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Sometimes, when allowed to, talks between two sides reach a point where no further compromise is possible. Both sides feel they have given enough or one side has done the far greater amount of giving while the other side has refused to make even the slightest of concessions. The talks have been ongoing with an on again off again drumbeat which marked the passage of time, not agreements. Even pressure put upon the talks with expressions of the grave and vital importance made clear. Grand schemes have been proposed and failed to force a change in either side. President Obama has made demands that were designed to facilitate progress, yet there was still no progress. Everybody around the world has had their two cents worth of advice and the talks have stalled again and again. Grand bargains have been offered and have caused a crack of light to appear signaling perhaps a miracle only to return to moribund silence between the two sides. The United Nations has pleaded and shown deep concern even to the point of offering to assist in any way they might be invited, but that too fell on deaf ears. What is a world to do when one side of a situation that screams out for justice and compromise refuses compromises and chooses to scream about the injustices that have been done to them. And all that has befell the intransigent side the other claims they have brought upon themselves by taking the path of refusal and obstinacy.
But with the New Year there are signs that President Obama will bring changes and by his will alone force movement in the talks towards a mutually beneficial resolution. His promises sound vaguely familiar; perhaps we have heard these promises before. Vice President Biden makes a plea restating an old offer expressing the hope that this is the time that perchance this offer should be accepted. Then, with only a moment's wait, a mere few days, and the obstinate side remains obstinate, refusing the offer with a steely cold denial. There is a deep exhalation as many had held their breathe anticipating a change, but alas there will be no movement. There is still hope that there can be a new round of talks made possible if only there is the perseverance to bring it to fruition. We wait often believing we caught sight of the glimmer of the light of hope but then again it may have just been flashes in our own eyes and nothing of the tangible sort. Can there be progress? Should we still hold out hope? What if the worst of the worst should come and the talks prove to be futile and have been merely a long exercise in futility? Will we be able to face the consequences and do what we know must be done? If we refuse to admit the failure, then what will become of us? Will the impasse lead to war as had been predicted by some who told us long ago that our faith in talks was fruitless? Will there be no other way out of the predicament which we now find ourselves having to admit? It is too harsh a reality. The talks must be reopened and another chance be given for progress, compromise, a last hope. We have to allow the time for talks to work, and they will work, they must work. But what if they don't?
President Obama has told us that the talks would lead to peace and security and put an end to any difficulties, any threats, any dangers. The President assured us in dulcet tones that he could make the talks work if only they would listen to his generous offers and reasonable requests. Kindness, after all, always calms and defeats harsh rhetoric, heals wounds and works wonders, after all, did not his promises and words win him election? All we had to do is allow his words to work their spell. But now his words have the hint of panic and defeat and have lost some of their melodic and hypnotic overtones. His sweet overtures have slowly changed taking on a rasp of harshness and now have the sharp retort-filled tones of rapid gunfire.
There is to be yet another round of talks, or so we have been led to believe. Can they really make any difference at this late date? Why should we continue to hold out hope as all has certainly proven hopeless? The last refusal of a generous offer of direct talks had the dead tones of finality. The discussions with the arm of the United Nations on their dual track was refused and abruptly cut off just a short while ago. Their track seems to have come to their end. They have reached the gorge and there does not appear to be a bridge. Are our tracks equally coming to that gorge that has no bridge? It will be a harsh pill to swallow if the warnings from Israel prove true. What do we do now that there is no path forward through discourse and all the talking has been revealed to be a ruse used to stall for time? What are we to do? Yes, sure we will go ahead with the talks we have managed to agree we will hold, but if they fail once again, then what?
And for the really big question, what is it that President Obama will be discussing on his trip to Israel next month? We have been told that President Obama will not be making any plans to force a reopening of the equally moribund talks between Israel and the Palestinians and they plan other discussion. Could it be that President Obama will be talking with Israeli Prime Minister Netanyahu to advise him of what will come should the last gasp talks with Iran continue to fail? With the growing reluctance and intransigence by Iran and the obvious failure of the P5+1 talks to produce even the smallest concession which could be verified, what can we expect other than a waste of breathe and time with another round of talks. It really does seem obvious that we have been talking just to hear ourselves talk. Perhaps we must admit to ourselves that we have been talking because the alternative is too frightening to even think about. We have been so determined to avoid what has been the inevitability of the rising menace named Iran that we have talked ourselves almost to death. While we aimed to avoid war Iran has aimed for the ultimate weapon of war and our determination of avoidance has brought them dangerously close to their goal, maybe even they have attained what they desired. What will we tell our children if we find that Iran has truly reached the goal and now already possesses a small cache of nuclear devices? How will we excuse our timidity which enabled the rising bully to so equip itself? Have we talked ourselves to the brink of doom or beyond, that is the question that needs an immediate answer. And what are we going to do even if the answer is affirmative? Will we then continue to talk only this time the talk will be about how much we surrender before it becomes too much. What if we talked ourselves into that oblivion? As Shakespeare wrote, "Methinks the Lady doth protest too much." Have we so protested too much and now are left with too little leverage to gain advantage? Did we whittle away any advantage we originally had? That would indeed be a sad state of affairs. Very sad.
Beyond the Cusp


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|Karen Tager has been in the interior design field for 20 years. Her design aesthetic goes from coastal chic
to contemporary classic to urban modern, depending on the location, architecture and style of her clients.
In addition, for the past 6 years, Karen has been designing top of bed luxury linens for Mystic Valley Traders
and her love of color, texture and attention to detail is exhibited in her designs.
She assists her clients in all aspects of the design process, including color schemes, space planning,
and fabric and furniture selection.
Karen lives with her husband, triplet boys, and a cockapoo named Daisy in Weston, MA.

subset: commoncrawl


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PHS Dance Company
By McKell Wall
Basketball games, football games, they do it all. Dance Company is one of the most well known dance groups in our school. With nine seniors, seven juniors, and five sophomores they strive to entertain audiences with their technique and emotion shown in their dance performances. Dance Company does many different styles of dance but their main style is definitely contemporary.


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Pen Show Calendar for USA & Canada
Pen Show Calendar for Europe
- Are there any shows in Canada?
- If you have links to comprehensive regional calendars for elsewhere (e.g., Asia), PM me I'll add them to this OP.
- If a better reliable comprehensive calendar develops, PM me and I'll change or add the link.
Feel free to bump (until stickies come back).


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The Automatic Product Callouts Magento extension by aheadWorks allows you to organize your top Product sets in blocks anywhere on your store's site. Though this extension is most commonly used to enable an automatic Category landing page that lists the category's top products, it can also be used for similar outcomes elsewhere on your site.
Dedicated Cache
The Automatic Product Callouts Magento module by aheadWorks has its own cache, reducing the extension load time to almost zero! Visitors will not experience any delays while being introduced to fresh automatic content on each store page.
Products retrieval options
You can define the place from which Products must be taken, such as the current store or a specific Category. You can also restrict product retrieval to in-stock only items, set the collection size, and more.


text: I still believe today as I always have that it is going to take all of us as one, to get the answers we seek. Rather it is in a picture, a video, or just an experience. If you think differently than fine don't get on the band wagon. It really chaps my donkey to see other teams attempting to go alone on this adventure and not even realizing how much further they could get with the help from others. Oh well I guess I am just venting. I do know that each of us and our teams go out on our adventures alone. Just like these other teams. I think the real big difference is the support they have behind them that is not there with them. I guess all I can say is "Come on people" we need to stick together. ~ Tracy


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Roger Federer's Favorite Title Is 'Dad'
But the 15-time Grand Slam champ still finds changing his twin girls' diapers "hard"
Roger Federer may be the world's top tennis champion, but when it comes to changing diapers as a first-time dad, he says he is still capable of a double fault.
"Thank God nobody is judging me on it," Federer told PEOPLE at a press conference Monday following his victory over Spain's Tommy Robredo at the U.S. Open in New York. "It's hard! But I'm still trying to be good at it."
The Swiss pro, 28, and his wife Mirka Vavrinec welcomed twin girls Charlene Riva and Myla Rose on July 23 in Switzerland.
RELATED: Roger Federer Marries His Longtime Love Miroslava Vavrinec
Off the court, the tennis ace takes his daddy duties in stride and tries to enjoy every moment with his babies.
"It's been a lot of fun being a father and spending time with them," he said. "I'm hands on as much as I can because everyday is something new and something different. I don't want to miss anything."
The 15-time Grand Slam champ says "Father" is definitely his greatest title.
"It's an amazing feeling to be called a dad," he said. "I take a lot of pride in that title."


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About Us
RheumExam Atlas is designed to help clinicians and trainees recognize important physical findings in the rheumatic diseases. To contribute images (with credit) to RheumExam Atlas, please email us at email@example.com. RheumExam Atlas was developed by Dr. Lori Albert, University of Toronto ©2015How to Use the AtlasMore About Us


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How do you get your creative inspiration? My best thinking hits about 3 a.m. The notebook next to my bed has been the catalyst for a lot of creative tornadoes through the years.
I'm currently giving back to the community by: Chairing the new Capital Campaign at my son's incredible school for kid's with learning disabilities – Havern School. They are a hidden gem.
Most memorable live music experience: William Topley at The Bluebird or the Pre-K Mother's Day 'concert'. My youngest decided to break into a rap during the ballad.
Favorite Denver hangout: The deck at TallGrass Spa for my sanity, and the deck at Izakaya for sake (also for my sanity).
Hometown: Action City, Oklahoma (a.k.a Oklahoma City). It doesn't sound like much, but I wouldn't have traded it for anything.


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Roman Blinds
For the ultimate luxury and lush designer fabrics – Roman blinds are the true finishing touch to any room, adding the warmth and beautiful design. Available in over 300 designs and colours ranging from plain textiles & see-throughs to sophistically crafted fabrics that will allow you to create the most unique style in your room.
We are working with Deco-Sun and Bill Beamount to deliver the absolutely best available range of products to meet any style and budget. Both deliver the most smooth and reliable systems meeting our highest quality standards.


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iconoclast called me fat last night* and said that we could never be together (Apparently caring about the sanitary status of your fruit makes you a "Huge fucking bottom." Who knew?)
And I am fat. But it's something I'm working on. Whenever I get even a whiff of an interesting female I immediately start to worry about my weight, hair, and various other inadequacies. It's loads of fun.
Anyway, to work on my weight I am using my treadmill, which is really the only form of cardiac exercise I can tolerate for extended periods of time. I don't like bikes because they make my ass hurt, I don't like walking or running outside because it's boring (treadmill is in front of my TV) I don't like sports because I absolutely suck at them.
And the treadmill is fine right now and everything's going well. Except for one thing. The smell. See I am the kind of guy who tends to sweat a lot when I work out. And by a lot I mean buckets upon buckets upon buckets. I also get hot, and with the weather the way it's been the only way I've been able to combat this has been to strip down to my boxers and aim a fan directly at my torso, thus taking advantage of my sweat spray to cool me off. The problem is that as the sweat dies it leaves residue on my skin and in my boxers, and by the time I'm done with my first session I smell like a ginkgo nut suppository that was recently discovered in the rectum of Chris Farley's corpse. By the time my second session's done I smell like chemical warfare.
So I strip down and shower, but then when I leave the shower there's the question of what to do with the clothing left over. See you don't want to pick it up right after a shower because that'll just get you FILTHY with sweat stink again. But you don't want to leave it on the bathroom floor because, I swear to god, it will eat right through. So I usually try to use some sort of tool or stick to move them to the laundry. But once there I don't want them in contact with any other clothing, because let's face it, that kind of stink never TRULY leaves cloth. I usually end up putting them in on their own, but then I feel guilty about doing such a small wash, even as the scent wafts from the machine and tells me to GET ON WITH IT!
I have a towel hanging off the handle that I use to wipe myself down. I left it on for 3 days once without washing. The first day it was fine. The second day there were flies buzzing around it. The third day there were no flies. They were all dead.
It's tough being toxic.
*What he actually said was that I couldn't fit in a dress made for Paris Hilton, so I guess the correct term is "non-emaciated" but it STILL STINGS.


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- Description
DetailsCare for your hardware. Show that you care by wrapping your laptop up in a protective skin. The lightweight neoprene skin protects your laptop from scratches and bumps. Its smooth interior and inner lip around the zip closure give a complete shield to your laptop when inside. Simple, clean design can be used on its own
- Specification
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Delivery information
To cater the needs of all customers, we offer two delivery options at checkout so you can choose one which best suits your requirements.
Free UK Delivery
In this option we will deliver your product free of charge but it will take 3 to 5 working days for the product to be delivered.
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- Reviews


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28 November 2017
Today was CJ's birthday. It was also a beautiful, blue sky, late autumn day so what better way to celebrate than with a little walk and a nice lunch? As CJ is fond of both history and graffiti, I thought I had just the walk for him. As for the lunch, neither of us had a clue where to eat but, as our walk would end up in town, we'd be fairly spoilt for choice.
We set off across Cobden Bridge mirroring my old walk to work at the bus mines. All the little boats bobbing about on the blue green river gave the impression of a summer's day but the temperature was more like winter. We stopped briefly on the middle of the bridge to take a photo then scurried to the other side, our ears burning from the cold wind. There was one more stop to capture the wonderfully delapidated Dyer Brothers building and then we turned off into Priory Road, thankful of the shelter of the houses.
The tide was low when we came to the slipway where I often saw a family of swans on my morning journeys. Today there were only a few gulls scattered between mud and water. Here the river, ruffled by the biting breeze, was dark blue, and rippled like watered silk.
Most of the moorings behind the Millennium Flats were empty and the boats that were there were not ones I recognised. There were no swans there either but a family of ducks were making a fearful din as we passed. The bank beside the steps, stripped of trees and shrubs towards the end of my bus mine days, looked bare and sad. Nothing much has grown back and I still can't understand why the trees had to be massacred.
On Horseshoe Bridge the familiarity of my old walk to work ended with a snap of a train passing beneath us. Now we were headed towards Bevois Mount, reputed to be either the burial mound of Bevois of Hampton or a hill built by him to defend the city against the Danes, or maybe the Normans, any real facts have long been lost. The story of Sir Bevois dates from a twelfth century Anglo Norman Romantic ballad and is irrevocably entwined with the story of Southampton.
According to the legend, Bevois (or Bevis, or Beavis medieval spelling being what it is) was the son of Guy, the Earl of Hampton and his unwilling bride, Murdina, who also happened to be a witch. Rejected by his mother, Bevois was passed off to wet nurses and nannies until she finally plotted to get rid of both her husband and son for good. With the help of her lover, Murdure, she killed Sir Guy and sold young Bevois into slavery in Armenia.
Luckily, Emryn, the King of Armenia, took Bevois under his wing and gave him a magical flying horse called Hirondelle and a magical sword called Morglay. He also gave him the hand of his daughter, Princess Josian, who Bevois rescued from two lions. Bevois used the sword to tame the giant, Ascupart, who became his squire and the three returned to England where Bevois founded the town of Southampton.
Bevois, Josian and Ascupart performed many heroic deeds, including, some say, building Arundel Tower and naming it after his horse. When Bevois was close to death, he climbed to the top of the tower and threw his magical sword. Wherever it landed was where he wished to be buried. That place, they say, was Bevois Mount. As this is almost a mile and a half away it must have been a very magical sword!
In 1723 Charles Mordaunt, third Earl of Peterborough combined Padwell Farm and land from St Denys Priory to build an estate. The land included the artificial mound, supposedly built by Bevois, and Mordaunt made a feature of it in his extensive and beautiful gardens. He called the estate Bevois Mount, in memory of the legend. Bevois Mount House stood somewhere near the junction of Lodge Road and Cedar Road. By the time I'd finished telling CJ the legend we were walking on Mordaunt's land. In fact we were standing in front of a new mural depicting him.
The painting was commissioned by the Bevois Mount History Group, formed by four former teachers, Ally Hayes, Fiona Barnes, Wendy Stokes and John Hayward who are all from the Bevois Mount area and have a love of history. The artist was Slam Daniels from Woolston, who also painted the murals in St Mary's Street and the underpass near the Holyrood Estate. Money was raised for the project by raffles, quiz nights and events at the nearby Guide Dog Pub.
The nobleman and military leader might not be everyone's cup of tea. He was a Whig, opposed to King James, and conspired with William of Orange in the invasion of England. When William became king Mordaunt was made Privy Councillor, First Lord of the Treasury and Earl of Monmouth but he made bad descisions and ended up in the Tower of London for a while. Later he was Commander in Chief of land forces in the War of the Spanish Succession but, by all accounts, he despised Archduke Charles who, through his efforts, became King of Spain. In fact he hated all foreigners, was eccentric and easily swayed by a pretty face. Despite several positions of high office including Colonel of the Royal Horse Guards and Knight of the Garter, he fell out of favour when George I came to the throne.
Despite his undoubted faults Mordaunt turned Bevois Mount into a thing of beauty. The gardens were a wonderous wilderness with a labarynth of paths, a vineyard, bowling green and parterre below the mound and a summerhouse with a cellar beneath at the summit. When the summerhouse was built part of a human skeleton was uncovered. Perhaps it was Sir Bevois, although no one seems to know what became of it.
Of course the house and the gardens are long gone now and we carried on along Earls road, slowly climbing towards the mount trying to imagine what they must once have been like. In typical fashion, we hadn't got very far before an interesting building caught my eye and had me wandering off the route I'd planned. The single story brick building had an interesting octagonal tower, topped by a cupola on thin blue columns. At the very pinnacle a copper weather cock seemed to glow in the cold sunlight.
The large arched doorway suggested it might once have been a Church or a School but neither of us could decided which and there was nothing to tell us even when we got up close. Later I discovered it was actually a listed building and had once been St Faith's Mission Hall. Today it's used as the Southampton Chinese Christian Church Centre.
Although Mordaunt had fallen out of favour with the King by the time he came to Southampton, he was popular with the writers, musicians and artists of his time and often entertained famous guests at Bevois Mount House, including Voltaire, Thomas Grey, Jonathan Swift and Alexander Pope. His second wife was Anastasia Robinson an opera singer and favourite of Handel. He was proud of his wonderfully landscaped gardens and would take his guests up onto the mount when the tide was high so they could enjoy the view across the Itchen from the top. Pope was especially fond of walking through the grounds and, in 1735, after Mordaunt died, he helped Anastasia complete the gardens. He especially loved the summerhouse and, in a letter, said "I write this from the most beautiful Top of a Hill I ever saw, a little house that overlooks the Sea, Southampton & the Isle of Wight; where I study, write, and have what Leisure I please."
After Anastasia died the Bevois Mount Estate was sold to William Betts, who built the Royal Pier and the Stag Gates at the estate entrance near the junction of Lodge Road and The Avenue. In the mid nineteenth century Betts sold the estate to J H Wolff, a shipping agent. Wolff soon began to develop the land for housing. Sadly neither the summerhouse or Bevois' mound survived. Both the artificial mound and the rock beneath it was quarried to build the roads and houses that now occupy the land. As for the house, it became a School for a while, then a student hostel. In World War I it was a prisoner of war camp and in the 1940's it was finally demolished.
These days the view of the river is interrupted by the houses Wolff built but, as we climbed higher, we could see the gasometers and the top of St Mary's Stadium, if not the river. Bevois Mount is still a steep hill, as our calves can attest, but, before all the quarrying, it would have been much steeper. Ordinance Survey maps of 1846 show that the ground rose from twenty six to seventy feet. It's probable that the artificial mound, created by Bevois or not, was on a natural spur of high ground and this is what remains today. The reason for all our climbing was another mural, right at the top of the hill.
This was also painted by Slam Daniels and commissioned but the Bevois Mount History Group. It covers three houses and is a record of the local history. The first house we came to was painted with a suffragette, the Titanic and a horse drawn bus, all things we might have seen in the city in another time. It also has a quote by Alexander Pope. The second building has a map dating from 1905 and Sir Bevois himself, standing in a doorway. The third house has a beautiful depiction of the stag gates. We stopped for quite some time looking at the detail of the mural and taking photographs.
We were now at the top of what is left of Bevois Mount and, with our mission completed, it was time to head into town for lunch. As we walked down The Avenue we should have been deciding where to eat. Instead we were talking about the Roman coins found at the top of Bevois Hill and the suggestion that there was a connection with those and the ones found at Clausentum. Some say the coins indicate a Roman watch station in both places. The mystery over who built the mound may never be solved but, when we reached Above Bar, I suddenly had a good idea about where to eat lunch. So far the day had been all about history so it seemed our lunch date should continue the theme and the most historic place I could think of was the Woolhouse.
On the way there we took a short detour to see if work had started on the demolition of the Bargate Centre. What we found there was a giant machine eating away at the car park. A workman was spraying an arc of water to keep the dust down, creating rainbows everywhere, although my camera didn't do a very good job of capturing them. We stood watching for a while, each remembering all the Sunday morning adventures that began in this car park, half sad and half excited at what the future would hold.
From there it was a short walk along Back of the Walls to our destination, with a quick shot of the birthday boy along the way. Our lunch in the Woolhouse was the perfect end to a great morning. The wonderful old building was once empty and in danger of falling into disrepair but, against a certain amount of objection, it was taken over but the Dancing Man Brewery. Now it's open to the public and filled to the brim with interesting things and wonderful food. Hopefully, this is how God's House Tower will be in a year or so.
The perfect birthday treat ended with a surprise visit from Bard, who joined us for coffee on his way to work. As we drank we talked about the things we'd seen and the ever changing face of the city. Bevois Mount and House, like so many of the grand old buildings of the past, were victims of progress and a growing population. We all agreed that some buildings derseved to be preserved and, looking around us, it seemed the best way to preserve history is to keep it alive and useful. The Woolhouse is a fine example of how well this can work, hopefully, God's House Tower will soon be another. Now if only the powers that be could see their way to doing something similar with The Bargate…
Please see my copyright information before you copy or use any of the above words or pictures.


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Microarray expression profiles reveal substantial changes in gene expression in the ipsilateral dorsal horn of the spinal cord in response to three peripheral nerve injury models of neuropathic pain. However, only 54 of the 612 regulated genes are commonly expressed across all the neuropathic pain models. Many of the commonly regulated transcripts are immune related and include the complement components C1q, C3, and C4, which we find are expressed only by microglia. C1q and C4 are, moreover, the most strongly regulated of all 612 regulated genes. In addition, we find that the terminal complement component C5 and the C5a receptor (C5aR) are upregulated in spinal microglia after peripheral nerve injury. Mice null for C5 had reduced neuropathic pain sensitivity, excluding C3a as a pain effector. C6-deficient rats, which cannot form the membrane attack complex, have a normal neuropathic pain phenotype. However, C5a applied intrathecally produces a dose-dependent, slow-onset cold pain in naive animals. Furthermore, a C5aR peptide antagonist reduces cold allodynia in neuropathic pain models. We conclude that induction of the complement cascade in spinal cord microglia after peripheral nerve injury contributes to neuropathic pain through the release and action of the C5a anaphylatoxin peptide.
Peripheral neuropathic pain typically presents with symptoms of spontaneous pain, pain in response to normally innocuous stimuli (allodynia), and an exaggerated response to noxious stimuli (hyperalgesia) (Woolf and Mannion, 1999; Dworkin et al., 2003). A particularly prominent feature of neuropathic pain is cold allodynia (Lindblom and Verrillo, 1979; Verdugo and Ochoa, 1992). Neuropathic pain results from any of multiple peripheral nerve lesions including compression, trauma, infection, metabolic disorders, toxin exposure, and autoimmune disease (Dworkin et al., 2003). Peripheral nerve damage drives a variety of changes in both the peripheral and CNS to produce pain. In the CNS, peripheral nerve injury results in amplified sensory transfer (central sensitization) attributable to augmented synaptic transmission between primary sensory and dorsal horn neurons, an increase in descending facilitatory influences from the brainstem, and a loss of inhibitory transmission in the spinal cord (Woolf and Salter, 2000; Waxman, 2001; Scholz and Woolf, 2002; Coull et al., 2003; Gebhart, 2004; Inoue et al., 2004; Scholz et al., 2005).
Several rodent partial peripheral nerve injury models have been developed to help study the mechanisms responsible for neuropathic pain. Among these are the spared nerve injury (SNI) model, in which two of the three peripheral branches of the sciatic nerve are transected, producing a distal partial nerve lesion (Decosterd and Woolf, 2000); the chronic constriction injury (CCI) model, in which loose ligatures cause compression and inflammation of the sciatic nerve, injuring mainly myelinated axons (Bennett and Xie, 1988); and the spinal nerve ligation (SNL) model, a proximal axonal injury model (Kim and Chung, 1992). All models generate prolonged peripheral hypersensitivity to noxious and innocuous mechanical and cold stimuli.
Many of the mechanisms responsible for neuropathic pain involve changes in mRNA levels because of altered gene expression or transcript stability. After complete transection of the sciatic nerve, hundreds of genes undergo altered expression in the dorsal root ganglion (DRG) when examined at a single time point (Costigan et al., 2002; Wang et al., 2002), and some of these are regulated over time (Xiao et al., 2002). In the dorsal horn of the spinal cord, gene expression also occurs after peripheral nerve injury, and studies of the global changes in gene expression after two different partial nerve injury models, L5 nerve root ligation and L5 spinal nerve transection, suggest that there is relatively little overlap in the gene expression between these models, although both produce tactile allodynia (Lacroix-Fralish et al., 2006). The extent to which changes in gene expression in the dorsal horn differs or is common across diverse peripheral neuropathic pain models is not known. In an effort to better understand the molecular mechanisms of neuropathic pain and to identify targets for potential novel analgesics, we performed a large-scale expression profile analysis in the dorsal horn, in three neuropathic pain models (SNI, SNL, and CCI) and five time points (0, 3, 7, 21, and 40 d). We find from this analysis that induction and action of the complement cascade in microglia contributes to neuropathic pain.
Materials and Methods
Animal surgery.
Three separate experimental groups were prepared for the microarrays: SNI, CCI, and SNL (Bennett and Xie, 1988; Kim and Chung, 1992; Decosterd and Woolf, 2000). Adult male Sprague Dawley rats were anesthetized using isoflurane. For SNI, the tibial and common peroneal branches of the sciatic nerve were ligated with a silk suture and transected distally, whereas the sural nerve was left intact. For CCI, three chromic gut sutures were loosely placed around the sciatic nerve at midthigh level. For SNL, an incision was made over the L4/L5 lumbar vertebrae, the transverse processes were removed on one side, and a spinal nerve (L4 or L5) was tightly ligated (Kim and Chung, 1992). All procedures were performed in accordance with the Massachusetts General Hospital (MGH) animal care regulations.
Tissue preparation, RNA extraction, and chip hybridization.
The ipsilateral lumbar L4 and L5 dorsal horn was dissected and rapidly frozen. The tissues were homogenized, and total RNA was obtained by acid phenol extraction (TRIzol reagent; Invitrogen, Carlsbad, CA). Biotinylated cRNA for hybridization was produced from the total RNA and hybridized to the Affymetrix (Santa Clara, Ca) RGU34A chip (Costigan et al., 2002). For each condition, three biologically independent hybridizations were performed, each using cRNA probes produced from independent RNA samples extracted from pooled tissue from five animals.
Data analysis.
CEL files were produced using MAS 5.0. All other data analysis was done using R software (R Development Core Team, 2005). Background correction and quantile-quantile data normalization were performed, followed by calculation of probe set intensities using the RMA (robust multiarray average) method (Bolstad et al., 2003; Irizarry et al., 2003) [www.bioconductor.org (Gentleman et al., 2004)]. To assess reproducibility, the correlation coefficients between all possible pairings of single chips within a triplicate were calculated. The weakest of the three correlation coefficients was used to represent that triplicate, with the worst within-triplicate correlation coefficient throughout the full data set still better than 0.97. The iteratively reweighted least-squares regression method was used to estimate expression level (Venables and Ripley, 2002; Diaz et al., 2003). The regression model treated time points (3, 7, 21, 40) as nested within the type of nerve injury (SNI, CCI, SNL). After estimating the expression level, Sammon's nonlinear mapping was implemented on the matrix of Euclidean distances between pairs of conditions using the MASS R library (Venables and Ripley, 2002). Bootstrap p values associated with contrasts between SNI and naive, CCI and naive, and SNL and naive for each gene were calculated by resampling from the residuals of the original model. The threshold p value consistent with a false discovery rate (FDR) near 5% was identified as 0.01 (Storey and Tibshirani, 2003), based on an estimate of the overall proportion of true null hypotheses derived from the observed distribution of p values. The q-value calculation was performed separately for each injury, and an overall p-value threshold of 0.01 was selected because it resulted in a q value near 5% for each model (SNI, 5.4%; CCI, 4.6%; SNL, 2.3%). In addition to the p-value threshold, we required that the expression ratio relative to naive averaged over the four postinjury time points reach at least 1.25-fold when converted to a linear scale, for a gene to be considered differentially expressed. Note that we have previously published a 1.5-fold cutoff with a p value of 0.05 (t test) (Costigan et al., 2002). Because the data are derived from five time points in this study (vs two in the previous study), we reduced the fold change cutoff for regulated gene identification to permit inclusion of transiently regulated genes, or genes with a consistent but relatively low magnitude of regulation. Furthermore, those genes quoted in the text of this study all displayed common regulation across three different pain models.
The temporal behavior of groups of genes was also assessed graphically. The data for each probe set meeting the criteria for regulation were scaled to mean zero, root mean square 1 over the data for a single model (Tavazoie et al., 1999). The scaled data were then grouped using k-means cluster analysis (Hartigan and Wong, 1979). The number of clusters was chosen empirically, by finding the elbow in the plot of the total within cluster sum of squares as a function of cluster number. The means of the k-means clusters were grouped using divisive hierarchical clustering (Kaufmann and Rousseeuw, 1990). For Venn diagram analysis, the number of genes regulated in a given condition was adjusted using the UniGene database such that multiple probe sets corresponding to the same gene were only counted once.
Quantitative real-time-PCR.
Quantitative real-time (RT) PCR was performed using the Sybr green detection system with primer sets designed on Primer Express. Specific PCR product amplification was confirmed using the dissociation protocol. Transcript regulation was determined using the relative standard curve method per the manufacturer's instructions (Applied Biosystems, Foster City, CA). Relative loading was determined before RT with RNA spectrophotometry, followed by gel electrophoresis and post-RT by amplification of glyceraldehyde-3-phosphate dehydrogenase. For each time point, four samples of pooled tissue from two rats were analyzed.
In situ hybridization.
Tissue was rapidly removed, embedded in Tissue Tek OCT (Sakura, Torrance, CA), and frozen. Sections were cut serially at 18 μm, and in situ hybridization histochemistry was performed using digoxygenin-labeled antisense riboprobes (0.6–2 kb in length) (Blackshaw and Snyder, 1997). For fluorescent in situ hybridization, we perfused the animals transcardially with 4% paraformaldehyde, dissected the spinal cord, and collected transverse cryosections (10 μm) of the L4 dorsal horn. We detected the hybridized riboprobes using Fab fragments from an anti-digoxigenin antibody conjugated to horseradish peroxidase (Roche, Basel, Switzerland) and a tyramide signal amplification kit (Invitrogen). Primary antibodies were rabbit anti-rat Iba1 (1:750; Wako, Richmond, VA), anti-mouse NeuN (1:2000; Chemicon, Temecula, CA), and rabbit anti-GFAP antibody (1:300; Chemicon). Fluorescent images were acquired either by using a Nikon (Tokyo, Japan) Eclipse E800 microscope or by confocal laser-scanning microscopy as described previously (Brenner et al., 2004)
Terminally anesthetized rats were perfused with 0.9% NaCl, followed by 4% paraformaldehyde with 0.025% picric acid in PBS. Twelve micrometer frozen sections were prepared, blocked for 1 h, and incubated for 24 h in 1% BSA with 0.1% Triton X-100 in PBS, with primary antibody [i.e., 1:1000 goat anti-rat C3 (MP Bio, Irvine, CA), 1:750 rabbit anti-rat Iba, 1:50 mouse anti-rat C5aR (R63; Hycult Biotechnology, Uden, The Netherlands), 1:100 Griffonia simplicifonica isolectin IB4 conjugated to FITC (Sigma-Aldrich, St. Louis, MO)]. Colocalization was performed using sequential application of each pair of primary and secondary antibodies. Fluorescent Alexa secondary antibodies were obtained from Invitrogen.
Primary microglial cell cultures.
Cerebral cortices from postnatal day 1 C57BL/6 mice were dissected, digested, and mechanically dissociated. Cells were plated in RPMI 1640 medium, 10% FBS, 5 mg/ml granulocyte macrophage colony-stimulating factor. After 14 d, microglial cells were dislodged by shaking at 220 rpm for 2 h. Microglial cells settled from the resulting suspension and were washed extensively with RPMI medium. This produced purified microglial cultures (≥99%), assessed by staining using antibodies against microglial markers Iba1 and CD11b (1:1000, rat anti-mouse AbD; Serotec, Raleigh, NC), with negative immunoreactivity against GFAP (astrocytes), NeuN (neurons), and myelin basic protein (oligodendrocytes) (data not shown).
Animal behavior.
Cold allodynia was assayed by applying a drop of acetone to the plantar hindpaw and measuring the time the animal spent licking, shaking, or lifting the paw within the first 20 s (Decosterd and Woolf, 2000). C5-deficient Hc0 mice and congenic controls were obtained from The Jackson Laboratory (Bar Harbor, ME). C6-deficient rats were supplied from the colony maintained by G.L.S. (Bohle and Stahl, 2004). For C5a intrathecal injection, an indwelling spinal catheter (Recathco, Allison Park, PA) was preimplanted 3 d before injection. C5a in saline or saline alone were injected intrathecally (C5a; 10 or 100 ng single 20 μl injection). Results for both paws were averaged. The C5a receptor (C5aR) antagonist, a synthetic cyclic AcF-[OPdChaWR] peptide, was produced by the MGH peptide core and stored at −80°C (0.5 mg/ml PBS and 5% ethanol) (Clark et al., 2006). A catheter (32 gauge; Recathco) was implanted into the intrathecal space of the vertebral column with its tip at the lumbar (L3–L5) level through a cisternal incision. The catheter was connected to an osmotic minipump (model 2002 delivering 0.5 μl/h for 14 d; Alzet, Cupertino, CA) containing antagonist in PBS [200 ng/ml, approximately 10 times the peptide ED50 concentration (March et al., 2004)]. Control catheters contained PBS alone. Primary baseline behavior was performed on day −1, before catheter and pump placement. Secondary baseline behavior was performed on day 0, before SNI surgery. Ten days after surgery therefore represented pump day 11.
Expression profiles after peripheral nerve injury
We used oligonucleotide microarrays to measure changes in mRNA expression in the dorsal horn in the SNI, CCI, and SNL peripheral nerve injury models. The three models produced a very similar pattern of pain hypersensitivity (data not shown). We used multidimensional scaling (Fig. 1 a) to assess the relationships between the global expression profiles of the models at the different time points. A priori, these analyses had three possible outcomes: no clustering, clustering according to time point, or clustering according to neuropathic pain model. The global expression profiles represent an average of the triplicate data for all probe sets on the Affymetrix RGU34A array. Displaying the distance matrix in two-dimensional space (Fig. 1 a) showed the dorsal horn data formed three distinct groups, one for each model. Time is, therefore, a less important contributor to the degree of similarity in global transcriptional regulation than the type of injury to sensory neurons, which differ by location (proximal SNL, distal SNI), numbers of primary sensory neurons with injured axons (almost all SNL, ∼40% CCI and SNI), and presence of substantial perineural inflammation (CCI).
We defined regulated genes using criteria of p < 0.01 and an overall fold difference from naive of >1.25 (see Materials and Methods). The p-value threshold was selected using an FDR control method (Storey and Tibshirani, 2003). The numbers of regulated genes within the dorsal horn for each model and combination of models is shown in Figure 1 b and are identified in supplemental Table 1 (available at www.jneurosci.org as supplemental material). To group the regulated genes according to change in expression over time within each model, we used a two-step clustering method (Hartigan and Wong, 1979; Kaufmann and Rousseeuw, 1990; Diaz et al., 2003).
Figure 1 c illustrates the time course of relative expression of the regulated genes for each model. Changes typically either peaked at 3 d, with rapid recession to near-naive values, or showed a sustained pattern of altered regulation over the full time course (Fig. 1 c). More genes were upregulated than downregulated, with the proportion downregulated varying according to the injury model. The genes regulated in all three neuropathic pain models were grouped according to functional class (supplemental Fig. 1, available at www.jneurosci.org as supplemental material). The largest group consisted of genes associated with immune function (Fig. 2). Other functional gene classes regulated in all three models included neurotransmission, signal transduction, transcriptional regulation, and the cytoskeleton (Fig. 2 and supplemental Fig. 1, available at www.jneurosci.org as supplemental material).
Induction of complement genes in the dorsal horn
We screened the commonly regulated genes for members of the same signaling pathways as means to detect potential key functional contributors to the pain phenotype. We have previously used a similar approach in the DRG that identified the contribution of the tetrahydrobiopterin synthesis cascade to the peripheral generation of neuropathic pain (Tegeder et al., 2006). Four genes encoding three complement components (C1qb, C1qg, C4, and C3) were among the immune genes regulated in the arrays across all three models (Fig. 2). C1qb and C3 were also the most highly regulated transcripts across all genes assayed, averaged over all time points and models (supplemental Table 2, available at www.jneurosci.org as supplemental material). Therefore, we decided to direct attention to the possible involvement of the complement cascade (Fig. 3 a) in neuropathic pain hypersensitivity. Relatively recent data by Twining et al. (2005) implicates complement in neuropathic pain using intrathecal treatment with sCR1 (soluble complement receptor 1). This study did not investigate the cellular origin of the cascade or the complement effector pathway responsible, however.
The spatial localization of C1qb, C3, and C4 mRNA expression in the dorsal horn after nerve injury was characterized by in situ hybridization (Fig. 3 b). The expression pattern for these complement genes closely matched the temporal regulation observed in the array data. We also validated by in situ hybridization the upregulation of these genes in the dorsal horn of SNL and CCI animals at 7 d (data not shown).
Expression of complement genes in microglia
All three of the complement components expressed in the dorsal horn after peripheral nerve injury were found only in myeloid cells, as identified by colocalization with the microglial marker Iba1 (Imai et al., 1996) and the absence of coexpression with either a neuronal (NeuN) or astrocytic (GFAP) marker (Fig. 4). To localize the spatial extent of the activated microglia relative to injured central afferent terminals in the superficial dorsal horn after SNI, we compared Iba1 immunoreactivity, a marker of activated microglia, with IB4 binding, a marker of C-fiber nociceptor central terminals that synapse in spinal cord lamina II (Fig. 5). IB4 staining in afferent central terminals decreases after peripheral nerve injury (Munglani et al., 1995; Shehab et al., 2004). Iba1 staining was strong in, but not limited to, the area innervated by injured nociceptive afferents as detected by decreased IB4 staining (Fig. 5 a). Iba1 staining in the deeper lamina was consistent with the medial innervation of the tibial and common peroneal nerves as opposed to the more lateral innervation of the spared sural nerve. C3 immunoreactivity colocalized to a subset of the Iba1-positive cells in the ipsilateral dorsal horn after SNI, indicating that this complement protein is produced after the injury in many but not all microglia (Fig. 5 b–g).
C5 is the pivotal terminal complement component before the C5a anaphylatoxin and membrane attack complex (MAC) complement effectors (Fig. 3 a). C5a acts directly on its receptor, C5aR, whereas C5b activity leads to MAC formation. We therefore examined expression of C5 mRNA and that of the C5aR (C5aR/CD88) in the dorsal horn after SNI. C5 mRNA progressively increased after SNI, reaching a level ∼7.5-fold higher than that present in uninjured rats at 21 d (Fig. 6 e), whereas C5aR increased rapidly, with an earlier peak at 3 d (Fig. 6 d). C5aR was detected immunohistochemically only in spinal cord microglia (Fig. 6 a), with low constitutive level expression in uninjured spinal cord that increased considerably early after SNI (Fig. 6 b,c).
Next, we analyzed potential mechanisms for complement C3 mRNA induction. Purified neonatal mouse microglial cell cultures (Fig. 7 a–d) showed minimal basal C3 expression (Fig. 7 e,f) but began to express C3 mRNA and protein after activation of the microglia by bacterial lipopolysaccharide (LPS) or tumor necrosis factor α (TNFα), but not interleukin-1β (IL-1β) (Fig. 7 e–h). These cells expressed C5aR protein constitutively in vitro (data not shown).
Activation of the complement cascade and pain
We find that mice with C5 deficiency (Frank, 1995), which blocks formation of both C5a and the MAC, show decreased pain sensitivity in the SNI model (supplemental Fig. 2, available at www.jneurosci.org as supplemental material). These findings confirm those of the Watkins group (Twining et al., 2005) and, in addition, show that the C3a anaphylatoxin is not involved in nerve injury-induced pain sensitivity, because C3a production occurs before C5 function in the complement cascade. To determine whether MAC formation is a potential mediator of complement-induced neuropathic pain hypersensitivity, we tested a strain of rats deficient in complement component C6, which is downstream of C5b and absolutely necessary for MAC assembly. We found no difference in pain hypersensitivity after SNI in C6-deficient rats relative to controls (supplemental Fig. 2, available at www.jneurosci.org as supplemental material) and conclude, therefore, that the MAC is not involved.
Collectively, these data appear to exclude a major role for C3a or the MAC as pain effectors, leaving only C5a. To determine whether the C5a anaphylatoxin peptide has a role in pain hypersensitivity, we injected C5a into the intrathecal space of the rat spinal cord in noninjured animals. The C5a peptide produced a dose-dependent increase in cold pain sensitivity that persisted for 6 h (Fig. 8 a). This suggests that C5a is sufficient to enhance nociceptive pain sensitivity, although the effect of C5a after peripheral injury may differ attributable to upregulation of its receptor. We then investigated whether C5a contributes to neuropathic pain hypersensitivity by infusing a cyclic peptide, specific C5aR antagonist AcF-[OPdChaWR] (Finch et al., 1999), continuously into the intrathecal space of rats subject to SNI over a period of 10 d. The C5aR antagonist significantly reduced cold allodynia relative to vehicle (PBS)-treated animals (Fig. 8 b). This suggests that C5a is necessary, at least for this feature of neuropathic pain. Mechanical responsiveness showed a nonsignificant trend toward lower sensitivity after the C5R antagonism (data not shown).
Induction of the complement cascade after nerve injury
Given that the SNI, CCI, and SNL models of peripheral nerve injury are all characterized by an increase in pain-related behavior, we hypothesized that at least some of the genes that are regulated in parallel across all the models may contribute to the shared pain phenotype. The largest group of commonly regulated transcripts are related to immune function, and most prominent of these are several members of the complement cascade. The complement cascade is part of the innate immune system and provides a rapid host defense mechanism before the slower but more specific acquired immune system is activated. The complement system relies on recognizing certain non-self or pathogen-associated molecular signatures. Approximately 30 activator and inhibitor proteins interact in a cascade to opsonize pathogens, initiate cell signaling, effect cell lysis, recruit inflammatory cells, and increase vascular permeability (Walport, 2001; Carroll, 2004). Proteins of the complement cascade are generally considered the product of hepatic synthesis, with distribution in plasma to their site of action, although increasingly it is recognized that local synthesis in injured tissues also occurs. Because CSF complement concentration is several hundred-fold lower than that in serum (Jongen et al., 2000), transfer from serum is unlikely to be the source of complement in the CNS. Microglia, astrocytes, and oligodendrocytes synthesize complement proteins in the CNS after injury, infection, and ischemia (Laufer et al., 2001; van Beek et al., 2003) and, as we now show, after peripheral nerve injury. Excessive activation of this cascade or expression in inappropriate sites can cause severe damage in many tissues, including the CNS (Laufer et al., 2001; van Beek et al., 2003).
Microglia are activated in the dorsal horn after peripheral nerve injury and lie in close proximity with the central terminal zone of injured afferents (Liu et al., 1998; Winkelstein et al., 2001; Tsuda et al., 2005). We find that a subset of Iba1-positive microglia upregulate components of the complement cascade. Inflammatory cytokines are prime candidates for inducing upregulation of complement genes in microglia. IL-1β, IL-6, TNFα, and interferon-γ (IF-γ) induce components of the complement cascade in liver and brain (Veerhuis et al., 1999; van Beek et al., 2003; Stapp et al., 2005) and are expressed in the spinal cord and DRG, where their levels increase after peripheral nerve injury (Arruda et al., 1998; Hashizume et al., 2000; Winkelstein et al., 2001; Tanga et al., 2004). We find, moreover, that TNFα strongly increases C3 expression in cultured microglia (Fig. 7). TNFα is a candidate of particular interest because after nerve injury it has been shown to be a mediator of both spinal microglial activation and neuropathic pain hypersensitivity (Svensson et al., 2005). Candidates for gene upregulation by complement are the chemokines CX3CL1 (fractalkine) and CCL2 (monocyte chemoattractant protein-1) (Abbadie et al., 2003; Albrecht et al., 2004; Verge et al., 2004; Tanga et al., 2005; Thurman et al., 2007). Increased expression of the receptors for CX3CL1, CCL3, CCL8, and IF-γ is found after peripheral nerve injury (supplemental Table 1 and supplemental Fig. 1, available at www.jneurosci.org as supplemental material), consistent with the possibility that these chemokines in turn activate microglia (Abbadie et al., 2003; Verge et al., 2004; Tanga et al., 2005).
Activation of the complement cascade after nerve injury
What triggers activation of the complement cascade in the spinal cord? Although immune complexes are the best known activator of the classical complement pathway, other molecular entities, both endogenous and exogenous, can activate C1q, including serine proteases, myelin, amyloid fibrils, DNA, and LPS (Vanguri et al., 1982; Elward and Gasque, 2003). C3 is centrally located in the complement cascade, representing the point of convergence of the three different arms of complement activation. C3 activity leads to opsonization and clearance, as well as activation of C5, which in turn leads both to the production of the terminal complement MAC and release of the anaphylatoxin C5a peptide.
The lack of a reduction in pain sensitivity after peripheral nerve injury in C6-deficient rats argues against a role for MAC in the generation of neuropathic pain. Our findings point instead to C5a as the effector of the complement pathway in neuropathic pain. We show that intrathecal injection of C5a produces cold allodynia in naive animals, whereas that of a C5aR antagonist reduces cold pain in rats with SNI. C5a has pleiotropic inflammatory effects, acting on numerous cell types via activation of nuclear factor-κB, activator protein-1, and cAMP response element-binding protein signal transduction pathways (Mastellos et al., 2005). C5a causes an oxidative burst in neutrophils, enhances phagocytosis (Guo and Ward, 2005), and acts as a chemoattractant for neutrophils, monocytes, and macrophages (Marder et al., 1985).
C5aR is a G-protein-coupled receptor that is expressed in the CNS (Stahel et al., 1997; Farkas et al., 2003). We find that C5aR is constitutively expressed at low levels by microglia in the intact dorsal horn and that its expression increases shortly after peripheral nerve injury, likely enhancing the responsiveness of microglia to C5a. C5a signaling may be involved, therefore, in the activation and/or recruitment of microglia in the dorsal horn after nerve injury and, in this way, contributes to the initiation of neuropathic pain.
Microglia and pain
Chemokines, purines, and cytokines all contribute to neuropathic pain via the activation of microglia in the dorsal horn from their normal quiescent state (DeLeo and Yezierski, 2001; Watkins et al., 2001; DeLeo et al., 2004; Tsuda et al., 2005), and we now propose that C5a is also involved. Activated microglia release BDNF, which causes a shift in the anion reversal potential in a subset of spinal lamina I neurons, leading to an excitatory response to GABA instead of inhibition within these cells (Coull et al., 2003, 2005). In addition, several other signal molecules that alter excitability or synaptic transmission are released from microglia (Marchand et al., 2005). Inhibition of microglia, using minocycline and propentophylline as well as mitogen-activated protein kinase p38 inhibitors, reduces neuropathic pain (Sweitzer et al., 2001; Jin et al., 2003; Raghavendra et al., 2003; Ledeboer et al., 2005; Tawfik et al., 2007), as do null mutations of chemokine and Toll-like receptors expressed by microglia (Abbadie et al., 2003; Verge et al., 2004; Tanga et al., 2005).
Increased expression of the complement cascade in the spinal cord is the most prominent transcriptional change found across multiple neuropathic pain models. C5a anaphylatoxin acting via C5aR expressed on microglia augments pain hypersensitivity. We conclude that a neuroimmune interaction involving induction and activation of the complement cascade in microglia contributes, by production of C5a, to the maladaptive responses to nerve injury that lead to the generation of pain.
This work was supported by the National Institutes of Health [Grants RDE017821A and NS038253 (C.J.W.), NS052623 (M.C.), and NS044139 (G.J.B.)] and Bayer AG. A.M. is the recipient of a Bogue research fellowship (University College London, London, UK). We thank Ashok Khatri, peptide core Massachusetts General Hospital for production of the C5a receptor antagonist, and Marissa Hamrick for technical assistance.
- Correspondence should be addressed to Dr. Clifford J. Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 4309, Charlestown, MA 02129. cwoolf{at}partners.org
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2014 RIS Software LeaderBoard
Now in its 14th year, the RIS Software LeaderBoard is a fact-based guide to the best software providers in retail. It is the only research study in retail tech that measures customer satisfaction. Find out where SAP, Oracle, Epicor, JDA, NCR, Manhattan Associates, MicroStrategy and other software vendors stack up in head-to-head rankings.


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Part 1 Comparative Overview of Concepts of Attorney–Client Privilege, 3 England and Wales
From: Attorney-Client Privilege in International Arbitration
Annabelle Möckesch
- Subject(s):
- Privilege — Choice of law — Conflict of laws — Arbitrators — Confidentiality
This chapter follows the structure of the previous chapter. It gives a brief introduction to the Woolf Reform and the Civil Procedure Rules, which regulate the conduct of civil court proceedings and are based to a large extent on Lord Woolf's recommendations. The chapter then briefly sets out the course of a lawsuit and presents the taking of evidence in civil litigation in the pre-action, the pre-trial, and the trial phase. Lastly and most importantly, the chapter explores legal professional privilege, which has two sub-heads under English law: legal advice privilege and litigation privilege.


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621 First Avenue South
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We Walk by Faith
During a lifetime we walk thousands of miles. On a deeper level in our lives we "walk by faith", seeking the friendship and face of God. This is the single most important walk of our lives! Fortunately, there is wisdom available to us for this journey. The words of the Scripture are a "light for our path" (Psalm 119). God is everywhere. "In him we live and move and have our being" (Acts 11:28). We are immersed in divine compassion.
Open your hearts to it! Emeritus Pope Benedict XVI has declared October 2012-2013 a Year of Faith. Join us at King's House as we reflect on how we are called to "Walk By Faith".
Our silent retreat format:
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Registration: Friday, May 10 at 7:00 pm Concludes: Sunday May 12, 12:45 pm
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A non-refundable deposit of $30.00 per person must be received in order to reserve a room.
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At Central Vermont Medical Center we carry and make a variety of orthotics that can be helpful to individuals experiencing various types of back, feet, or knee issues.
At CVMC Rehabilitation Services, we carry and make a variety of orthotics that can be helpful to individuals experiencing back pain, bunions, plantar fasciitis, knee pain, flat feet (pes planus), over pronation, etc.
Please check with your insurance company to see if orthotics are a covered service.
What Are Orthotics?
An orthosis, by definition, is an external, custom-made medical device that is used to support, align, prevent or correct deformities of a body party, or to assist a physical weakness or improve function of moveable parts of the body. In other words, an orthotic that can be placed in your shoe, is intended to minimize abnormal motion (whether it is too little motion or too much motion) in your lower body.
Orthotics Evaluation
After a detailed examination of your posture, foot alignment and gait, it may be determined that you are a candidate for orthotics.
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Off-the-shelf orthotics are most appropriate for people that have mild impairments and need light support. These orthotics typically last 6-12 months before they need to be replaced.
Our custom-made orthotics are for more involved impairments and can last up to 10 years depending on the type of orthotic and the amount of wear over the years. Some custom orthotics can be fabricated in our clinic and are available 2 to 3 days after your visit. For others, we make plaster molds of your feet and send them away for fabrication. These orthotics take about 3 weeks to be completed and returned to our clinic.
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In addition to orthotics, patients will be instructed in a home exercise program to complement the orthotics, as the orthotics alone typically will not resolve your symptoms.
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User:RobertC/Heavenly Banner
Below are quotes from Ezra Taft Benson's The Constitution: A Heavenly Banner (1986, Deseret Book)
- 1 Some Basic Principles (pp. 1-10)
- 2 The Constitution and Its Coming Forth (pp. 10-11)
- 3 God Raised Up Wise Men to Create the Constitution (pp. 11-15)
- 4 The Lord Approved the Constitution (pp. 15-17)
- 5 The Document Itself (pp. 17-18)
- 6 Major Provisions of the Document (pp. 18-23)
- 7 The Crisis of Our Constitution (pp. 23-31)
- 8 The Constitution Requires Our Loyalty and Support (pp. 31-33)
Some Basic Principles (pp. 1-10)[edit]
The Principle of Agency[edit]
The first basic principle is agency. We understand the purpose of the council in heaven was to announce and present the plan of redemption for the salvation of all of God's children. The council was called so that every man and woman could sustain the provisions of the Father's plan, which required that all people obtain mortal bodies, be tried and proven in all things, and have opportunity to choose of their own free will to obey the laws and ordinances essential to their exaltation.
Because a fallen condition was an essential part of the plan, an infinite, eternal sacrifice was also required to redeem us from this state. We are all familiar with the facts: how Lucifer—a personage of prominence—sought to amend the plan, while Jehovah sustained the plan. The Prophet Joseph Smith explained how this difference wled to the war in heaven: "The contention in heave was—Jesus said there would be certain soulds that would not be saved; and the devil said he could save them all, and laid his plans before the grand council, who gave their ovte in favor of Jesus Christ. So the devil rose up in rebellion against God, and was cast down." [No reference provided.]
The central issue in that council, then, was: Shall the children of God have untrammeled agency to choose the course they should follow, whether good or evil, or shall they be coerced and forced to be obedient? Christ and all who followed Him stood for the former proposition—freedom of choice; Satan stood for the latter—coercion and force. Because Satan and those who stood with him would not accept the vote of the council, but rose up in rebellion, they were cast down to the earth, where they have continued to foster the same plan. The war that began in heaven is not yet over. The conflict continues on the battlefield of morality. And one of Lucifer's primary strategies has been to restrict our agency through the power of earthly governments. Proof of this is found in the long history of humanity.


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2 Sep 1939
- Germany annexed the Free City of Danzig. Adolf Hitler advised the United Kingdom and France that he would withdraw from Poland if allowed to keep Danzig and the Polish corridor. ww2dbase [The Danzig Crisis | TH, CPC]
- The Germans began the construction of Stutthof Concentration Camp in Sztutowo (German: Stutthof) in the Free City of Danzig with labor of 65,000 Polish Christians. ww2dbase [Discovery of Concentration Camps and the Holocaust | Sztutowo | CPC]
- No. 1 Group, British RAF Bomber Command, relocated to France with its squadrons of single-engine Fairey Battle aircraft. ww2dbase [AC]
- Benito Mussolini continued to urge peace between Germany, United Kingdom, and France, without any success. ww2dbase [Benito Mussolini | CPC]
- In a fateful cabinet meeting South African Prime Minister Barry Hertzog declared that he was going to remain neutral and that under no circumstances would he allow the Union of South Africa to enter the war. ww2dbase [AC]
- The National Service (Armed Forces) Act was passed in Great Britain. It would be enacted on the following day upon Britain's official entry into the European War. ww2dbase [TH, AC]
- During the day, British Prime Minister Neville Chamberlain and French Prime Minister Édouard Daladier issued a joint ultimatum to Germany, demanding the withdraw of troops from Poland within 12 hours. During the late hours of the night, Chamberlain attempted to convince Dalalier to carry out the threat from the earlier ultimatum by declaring war on Germany early in the next morning. ww2dbase [Invasion of Poland | TH, CPC]
- The Times Literary Supplement reported that the copy of the Magna Carta owned by the Lincoln Cathedral of England, United Kingdom, currently on display at the 1939 New York World's Fair, would remain in the United States under the care of the Library of Congress for the duration of the war. It would be stored at Fort Knox until its return to Lincoln in 1944. ww2dbase [England | CPC]
Timeline Section Founder: Thomas Houlihan
Contributors: Alan Chanter, C. Peter Chen, Thomas Houlihan, Hugh Martyr, David Stubblebine
Special Thanks: Rory Curtis
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Famous WW2 Quote"All that silly talk about the advance of science and such leaves me cold. Give me peace and a retarded science."
Thomas Dodd, late 1945


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Key Features
Release Date: 12.28.2016
The Harley Quinn Metal Bottle Opener is at your service! Harley wears her classic jester costume as she pops open a bottle of your favorite beverage.
Product Details
- Metal bottle opener of Harley Quinn in her classic animated look.
- Approximately 3.75" tall x 3.5" wide x .5" deep
- Window box packaging


text:
Australian authorities are planning to pass a law that would ban to indicate the name of the manufacturer on cigarette packs. The packages will no longer represent logos, and the packs themselves will be olive green. Also, they will display the photographs demonstrating the consequences of smoking.
The authorities expect that these measures will reduce the number of smokers in the country. If the bill is passed, Australia will become the first country to venture such a radical step.
Tobacco manufacturers are outraged by the suggested innovations. In their opinion, the design of the package will not affect the statistics of smokers.
Previously, similar measures were suggested in New Zealand, Canada and Britain, but they were not put into practice.
Source of the image: Photl.


text:
"Once upon a time, a girl named September grew very tired indeed of her parents' house, where she washed the same pink-and-yellow teacups and matching gravy boats every day, slept on the same embroidered pillow, and played with the same small and amiable dog."
The summary is hidden because it may contain spoilers. If you would like to read the full summary, simply use your cursor to highlight the next few lines and it will magically appear.
|Twelve-year-old September's ordinary life in Omaha turns to adventure when a Green Wind takes her to Fairyland to retrieve a talisman the new and fickle Marquess wants from the enchanted woods.
Publisher: Feiwel and Friends; 247 pages


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