
While you are enjoying your Christmas, Kwanzaa, or Chanukah, look up and think about how some of our greatest gifts are free. The Christmas Tree Cluster is composed of bright blue stars in front of a red gas background. It was first discovered in the 18th century, but was captured again from the European Southern Observatory in Chile. The cluster is in the constellation of Monoceros, the unicorn, about 2,600 light years from Earth.
Read More | Wired
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- christmas tree cluster, constellation, gases, monoceros, space, stars, unicorn
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Wow, That is such a Amazing backround. Im saving that into picture because i might set it as my WallPaper ^.^
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Craig E. Runde is director of the Center for Conflict Dynamics. He oversees product development and training programs, and alliances. Craig is the coauthor of Building Conflict Competent Teams (Jossey-Bass, 2008), Developing Your Conflict Competence (Jossey-Bass, 2010), and Becoming a Conflict Competent Leader - Second Edition (Jossey-Bass,2012). He is a frequent speaker and commentator on workplace conflict issues and a member of the editorial board of the Journal of Conflict Management. Before joining Eckerd College, he was the director of the International Center for Computer Enhanced Learning at Wake Forest University. Craig received his B.A. from Harvard University, M.L.L. from the University of Denver, and J.D. from Duke University. He has practiced law in Colorado and has taught at the University of Minnesota Law School and Wake Forest University.
Patricia Viscomi is the associate director of the Center for Conflict Dynamics. She oversees all marketing, sales, testing and logistics associated with the Conflict Dynamics Profile and program support for the Center. She provides training, support and marketing assistance to Center consultants and clients. Patty received her BA with high honors from Eckerd College and her MBA and MA in Human Resource Management from Webster University. She was in the 2007 edition of Who's Who Among Students in American Universities and Colleges. Patty also served as Chair of Staff Council at Eckerd College for the 2007-08 academic year.


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George Clooney threw the ultimate baller's dinner for President Obama -- but for some reason Billy Crystal wasn't exactly thrilled on the way out. Must be the $40k tab.
Check out TMZ on TV -- click here to see your local listings!
Maybe he was so ticked off because he payed 40,000 dollars and just like at the oscars....still got stuck with wolfgang pucks cooking.
I'd be mad too. Heck I'm still mad after spending 5 bucks on some of his soup, that stuff was terrible.
Ha ha.....Maybe the wife got on his neck?!.....TIME TO KEEP YOUR NOSES OUT OF POLITICS.
Lest we forget, Obama doesn't like jews.
Billy Who? lol He sucked at the Oscars and the Oscars sucked for not having Eddie Murphy lol
Billy Crystal is a bitter old man, he needs to get laid or something.. I had always heard he was an *******, and judging by that little clip I believe it.
I can't believe he supports this prick. He is currently making promises he won't keep ONLY BECAUSE ELECTIONS ARE RIGHT AROUND THE CORNER. Not to mention he has not accomplished **** since getting into office......
I'm boycotting Clooney and every other actor/idiot that supports him....
Billy was pissed when he found out who the real Obama was after listening to his real agenda. He couldn't believe he had been duped.
I waited thru an ad just to hear Billy say: "Go away". Another non-story by TMZ to get you to watch an ad. When will we learn?
F U Clooney you moronic jerk*ff! Only a wack job like U would hold a fundraiser for a man who is giving away free "you can now be a legal citizen of the U.S." tickets to all illegal aliens. Shows your mental state dumbf*ck! Many of these illegals are criminals from other countries. Yeah, we need THAT in the U.S.!!! Obama wants all the illegals to get social security and healthcare and medicare and all that on THE AMERICAN PEOPLE. Not to mention not following the Constitution and just doing things as he sees fit. Anybody have ANY idea how much money illegal aliens are costing you and you state right now??? Look into it - it's no bullsh*t. Not to mention that Obama and his administration are behind the ACLU who wants to take God off the constitution, off the money, and out of our lives. WHO GIVES THIS F-ING MUSLIM THE RIGHT TO DO THAT IN OUR COUNTRY. We do if he is allowed to continue to get away with this. YOU ARE GONE OSAMA, I MEAN OBAMA. Be glad someone has not put a bullet in your head during your term in office. Clooney, just go live in Italy, keep your unintelligent mouth shut and disappear!
How about instead of a separation of church and state, we have a separation of Hollywood and state?
A special thank you for wasting MY tax dollars on getting Obama there and the cost of all that security. Not to mention the cost of hookers.
Thanks George. You and your gang ate well, while some Americans went to bed hungry.!!!!!!!
Sleep well.
Obama said NOTHING about gay marriage that Dick Cheney's hasn't already said but YEARS earlier. Obama won't get my vote.
I am just waiting for my Clooney or any stars check.. This president is about spread the wealth. So these people have it.. Shouldn't they practice what they preach. We need to let these stars know that if they want to be a idiot.. We wont support them. Bad numbers at box office will wake them up.Why don't the stars have dinners to support families who lost their jobs or homes? I mean it is the average guy who see's the movie and supports them.. It was reported that it cost the tax payers 15 million to get Obama there.. Think what we could have done with that money..
If President Obama was a serious president then bringing an alleged prostitute to his fundraising event would be considered offensive. Hollywood's legendary in the "closet" actor Rock Hudson lived a lie until AIDS caught up with him…isn't that when he came out of the closet? Frankly, I am sick of seeing George Clooney and his alleged contract prostitute girlfriends almost every time I go to an online gossip site. He looks tired and she looks like a twin to Hulk Hogan. I used to subscribe to and buy many magazines, but not since Clooney's latest alleged contract girlfriend began popping up in the middle of the magazines.
Thanks to George Clooney and the $40,000 plate dinner at his home in the middle of a recession for a jerk of a president, I am done with him…I don't ever want to see another George Clooney movie, even the ones he produces.
Clooney and BO make a great pair. Now hopefully they both will start fading from the scene.
Strange how V.P. Joe Biden stated last weekend he was now for same sex marriage and 2 days later Obama said the same thing, and 2 days later Harry Reid said the same thing. How stupid do these 3 democrats think the public is? Same sex marriage is legalized by the individual States not the Feds. These 3 boys play the political game willing to say anything to get votes.


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If you were the only girl in the world, and I were the only boy.
(via fuckyesdowntonabbey)
Graduate Student at Loyola University Chicago. Check out the blog for what I'm currently obsessed with in film and culture. Michael Fassbender, Leonardo DiCaprio, Bradley Cooper, Jennifer Lawrence, Kate Winslet, Christian Bale, Jesse Eisenberg, David Lynch, David Fincher, Christopher Nolan, Martin Scorsese, and Daniel Radcliffe are regulars here.
If you were the only girl in the world, and I were the only boy.
(via fuckyesdowntonabbey)
To my surprise the indomitable Lady Mary Crawley (Michelle Dockery) has become my favorite character on "Downton Abbey." Last season her scheming and self preservation ruined her honor, crushed poor Matthew (Dan Stevens), and kept her (maybe deserving) sister Edith (Laura Carmichael) from a good marriage. Now we see Mary dutifully helping Matthew recover from his wounds, keeping quiet about Sybil and Branson, and singing with Edith, in public. On every score Lady Mary Crawley has changed and in this transformation lies the greatness of the entire show.
In the first season everyone upstairs and downstairs had a set opinion of Lady Mary: arrogant, uptight, conniving, and cold. Even her parents came to accept their intractable eldest daughter and resigned themselves to her ignoring their advice. Her only advocate was Mr. Carson (Jim Carter). Carson could always be counted upon to defend Mary's honor downstairs and pay her a reasoned compliment upstairs. Like Mrs. Hughes, I wondered what normally astute Carson saw in pompous Lady Mary.
It wasn't until the Garden Party - a social occasion of much emotional turmoil- that I realized whatever Carson saw in Lady Mary must be the entire reason for this show. Those two, the heiress and the butler, standing in the final shot of the series encapsulates 'Downton." The people who know the rich best are the people that watch and serve them everyday. Only in their company do the masks fall away and the true self can breathe, cry, and laugh. Carson and Anna know Mary better than anyone because they are the only people with which she can be honest. This season has grown on that theme, deepening the relationships between Cora and O'Brien, Matthew and William, and Sybil and Branson. The development of Lady Mary is the best part because her change reverberates through the entire series.
In each episode Lady Mary surprises her relatives with her patience, caring, and selflessness. The best example of this was episode 4 when Lord Grantham simply stared at Mary as she insisted Lavinia stay at Downton while waiting for Matthew to recover. In that moment Lord Grantham (Hugh Bonneville), who thought he knew everything about his eldest daughter, saw as if for the first time. In his eyes I could see surprise, but also a fulfillment of some long held wish that Mary would grow to be a generous and loving person. Even beyond Matthew, Mary's goodness is consistent. She defends her romantic rival to the Dowager Countess, holds back confessing her feelings to Matthew to keep from hurting Lavinia, and volunteers to help Anna find Bates. Lord and Lady Grantham, Anna, Edith, Isobel, and even Lady Violet now see glimpses of the Mary that Mr. Carson always knew and trusted.
Now if only Matthew Crawley would wise up, we'd have something to celebrate.


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Booshlr, fieldmouse, barrattone.
I also like quite a lot of stuff, like doctor who, welcome to night vale, misfits, skins, teen wolf and much more.
When Noel came back for encores he had to change in his hitcher costume very quickly and he didn't zip his boots. It was so cute :) And he kept trying to stick his eyepatch to his face about a dozen times and it kept coming off.


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Walking on sunshine by rosy outlook photography on Flickr.
"Flowers always make people better, happier, and more helpful. They are sunshine, food and medicine to the soul."
--Luther Burbank
Check out my other blog (it's more than just flowers) here.
Please note that most of these photos do not belong to me and the copyrights are held by the respective owners. You may click on any image to find the original photo. If you are the owner of a photo that I have posted and would like it removed, please send me a message.
Walking on sunshine by rosy outlook photography on Flickr.
Want more posts like this? Follow for a great dash! Nature/All of the wonderful things in life/Love blog(:
Los amo


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Narrow your search
Ancient amphitheater is leaning, authorities say, with north side more than 15 inches lower than south.
Strap on your sandals and grab your sword for the centurion combat epic, Ryse: Son of Rome.
Google Earth takes you to ancient Rome; YouTube starts to monetize its videos; and Cisco lets you check the length of the bathroom line at the new Yankee Stadium before you leave your seat!
The barbarians are at the gates, and increasingly winning.
For whatever you want from abroad, Bringsome hopes to connect you with a courier.
A team has just unveiled a sprawling 3D digital simulation of the ancient city as it appeared at the height of its development as the capital of the Roman Empire.
Microsoft is giving a free copy of Dead Rising 3, Ryse: Son of Rome, Forza Motorsport 5, or Zoo Tycoon to gamers with a broken Xbox One.
Making its debut next week, the Italo has a top speed of 186 mph and will connect Milan, Rome, and Naples in high style.
Fans of "300," "Gladiator," and "Spartacus" will enjoy this Kinect-enabled Xbox exclusive from Crytek set during the height of Imperial Rome.


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This past week, the Borger High School Head Volleyball and Girls Basketball positions became open.
On Wednesday Jason Carter informed the volleyball players that he is leaving Borger to take a principal position within the Roby Consolidated School District, which is near Sweetwater.
In December, Carter was promoted to the head volleyball coaching position after spending several years coaching and teaching in the Borger school district, including serving as an assistant volleyball coach under Cara Adams and Michael Littlejohn.
From hitting clutch jump shots to scoring touchdowns, West Texas High School senior Alex Ramirez did a little bit of everything during the 2011-12 school year.
The people in Stinnett and 1A schools in the Texas Panhandle have known how good of an athlete Ramirez has been for the past three years, especially on the basketball court.
Ramirez has been named the District 1-1A Offensive MVP three years in a row, which includes the senior averaging 18.4 PPG, 8.7 RPG, 4.4 APG, and 2.1 SPG this past season.
West Texas High senior Abby Summers was selected as the 2011-12 Borger News Herald's Female Athlete of the Year due to academic and athletic success in volleyball, basketball, softball, tennis and cheerleading during her senior year.
Competing in sports has always been a big part of Summer's life, with the senior commenting, "Due to having a dad who is a coach, I have always been busy playing sports or having him working with me to get better."
Sanford-Fritch High School Girl's Basketball Coach Jason Hale was named the 2011-12 Borger News Herald Coach of the Year for leading the Lady Eagles to a 20-win season and a second place finish in District 1-2A.
Hale is finishing his seventh year as a coach, which includes stops at Spade and Springlake-Earth before coming to Sanford-Fritch three years ago. Hale spent one year leading the Sanford-Fritch varsity boys before taking over the Lady Eagles head coaching position prior to the 2010-11 season.
The First Nazarene Church of Borger is planning to offer a free mega sports camp this summer, titled "Beyond the Gold," to help kids 5-12 years old to learn more about sports.
First Nazarene Church Pastor Terry Porter said, "We want to give kids a chance to learn more about sports, discover character building concepts and have a whole lot of fun, all for free."
Former Borger Bulldog player and Claude Head Baseball Coach Matt Green will be the camp's Baseball Head Coach and Borger Bulldog Cheerleader Southern Shira will be the camp's Cheerleading Coach.
On Wednesday afternoon, a soccer commitment reception was held for Borger High School Soccer players Francisco "Paco" Ibarra, George Sifuentes, and Kaleen Dean.
While Ibarra has yet to announce where he will play after high school Sifuentes will join the Crusaders soccer team at the University of Dallas, while Dean will head to South Texas to play for the Schreiner University Mountaineers in Kerrville.
Both Sifuentes and Dean said their decisions were based on finding a good fit and a great opportunity to play soccer while receiving an education.
Four West Texas High Comanches baseball players earned District 6-1A All-District honors for their play on the baseball diamond during the 2012 season. The Comanches were 10-13 overall, 6-4 in district play. Booker and Claude each had five players earn All-District honors.
6-1A All-District Baseball Team
MVP-Manny Ramirez Sr. Booker
First Team
Brett Cox Jr. Booker
Hunter Lile Fr. Booker
Jared Reagan Fr. Booker
Jourdan Payan Sr. Boys Ranch
Jabe Thompson Soph. Boys Ranch
Seth Sharke Jr. Claude
Tate Wilkerson Soph. Claude
Dakota Woods Soph. Follett
Daniel Saucedo Sr. Shamrock
Five West Texas High Lady Comanches softball players were named to the District 6-1A All-District softball teams.
The Lady Comanches posted a 16-11 record and making the 1A Bi-District playoff round.
2012 6-1A All-District Softball Team
MVP Kelsi Lile Booker Senior
1st Team
Ana Guerrero Booker Junior
Trevela Dronzek Clarendon Senior
Jentry Shadle Clarendon Junior
Maci White Clarendon Junior
Jocelin Laubhan Claude Sophomore
Kelsee Roberts Claude Freshman
Tori Bybee McLean Senior
Devin DeLapp West Texas Junior
Sarah Kelly West Texas Senior
2nd Team
The Borger Bulldogs had six players earn District 1-3A First Team All-District honors for their play on the baseball diamond, during the 2012 season.
Borger had more players on the First Team than anyone else in the district, with the district champion Perryton Rangers having four make the first team.
District 1-3A All-District Team
First team
MVP-Tony Loustaunau Sr. Perryton
Pitcher-Chayse Tracy Sr. Borger
Pitcher-James Thompson Jr. Pampa
Pitcher-Blake Turner Sr. Perryton
Catcher-Dakota Dillard Jr. Borger
1st Base-Collin Kilgo Sr. Pampa
2nd Base-Clay Ellis Sr. Borger
Please join the Borger High School faculty and students for a Soccer Commitment Reception on May 16, 2012 at 3:00 p.m. in the Borger High School Foyer (in front of the Auditorium) for Kaleen Dean, George Sifuentes and Francisco "Paco" Ibarra.
Kaleen Dean will attend Schreiner University in Kerrville, TX and play soccer for the Mountaineers.
George Sifuentes will attend the University of Dallas in Irving, TX where he will play soccer. Francisco "Paco" Ibarra plans to attend college and play soccer but at this time his college of choice is undecided.


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Do you think children might be responding to fructose in food like lab animals used to test diabetes medications in the 1990s?
Sugar Basics...There are three sugar molecules commonly found in our food. Glucose, galactose and fructose. Grains like rice quickly digest into mostly GLUCOSE. Glucose is required as a fuel for brain and other functions. If you do not eat glucose your body converts protein you eat into needed glucose and fat. If you don't eat enough protein the body converts your muscle into needed glucose. Starvation is complete when the is no muscle left to convert to needed glucose. GALACTOSE is the milk sugar and is found naturally in breast milk. Lactose is a combination of one galactose and one glucose molecule. FRUCTOSE is found naturally in fruit and some vegetables such as sugar beets. You don't have to eat any fructose, your cells make the little they need for replication from glucose.
The fructose your body doesn't need is found mainly in sucrose (table sugar) 50% by dry weight, High Fructose Corn Syrup (HFCS) usually 55% or more by dry weight and fruit 10-50% fructose by dry weight of part you eat. Before any food you eat gets into your blood, it digested (processed) into molecules such as galactose or glucose. Only molecules make it in, not containers like "fruit" or vitamin pills.
When I first looked into fructose over 23 years ago, drug companies were testing type2 diabetes (T2D) drugs on healthy rats they had turned into type2 diabetics. This was done by replacing half a young rat's chow with same fructose sold in health food stores as good for diabetics. Thus fed, healthy rats became lethargic, obese, hypertensive, insulin resistant (metabolic syndrome) and developed many other chronic diseases. The same happens with hamsters, guinea pigs, dogs, cats, etc.. You decide if it happens to some of our children.
If you think kids today are responding like young rats, you might want to know the mechanisms that make dietary fructose a problem and what individuals like you can do. Drug and food marketers and the organizations they fund knew even before 1990. If they didn't tell you, I can help you catch up.
By 1990 the incidence of many chronic disease including T2D had already increase over 10 fold since 1900. If the public for good reason stopped eating fructose it meant a 10 fold decrease in profits from treatments over time. It meant a 10-fold increase in $profits and donations overtime if the public was not warned and kept eating fructose. If this seems ridiculous see www.motherjones.com/environment/2012/10/sugar-industry-internal-documents-revealed (and related articles)
ASBESTOSIS is a name given a chronic inflammatory disease of the lungs described in 1924 and caused by asbestos molecules found in nature. Governmental controls to protect humans from asbestos were started in 1932 just eight years after the initial finding that asbestos is highly adverse to humans when inhaled.
OBESITY... From what I have observed and researched, obesity is not the problem. It is just the most obvious effect of eating fructose or having hyperglycemia. Hyperglycemia is adverse because it pushes sorbitol pathway producing fructose in cells. Metabolic syndrome is mainly caused by dietary fructose and intracellular fructose created by hyperglycemia. High triglycerides in most cases are due to dietary fructose or hyperglycemia. Fructose is probably addicting to 10% of population and this is why the number of extremely obese will approach about 10% and like alcoholics be difficult to treat. . Unhealthy obesity is one of hundreds of conditions expressed when fructose is eaten or hyperglycemia is present. Most extremely obese individuals and most NASH folks are addicted to fructose, just as most folks with alcohol cirrhosis are addicted to alcohol. So in effect you are treating "Sugarholics"as explained by Jack Lalanne in the 1950s. The magic pill is getting them off alcohol (fructose)… it isn't easy when everyone else is guzzling it. See http://www.youtube.com/watch?v=LJVEPB_l8FU …Jack LaLanne.
So how much fructose is safe? The answer is just enough to make the new nuclear material needed when healthy cells replicate no more, no less. To repeat, this is normally provided by sorbitol pathway in just the amount needed in the moment. Many cancer cells lack this ability and depend on dietary fructose or hyperglycemia to replicate. (A reason to avoid fructose and keep blood glucose normal if you have cancer)
In third world populations the incidence of diabetes is very low. A 20.6 gram/day increase in dietary fructose over time raises diabetes prevalence 11-fold. This fits well with 20 grams of alcohol being significant and that there probably is no safe lower limit for alcohol, fructose or cigarette smoke. See…
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057873 This includes many good references.
Quote from Lustig…"Bottom line -- only changes in sugar availability explained changes in diabetes prevalence worldwide; nothing else mattered.
Total caloric availability was unrelated to diabetes prevalence; for every extra 150 calories per day, diabetes prevalence rose by only 0.1 percent. But if those 150 calories per day (20.6 grams of fructose jw note) happened to be a can of soda (usually sucrose outside US, not HFCS note jw), diabetes prevalence rose 11-fold, by 1.1 percent (and Americans on average consume the added sugar equivalent of 2.5 cans of soda per day, so that's 2.75 percent!). And this effect of sugar was exclusive of obesity; controlling for body mass index did not negate the effect. Even more important, we showed that the change in sugar availability preceded the change in diabetes (that's cause, not effect); and we showed directionality -- those countries where sugar availability rose showed increases in diabetes, while those where sugar availability fell showed decreases in diabetes. This is a very robust signal, with little noise. While epidemiology can't prove scientific causation, the data allow for objective inference. Sugar drives diabetes world-wide and unrelated to its calories." End quote… Too bad the story is probably the same with many chronic diseases. I know it is true with CAD, NASH, PCOS, metabolic syndrome and many others.
Until proven otherwise mothers may want to avoid what is becoming recognized as a toxin. Fructose like alcohol is proving to be adverse before conception, in the womb and as child grows. Pregnant mother, baby, child or students eating lots of what gram for gram may be worse than alcohol is a healthy diet tradition in USA. Unlike alcohol, students are not intoxicated after 12 ounces of apple juice so it seems alcohol must be worse than the sweet fruit sugar God provided. It doesn't seem possible that fruit sugar can be addicting and cause liver failure, cancer and death like alcohol! It is inconvenient I know, but fructose is addicting for many. Both alcohol and fructose are mainly detoxified in the liver. Fructose is the leading cause of liver disease in USA, not alcohol, not infection. NASH (caused by unhealthy amount of fructose in cells) is second only to hepatitis C as a reason for liver transplantation. Liver disease is only one of many diseases that fructose started before one is born can increases 10 to 20 fold or more. 1½ shot (drinks) is 20 grams of alcohol molecules. One medium sized apple contains 10 grams of fructose molecules. A 12 oz soda contains 20 grams. 12 oz apple juice has 24 grams of fructose.
What is significance of only 20 grams of alcohol per day? The American Journal of Public Health concludes… (Daily consumption of up to 20 grams of alcohol (≤ 1.5 drinks) accounted for 26% to 35% of alcohol-attributable cancer deaths. Alcohol remains a major contributor to cancer mortality and Years per Life Lost. Higher consumption increases risk but there is no safe threshold for alcohol and cancer risk.) http://www.ncbi.nlm.nih.gov/pubmed/23409916 I suspect that if there is no safe amount of alcohol, there is also no safe threshold for fructose in cells either. It is the alcohol metabolite acetaldehyde that is a carcinogen and triggers liver disease. It is the fructose metabolite glyceraldehyde that is a carcinogen and triggers liver disease. Both aldehydes are toxic to functional proteins in cells where they are formed. Both cause toxic advanced glycation end products (TAGE).
Would you help reduce chronic disease by 90% if you could? We live in amazing times when it may be possible for young women who understand what I am saying to personally do something amazing in addition to having a baby. Why not include reducing the probability their children will express a major mental illness, type one and two diabetes or other genetic disease predispositions including NASH and maybe cancer by 90% compared to USA norm.
https://www.youtube.com/watch?v=jj69eDFu-_A&feature=related Latest Lustig Video Part 1
https://www.youtube.com/watch?v=nac7Ydoj0Rg&feature=relmfu Part 2 Lustig
https://www.youtube.com/watch?v=kzdxeO6LKlc&feature=relmfu Part 3 Lustig
https://www.youtube.com/watch?v=Rj8uQUkhEAg&feature=relmfu Questions Lustig
What can be done?
Cesar Chavez
Social injustice from working conditions to pesticides led Cesar Chavez to action. Non-violet confrontations, boycotts and Gandhi-like fasts. He studied the plague of pesticides and found it was a far greater problem than he had thought. The solution came from actions of concerned individuals created by Cesar's personal suffering as he fasted 36 days.
We don't have to starve for 37 days. We can now do wonders by not eating fructose and be able to explain why to others!
Help folks to be aware of FRUCTOSIS and realize why they need to limit their cell fructose to only what is needed for cell replication by keeping their blood glucose normal (by diet and exercising effectively and if necessary medication).
Make it easy to avoid fructose by encouraging marketers to provide fructose free options of favorite foods (this includes food labels with amount of fructose and warnings as for alcohol).
If necessary boycott prepared and processed foods containing fructose until marketers feel it is profitable to provide fructose free options.
Encourage informed folks to create and volunteer to staff effective ways to help folks addicted to fructose to get off fructose.
What has been done?
Ancient cultures including native Californians were smart enough to realize acorns from oak trees would make a wonderful food similar to corn meal or flour, but only if they learned to process out the toxin (gallotannin). Modern Americans are smart enough to realize fruit will make a wonderful food when the toxin (fructose) is removed. Ancients solved their problem. Can we solve ours? Wiki… acorn
Some folks feel eating meat for various reasons is not a good thing, so they stop eating meat.
Some folks eat only foods labeled "organic", others a void "processed" foods.
John E Weaver MD email@example.com
If you have time the following article and references many include the best explanations of the mechanisms involved in fructose triggering disease predispositions. The references are many.
http://www.hindawi.com/journals/jop/2010/170393.html TAGE and RAGE
Involvement of TAGE-RAGE System in the Pathogenesis of Diabetic Retinopathy
Masayoshi Takeuchi,1 Jun-ichi Takino,1 and Sho-ichi Yamagishi2
1Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan
2Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan
Received 25 November 2009; Accepted 29 March 2010
Academic Editor: Susanne Mohr
Copyright © 2010 Masayoshi Takeuchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetic complications are a leading cause of acquired blindness, end-stage renal failure, and accelerated atherosclerosis, which are associated with the disabilities and high mortality rates seen in diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, recent evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications. In this paper, we discuss the pathophysiological role of the TAGE-RAGE system in the development and progression of diabetic retinopathy.
1. Introduction
Diabetic complications are a leading cause of end-stage renal failure, acquired blindness, and cardiovascular disease (CVD) and are involved in the disabilities and high mortality rates observed in patients with type 1 or type 2 diabetes [1]. Although various hyperglycemia-induced metabolic and hemodynamic conditions are proposed to contribute to complications in diabetes [2, 3], recent clinical studies have suggested the concept of "hyperglycemic memory" in the pathogenesis of vascular injury in diabetes [4–6]. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Study demonstrated that the reduction in the risk of progressive retinopathy and nephropathy brought about by intensive therapy in patients with type 1 diabetes persisted for at least eight years, despite increasing hyperglycemia [4, 5]. The intensive therapy administered during the DCCT resulted in decreased progression of intima media thickness (IMT) and had reduced the risk of nonfatal myocardial infarction, stroke, or death from CVD by 57% by 11 years after the end of the trial [6].
Furthermore, a recent follow-up study, the United Kingdom Prospective Diabetes Study (UKPDS), has also shown that the benefits of intensive therapy in patients with type 2 diabetes were sustained after the cessation of the trial [7]. In this study, despite the early loss of glycemic differences between intensive and conventional therapy, the reductions in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were maintained during 10 years of posttrial follow-up [7]. These observations indicate that intensive therapy to control blood glucose has long-term beneficial effects on the risk of diabetic retinopathy, nephropathy, CVD, and death in patients with type 1 or type 2 diabetes, strongly suggesting that so-called "metabolic memory" causes chronic damage in diabetic vessels that is not easily reversed, even by subsequent, relatively good control of blood glucose. Among the various pathways activated under diabetes, as described above, the biochemical nature of advanced glycation end-products (AGEs) and their mode of action are the most compatible with the theory of "hyperglycemic memory" [8, 9].
There is a growing body of evidence to suggest that continuous hyperglycemia under diabetic conditions enhances the formation of AGEs, senescent macroprotein derivatives, through nonenzymatic glycation (called the "Maillard reaction"). There is also accumulating evidence that the binding of the receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes inflammatory and/or thrombogenic responses in various types of cells, thus participating in the development and progression of diabetic angiopathies [10–18]. Recently, we demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients [10, 19, 20]. Furthermore, there is a growing body of evidence to suggest that the interaction of TAGE with the RAGE alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes seen in diabetic complications. Therefore, the inhibition of TAGE formation, blockade of TAGE-RAGE interactions, and the suppression of RAGE expression or its downstream pathways are promising targets for therapeutic intervention against diabetic complications.
In this paper, we discuss the pathophysiological role of the TAGE-RAGE-oxidative stress system in the development and progression of diabetic retinopathy and related therapeutic interventions.
2. Alternative Routes for the Formation of AGEs In Vivo
AGEs are formed by the Maillard process, a non-enzymatic reaction between aldehyde or ketone group of the reducing sugars (such as glucose, fructose, and trioses etc.) and the amino groups of proteins that contribute to the aging of proteins and to the pathological complications of diabetes [10–13, 19–24]. In the hyperglycemia elicited by diabetes, this process begins with the conversion of reversible Schiff base adducts to more stable, covalently bound Amadori rearrangement products. Over the course of days to weeks, these Amadori products undergo further rearrangement reactions to form irreversibly bound moieties known as AGEs. AGEs were originally characterized by their yellow-brown fluorescent color and their ability to form cross-links with and between amino groups, but the term is now used for a broad range of advanced products of the glycation process, including N-(carboxymethyl)lysine (CML) and pyrraline, which show neither color nor fluorescence and are not cross-linked proteins [8, 21–25]. The formation of AGEs in vivo is dependent on the turnover of the chemically modified target, the time available, and the sugar concentration. The structures of the various cross-linked AGEs that are generated in vivo have not yet been completely determined. Due to their heterogeneity and the complexity of the chemical reactions involved, only some AGEs have been structurally characterized in vivo. The structural identities of AGEs with cytotoxic properties therefore remain unknown.
Recent studies have suggested that AGEs can arise not only from reducing sugars, but also from carbonyl compounds derived from the autoxidation of sugars and other metabolic pathways [26–28]. Indeed, we have recently demonstrated that glucose,
-hydroxyaldehydes (glyceraldehyde and glycolaldehyde), and dicarbonyl compounds (methylglyoxal; MGO, glyoxal; GO, and 3-deoxyglucosone, 3-DG) are actively involved in the protein glycation process [21, 29–31]. Six immunochemically distinct classes of AGEs (glucose-derived AGEs; Glc-AGEs, glyceraldehyde-derived AGEs; Glycer-AGEs, glycolaldehyde-derived AGEs; Glycol-AGEs, MGO-derived AGEs; MGO-AGEs, GO-derived AGEs; GO-AGEs, and 3-DG-derived AGEs; 3-DG-AGEs) are found in the sera of type 2 diabetic patients during hemodialysis [21, 29–31]. Based on these data, we proposed a pathway for the in vivo formation of distinct AGEs involving the Maillard reaction, sugar autoxidation, and sugar metabolic pathways, as shown in Figure 1.
Figure 1: Alternative routes for the formation of various distinct AGEs in vivo. Glc-AGEs; glucose-derived AGEs, Glycer-AGEs; glyceraldehyde-derived AGEs, Glycol-AGEs; glycolaldehyde-derived AGEs, MGO-AGEs; methylglyoxal (MGO)-derived AGEs, GO-AGEs; glyoxal (GO)-derived AGEs, and 3-DG-AGEs, 3-deoxyglucosone (3-DG)-derived AGEs, CML; N-(carboxymethyl)lysine, and P-NH2; free amino residue of protein.
3. Receptors for AGEs
Such receptors may play a critical role in AGEs-related biology and the pathology associated with diabetic complications and aging disorders. Several types of AGEs binding proteins and/or receptors for AGEs such as RAGE [32–36]; oligosaccharyl transferase-48 (AGE-R1) [37]; galectin-3 (AGE-R3) [38]; CD36 [39]; macrophage scavenger receptors types 1 and 2 (MSRs-1 & -2) [40]; and fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptors 1 and 2 (FEELs-1 & -2) [41] have been reported. The relative pathogenic contributions of these receptors to diabetic complications are poorly defined, although RAGE is by far the best characterized, and mechanistic in vitro and in vivo studies on AGEs and their regulatory fragments such as soluble RAGE (sRAGE) have indicated that they play important roles in pathobiology [36, 42]. RAGE is normally expressed in a variety of cells, including endothelial cells (EC), pericytes, neurons, and microglia, [32–34]. We have recently found that glyceraldehyde rapidly reacts with the amino groups of proteins to form Glycer-AGEs both in vitro and in vivo [19, 21, 30]. Furthermore, Glycer-AGEs have the strongest binding affinity for RAGE and subsequently elicit oxidative stress generation and vascular inflammation and are therefore implicated in accelerated atherosclerosis in diabetes [43, 44]. Recently, we also demonstrated that Glycer-AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients [19, 20]. Moreover, there is a growing body of evidence to suggest that the interaction of TAGE with RAGE elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications [10, 19, 20].
4. Pathway of Glycer-AGEs (TAGE) Formation In Vivo
Glyceraldehyde is derived from two distinct pathways in vivo, (1) the glycolytic pathway and (2) the fructose metabolism pathway [19, 20, 45]. (1) The glycolytic intermediate glyceraldehyde-3-phosphate (G-3-P) is normally catabolized by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). With a decline in GAPDH activity, G-3-P accumulates intracellularly. G-3-P metabolism then shifts to another route, and the amount of glyceraldehyde is increased, which leads to an increase in the formation of TAGE. This suggests a positive feedback mechanism; that is, the TAGE-induced GAPDH suppression further stimulates the generation of TAGE. (2) Under hyperglycemic conditions, the increased intracellular glucose concentration stimulates the polyol pathway to generate fructose in insulin-independent tissues such as the lens, kidney, nerve tissue, brain, and red blood cells [46–48]. Furthermore, fructose, a component of table sugar and high-fructose corn syrup, is also obtained from the diet [49]. Fructose is phosphorylated to fructose-1-phosphate (F-1-P) and then catabolized to glyceraldehyde and dihydroxyacetone-phosphate by aldolase B [48–51]. The newly synthesized glyceraldehyde is then transported or leaks passively across the plasma membrane. Glyceraldehyde promotes the formaion of TAGE both intracellularly and extracellularly (Figure 2).
Figure 2: Production routes of glyceraldehyde-derived AGEs (Glycer-AGEs) in vivo. TAGE; toxic AGEs (glyceraldehyde-derived AGEs), RAGE; receptor for AGEs, ROS; reactive oxygen species, HFCS; high-fructose corn syrup, AR; aldose reductase, SDH; sorbitol dehydrogenase, FK; fructokinase, GAPDH; glyceraldehyde-3-phosphate dehydrogenase, *; TAGE.
5. Diabetic Retinopathy
Diabetic retinopathy is one of the most important microvascular complications in diabetes and is a leading cause of acquired blindness among people of occupational age [52]. Hyperglycemia damages retinal microvascular cells and causes various changes in retinal tissues such as enhanced vascular permeability due to pericyte loss, which is followed by microvascular occlusion in the retina [53, 54]. Pericytes are elongated cells of mesodermal origin, which wrap around and along the EC of small vessels [55]. As pericytes contain contractile muscle filaments on their EC side, they are regarded as microvascular counterparts of smooth muscle cells and are considered to be involved in the maintenance of capillary tone [56, 57]. AGEs have been postulated to play a role in the development and progression of microvascular disease in diabetes. Vascular endothelial growth factor (VEGF) is a specific mitogen to EC, which is also known as vascular permeability factor and is generally thought to be involved in the pathogenesis of proliferative diabetic retinopathy. Indeed, clinical observations have demonstrated that the VEGF level in ocular fluid is positively correlated with the amount of neovascularization in diabetic retinopathy [58, 59].
Retinal pericytes accumulate AGEs during diabetes [60], which is expected to have a detrimental influence on pericyte survival and function [61]. We have found that TAGE causes the apoptosis of retinal pericytes and induces the expression of VEGF by interacting with RAGE, indicating the involvement of TAGE in the pathogenesis of diabetic retinopathy, especially in the early stage [62–64]. TAGE also induces VEGF expression, DNA synthesis, and angiogenesis in EC. These changes are the hallmark of proliferative diabetic retinopathy [65, 66]. These findings suggest that the TAGE-RAGE interaction facilitates angiogenesis by two distinct mechanisms, by relieving the restriction on EC growth due to the apoptotic cell death of pericytes and by autocrine and paracrine induction of VEGF proteins by vascular wall cells. Although the molecular mechanisms of the VEGF overexpression elicited by TAGE are not fully understood, our recent investigation suggested that the TAGE-RAGE interaction increases VEGF gene transcription in EC by NADPH oxidase-mediated reactive oxygen species (ROS) generation and the subsequent activation of nuclear factor
B) via the Ras-mitogen activated protein kinase pathway [65, 66]. There has been increasing interest in the role of inflammatory reaction in diabetic retinopathy [67]. AGEs have recently been shown to increase leukocyte adhesion to cultured retinal microvascular EC by inducing intracellular cell adhesion molecule-1 (ICAM-1) expression [68]. Furthermore, TAGE also induces monocyte chemoattractant protein-1 (MCP-1) expression in EC through intracellular ROS generation [69].
6. Postprandial Hyperglycemia is Associated with Increased Risk of Diabetic Retinopathy
While it is well known that postchallenge and postprandial hyperglycemia are related to the development and progression of diabetic macrovascular disease [70, 71], there are limited data on the relationship between postprandial hyperglycemia and microvascular complications. A recent observational prospective study from Japan demonstrated that postprandial hyperglycemia is a better predictor of diabetic retinopathy that glycated hemoglobin A1c (HbA1c) [72]. Shiraiwa et al. performed a cross-sectional study of 232 people with type 2 diabetes who were not being treated with insulin injections. Multiple regression analysis revealed that postprandial hyperglycemia was independently correlated with the incidence of diabetic retinopathy and neuropathy. Additionally, postprandial hyperglycemia was also found to be associated, although not independently, with the incidence of diabetic nephropathy.
We have previously shown that glyceraldehyde reacts rapidly with the amino groups of proteins to form TAGE in vivo, which evokes vascular inflammation and oxidative stress generation, thereby implicating them in accelerated atherosclerosis in diabetes [10, 19, 20]. More recently, we investigated the effects of nateglinide, which has been known to improve postprandial hyperglycemia, on HbA1c, Glc-AGE, and TAGE levels in Goto-Kakizaki (GK) rats, one of the rat models of type 2 diabetes, fed twice a day [73]. After 6 weeks, nateglinide treatment was found to not only prevent postprandial hyperglycemia, but also to reduce TAGE levels in GK rats. However, it did not cause a significant difference in HbA1c or Glc-AGE levels [73]. This study suggests that TAGE is formed more rapidly than HbA1c, a precursor of Glc-AGEs, under postprandial hyperglycemic states and shows potential as novel markers of cumulative postprandial hyperglycemia. In this study, although we did not clarify the exact molecular mechanism by which TAGE is formed under postprandial hyperglycemic conditions, hyperglycemia-induced oxidative stress-mediated inhibition of GAPDH may lead to the elevation of glyceraldehyde levels and subsequently enhance the formation of TAGE during the postprandial period [74]. The relative contribution of postprandial glucose decreased progressively from the lowest to the highest quintile of HbA1c; whereas, the relative contribution of fasting glucose increased gradually with increasing levels of HbA1c [75]. These observations suggest that a decrease in HbA1c levels does not necessarily reflect a reduction in postprandial hyperglycemia, especially in poorly controlled diabetic patients.
7. Serum Levels of TAGE in Diabetes
The above-discussed effect of TAGE strongly suggests a pathological role for these senescent macroproteins in diabetic complications. Furthermore, Glc-AGEs and TAGE are present in human serum, and the level of both AGEs is elevated in type 1 and type 2 diabetes [76–79]. These AGEs, especially TAGE-epitopes, elicit angiogenesis at the concentrations present in the sera of diabetic patients. These results suggest the involvement of TAGE-epitopes in pathologic angiogenesis in vivo. Recently, we demonstrated that the vitreous levels of both TAGE and VEGF were significantly higher in diabetic patients than in control subjects and that these levels were elevated in association with the severity of neovascularization in diabetic retinopathy. In addition, there was a significant correlation between vitreous TAGE and VEGF levels [80, 81]. Furthermore, we have recently found that serum TAGE levels are positively correlated with thrombogenic markers in humans. Plasminogen activator inhibitor-1 and fibrinogen levels are positively associated with serum TAGE levels [82].
While many of the reported studies measured a range of ill-defined AGEs moieties, others evaluated defined adducts such as CML, pentosidine, and crossline in association with diabetic retinopathy [83, 84]. In addition, other studies have reported no correlation between AGE levels and retinopathy in diabetic patients [83, 85], although the apparent disparity between the findings of various studies may be related to variations in patient populations and/or the nonuniform assays used for plasma AGEs-quantification. Our studies suggest that an elevated TAGE level in diabetic patients is an important factor for the initiation and progression of retinopathy. Therefore, the inhibition of TAGE formation and the blockade of TAGE-RAGE interactions are potential therapeutic strategies for the prevention of diabetic retinopathy.
8. Serum Levels of Soluble RAGE in Diabetes
The administration of a recombinant soluble form of RAGE (sRAGE) consisting of its extracellular ligand-binding domain has recently been shown to not only suppress the development of atherosclerosis but also to stabilize established atherosclerosis in diabetic apolipoprotein E-null mice [86, 87]. The blockade of the AGEs-RAGE axis by the administration of sRAGE also ameliorates neuronal dysfunction and reduces the development of acellular capillaries and pericyte ghosts in hyperglycemic and hyperlipidemic mice [88]. Furthermore, Kaji et al. have also shown that attenuation of the RAGE axis with sRAGE inhibits retinal leukostasis and blood-retinal barrier breakdown in diabetic C57/BJ6 and RAGE-transgenic mice, which are accompanied by decreased expression of VEGF and ICAM-1 in the retina [89]. These observations suggest that exogenously administered sRAGE captures and eliminates circulating AGEs, thus protecting against AGEs-elicited tissue damage by acting as a decoy.
Recently, endogenous sRAGE has been identified in humans [42]. Endogenous sRAGE may be generated from the cleavage of cell surface full-length RAGE or novel splice variants of RAGE (the C-truncated splice isoform of secretory RAGE; esRAGE) [42]. Endogenous total sRAGE levels are elevated in patients with type 1 or 2 diabetes [90–93]. Furthermore, we, along with others, have recently demonstrated that serum total sRAGE levels are positively, rather than inversely, associated with TAGE levels in both nondiabetic and diabetic subjects [93, 94]. Age-, sex-, and body mass index-adjusted TAGE levels are also significantly increased in proportion to the increasing levels of sRAGE in nondiabetic subjects [93, 94]. These findings suggest that the sRAGE pool is not able to efficiently capture and eliminate circulating TAGE in vivo by working as a decoy receptor. Since TAGE is a positive regulator of the cell expression of RAGE, circulating sRAGE levels may reflect tissue RAGE expression and be elevated in parallel with serum TAGE levels as a counter system against TAGE-elicited tissue damage [95–98].
The serum levels of esRAGE are also correlated with the levels of circulating AGEs such as CML and pentosidine in type 1 diabetes [99]. However, in contrast to the case for total sRAGE, circulating esRAGE levels are decreased, rather than increased, in both type 1 and 2 diabetes. Katakami et al. reported in Japanese that the serum levels of esRAGE were significantly decreased in patients with type 1 diabetes compared with nondiabetic subjects [100], and esRAGE levels were found to be significantly lower in type 1 diabetic patients with retinopathy than in those without retinopathy [100, 101]. Decreased esRAGE levels were also found to be an independent risk factor for carotid atherosclerosis [102]. Indeed, Koyama et al. reported that esRAGE levels were decreased in Japanese type 2 diabetic patients compared with nondiabetic subjects and that low levels of esRAGE were associated with the components of metabolic syndrome and carotid atherosclerosis [102]. These observations were contrary to the finding of previous reports that total sRAGE levels were associated with conventional coronary risk factors including inflammatory markers and were independent determinants of coronary artery disease in diabetes [91, 95, 96]. Therefore, the kinetics and role of sRAGE and esRAGE in diabetes may differ [97]. Decreased levels of esRAGE may be associated with comorbidities such as diabetic retinopathy and atherosclerosis via mechanisms other than its role as a decoy because esRAGE levels are approximately 3
4-fold lower than total sRAGE levels and may not be sufficient to efficiently eliminate circulating AGEs in humans. Furthermore, sRAGE, but not esRAGE, was recently found to be independently correlated with albuminuria in type 2 diabetic patients [103].
9. Agents That Could Potentially Suppress TAGE-RAGE Interaction
9.1. Inhibitors of the Renin-Angiotensin System (RAS)
The interaction of the RAS and TAGE-RAGE systems has also been proposed. We have found that angiotensin II potentiates the deleterious effects of TAGE in pericytes by inducing RAGE protein expression [64]. In vivo, TAGE-injection stimulated RAGE expression in the eyes of spontaneously hypertensive rats, which was blocked by telmisartan. In vitro, angiotensin II-type 1 receptor-mediated ROS generation elicited RAGE gene expression in retinal pericytes through NF-
B activation. Furthermore, angiotensin II augmented TAGE-induced pericyte apoptosis, the earliest hallmark of diabetic retinopathy. Telmisartan also blocks angiotensin II-induced RAGE expression in EC [104].
There is an increasing interest in the role of inflammatory reactions and immune phenomena in the pathogenesis of diabetic complications [105–107]. Indeed, leukocyte adhesion to diabetic retinal vasculature is considered to be a critical early event in diabetic retinopathy, the development of which is mainly mediated by VEGF, ICAM-1, and MCP-1 expression [105–107]. ICAM-1 and MCP-1 are essential chemokines that mediate the recruitment of leukocytes to mesangial lesions [108, 109]. The selective targeting of ICAM-1 or MCP-1 was also shown to markedly decrease albuminuria and renal injury in experimental diabetic nephropathy [108, 109]. Furthermore, several experimental studies have supported the pathological role of VEGF in diabetic nephropathy: antibodies raised against VEGF have been reported to improve hyperfiltration and albuminuria in diabetic rats [110, 111]. In addition, atherosclerosis is also an inflammatory-proliferative disease [112], and the administration of VEGF is reported to enhance atherosclerotic plaque progression in animals [113]. We have recently found that treatment with telmisartan or olmesartan inhibits the TAGE-evoked inflammatory responses in EC via downregulation of RAGE expression [114–118]. These observations suggest that the blockade of the TAGE-RAGE signaling pathways by RAS inhibitors may be clinically relevant to the prevention of diabetic complications.
9.2. Pigment-Epithelium-Derived Factor (PEDF)
PEDF is a glycoprotein that belongs to a superfamily of serine protease inhibitors with complex neurotrophic, neuroprotective, antiangiogenic, antioxidative, and anti-inflammatory properties, any of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes [119, 120]. PEDF inhibits TAGE-induced ROS generation and subsequently prevents apoptotic cell death in pericytes by restoring downregulation of the gene expression of the antiapoptotic factor bcl-2 [121]. Furthermore, PEDF also inhibits TAGE-induced ICAM-1, VEGF, and MCP-1 upregulation as well as NO suppression in EC by blocking NADPH oxidase-mediated ROS generation [69, 122–126]. In vivo, the administration of PEDF or pyridoxal phosphate, an AGEs inhibitor, decreased the retinal levels of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats [127]. Moreover, intravenous administration of TAGE to normal rats increased ICAM-1 gene expression and retinal leukostasis, which were blocked by PEDF [127]. PEDF inhibited diabetes- or TAGE-induced RAGE gene expression by blocking superoxide-mediated NF-
B activation [128]. In addition, we have recently found that intravenous administration of TAGE to normal rats not only increases retinal vascular permeability by stimulating VEGF expression, but also decreases retinal PEDF levels [129]. Simultaneous treatment with PEDF inhibited TAGE-elicited VEGF-mediated permeability by downregulating the mRNA levels of
, membrane components of NADPH oxidase, and subsequently decreasing retinal levels of the oxidative stress marker, 8-OHdG. PEDF also inhibited TAGE-induced vascular hyperpermeability (as measured by transendothelial electrical resistance) by suppressing VEGF expression. PEDF decreased ROS generation in TAGE-exposed EC by suppressing NADPH oxidase activity via downregulation of the mRNA levels of
. This led to blockade of TAGE-elicited Ras activation and NF-
B-dependent VEGF gene induction in EC. These results indicate that the central mechanism of PEDF inhibition of the TAGE-signaling related to vascular permeability is the suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression [129].
The PEDF levels in the aqueous humor and vitreous are decreased in diabetic patients, especially in those with proliferative retinopathy, suggesting that loss of PEDF in the eye contributes to the pathogenesis of proliferative diabetic retinopathy [130, 131]. We have also found that the vitreous levels of TAGE and VEGF are significantly higher in diabetic patients than in control subjects [81] and detected a significant correlation between vitreous TAGE and VEGF levels. Total antioxidant status was also decreased in the vitreous in patients with diabetes compared with that in the controls. Furthermore, both the TAGE and VEGF levels (inversely) and those of PEDF (positively) were associated with the total antioxidant status of the vitreous [132, 133]. These observations further support the concept that PEDF is an endogenous anti-inflammatory and antioxidative agent that blocks the TAGE-VEGF axis, thereby protecting against the progression of diabetic retinopathy.
9.3. Statins and Bisphosphonates
We have found that protein prenylation is crucial for TAGE-RAGE signaling in EC [65, 66]. Cerivastain completely prevented TAGE-induced increases in NF-
B activity and VEGF expression and the resultant increase in DNA synthesis as well as tube formation in microvascular EC [65]. Since mevalonate blocked the growth-inhibitory effects of cerivastatin on TAGE-exposed EC and that FTI-276, an inhibitor of farnesyltransferase, mimicked the effects of cerivastatin, cerivastatin may block the TAGE-RAGE signaling involved in vascular hyperpermeability and angiogenesis via the suppression of protein prenylation. Furthermore, we have recently found that atorvastatin dose-dependently inhibited TAGE-induced ROS generation in Hep3B cells [134]. Atorvastatin as well as the antioxidant N-acetylcysteine (NAC) was found to suppress C-reactive protein (CRP) expression in TAGE-exposed Hep3B cells at both the mRNA and protein levels [134]. These results demonstrate that atorvastatin is able to block the TAGE-signaling involved in CRP expression through its antioxidative action. Taken together, these observations suggest that statins have vasculoprotective effects by inhibiting the deleterious effects of TAGE via the suppression of their downstream signaling.
Bisphosphonates are potent inhibitors of bone resorption and are widely used for the treatment of osteoporosis, osteolytic bone metastasis, and tumor-associated hypercalcemia [135–137]. These compounds have a high affinity for calcium ions and therefore target bone mineral, where they are internalized by bone-resorbing osteoclasts and inhibit osteoclast function. Recently, farnesyl pyrophosphate synthase has been shown to be a molecular target of nitrogen-containing bisphosphonates such as incardronate disodium and minodronate, and the inhibition of the posttranslational prenylation of small molecular weight G proteins including Ras and Rac-1 is probably involved in their antiresorptive activity in osteoclasts [135–137]. Since the protein prenylation of GTP-binding proteins is associated with various cellular functions such as cell growth and differentiation [135–137], nitrogen-containing bisphosphonates may have pleitrophic effects by blocking the synthesis of isoprenoid intermediates. Indeed, incardronate disodium was found to inhibit TAGE-induced increases in NF-
B activity and VEGF expression as well as the proliferation and tube formation of EC [66]. Furthermore, we have recently found that minodronate inhibits TAGE–induced NF-
B activation and subsequently suppresses VCAM-1 gene expression by reducing ROS generation in EC [135]. Geranylgeranyl pyrophosphate reversed the antioxidative properties of minodronate in TAGE-exposed EC [135]. Taken together, these findings suggest that nitrogen-containing bisphosphonates are able to inhibit TAGE-elicited inflammatory-proliferative changes in EC by suppressing NADPH oxidase-derived ROS generation, probably via the inhibition of the geranylgeranylation of Rac-1, a component of endothelial NADPH oxidase [136, 137].
10. Conclusion
There is accumulating evidence that the TAGE-RAGE-oxidative stress system is actively involved in the pathogenesis of diabetic complications, especially diabetic retinopathy. We have reviewed the inhibitors of the TAGE-RAGE axis and their potential therapeutic implications in these devastating disorders.
Expert Opinion
Two recent large prospective clinical studies, DCCT and UKPDS, have shown that intensive blood glucose control effectively reduces the incidence of vascular complications among patients with diabetes [138, 139]. However, strict control of hyperglycemia is often very difficult to maintain and may increase the risk of severe hypoglycemia in diabetic patients. Inhibition of TAGE formation, blockade of TAGE-RAGE interactions, and the suppression of RAGE expression or its downstream pathways by the agents discussed here are promising novel therapeutic strategies for the treatment of patients with diabetic retinopathy. Further clinical studies are needed to clarify whether the use of these agents is able to reduce the risk of diabetic retinopathy beyond blood glucose-, blood pressure- or cholesterol-lowering effects.
Copyright © 2010 Hindawi Publishing Corporation. All rights reserved.


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1 Thessalonians / chapter 5 (read the chapter)
You've heard the term "shock jock," haven't you? It refers to a person who intentionally tries to surprise or shock people—usually in disturbing or disgusting ways. They specialize in the unexpected, in catching people off guard.
In this chapter of 1 Thessalonians, Paul is very clear that God is not a shock jock: "You aren't in the dark about these things, dear brothers and sisters, and you won't be surprised when the day of the Lord comes like a thief. For you are all children of the light and of the day; we don't belong to darkness and night. So be on your guard, not asleep like the others. Stay alert and be clearheaded." (vs 4-6)
Paul is writing about the second coming of Christ, a day that he says "will come unexpectedly, like a thief in the night." (vs 2) But, he says, it doesn't have to be that way, because those who choose to have relationship with God now—while they won't know the specific day of His return—do not have to be caught off guard by His return. They will be watching and waiting, anticipating.
I have long been intrigued by the description of how others will experience His coming—those who have chosen not to have a relationship with God: "When people are saying, 'Everything is peaceful and secure,' then disaster will fall on them as suddenly as a pregnant woman's labor pains begin. And there will be no escape." (vs 3)
It's hard to imagine a time in this world when people will be commenting on the widespread peace and security of life, but there are certainly a lot of people around the globe who are always working toward ushering in such an era. And, while there's absolutely nothing wrong with peace and security, it appears that those who will think they have found it will be sorely unprepared for the calamity right around the corner.
Apparently, what masquerades as peace and security may be anything but.
And this is why Paul reminds us that God has prepared His people for what is to come—so we won't be lulled into a false sense of security. I must admit, however, that sometimes it's easy not to be lulled into that. Especially in America, where we enjoy freedom and opportunity, it's very easy to get caught up in the idea that we are in control of our lives. It's very easy to feel like we are captains of our own destiny—and that we can save ourselves and save the world.
God doesn't want us to be lulled into that kind of thinking. While it's true that we make choices about our lives every day and while it's true that those choices have a direct impact on our lives temporarily, we're not just here to live our lives temporarily. Our lives are headed somewhere. This world is headed somewhere. History is headed somewhere. It's on a big collision course with the climactic ending of a war that's been raging in the universe over the character and government of God.
The more we remove ourselves from the context of that universe-wide war and perceive that we are simply "living our lives" here, the more we are in danger of being lulled into that sleep Paul was talking about.
God wants us to be alert and awake, meeting each day with expectant anticipation for what He's doing—even when we don't know exactly what it is! He isn't a shock jock; He doesn't want us to be surprised, startled, or caught off guard. He wants us to not only know what's coming, but Who's coming.
We may not know when. And we may not know how.
But we shouldn't live a single day without the awareness that He's on the way.


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