text:
Closing window in BeOS Mozilla results in closing native children only (BViews),
but not child windows in Mozilla sence.
E.g. - open Find Dialog. Then close its "parent" window via Menu->File->Close or
closing button in titlebar. Main window is gone, but dialog is still alive.
This does not happen on my build. Sergei, can you try again, with a clean tree,
or download a nightly build?
I see this with a current trunk build. The Find dialog just hangs around until
you hit the Cancel button and then the application exits (if you only had one
browser window open).
Currently BeOS port handles parent/children realations only inside single
BWindow - all children are treated as BViews and it only cares about BeOS-native
children in Destroy(). Same in GetParent() function - it casts BView::Parent()
to nsWidget, ignoring some other Mozilla's parent/children relations, like those
between content windows and dialogs.
This approach makes simpler implementation of Move/Resize methods in BeOS ports,
but seems causing some other problems, like annoying scrolling:
Also it is possible that mentioned parent/children relations handling is related
to bug http://bugzilla.mozilla.org/show_bug.cgi?id=157303 - "Mozilla for BeOS
doesn't display images on many sites." - BeOS API has some flackyness not only
for BWindow Z-order handling, but also for BViews belonging to same parent.
seems problem is borrowed from Win32 code check for GuiThread
if (toolkit != nsnull && !toolkit->IsGuiThread()) {
MethodInfo info(this, this, nsWindow::DESTROY);
return NS_ERROR_FAILURE;
in NS_METHOD nsWindow::Destroy()
taking assignment
Unsure if it is really fixed.
Closing main window don't close related dialogs, like Find.
also, my opinion about bug
http://bugzilla.mozilla.org/show_bug.cgi?id=187286 is releated to this.
btw, i observed bug with mail composing a bit related to this bug.
after Reply-To and pushing send button, Mozilla freezes again for some, not so
long time at status indicator, and then zombie "Compose" window appears.
It cannot be closed in any way besides closing whole app.
But i have feeling that i saw similar bug for other platforms.
*** Bug 226888 has been marked as a duplicate of this bug. ***
One of problems for improper quitting behaviour is invisible window specifics.
From Mozilla side such window never receives Show() call, but for BWindow it
means that its looper is never started.
Maybe i will open separate bug to fix just BLooper/BWindow->Run() issue, as
Destroy and Quit problem is bit larger, but fixing looper start problem may help
lot of other issues.
Created attachment 199103 [details] [diff] [review]
draft of better destroy.
Now recurses nsIWidget kids, not BView's children.
also some other things are set in more logical manner
Comment on attachment 199103 [details] [diff] [review]
traversing kids such way wouldn't work. old classical mistake. preparing new
Created attachment 222252 [details] [diff] [review]
nsWindowBeOS::DispatchMessage() now catches B_QUIT_REQUESTED and does what QuitRequested did before - sends CLOSEWINDOW message.
nsWindowBeOS::QuitRequested() now returns true,checking if there are some children remained and sending then CLOSEWINDOW message.
nsWindow::CallMethod() case CLOSEWINDOW now iterates through all mozilla children of this widget and sends B_QUIT_REQUESTED to BWindows of those children. It is intended to close dependent dialogs (like those "Find" in SeaMonkey) and hidden popups (like menu items).
StandardWindowCreate for dialogs and popups now adds those "dependent" widgets (with some sort of parents) presented to hierarchy using nsWidget::AddChild(this).
NB!This is only thing I doubt in this patch. It works, but how Mozilla reacts on children which weren't added by "gecko"?
nsWindow::Destroy() restructured for more safe look.
nsDrawingSurface::UnlockDrawable was fixed for safety - because mBitmap may be gone already, UnlockDrawable could decide that we are unlocking onscreen mView and try to unlock non-existent Looper().
Looks like there are problems with destroying from outside (like Deskbar) if there are some hidden windows remained. Probably removing option if (CountChildren() != 0) in QuitRequested may help a bit.
Or maybe in children iteration loop in CloseWindow we should activate those windows to whose we are sending B_QUIT_REQUESTED.
Need bit more experiments. Also, I'm wondering if we really now call Run() (via Show()) for all BLoopers we created, after throuwing away Invisible windows from our code.
Created attachment 222257 [details] [diff] [review]
Last guess was bingo!
We really need Run() looper explicitly in StandardWindowCreate. Without that message chain tends to broke.
IIRC we had it once in code (maybe in Show()/Hide() form, but tqh removed in together with invisible windows when refactored the method).
With Run() we even don't need dirty trick with adding nsChildren artifically.
So new patch
Hmm, did I remove that? That wasn't my intention.
Also if I remember correctly, run left the looper unlocked. So didn't we call some Show, Hide combo?
Comment on attachment 222257 [details] [diff] [review]
Comment on attachment 222257 [details] [diff] [review]
I do think this is a bit 'nasty' and would hope there was a more elegant solution. Can't see anything wrong with it though. Have you checked for leaks?
Only real thing which was added and may look nasty (besides restored Run()) is native children cleanup iteration loop. But seems quite logical safety measure, preventing some leaks. But you are right, maybe we can reach that all with less code in future
And only real essential change is "return true" instead "return false" in nsWindowBeOS::QuitRequested.
Didn't notice anything like mem-leak, and those threads visible in ProcessController - new code seems handling it very nice.
I think if there are some problems, people will report it with new FireFox build, published by tigerdog today. IIRC DownloadManager there was quite sensitive to leaking.
Checking in mozilla/widget/src/beos/nsWindow.cpp;
/cvsroot/mozilla/widget/src/beos/nsWindow.cpp,v <-- nsWindow.cpp
new revision: 1.124; previous revision: 1.123
Checking in mozilla/widget/src/beos/nsPopupWindow.cpp;
/cvsroot/mozilla/widget/src/beos/nsPopupWindow.cpp,v <-- nsPopupWindow.cpp
new revision: 1.2; previous revision: 1.1
Checking in mozilla/gfx/src/beos/nsDrawingSurfaceBeOS.cpp;
/cvsroot/mozilla/gfx/src/beos/nsDrawingSurfaceBeOS.cpp,v <-- nsDrawingSurfaceBeOS.cpp
new revision: 1.24; previous revision: 1.23
Should we also land this on the 1.8 branch for Firefox 2.0?
I think we do.
As, besides other things, this patch may fix some potential leaks.
Wondering if we really landed that to branch...
Sergei, I am pretty sure we did not. Just looking at the patch, it applies to nsPopupWindow. If I recall, nsWindow and nsPopupWindow were split after the branch was created. So this code could not have been applied.
I double checked. nsWindow code was restructured as part of bug 322051, landed on 2006-04-11, long after the branch was created.
Created attachment 282824 [details] [diff] [review]
patch for branch
Looks like we need to add minimal part of original patch code to branch to put Mozilla perform "close" operations properly - that is, code in CallMethod case
I'm wondering if it affects, when applied, also Thunderbird problem, when Compose window stays opened after sending mail.
Created attachment 282827 [details] [diff] [review]
more complete patch for branch
Ignore previous comment. It worked for single window only.
This one is complete version of trunk patch, adapted to branch.
Only part for gfx is missing - I will investigate if we really need that cleanup in gfx
Comment on attachment 282827 [details] [diff] [review]
more complete patch for branch
gfx changes were already aplied in some other branch patch. So this is final.
Do we need review for this, Doug?
Comment on attachment 282827 [details] [diff] [review]
more complete patch for branch
Patch applies cleanly and works as intended. 184.108.40.206pre Firefox and Thunderbird both close cleanly from Deskbar and on shutdown with the patch applied.
Requesting approval for 220.127.116.11.
(In reply to comment #26)
> I'm wondering if it affects, when applied, also Thunderbird problem, when
> Compose window stays opened after sending mail.
It doesn't affect this problem. Compose window still stays open.
One more for the branch. It appears 188.8.131.52 will be freezing very soon. I'm currently unable to update CVS. If this is approved (I hope it is!) I hope Sergei or maybe Biesi can make the change in CVS.
Comment on attachment 282827 [details] [diff] [review]
more complete patch for branch
approved for 220.127.116.11, a=dveditz for release-drivers
Checking in mozilla/widget/src/beos/nsWindow.cpp;
/cvsroot/mozilla/widget/src/beos/nsWindow.cpp,v <-- nsWindow.cpp
new revision: 184.108.40.206; previous revision: 18.104.22.168


text:
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subset: commoncrawl


text:
We all know that ideas are the currency of the modern economy. So whenever we're in need of new ones, we dutifully round everyone up for some caffeine-fueled sessions with the white board.
Halsbrook, an online clothing retailer that targets the 40-ish, fashionable woman, is no different. Founder Halsey Schroeder says that at first, she tried the standard approach: "Let's all come and have some general blue sky ideas of how to improve the company!"
But she soon realized that these discussions were "super unfocused," she says. "Open-ended doesn't work." So Schroeder and her team tried a different approach to brainstorming that's helped them grow 20% per month over the past year. Here's what they do:
1. Designate a topic
Schroeder and crew choose a topic for each innovation meeting. An early one defined—in detail—who is the Halsbrook woman. Another focused on customer retention. Another looked at the user experience.
2. Require research
Everyone is supposed to come with two to three ideas that they've thought through. "It can't be from the seat of your pants," Schroeder says. What other online retailers have tried what you're proposing? How did it work for them?
3. Put teeth to that requirement
Halsbrook meetings start randomly. "We pick somebody to start and cold call on them," she says. If you never know when you'll be presenting your ideas first, you'll probably have them ready to go.
4. Don't lose ideas to meeting dynamics
There are always people who don't like speaking in groups, and there are always people who like to attack or inflate everything based on the person who said it. Get everyone's ideas first, and put them up on the board, where ownership is less immediately important.
5. Debate with purpose
After the ideas are up on the board? Have at them. "We have a giant profile of the Halsbrook woman that sits above my brother's desk," says Schroeder (he works at the company, too). "Whatever we come up with at our meeting, when our white board is filled, we say this is our customer, and translate how this affects our customer. Here's our customer, here's how she uses technology, is this going to help her or not help her?"
6. Put a few ideas to work fast
There are downsides to being a small startup, but "the good part is being able to make decisions quickly," says Schroeder. If too many ideas get shelved, then people stop trying. "We can actually do what happens in a meeting. And when people feel that kind of agency, it's kind of fun to come up with ideas."


text:
April Fools' Day Game Pranks Wiki Guide
Edit Page Last Edit:
The April Fools' Day Game Pranks wiki collects the many pranks from around the Internet on April Fools' Day. Jump to a year below to read about how game companies are punking each other this year -- and be sure to add any awesome pranks you come across.
Top Wiki Contributors
Edits: 176
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text:
|by Philip F.
|Date Added: Tuesday 21 June, 2016
Feels good in your hand, I use it to count walking laps in my long driveway 10 at a time. not heavy or cumbersome to carry, it has a finger grip bar to secure it in your hand.
|by Katie Lady
|Date Added: Tuesday 03 May, 2016
Perfect for tallying interactions at our outreach table. The yellow clicker got stuck a few times, but after a few run throughs, it was great!
|by Lee Taylor
|Date Added: Sunday 03 April, 2016
the electronic counters have some kind of defect and will not count properly they go back to zero as you are counting. The plastic finger rings break easily.
|by Casey
|Date Added: Saturday 19 March, 2016
fast ship. great pieces. thanks!
|by Curmudgeon
|Date Added: Thursday 03 March, 2016
I use it nearly every day when I walk the track @ YMCA. It is light weight but seems durable. Beats trying to remember which lap of 60 that I'm one. Great value, too!
|by Amber Crawford
|Date Added: Monday 18 January, 2016
Bought this for my boss as a gag gift for our crew. worked for its' purpose and got a lot of use out of this!


text:
Conan O'Brien Fires Back at NBC
Amid reports that Conan O'Brien and NBC could be on the verge of parting ways, Conan and Jay Leno alike cracked jokes about the Peacock network in their monologues Friday night -- with Conan even depicting himself in a satirical shootout against the network!
Jay mentioned the Winter Olympics are kicking off next month in Vancouver, "and if you can't wait 'till next month, stay on this channel between ten o'clock and midnight, and you'll see NBC's coverage of two hosts skating on thin ice."
Meanwhile, Conan introduced himself in his "Tonight Show" monologue as the "future answer to a $200 'Jeopardy' question." "Welcome to tonight's show," he continued. "By the time you see this, I'll be halfway to Rio in a stolen NBC traffic copter."
He added: "In the press this week, NBC has been calling me every name in the book. In fact, they think I'm such an idiot they now want me to run the network."
Conan then joked that his relationship with the network had grown so tense that simply arriving at work in the morning was "uncomfortable" for him. He cut to a satirical sketch that depicted him and sidekick Andy Richter dodging bullets and returning gunfire at unseen shooters outside their office building.
Related stories: Jay Leno Leaves Primetime, Jerry Seinfeld Steps In?Rosie O'Donnell Takes a Stance on Leno-O'Brien Shakeup
We Recommend
- Feb. 12, 2017 The cutest kiddos of the 2017 Grammy Awards


text:
Under Armour
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- By Under Armour; imported.
- Men's Furnishings.


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Building information models -- Information delivery manual -- Part 2: Interaction framework
ISO 29481-2:2012 specifies a methodology and format for describing ?coordination acts' between actors in a building construction project during all life cycle stages.
It therefore specifies
- a methodology that describes an interaction framework,
- an appropriate way to map responsibilities and interactions that provides a process context for information flow,
- a format in which the interaction framework should be specified.
ISO 29481-2:2012 is intended to facilitate interoperability between software applications used in the construction process, to promote digital collaboration between actors in the building construction process, and to provide a basis for accurate, reliable, repeatable, and high-quality information exchange.
Document published on: 2012-12 Edition: 1 (Monolingual) ICS: 91.010.01 Status: Published Stage: 60.60 (2012-12-12) TC/SC: ISO/TC 59/SC 13 Number of Pages: 74
This standard has not been revised
No corrigenda or amendments available


text:
Travel: Departures: Cannes package
Click to follow
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MOVIE fans keen to enjoy a budget trip to the Cannes Film Festival from 12 to 23 May can take advantage of Riviera mobile holidays being offered by Allez France (0903 742345) on a site in nearby Antibes. Two weeks in a mobile home costs pounds 260 from 7 May. The price includes ferry travel for car, two adults and all children under 14. For families wishing to stay longer than a fortnight, a third week is free of charge. Reuse content


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Hotfrog Philippines provides information regarding Gapok Academy in Sultan Kudarat. Gapok Academy is located at National Hi-Way, Gapok, Sultan Kudarat Sultan Kudarat and provides Education services.
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Dartmouth Backpack Melbourne
Product Actions
Additional Information
An all-leather backpack that leaves your hands free and offers plenty of space to carry everything you need. Comfortable shoulder straps adjust to your height; while the three zip compartments keep you organized. Finished with a convenient top handle, footed bottom, interior pockets and a keyclip.
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2" handle drop
29" strap length
Average rating:


text:
Situated in the middle of Chinatown and close to Darling Harbour, you could not dream of a handier location to stay in Sydney. Step outside, and you will find yourself in Sydney's major tourist area - the heart of the theatre and entertainment district, city attractions and restaurants.
Max 4 guestsMore
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Please read these Important Booking Conditions carefully.
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text:
A Florida man, Robert M. O'Ryan, 34, was arrested Tuesday and has been charged today with one felony count of stalking of "Dancing with the Stars" contestant and Olympic gymnast Shawn Johnson.
O'Ryan was also charged with two misdemeanor counts of carrying a loaded firearm in a vehicle, said a spokeswoman for the Los Angeles County district attorney's office.
He's due to be arraigned today, according to a blog post on The Times' L.A. Now.
Police discovered a loaded shotgun and handgun in O'Ryan's vehicle. His bail was previously set at $35,000, but the district attorney's office said it would seek a higher bail today.
According to People, prosecutors will ask that bail be set at $220,000. If convicted, he faces up to four years in state prison.
A temporary restraining order was issued Wednesday against O'Ryan. He must stay at least 100 yards away from Johnson and her parents. He cannot contact Johnson or her family.
The order is in effect through at least April 14.
"This incident has caused us severe emotional distress," Johnson's mother, Teri, said in court documents. "We have been on the move ever since and have not been able to rest at all for fear that this disturbed person will attempt to make good on his statements and attempt to harm my daughter and possibly us as well."
Can't blame them one bit!
Related Shawn Johnson dish:
Shawn Johnson, victim of kidnapping plot?
Photo: Robert O'Ryan. Credit: TMZ.com
To see another photo of the alleged stalker, keep reading …


text:
Friday, 22 November 2013
New look, same great features – FSC launches its Trademark Portal
The FSC Secretariat is pleased to launch the new Trademark Portal. This is an online resource center for FSC Certificate Holders and Trademark Service License Holders. Label generators can also access this for labels, promotional panels and supporting documents regarding trademark use.
Roughly 28,000 users of FSC's old Trademark Portal have already been transferred over to the newly designed platform. This has been a smooth process; as Saija Hotti, FSC's Trademark Director, notes: "Functionality wise, there is nothing new for users; we have only changed the look and feel of the portal." The old portal had not changed since its inception four years ago, so an update was due.
Please see 'How to use FSC Trademarks' for more information, or contact trademark support at trademark at fsc point org.


text:
eCommerce Website and Design - Reseller
- Status Closed
- Budget $750 - $1500 USD
- Total Bids 16
Project Description
Website overview:
An ecommerce website which will function as a sales and group buying site.
The site will be importing last call and clearance sales from various websites with the ability to change the price and the description of the products.
The sales will be grouped into categories which will change according to the seller or a manual display of the products.
The operators on the site will change the description and pricing into a different language (English) so the site will be multi language as-well as the layout which will change to RTL when switching to English.
The backend function of the website purchase will be as following:
My Site:
import products listed on sales site
operator will changethe listed pricing and will add a discription in other language and group them into a sales event (category)
The Customer
will see the product on my site
place the product into his cart
Press chuckout to pay for the product
My Site
recheck that the product is still available on the original sales site
purchase the product from the original sales site
the product will be sent to a predetermined address for proccessing
Eventually I want sellers to start placing there sales by themselves on my site without the need to import sale products from other websites but till that happens I'd want to be self-dependent and import the products from other sites.
I'm not interested in having a cooperation with the sites I'm buying from (or more accurately most of them aren't interested in cooperation) so I'll be doing the purchase and then the resell.
In order to motivate visitors to make purchases, the products in the site will be changed on a daily basis, and that's why I eventually got to the conclusion that I'll need it to be automated somehow.
From the research I made it would be rather easy to create such function if the online store have an api (sorry I'm not a technical guy), such as amazon & Ebay and harder to import from other sites.
The only problem is that I can't guarantee if the products sold from these sites are original or replicas which would be a major so I prefer to get the listed products from other sites.
The list of sites I'm interested to import from are the following:
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
• [url removed, login to view]
to make it easiest for you to understand, I'm interested in creating something close to this site:
[url removed, login to view]
but instead of referring to the original site, I want to do the purchase and processing myself .
If you CAN and interested in building the website contact me to send the full features spec in an excel fileGet free quotes for a project like this
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Eric Winter joined the UFC in July 2015 to spearhead the promotion's online digital network. Now, he's departing the company to spend more time with his family.Filed under: News, UFC read news >>
The UFC's dearth of pay-per-view headlining title fights continues, as middleweight champion Michael Bisping looks to be sidelined until late spring. read news >>
Leading up to their UFC 209 bout being signed, Khabib Nurmagomedov offered Tony Ferguson $200,000 to take the fight. read news >>
Saturday night in Inglewood, California, a legend will make his walk one last time while another will return to make it for the first time in three years at Bellator 170. Tito Ortiz, he of the flamin read news >>
Ovince Saint Preux has a new opponent for next month's UFC Fight Night 104 event.Filed under: News, UFC read news >>
Former Bellator fighter and Colorado native Jeremy Kimball has scored a spot on next week's UFC lineup in Denver.Filed under: News, UFC read news >>
Former UFC light heavyweight champion Tito Ortiz can remember the day his life changed. March 21, 2013 was remarkable for many reasons, but mostly because he didn't sit alone in his bed and cry. That read news >>
Watch Julianna Pena defeat Jessica Rakoczy to win The Ultimate Fighter Season 18. read news >>
Former UFC light heavyweight champion Tito Ortiz fought for the last time on Saturday at Bellator 170, defeating Chael Sonnen by submission in the first round. read news >>
The UFC is off this weekend but returns Saturday. Check out the latest fight card for "UFC on FOX 23: Shevchenko vs. Pena."Filed under: Featured Videos, News, UFC, Videos read news >>


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- Age / Gender:
- n/a, Male
- Location:
- Location not disclosed
- Joined:
- 11/17/12
- All Stats >
User Statshot
- Community Stats
Level 2 Blank Slate
Normal Whistle
Ranked as Civilian
Contact Info / Websites
Recent Game Medals
Quizler 100 Points So you know your Mario games, eh ? Medal Stats.
Thunder Bolt 5 Points Catch a thunder type Pokemon Medal Stats.
Save The Day 100 Points Well aren't you a fucking hero?! Medal Stats.
Total Medals Earned: 5 (From 2 different games.)
Latest Favorite Audio
|Super Mario RPG - Docaty Mountain Railroad
|Video Game Song
|Super Mario RPG - Big Boss
|Video Game Song
|Bean Valley
|Video Game Song
|Booster's Swing Club
|Jazz Song
Latest Favorite Movies
A Link to the Zelda Rated 3.3900 Stars See what surprises await Link as he falls into a deep slumber. Comedy - Parody Sugo - Episode 1, "From t Rated 3.7400 Stars Episode 1 : "From the Ashes" Action Date Night Rated 4.4300 Stars There's a reason Matt never brings a girl home.. Comedy - Original TmsT's "Spy and Sentry" Rated 4.4400 Stars From the creator of "Spy and Pyro", a sentry seduces an enemy Spy. Ooh la la! Comedy - Parody
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Megaman Reborn (Prototype V 2.0.1) Rated 1.4600 Stars Relive The ClassicsWith mmrb! Action - Platformer - Other Dead Detention After Story Rated 3.9900 Stars As DD's story comes to a close, another looms from the not-so-distant shadows.... Adventure - Other CrossCode Rated 4.5000 Stars A retro-inspired 2D Action RPG set in the distant future (DEMO) Adventure - RPG It's A Beautiful World Rated 4.2000 Stars Follow our characters as they explore this strange post-apocalyptic world. Adventure - Other


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- Photos
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- Things Nearby
img src="http://www.ardorny.com/i.aspx?t=a&s=t2&r=1681936" / Ardor Web ID: 1681936 - Stunningly spacious west village studio in this elevator building. Beautifully renovated with hard wood floors and high ceilings. A completely separate kitchen outfitted with white kitchen cabinets and stainless steel appliances. Ceramic tiled bathroom epitomizes the cleanliness and luxury → Read More
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Video: 50 Years of Loton Park Hillclimb
Loton Park Speed Hillclimb
Loton Park Speed Hill Climb course is set in the beautiful surroundings of a deer park owned by Sir Michael Leighton, and is situated 9 miles west of Shrewsbury on the B4393 road in the village of Alberbury. The course is 1475 yards (1349 metres) long with an average gradient of 1 in 25 (4%) and the steepest of 1 in 7 (14%) and is rated as one of the country's most demanding hills by competitors.
The Club runs a number of events though out the season, which normally runs from Easter to the end of September, including rounds of the MSA British Championship & The Midland Hill Climb Championship, which cater for the top drivers who run the ultimate in single seater racing cars, together with a number of "Club" events aimed at the "one make" (Ferrari, Lotus, Porsche, Aston Martin, MG, Ginetta, TVR etc.) championships or groups (Vintage, Classic, etc.), as well as regional championships. All events are also rounds of our own LOTON PARK Championship, which covers everyone from first-time competitors to seasoned regulars.
All are welcome to join us either as a spectator, competitor or marshal/official. More information is available from the Club's Secretary, Martyn Silcox – firstname.lastname@example.com – or 01384 877502.
Visit Tripadvisor for details of accommodation near Loton Park »
Click here for a Google Map of Loton Park »
For information on visting the area Visit Shropshire


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Peachy Ice Cream Desserts
|Vanilla low fat ice cream
|2 1⁄2 Cup (40 tbs), softened
|Frozen sliced peaches
|1 1⁄2 Cup (24 tbs), thawed and coarsely chopped
|Lemon juice
|2 Teaspoon
|Peach preserves
|1⁄2 Cup (8 tbs)
|1⁄4 Cup (4 tbs), divided (Almond-Flavored Liqueur)
|Fat free soft oatmeal raisin cookies
|11 Ounce (Such As Archway, 1 Package)
1. Combine first 3 ingredients in a large bowl, and stiir well. Spread ice cream mixture into an 8-inch square baking pan. Cover and freeze 2 hours or until firm.
2. Combine peach preserves and 2 tablespoons amaretto in a small saucepan; cook over low heat until preserves melt, stirring constantly. Remove from heat; set aside, and keep warm.
3. Place 1 cookie in each of 10 (2 1/2-inch) muffin cups. Firmly press cookies against bottoms and up sides of cups. Brush remaining 2 tablespoons amaretto evenly over cookies; let stand 15 minutes. Remove cookie cups from pan, and place on individual dessert plates. Scoop ice cream mixture into cookie cups. Drizzle evenly with peach preserves mixture.
Recipe Summary
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 1364 Calories from Fat 30
% Daily Value*
Total Fat 3 g5.1%
Saturated Fat 0 g
Trans Fat 0 g
Cholesterol 0 mg
Sodium 449.8 mg18.7%
Total Carbohydrates 311 g103.8%
Dietary Fiber 3.8 g15.1%
Sugars 236.4 g
Protein 27 g53.2%
Vitamin A 12.1% Vitamin C 368.3%
Calcium 0.07% Iron 3%
*Based on a 2000 Calorie diet


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How come when I save a liveset the liveobjects settings are saved, however, when I restore from a crash, the liveobjects go back to their initial settings? ie not saved.
It seems there is something different happening when a set is restored vs being saved. Id be very grateful if someone could enlighten me as to what these differences are?
Another bug it seems… Pattr doesnt always restore as expected when restoring the live set
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February 17, 2017
February 17, 2017
Yes. It has been this way for long time. Oh, and mods' friends too. How many more times will that walmart tailgate deal be shown? It's the same stores pretty much every day and it is getting a bit boring - No offense to any of you or the other moneymakers.
For now, keep doing what you are doing and post your deals to the various social networks like twitter for added exposure. Things may change.
jmucha1202 (rep: 4.2k) posted Sep 09, 2013
I have an idea.... what is needed are more "shoppers" using this site. Perhaps an incentive program to encourage new people to shop through the site rather than all the new people want to be on the moneymaker program. A new user referral link BUT it must include a welcome letter and verification of email address for the new user.
jmucha1202 (rep: 4.2k) posted Sep 09, 2013
They changed it back,who knows for how long,to number of saves,but we all know we've been down this road before,friends plussing (saving) each others deals and getting most plusses....been there,done that,
The MOST fair thing would be to front page by CLICKS,that is what sells....I can have 30 clicks and no saves...makes no sense to put front page by saves,it doesn't really reflect what shoppers are interested in and buying.
Stop shoving the "popular" people's deals down consumers throats...they're not interested in 90% of what a small percentage of the people on here deem front page worthy and the consumers probably just go to another site.
Somewhere along the way what was a great idea went terribly wrong.
Just my opinion but greed is usually the main culprit.
xptrish (rep: 101k) posted Sep 09, 2013
I barely even check out dealsplus.com anymore. I tend to agree that greed is playing into the site now. Anything and everything is posted just so they can earn money. I used to come here looking for DEALS but they are becoming less and less. There have been a lot of things posted that have bad reviews and are NOT deals at all, but it doesn't matter because the MM earned his/her payment. And, since when does something with two thumbs up deserve to be found on the HOT tab? I've always questioned whether the mods are showing favoritism...time to move on...
minamesk (rep: 3.4k) posted May 30, 2014
16 days ago
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Nov 23, 2016


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Sustainability expo Saturday in Pahoa
Malama O Puna will host the seventh annual Sustainability Expo from 11 a.m.-3 p.m. Saturday at the Leilani Estates Community Association pavilion at 13-3441 Moku St., Pahoa.
"It has been seven years now that Malama O Puna has been putting on sustainability expos, and the fact that there are always new and different displays speaks to the creativity and diligence of the exhibitors," said a spokesman for the coordinating committee.
"This year's Expo will host an array of resources, products and inspirations for those of us who want to increase the sustainability of our homesteads."
Here are some of the participants:
l Stone Cold will exhibit a new improved solar refrigerator;
l Pacific Biodiesel will feature farming projects throughout the state that will support future biodiesel production as well as its logistics program, "Restaurants & Renewables";
l Paradise Nectar will offer bee-related products and information about hive management, with a live hive on exhibit;
l Just Tom's friendly fluffy chickens not only ride bikes but also star in slide shows and chicken mini-movies;
l Russell Ruderman will have a brochure on sustainability, "Ten Ways to be more sustainable, and why," a clean-elections petition and info on the politics of sustainability.
The event is free to the public. The facility has ample paved parking, restrooms and a playground for the kids. For more info, email firstname.lastname@example.com.
— Lehua Lena Nursery will be selling plants for food, home gardens and ecological landscaping;
— Dean Cail will not only sell palms, but he will donate a very large one to the winner of a $1 raffle donation to benefit Malama O Puna;
— Malama O Puna will have more than one exhibit: one will inform about the red mangrove removal project at Alula Bay and sign up volunteers (a great excuse to go to the beach on the Kona side), and the other will provide information about GMOs and sell edible and medicinal plants;
— Pahoa Feed & Fertilizer will also be selling plants for the sustainable garden, and
— Master Gardeners will answer garden questions, have free literature, and show how to make fruit fly traps.
There will be other exhibits, as well, covering various elements of sustainability such as agriculture (plants and animals), cultural and traditional practices, education, home energy systems, energy conservation, green jobs and right livelihood, herbal and traditional medicine, recycling and solid waste, green building practices, transportation, water (agricultural, potable, conservation, catchment) and other topics of interest.
There will also be several presentations during the course of the day.
"Exhibitors are still signing up. All the ideas and products on display will be affordable and most will be DIY (do it yourself) from inexpensive materials," said the Expo spokesman. "Great ideas and interesting discussions will keep attendees fully engaged."
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Lot 205: Darrell Fusaro, Good Night from Grown Ups, Pastel Drawing
October Fine Art Auction
by RoGallery
October 20, 2016
Long Island City , NY, USALive Auction
Darrell Fusaro (1962-) Please Register/Login to access your Invaluable Alerts
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Artist: Darrell Fusaro, American (1962 - )
Title: Good Night from Grown Ups
Year: circa 1990
Medium: Pastel on BFK Rives Paper, signed l.l.
Size: 29.5 x 22 in. (74.93 x 55.88 cm)
Frame Size: 38.5 x 30 inches
Artist or Maker: Darrell Fusaro
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CLEP History of the United States II
Research & Education Assoc., Aug 11, 2003 - Study Aids - 232 pages
Earn College Credit with REA's Test Prep for
CLEP History of the United States II
Everything you need to pass the exam and get the college credits you deserve.
CLEP is the most popular credit-by-examination program in the country, accepted by more than 2,900 colleges and universities. For over 15 years, REA has helped students pass CLEP exams and earn college credit while reducing their tuition costs. Our CLEP test preps are perfect for adults returning to college (or attending for the first time), military service members, high-school graduates looking to earn college credit, or home-schooled students with knowledge that can translate into college credit.
The CLEP History of the United States II test prep assesses the skills tested on the official CLEP exam. Our comprehensive American History review covers the end of the Civil War to the present, with emphasis on the 20th century.
The book includes two full-length practice tests. Each exam comes with detailed feedback on every question. We don't just say which answers are right-we explain why the other answer choices are wrong-so you can identify your strengths and weaknesses while building your skills.
REA is the acknowledged leader in CLEP preparation, with the most extensive library of CLEP titles available. Our test preps for CLEP exams help you earn college credit, save on tuition, and get a college degree.
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Administration African Americans Allies Amendment Ameri answer choices assassination attack became began benefits blacks bomb Britain civil rights CLEP CLEP History Communist Congress convicted Cuba Cuban defeated Democrats Depression economic Eisenhower election Europe European exam farmers farms federal first forces Fourteen Points George H. W. Bush Germany immigrants impeached increased Indians industry inflation influence Japan Japanese Johnson Kennedy labor land Latin America leaders major ment military million missiles movement National Native Americans Nixon office official Pacific party Pearl Harbor political practice tests President presidential programs racial railroads ratified Reagan Reconstruction reform Republican score segregation Senate significant social South Southern Soviet Union specific Supreme Court tariffs Theodore Roosevelt tion trade treaty troops Truman Truman Doctrine U.S. Supreme Court United Vietnam Vietnam War vote W. E. B. Du Bois Watergate whites Wilson women workers World


text:
Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy
DOI: 10.1186/ar3431
© Chen et al.; licensee BioMed Central Ltd. 2011
Received: 28 March 2011
Accepted: 30 July 2011
Published: 30 July 2011
The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-α inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA).
The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-α therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria.
Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-α therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-α therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response.
The beneficial effect of anti-TNF-α therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-α therapy.
Rheumatoid arthritis (RA) is characterized by the infiltration of macrophages and T cells into the joints, synovial hyperplasia, cartilage degradation and bone erosions [1]. Tumor necrosis factor (TNF)-α is a crucial inflammatory mediator in rheumatoid synovitis and subsequent tissue damage in RA [2, 3]. Although TNF-α inhibitors can be an effective and well-tolerated therapy for RA patients [4–6], a significant proportion of patients do not acquire advantageous effects [7]. In addition, the effect of TNF-α inhibitors on the immune response has not been fully explored.
T helper-type 17 (Th17) cells, a novel and distinct subset of Th cell, can secrete interleukin (IL)-17 in humans [8–10]. Interleukin-17 is a pleiotropic cytokine that participates in tissue inflammation and destruction by inducing the expression of pro-inflammatory cytokines and matrix metalloproteases [8, 11, 12]. The frequencies of Th17 cells were found to increase in peripheral blood mononuclear cells (PBMCs) of RA patients compared to healthy controls [13, 14]. An enhanced expression of IL-17 has been observed in the rheumatoid synovium [15] and synovial fluids of patients with early RA [16]. Interleukin-17 in vitro stimulates the production of TNF-α and IL-1β, and also synergizes with TNF-α to induce cartilage loss and promote osteoclastogenesis [17, 18]. A recent study showed that Th17 cells, but not Th1 cells, cooperate with synovial fibroblasts in a pro-inflammatory feedback loop that drives chronic destruction in RA [19]. Moreover, IL-17 has become a new therapeutic target for animal models with collagen-induced arthritis (CIA) and human RA [20–22]. These observations suggest that Th17 cells and IL-17 critically contribute to synovitis and bone destruction associated with RA.
Recently, TNF-α was shown in vitro to drive the production of IL-17 with the ability to differentiate T cells towards a Th17 phenotype [23]. In a psoriasis-like skin inflammation model, TNF-α enhanced the expression of Th17-related cytokine genes during priming but suppressed these cytokine transcripts when present during re-stimulation [24]. In CIA, TNF-α inhibitors reduced the number of Th17 cells in pathologic joints despite an increase of Th17 cells in inguinal lymph nodes [25]. Taken together, these findings show that TNF-α blockade has paradoxical effects on the expression of Th17-related cytokines in animal models of autoimmune diseases.
In humans, an engineered p75 TNFRII dimer, etanercept, suppressed the gene expression levels of Th17-related cytokines including IL-6 and IL-23 in cutaneous lesions of psoriasis [26]. Kageyama et al. also reported a significant decrease in serum levels of IL-23 at three and six months after etanercept therapy in RA patients [27]. TNF-α inhibitor, adalmumab, reduced the frequency of circulating Th17 cells and serum IL-6 levels in RA patients [28]. However, a recent study showed that an increased frequency of circulating Th17 cells after TNF-α blockade is accompanied by a decrease in Th17-specific chemokine receptor expression in RA [29]. When taken together, these results reveal conflicting effects of TNF-α inhibitors on Th17 cells and IL-17 in humans.
In the present study, we attempted to determine whether or not the clinical response to anti-TNF-α therapy of RA patients led to changes in the levels of circulating Th17 cells and Th17-related cytokines, and we also investigated their clinical implication.
Materials and methods
A total of 48 consecutive patients (39 females and 9 males; mean age ± SD 50.1 ± 13.5 years), who fulfilled the 1987 revised criteria of the American College of Rheumatology for RA [30], were evaluated before and six months after anti-TNF-α therapy. All patients remained in active disease in spite of treatment with methotrexate (MTX) and other disease-modifying anti-rheumatic drugs (DMARDs), for whom anti-TNF-α therapy was initiated based on the British Society for Rheumatology guidelines [31]. Fourteen patients received etanercept at a dose of 25 mg twice weekly and 34 patients received adalimumab at a dose of 40 mg every other week in combination with a stable dose of MTX of 7.5 to 15 mg weekly. Corticosteroids (≦10 mg/day) and non-steroid anti-inflammatory drugs (NSAIDs) were allowed but were given at stable doses for at least four weeks before and during the six-month anti-TNF-α therapy. Disease activity was assessed by the 28-joint disease activity score (DAS28) [32]. The therapeutic response was evaluated six months after anti-TNF-α therapy was started, according to the European League Against Rheumatism (EULAR) response criteria [33]. The patients were categorized into good, moderate or non-responders based on the amount of change in the DAS28 and the level of DAS28 reached. Good responders are defined as patients who have a decrease in DAS28 from baseline (ΔDAS28) of >1.2 and a DAS28 at the sixth month of < 3.2; moderate responders have either ΔDAS28 of >1.2 and a DAS28 at the sixth month of ≧3.2 or ΔDAS28 of 0.6 to 1.2 and a DAS28 at the sixth month of < 5.1; and non-responders are those who have either ΔDAS28 of < 0.6 or a DAS28 at the sixth month of ≧5.1 [33]. To obtain a better analysis, we combined good responders and moderate responders into EULAR responders. Twelve age- and sex-matched healthy volunteers (10 females and 2 males, 47.6 ± 8.1 years), who had no rheumatic disease, were used as normal controls. Blood samples were collected at baseline (before starting anti-TNF-α therapy) and six months after anti-TNF-α therapy. The Ethics Committee of Taichung Veterans General Hospital approved this study and the written consent of each participant was obtained.
Quantitation of circulating Th17cells using flow cytometry analysis
In order to detect circulating Th17 cells, phycoerythrin (PE)-conjugated anti-IL-17 (eBioscience, San Diego, CA, USA) and Phycoerythrin-Cyanin 5 (PC5)-conjugated anti-CD4 (Beckman Coulter, Marseilles, France) were quantified using flow cytometry according to the manufacturer's protocol and a technique previously described [34, 35]. Briefly, aliquots of 1,000 μl of the sterile heparinized whole blood were stimulated with a combination of 25 ng/ml of phorbol myristate acetate and 1 μg/ml of ionomycin (Sigma, Deisenhofen, Germany) and cultured for one hour at 37°C in a humidified 5% CO2 incubator. Whole blood was treated with 10 μg/ml of Brefeldin A (Sigma, Germany) to inhibit intracellular protein transport. Activated cultures of blood samples were washed in wash buffer (phosphate buffered saline, 5% foetal bovine serum, 0.1% sodium azide; Merck, Darmstadt, Germany) and then stained with 20 μl of PC5-conjugated CD4-specific monoclonal antibody (mAb) (Beckman Coulter, Marseilles, France) for 15 minutes at room temperature (RT). Erythrocytes were lysed by adding 2 ml of fluorescence-activated cell sorter (FACS) lysing solution (Becton Dickinson, Lincoln Park, NJ, USA). After five minutes of incubation, the samples were centrifuged and washed with 0.1% BSA-PBS, and subsequently fixed with 100 μl Reagent 1 (Beckman Coulter, Marseilles, France) for 10 minutes. After washing, the pellet was incubated with 100 μl Reagent 2, saponin (Beckman Coulter, Marseilles, France) for five minutes at RT in the dark. The samples were washed twice with 0.1% BSA-PBS and then incubated with PE-conjugated IL-17-specific mAb (eBiosciences, San Diego, CA, USA) for 30 minutes at RT in the dark. An isotype control IgG1-PE (eBiosciences, USA) was used for the IL-17 staining at RT in the dark. After staining, the cells were washed and immediately analysed using flow cytometry (Beckman Coulter, USA). Lymphocytes were gated on the basis of forward- and side- scatter properties and at least 10,000 CD4+ cells were analysed. The results were analysed using Expo32 software (Beckman Coulter, Miami, FL, USA).
Determination of serum levels of Th17-related cytokines by ELISA
Serum levels of IL-6, IL-17, IL-21, IL-23 and TNF-α were determined in 48 RA patients at baseline and after six months of anti-TNF-α therapy, and in 12 healthy controls using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions (eBiosciences, USA).
Determination of serum levels of anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF)-IgM
Determination of the anti-CCP antibody was performed by ELISA using a commercial kit (INOVA Diagnostics Inc., San Diego, CA, USA). A result was considered positive for anti-CCP antibodies if the titer was above 20 IU/ml. Serum levels of RF-IgM were measured by nephelometry (Dade Behring Inc., Newark, DE, USA). A result was considered positive for RF when the concentration was above 15 IU/ml.
Statistical analysis
The results are presented as the mean ± SD or median (interquartile range, IQR). The non-parametric Mann-Whitney U test was used for between-group comparisons of serum levels of IL-6, IL-17, IL-21, IL-23 and TNF-α, and for the percentages of circulating Th17 cells. The correlation coefficient was obtained by the non-parametric Spearman's rank correlation test. The Wilcoxon signed rank test was used to compare the percentages of circulating Th17 cells and serum levels of Th17-related cytokines during follow-up for the RA patients after anti-TNF-α therapy. A probability of less than 0.05 was considered significant.
Baseline characteristics of RA patients with a different therapeutic response
Baseline clinical characteristics and laboratory findings in RA patients with different response to anti-TNF-α therapy
RA with anti-TNF-α Rx.
Healthy control
Moderate-good responders (n= 36)
Non- responders (n= 12)
(n= 12)
Mean age, years
50.4 ± 14.5
49.3 ± 10.8
47.6 ± 8.1
Female (%)
29 (80.6%)
10 (83.3%)
10 (83.3%)
Disease duration, years
5.44 ± 2.42
5.37 ± 2.37
RF positivity (%)
30 (83.3%)
11 (91.6%)
Anti-CCP positivity (%)
29 (80.6%)
10 (83.3%)
ESR (mm/1st hr)
48.9 ± 25.4
63.8 ± 24.4
7.18 ± 0.74
7.33 ± 0.94
Daily steroid dose (mg)
6.5 ± 2.1
6.9 ± 2.4
TNF-α inhibitors
Etanercept (n = 14)
10 (71.4%)
4 (28.6%)
Adalimumab (n = 34)
26 (76.5%)
8 (23.5%)
Used DMARDs
33 (91.7%)
11 (91.6%)
31 (86.1%)
10 (83.3%)
32 (88.9%)
10 (83.3%)
14 (38.9%)
5 (41.7%)
The frequencies of circulating Th17 cells in RA patients before anti-TNF-α therapy
Serum levels of Th17-related cytokines in RA patients before anti-TNF-α therapy
Changes in levels of Th17-cells and Th17-related cytokines in RA patients with different therapeutic responses
Moderate-good responders (n= 36)
Non-responders (n= 12)
Th17 cells (%)
Before Rx.
1.13 ± 0.16
2.94 ± 0.77#
After Rx.
0.79 ± 0.11***
4.23 ± 0.80*
IL-17 level (pg/ml)
Before Rx
43.1 ± 7.0
92.1 ± 22.2#
After Rx
27.8 ± 3.8***
148.6 ± 31.5*
IL-6 level (pg/ml)
Before Rx
282.9 ± 37.1
453.7 ± 120.9
After Rx
171.7 ± 22.2*
471.6 ± 124.0
IL-21 level (pg/ml)
Before Rx
1147.0 ± 216.3
863.5 ± 133.9
After Rx
769.8 ± 104.7**
942.9 ± 140.4
IL-23 level (pg/ml)
Before Rx
166.1 ± 35.1
158.4 ± 67.6
After Rx
83.3 ± 19.7***
161.3 ± 63.3
TNF-α level (pg/ml)
Before Rx
22.0 ± 2.4
29.2 ± 7.2
After Rx
11.0 ± 1.3***
15.2 ± 3.9**
RF titer (IU/ml)
Before Rx
116.6 ± 32.7
368.7 ± 257.9
After Rx
101.2 ± 28.2
440.0 ± 324.4
Anti-CCP titer (IU/ml)
Before Rx
58.7 ± 9.6
72.4 ± 22.0
After Rx
51.8 ± 8.7**
68.8 ± 20.3
Correlation between the frequencies of circulating Th17 cells and disease activity or serum levels of Th17-related cytokines in RA patients
The frequencies of circulating Th17 cells were positively correlated with DAS28 scores (r = 0.294, P < 0.05), IL-17 levels (r = 0.737, P < 0.001), IL-6 levels (r = 0.347, P < 0.05), and TNF-α levels (r = 0.495, P < 0.001) in RA patients before the anti-TNF-α therapy was started. Serum IL-6 levels were also positively correlated with IL-17 levels (r = 0.303, P < 0.05) in RA patients. After six months of anti-TNF-α therapy, the frequencies of circulating Th17 cells remained positively correlated with DAS28 scores (r = 0.375, P < 0.01), IL-17 levels (r = 0.727, P < 0.001), IL-6 levels (r = 0.311, P < 0.05), and TNF-α levels (r = 0.362, P < 0.05).
Effects of TNF-α inhibitors on the levels of Th17 cells and Th17-related cytokines
As illustrated in Figure 2 and Table 2, the mean levels of circulating Th17 cells and IL-17 significantly declined after six-month anti-TNF-α therapy (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001), in parallel with the decrease in DAS28 (7.18 vs. 5.21, P < 0.001) and in anti-CCP titers (58.7 ± 9.6 vs. 51.8 ± 8.7 IU/ml, P < 0.005) in responders. Serum levels of IL-6, IL-21, IL-23 and TNF-α were also significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05), while TNF-α levels decreased after anti-TNF-α therapy (29.2 pg/ml vs. 15.2 pg/ml, P < 0.005) in non-responders. There were no significant changes in RF titers after anti-TNF-α therapy in either responders or non-responders.
Multiple logistic regression analysis of the effects of Th17 cell frequencies and serum Th17-related cytokines on therapeutic efficacy
Multiple logistic regression analysis showed that only a high baseline IL-17 level (≧40.0 pg/ml) could significantly predict a poor response to anti-TNF-α therapy (P < 0.01), with a medium level of specificity (83.3%) and sensitivity (66.7%).
Consistent with the findings of previous reports [36, 37], our results showed that 36 (75.0%) patients have moderate or good EULAR response to the six-month anti-TNF-α therapy and 12 (25.0%) were non-responders. Although non-responders seem to have higher baseline ESR, titers of RF and anti-CCP antibodies, and serum levels of TNF-α and IL-6, when compared to responders, the differences do not reach statistical significance. Our findings suggest that an inadequate response to anti-TNF-α therapy is not merely a reflection of high disease activity.
The present study is the first attempt to investigate the effects of TNF-α inhibitors on the levels of circulating Th17 cells and Th17-related cytokines in RA patients with a different therapeutic response. In order to obtain a better reflection of in vivo cytokine patterns than is achievable with PBMCs, whole blood was stimulated with mitogens and lymphocytes double-stained with IL-17 and CD4 were analysed using flow cytometry. Our results showed significantly higher baseline frequencies of circulating Th17 cells in active RA patients compared with healthy controls, confirming the findings of previous studies [13, 14, 29]. We also showed that the baseline levels of circulating Th17 cells were positively correlated with DAS28 scores in RA patients. Our data and the findings of previous studies [15, 16] suggest a potential role of Th17 cells in the pathogenesis of RA.
Similar to the results of recent studies [28], our findings showed a significant decrease in the frequencies of circulating Th17 cells after anti-TNF-α therapy, in parallel with the decrease in DAS28 in EULAR responders. Although the diseases studied were different, our results were also consistent with the findings of previous studies which showed that the TNF-α inhibitor reduced Th17 cell responses with the amelioration of psoriatic skin lesions [38] and that the TNFR1 inhibitor suppressed the Th17 response with clinical benefits in experimental autoimmune encephalomyelitis mice [39]. In contrast, our results showed a significant increase in circulating Th17 cell frequencies in non-responders. Our findings in non-responders were similar to the results of a recent study that showed an increased frequency of circulating Th17 cells after TNF-α blockade in RA patients [29]. The divergent effects on Th17 cells in vivo after anti-TNF-α therapy for RA patients suggest that there may be different subsets of the immune response to TNF-α inhibitors. It is tempting to speculate that the change in frequencies of circulating Th17 cells may help to differentiate between EULAR responders and non-responders because these changes occur within the first six months of anti-TNF-α therapy.
The Th17 cells have a specific role in immune function through the production of effector cytokines. Through the secretion of IL-17, Th17 cells act on the differentiation of osteoclasts and bone resorption [40], and can stimulate the monocytes to produce pro-inflammatory cytokines, thus amplifying the inflammatory cascade [11, 17, 18]. In the present study, we showed that serum IL-17 levels were significantly elevated and correlated with DAS28 in active RA patients. Our data were consistent with the results of recent studies describing an increase in IL-17 levels in RA patients [14, 41], and they also supported the results of clinical trials showing the therapeutic benefits of IL-17 blockade [20–22]. During a longitudinal follow-up of RA patients who received anti-TNF-α therapy, we found that serum IL-17 levels significantly decreased, in parallel with the clinical remission in the responders, whereas increasing IL-17 levels were found in non-responders. Whether or not this imbalance of Th17 cells and IL-17 between PB and affected joints contributes to the change in Th17-related cytokines after anti-TNF-α therapy remains unclear.
Accumulating evidence indicates that IL-6 can enhance Th17 cell differentiation by promoting the sequential engagement of IL-21/IL-23 pathways and that it plays a critical role in Th17-dependent autoimmune diseases [42]. In the present study, we showed that the high baseline levels of IL-6 were positively correlated with the frequencies of circulating Th17 cells in RA patients. After anti-TNF-α therapy, a significant decrease in the levels of circulating Th17 cells and IL-17, in parallel with the decrease in DAS28 and serum IL-6 levels was observed in responders. These observations support the role of IL-6 in the differentiation of Th17 cells [42–44], and the therapeutic benefits of IL-6 receptor inhibitors in RA patients [45].
Interleukin-21 is required to reinforce differentiation of Th17 cells, and it plays a critical role in Th17-dependent autoimmune diseases [46]. In contrast to IL-12, IL-23 does not promote the development of Th1 cells, but it is crucial for the expansion and maintenance of Th17 cells [47]. In the present study, we showed that the baseline levels of IL-21 and IL-23 were significantly elevated in active RA patients, supporting their role in the pathogenesis of this disease [42, 48]. In addition, we found that serum levels of IL-21 and IL-23 significantly decreased, in parallel with the clinical remission in responders after anti-TNF-α therapy. Consistent with our data, the results of the study by Kageyama et al. also showed a significant decrease in serum IL-23 levels at three and six months after anti-TNF-α (etanercept) therapy in RA patients [27].
The mechanisms of the therapeutic effects of TNF-α inhibitors on RA have not been fully explored. Lundy et al. showed that TNF-α has a positive feedback effect on Th17 cells, causing a vicious cycle of synovitis [49]. TNF-α also promotes IL-17 production by inducing dendritic cells to direct the differentiation of Th cells towards the Th17 phenotype [23], and by the administration of TNF-like ligand 1A enhancing Th17 differentiation with IL-17 production [50]. Our results showed a significant decrease in the levels of circulating Th17 cells and TNF-α after effective therapy with TNF-α inhibitors, suggesting that the down-regulation of both Th17-related cytokines and TNF-α may be one of the mechanisms of anti-TNF-α therapy [19]. Our findings support the hypothesis that anti-TNF-α therapy could reduce Th17 responses by blocking the TNF-α-dependent positive feedback system [23]. Another explanation may be the inhibition of emigration of Th17 cells from lymphoid organs after anti-TNF-α therapy [24].
In the present study, we showed that one-fourth of RA patients have an inadequate response to anti-TNF-α therapy despite a significant decrease in serum TNF-α level, suggesting that neutralization of TNF-α cannot fully explain the therapeutic effect of TNF-α inhibitors in non-responders. Additionally, significantly higher baseline levels of circulating Th17-cells and IL-17 were observed in non-responders when compared to responders. During a longitudinal follow-up of RA patients undergoing anti-TNF-α therapy, we found a significant increase in circulating levels of Th17-cells and IL-17 in non-responders. Although the cut-off value for baseline IL-17 (40 pg/mL) used in our study was not absolute, a multivariate logistic regression analysis showed that only a high baseline level of IL-17 could be a significant predictor of poor therapeutic response to TNF-α inhibitors. Our observations suggest that an inadequate response to anti-TNF-α therapy may reflect TNF-independent but Th17-dominant inflammatory process, which has been observed in previous studies [15, 16].
This was a preliminary study that enrolled a limited number of active RA patients who were followed up for six months. Because we mainly investigate the effects of anti-TNF-α therapy on Th17 cells and Th17-related cytokines, we did not include a group of RA patients without anti-TNF-α therapy as a disease control. Because the patients enrolled in our study were not an early RA population, our results might not be directly applicable to early RA patients undergoing anti-TNF-α therapy. Therefore, a long-term study enrolling a larger group of patients, including an additional early RA population, or a control group using DMARDs only, is required to validate these findings. Although the erroneous increase in IL-17 levels may have been due to the heterophilic binding by serum RF [51, 52], there were no significant differences in RF positivity or titers between responders and non-responders in the present study.
Our results show that anti-TNF-α therapy not only neutralizes the effects of TNF-α, but it also down-regulates the IL-6/Th17 axis in EULAR responders. In contrast, anti-TNF-α therapy causes a significant increase in Th17 cells in RA patients with an inadequate response to anti-TNF-α therapy. A high baseline level of IL-17 may have a predictive value for poor therapeutic response to TNF-α inhibitors. Although the small sample size of this study did not allow for a definitive conclusion, our findings at least suggest that Th17-dependent inflammation is implicated in the pathogenesis of a subset of RA patients with poor response to TNF-α inhibitors, and that treatment targeting IL-17 may be beneficial for these patients [21, 22].
- Anti-CCP:
anti-cyclic citrullinated peptide
collagen-induced arthritis
28-joint disease activity score
- DMARDs:
disease-modifying anti-rheumatic drugs
enzyme-linked immunosorbent assay
erythrocyte sedimentation rate
European League Against Rheumatism
- NSAIDs:
non-steroid anti-inflammatory drugs
- PBMCs:
peripheral blood mononuclear cells
Phycoerythrin-Cyanin 5
rheumatoid arthritis
rheumatoid factor
room temperature
- Th17 cells:
T helper-type 17 cells
- TNF-α:
tumor necrosis factor-α.
This study was supported by grant TCVGH-993803C from Taichung Veterans General Hospital, Taiwan.
Authors' Affiliations
- Christodoulou C, Choy EH: Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clin Exp Med. 2006, 6: 13-19. 10.1007/s10238-006-0088-5.View ArticlePubMedGoogle Scholar
- Choy EH, Panayi GS: Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001, 344: 907-916. 10.1056/NEJM200103223441207.View ArticlePubMedGoogle Scholar
- Feldmann M, Maini RN: TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. 2003, 9: 1245-1250. 10.1038/nm939.View ArticlePubMedGoogle Scholar
- van der Heijde D, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S, TEMPO Study Investigators: Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006, 54: 1063-1074. 10.1002/art.21655.View ArticlePubMedGoogle Scholar
- Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT: The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006, 54: 26-37. 10.1002/art.21519.View ArticlePubMedGoogle Scholar
- Kievit W, Fransen J, Adang EMM, den Broeder AA, Moens HJB, Visser H, van de Laar MA, van Riel PL: Long-term effectiveness and safety of TNF-blocking agents in daily clinical practive: results from the Dutch rheumatoid arthritis monitoring register. Rheumatology. 2011, 50: 196-203. 10.1093/rheumatology/keq325.View ArticlePubMedGoogle Scholar
- Rubbert-Roth A, Finckh A: Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009, 11: S1-10.1186/ar2666.PubMed CentralView ArticlePubMedGoogle Scholar
- Bettelli E, Oukka M, Kuchroo VK: Th-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007, 8: 345-350.View ArticlePubMedGoogle Scholar
- Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT: Interleukin17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineage. Nat Immunol. 2005, 6: 1123-1132. 10.1038/ni1254.View ArticlePubMedGoogle Scholar
- Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C: A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005, 6: 1133-1141. 10.1038/ni1261.PubMed CentralView ArticlePubMedGoogle Scholar
- Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP: IL-17 stimulates the production of proinflammatory cytokines, IL-1β and TNF-α, by human macrophages. J Immunol. 1998, 160: 3513-3521.PubMedGoogle Scholar
- Agarwal S, Misra R, Aggarwal A: Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol. 2008, 35: 515-519.PubMedGoogle Scholar
- Shen H, Goodall JC, Gaston JSH: Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009, 60: 1647-1656. 10.1002/art.24568.View ArticlePubMedGoogle Scholar
- Colin EM, Asmawidjaja PS, van Hamburg JP, Mus AMC, van Driel M, Hazes JMW, van Leeuwen JP, Lubberts E: 1,25-Dihydroxyvitamn D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 2010, 62: 132-42. 10.1002/art.25043.View ArticlePubMedGoogle Scholar
- Chabaud M, Lubberts E, Joosten L, van den Berg W, Miossec P: IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res Ther. 2001, 3: 168-177.View ArticleGoogle Scholar
- Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M: Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cells and stromal cell origin. Arthritis Res Ther. 2005, 7: R784-795. 10.1186/ar1733.PubMed CentralView ArticlePubMedGoogle Scholar
- Katz Y, Nadiv O, Beer Y: Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins1, 6, and 8 in skin and synovial fibroblasts: a possible role as a "fine-tuning cytokine" in inflammation processes. Arthritis Rheum. 2001, 44: 2176-2184. 10.1002/1529-0131(200109)44:9<2176::AID-ART371>3.0.CO;2-4.View ArticlePubMedGoogle Scholar
- Van Bezooijen RL, Van Der Wee-Pals L, Papapoulos SE, Lowik CW: Interleukin 17 synergies with tumor necrosis factor alpha to induce cartilage destruction in vitro. Ann Rheum Dis. 2002, 61: 870-876. 10.1136/ard.61.10.870.PubMed CentralView ArticlePubMedGoogle Scholar
- Van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AMC, Colin EM, Hazes JMW, Dolhain RJ, Lubberts E: Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011, 63: 73-83. 10.1002/art.30093.View ArticlePubMedGoogle Scholar
- Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB: Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004, 50: 650-659. 10.1002/art.20001.View ArticlePubMedGoogle Scholar
- Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ, Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD, Uveitis Study Group, Rose K, Haider A, Di Padova F: Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis and uveitis. Sci Transl Med. 2010, 2: 52ra72-10.1126/scitranslmed.3001107.View ArticlePubMedGoogle Scholar
- Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J: LY2439821, A humanized anti-IL-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase 1 randomized double-blind, placebo-controlled, proof of concept study. Arthritis Rheum. 2010, 62: 929-939. 10.1002/art.27334.View ArticlePubMedGoogle Scholar
- Iwamoto S, Iwai S, Tsujiyama K, Kurahashi C, Takeshita K, Naoe M, Masunaga A, Ogawa Y, Oguchi K, Miyazaki A: TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evolving Th1 and Th17 responses. J Immunol. 2007, 179: 1449-1457.View ArticlePubMedGoogle Scholar
- Ma HL, Napierata L, Stedman N, Benoit S, Collins M, Nickerson-Nutter C, Young DA: Tumor necrosis factor α blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 2010, 62: 430-440.View ArticlePubMedGoogle Scholar
- Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO: Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J Exp Med. 2008, 205: 2491-2497. 10.1084/jem.20072707.PubMed CentralView ArticlePubMedGoogle Scholar
- Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG: TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 2005, 175: 2721-2729.View ArticlePubMedGoogle Scholar
- Kageyama Y, Ichikawa T, Nagafusa T, Torikai E, Shimazu M, Nagano A: Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis. Rheumatol Int. 2007, 28: 137-143. 10.1007/s00296-007-0388-4.View ArticlePubMedGoogle Scholar
- Yue C, You X, Zhao L, Wang H, Tang F, Zhang F, Zhang X, He W: The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL-6 secretion in the rheumatoid arthritis patients. Rheumatol Int. 2009, 30: 1553-1557.View ArticlePubMedGoogle Scholar
- Aerts NE, De Knop KJ, Leysen J, Ebo DG, Bridts CH, Weyler JJ, Stevens WJ, De Clerck LS: Increased IL-17 production by peripheral T helper cells after tumor necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration-associated chemokine receptor expression. Rheumatology. 2010, 49: 2264-2272. 10.1093/rheumatology/keq224.View ArticlePubMedGoogle Scholar
- Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002/art.1780310302.View ArticlePubMedGoogle Scholar
- Ledingham J, Deighton C, British Society for Rheumatology Standards, Guidelines and Audit Working Group: Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford). 2005, 44: 157-163.View ArticleGoogle Scholar
- Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38: 44-48. 10.1002/art.1780380107.View ArticlePubMedGoogle Scholar
- Van Gestel AM, Prevoo ML, van't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL: Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996, 39: 34-40. 10.1002/art.1780390105.View ArticlePubMedGoogle Scholar
- Yamada H, Nakashima Y, Okazaki K, Mawatari T, Fukushi JI, Kaibara N, Hori A, Iwamoto Y, Yoshikai Y: Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann Rheum Dis. 2008, 67: 1299-1304.View ArticlePubMedGoogle Scholar
- Chen DY, Lan JL, Chen YM, Lin CC, Chen HH, Hsieh CW: Potential role of Th17 cells in the pathogenesis of adult-onset Still's disease. Rheumatology. 2010, 49: 2305-2312. 10.1093/rheumatology/keq284.View ArticlePubMedGoogle Scholar
- Atzeni F, Antivalle M, Pallavicini FB, Caporali R, Bazzani C, Gorla R, Favalli EG, Marchesoni A, Sarzi-Puttini P: Predicting response to anti-TNF treatment in rheumatoid arthritis patients. Autoimmun Rev. 2009, 8: 431-437. 10.1016/j.autrev.2009.01.005.View ArticlePubMedGoogle Scholar
- Kameda H, Ueki Y, Saito K, Nagaoka S, Hidaka T, Atsumi T, Tsukano M, Kasama T, Shiozawa S, Tanaka Y, Takeuchi T, Japan Biological Agent Study Integrated Consortium: Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial. Mod Rheumatol. 2010, 20: 531-538. 10.1007/s10165-010-0324-4.View ArticlePubMedGoogle Scholar
- Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Fuentes-Duculan J, Novitskaya I, Khatcherian A, Bluth MJ, Lowes MA, Krueger JG: Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007, 204: 3183-3194. 10.1084/jem.20071094.PubMed CentralView ArticlePubMedGoogle Scholar
- Nomura T, Abe Y, Kamada H, Shibata H, Kayamuro H, Inoue M, Kawara T, Arita S, Furuya T, Yamashita T, Nagano K, Yoshikawa T, Yoshioka Y, Mukai Y, Nakagawa S, Taniai M, Ohta T, Serada S, Naka T, Tsunoda S, Tsutsumi Y: Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNFF in experimental autoimmune encephalomyelitis mice. J Control Release. 2011, 149: 8-14. 10.1016/j.jconrel.2009.12.015.View ArticlePubMedGoogle Scholar
- Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H: Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006, 203: 2673-2682. 10.1084/jem.20061775.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim KW, Cho ML, Park MK, Yoon CH, Park SH, Lee SH, Kim HY: Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor kappaB-dependent pathway in patients with rheumatoid arthritis. Arthritis Res Ther. 2005, 7: R139-148. 10.1186/ar1470.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR: IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007, 8: 967-974. 10.1038/ni1488.View ArticlePubMedGoogle Scholar
- Romagnani S: Human Th17 cells. Arthritis Res Ther. 2008, 10: 10-16. 10.1186/ar2360.View ArticleGoogle Scholar
- Chen Z, Tato CM, Muul L, Laurence A, ÓShea JJ: Distinct regulation of interleukn-17 in human T helper lymphocytes. Arthritis Rheum. 2007, 56: 2936-2946. 10.1002/art.22866.PubMed CentralView ArticlePubMedGoogle Scholar
- Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J: IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor biologicals: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum Dis. 2008, 67: 1516-1523.PubMed CentralView ArticlePubMedGoogle Scholar
- Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK: IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007, 448: 484-487. 10.1038/nature05970.PubMed CentralView ArticlePubMedGoogle Scholar
- Stritesky GL, Yeh N, Kaplan MH: IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol. 2008, 181: 5948-5955.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu FL, Chen CH, Chu SJ, Chen JH, Lai JH, Sytwu HK, Chang DM: Interleukin (IL)-23 p19 expression induced by IL-1β in human fibroblast-like synoviocytes with rheumatoid arthritis via active nuclear factor-κB and AP-1 dependent pathway. Rheumatology. 2007, 46: 1266-1273. 10.1093/rheumatology/kem055.View ArticlePubMedGoogle Scholar
- Lundy SK, Sarkar S, Tesmer LA, Fox DA: Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther. 2007, 9: 202-212. 10.1186/ar2107.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhang J, Wang X, Fahmi H, Wojcik S, Fikes J, Yu Y, Wu J, Luo H: Role of TL1A in the pathogenesis of rheumatoid arthritis. J Immunol. 2009, 183: 5350-5357. 10.4049/jimmunol.0802645.View ArticlePubMedGoogle Scholar
- DeForge LE, Loyet KM, Delarosa D, Chinn J, Zamanian F, Chuntharapai A, Lee J, Hass P, Wei N, Townsend MJ, Wang J, Wong WL: Evaluation of heterophilic antibody blocking agents in reducing false positive interference in immunoassays for IL-17AA, IL-17FF, and IL-17AF. J Immunol Methods. 2010, 362: 70-81. 10.1016/j.jim.2010.09.004.View ArticlePubMedGoogle Scholar
- Todd DJ, Knowlton N, Amato M, Frank MB, Schur PH, Izmailova ES, Roubenoff R, Shadick NA, Weinblatt ME, Centola M, Lee DM: Erroneous augmentation of multiplex assay measurements in patients with rheumatoid arthritis due to heterophilic binding by serum rheumatoid factor. Arthritis Rheum. 2011, 63: 894-903. 10.1002/art.30213.View ArticlePubMedGoogle Scholar
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There is no question that the coal companies are undervalued after a year of poor performance due to power generation companies switching to the lower cost of using natural gas for electricity generation. The fall in natural gas prices was accelerated by increased supply as a result of a mild winter. The falling price of natural gas is also due to increased production which has led to a supply glut.
It looks like the bottom may be in for the price of natural gas as it hit a low of $1.82 per MMBtu in April. The price of natural gas has since risen to $2.63 per MMBtu. However, this doesn't necessarily mean that the uptrend in the price of natural gas will continue. Significant increases in natural gas supply or decreases in consumption could cause the price of natural gas to retest the lows or remain low for quite some time.
The challenges facing coal in addition to the low cost of natural gas are regulations and cost effectiveness. Stricter EPA rules to reduce pollution from coal combustion could add significant costs to generating electricity from the commodity. Monday June 25 begins the EPA's regulation that any new coal plants built cannot emit more carbon dioxide than a natural gas plant of comparable size and capacity. Since the burning of natural gas creates half of the carbon dioxide emissions than coal, it is just not cost effective to build new coal plants in the U.S.
The positive news for coal mining companies that export is that China and India have an increasing demand for the commodity. This should allow the U.S. coal exporters to offset losses from the shrinking U.S. coal market.
I don't think that the bottom is in for the coal companies. Only 10% of U.S. mined coal is exported. Currently, the exporting of coal does not compensate for the losses that these companies are facing domestically.
I think the key factor for a bottom to occur in coal stocks is more coal export terminals being approved for development. The city of Seattle recently passed a resolution that opposes the development of a coal export terminal in the state of Washington. This was decided by a city council that doesn't have a say in the final outcome, but it reflects the environmentally-friendly sentiment of the Seattle region. There is an ongoing battle between environmentalists and those who are pro-coal. This battle is an obstacle for any coal related development.
There are currently six proposals for new coal export terminals in the Pacific Northwest. Currently the only coal export terminals that exist on the West Coast are in British Columbia. These terminals handle about 38 million tons of coal annually with a total capacity to handle about 49 million tons. If the proposed terminals were built, exports could rise to 150 million tons annually. This is equivalent to approximately 50% more than the U.S. 2011 export figure.
The other key factor for coal stocks to bottom is for the price of natural gas to remain above $3 per MMBtu. This would allow electricity generators to switch back to coal burning. However, the EIA is projecting that the average natural gas price will be $2.55 per MMBtu in 2012. The higher prices are expected in 2013 where the average price is expected to $3.23 per MMBtu. The 2013 prices would make switching back to coal more feasible.
The largest U.S. coal producer, Peabody Energy (BTU), is the best positioned coal miner for world coal growth as it has operations in the U.S. and Australia. Peabody has a number of projects in the works to capitalize on China's 80% usage of coal for electricity generation. The company also has a growing presence in Indonesia and Mongolia.
Peabody has 2 upward earnings revisions for 2013. It is expected to grow earnings annually at 10.23% for the next five years. The company also pays a modest dividend of 1.5%.
Those interested in investing in coal may want to consider putting a portion of money in Peabody now. Then if the stock falls further, buy more. The sell-off in coal stocks has been significant and created an undervaluation in the stocks. Peabody is the best of breed coal producer and this should reflect in its future stock price.
Alpha Natural Resources (ANR) also looks interesting. It has increased exports to China and India, capitalizing on growing international demand. The company's exporting activity is needed as U.S. demand remains weak.
ANR is expected to grow earnings annually at only 5% for the next five years. The stock price has dropped under its book value per share, creating an unusual low valuation. The stock is trading at only a quarter of its book value per share. Despite the low earnings growth expectations, the stock may do well as it "catches up" to its book value per share.
Arch Coal (ACI) is trading at less than half its book value per share. This makes the stock attractively undervalued. However, the company has not met earnings expectations in its last four quarters. It missed Q1 2012 earnings by 125%. This trend will need to be reversed for the stock price to reverse.
Arch currently pays a dividend of 2%. The company is expected to grow earnings annually at 6.5% for the next five years.
Patriot Coal (PCX) is trading under a quarter of its book value per share. This undervaluation is due to some serious bleeding as the company reported negative earnings in the last four quarters. Patriot's balance sheet is in tough shape as it has more current liabilities than current assets as reflected in its current ratio of 0.87. This puts the company at risk of being unable to pay-off short-term debt.
The company will need to ramp up exports to dig its way out of the basement. Patriot Coal reported that it will increase thermal exports to 7 million tons in 2012. I think that Patriot also needs higher natural gas prices to get back in the black. PCX is expected to grow earnings annually at 5% for the next five years.
CONSOL Energy (NYSE:CNX) is in an interesting position since it produces natural gas and coal. The company has access to over 3.7 trillion cubic feet of natural gas reserves. CONSOL has about 13,000 net producing wells.
CONSOL is also one of the nation's largest coal producers with more than 4.5 billion tons of reserves. The expansion of the Baltimore Marine Terminal will allow CONSOL to increase the amount of exported coal to 14 to 16 million tons annually.
CNX is not as undervalued as the other coal companies, but it is in better financial shape than most of them. The stock is trading at 1.6 times book value per share. The company exceeded earnings expectations in 2 of its last 4 quarters. It is expected to grow earnings annually at 13.43% for the next five years. CNX also pays a dividend of 1.8%.
Peabody and CONSOL look like the standouts among the major coal producers. Although the exact bottom may not be in for coal stocks, I think that starting a small position in either of these two would not be a bad idea at this point. If the stocks fall further, you can add to the position. If they rise, you can also add to your position, raising the average cost basis of your investment.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.