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The World Health Organisation (WHO) once ranked Obsessive-Compulsive Disorder (OCD) as the tenth most disabling illness of any kind, in terms of lost earnings and diminished quality of life.
OCD also presents a considerable burden to the individual, family, health services, and society as a whole. The total cost accrued as a result of OCD is difficult to measure because it extends beyond treatment settings. Often sufferers accrue costs attributed to work-related absences, and beyond the immediate family. These latter costs may arise from the affected individuals as well as from family and friends who care for them.
Obsessive-Compulsive Disorder, compared with other anxiety related disorders is associated with more marked social and work related occupational impairment.
One US report suggests that the economic impact of OCD in the US has been estimated at $8.4 billion every year. Here in the UK mental illness accounts for over a third of the burden of illness in Britain. For example, some 40% of all disability (physical and mental) is due to mental illness. It is reported that by comparing the employment rates of people with depression and anxiety with those of the rest of the population, allowing for increased absenteeism that the total loss of output due to depression and chronic anxiety is some £12 billion a year – 1% of our total national income. Of this the cost to the taxpayer is some £7 billion – including incapacity benefits and lost tax receipts.
One report once estimated that, on average, a person with OCD loses fully 3 years of wages over their lifetime and if an OCD sufferer incurs losses of £483.04 for every week they are absent, this would amount to a total of £75,354 due to unemployment over this 3-year period, not including lost opportunities for career advancement and the cost to families and carers over their respective working lifetimes.
The long-term social and economic costs are still likely to be greatly underestimated but this highlights the importance of providing early intervention and the highest quality of care and treatment for people with OCD, which is likely to be economically, not to mention morally, a much more cost effective solution to the social and economic impact of OCD.


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Oklahoma congressman Bridenstine re-nominated to head NASA
Updated 5:48 pm, Monday, January 8, 2018
OKLAHOMA CITY (AP) — President Donald Trump has re-nominated Republican Oklahoma Rep. Jim Bridenstine to head NASA.
A news release from the White House on Monday announced dozens of nominations, including that of Bridenstine to replace Charles F. Bolden, Jr., who resigned.
Bridenstine's original nomination expired in December when the Senate left town for the year without acting on dozens of Trump's nominees, including Bridenstine, and returned the nomination to the White House.
Nominees in limbo included former pharmaceutical company executive Alex Azar II of Indiana to run Health and Human Services and Kansas Gov. Sam Brownback for an ambassador's post. The list of nominees include both Azar and Brownback to the same posts.
- Sinkhole discovered on the West Side 21 Pro Video
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- San Antonio man records burglar breaking into home, shares over social Courtesy
- San Antonio firefighters escape home engulfed in flames Saturday night Courtesy
A spokesman for Senate Majority Leader Mitch McConnell has said the nominees will be considered once resubmitted.

domain: news


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We don't have any photos of this building yet. Why don't you be the first to send us one?
Latitude: 50.7844 / 50°47'3"N
Longitude: -4.1103 / 4°6'36"W
OS Eastings: 251337
OS Northings: 100435
OS Grid: SS513004
Mapcode National: GBR KN.ZYC2
Mapcode Global: FRA 2780.QHL
Entry Name: South Yeo
Listing Date: 29 February 1988
Source: Historic England
Source ID: 1147399
English Heritage Legacy ID: 93334
Location: Northlew, West Devon, Devon, EX20
District: West Devon
Civil Parish: Northlew
Traditional County: Devon
Lieutenancy Area (Ceremonial County): Devon
Church of England Parish: Northlew St Thomas of Canterbury
Church of England Diocese: Exeter
SS 50 SW
- South Yeo
Farmhouse. Circa early C17 possibly with earlier origins, C19 addition. Plastered
stone rubble walls. Gable ended slate roof. Brick stack at either end and granite
ashlar axial stack with moulded dripcourse and tapering cap.
Plan: 3-room and through passage plan witn lower end to the right. Hall stack
backs onto the passage. Unheated rear wing behind hall probably a later C17 or
early C18 addition. In the C19 an addition was made at the left-hand end of the
house probably as a dairy or for some subsidiary purpose.
Exterior: 2 storeys. Asymmetrical 4-window front. The 2 left-hand windows on the
first floor are early C19 hornless 20-pane sashes. The right-hand windows on both
floors are later C20 12-pane sashes. Later C20 2-light small-paned casements to
left on ground floor. C19 studded plank door to passage at right of centre under
corrugated iron doorhood supported on C19 carved wooden brackets. The lower
addition at the left-hand end has a shuttered unglazed window on the first floor
with a C20 2-light casement below and C19 plank door to its right. Rear wing
projects from centre ofhouse with C19 outshut to its right.
Interior inaccessible at time of survey but likely to contain features of interest
and possibly an early roof structure.
Listing NGR: SS5133700435
This text is from the original listing, and may not necessarily reflect the current setting of the building.
Other nearby listed buildings

domain: history


The Phantom Arc is a craftable Hardmode magic weapon. It fires a beam of souls that pierces an unlimited amount of enemies, dealing damage over time. Similar to the Last Prism, it starts by using mana slowly, then ramps up to very fast consumption, which encourages the player to fire only in short bursts.
| Ore • Bar|
Saber • Spear • Boomerang • Revenant • Burst • Wand • Phantom Arc
Pickaxe • Drill • Hamaxe
Armor • Wings


I’ve installed xtrabackup through Yast on an Opensuse 12.1 system.
When running innobackupex, I get the error
sh: xtrabackup_55: command not foundinnobackupex: fatal error: no ‘mysqld’ group in MySQL options
I can only find /usr/bin/xtrabackup_51 and /usr/bin/xtrabackup_innodb55 on my system, but not xtrabackup_55.
When defining a symbolic link from xtrabackup_51 to xtrabackup_55, I don’t get this error anymore. However I’m not sure if the backup is consistent and can be restored.
How should I solve this problem?


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Demo slots at casinos are among the best ways you can play slot machines without actually laying the barefoot on real money. You can discover how slots function and learn ways to increase dux your winnings. But, there is nothing more enjoyable than playing demo slots. When you think about all the times that you have won with a real slot machine, and you are then told that you have no idea how the slots operate it is clear why so many gamblers opt to play slot machines using demo machines.
You will find a variety of casinos with video slots at every online casino. They are everywhere. This is due to the fact that online casinos realize that they must provide incentives to people who visit their sites. Online casinos can’t make money when no one visits their sites. This is the reason why many casinos online offer different kinds of bonuses for playing the slot machines. These bonuses could be as free slots spins or cash for slots when you win a certain amount of money.
One of the best ways for casinos to encourage gambling is to offer free spins on their slot machines. With no requirement to gamble the slot players are able to play their favorite games without worrying about losing money. While there is nothing wrong in encouraging gamblers to play on these websites but it is important to remember that you do need to have some gambling capital to place a bets on the slot machines. However, it is possible to win free spins on these online slots without having to gamble.
Free slot machine games aren’t the only thing you can win from playing online games. No matter where you are, there’s always a table game to play. It could be a game at your local bar or coffee shop. It could even be a game organized by an individual online casino. Online casino tables offer people of all betway casino ages and walks of life the chance to engage in gambling in a safe and secure environment. They also offer players the opportunity to study different types of gambling while at the same time playing a fun game of poker or other card games.
Many online casinos will provide players with free spins on their slot machine games. These free spins are offered to draw more slot machine players to join the casino. In exchange for players’ participation, online casinos will offer them free spins on their slot machine games. In many instances, casinos will give the player a number of free spins on a variety of slot machines in order to get them hooked on to online casinos. At the end of the day, players will play games on slot machines to enjoy the thrill of gambling without having to feel guilty about spending money. If a player wins they will feel satisfied and will be able to lend money to casinos online.
You can also get casino bonuses when you play slot machines for fun, without having to make a deposit. Casino bonuses are used to attract people to play more slot machines. You can earn bonuses by playing non-deductible slot machines or by using specific codes that are available on various websites. In most instances, you’ll receive a code that needs to be input to the website in order to be able to use the bonus. After activating the code you will be eligible for bonus points that could be used to get free spins on the slot machines.
Another type of casino bonuses is free gift cards for casinos online. In many casinos gifts are handed out to members as a way of thanking them for playing their casino games. A gift card can be used for a range of different things, including buying gift certificates for items from participating online retailers. The reason for receiving and using these types of gift cards are two fold the first one is to express gratitude to the person who played a machine for you and the second is to thank the online retailer that you are shopping at. This allows both individuals to enjoy discounts on purchases, without having to make a deposit or pay a cost. Casinos online generally provide these kinds of gift cards for free to players because they are considered promotional items.
Another type of casino bonus is mobile casino. It is possible to play games on mobile without having an account or making any deposits. Mobile casino games let players participate in a casino game when in motion. In most cases, you’ll receive an icon that lets you connect to your casino games on mobile. From this, you will be able place bets and play live games. You do not need to sign up to create an account or deposit funds to play mobile casino games and enjoy the game without worrying about money at all.

domain: game


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NEW YORK (CNNMoney.com) -- The number of Americans who own homes fell in the second quarter of the year to the lowest level since 1999, said a government survey released Tuesday.
The Census Bureau said the home ownership rate fell to 66.9% in the second quarter of 2010, down half a percentage point from the previous year. The home ownership rate was 67.1% in the first quarter of the year.
In the second quarter rates were highest in the Midwest, where 70.8% of people are homeowners, and lowest in the West, where 61.4% of people own.
Rates in the South and West were lower than a year ago, while the Northeast and Midwest stayed the same.
Vacancies: The vacancy rate in non-rental units also fell in the second quarter, to 2.5%. Meanwhile, the vacancy rate in rental homes stayed steady at 10.6%.
Almost 86% of U.S. homes were occupied in the second quarter, with owner-occupied housing comprising 57.3% of all housing units. Renter-occupied homes were 28.3% of all units.
A separate report released Tuesday, the Case-Shiller index, showed home prices rose 1.3% in May compared with the previous month.
|Overnight Avg Rate||Latest||Change||Last Week|
|30 yr fixed||3.89%||3.85%|
|15 yr fixed||3.10%||3.05%|
|30 yr refi||3.87%||3.85%|
|15 yr refi||3.08%||3.07%|
Today's featured rates:
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Garry Monk is the latest Premier League manager to be churned up by the Premier League manager rumour mill after a run of difficult results seemingly piles pressure on the 36-year-old.
After Swansea’s 1-0 defeat at home to Stoke on Monday night the bookies slashed odds Monk becoming the next manager to be sacked, Sky Bet now make him 9/4 second favourite behind Tim Sherwood.
If six games without a win wasn’t difficult enough for Swans fans to endure, rumours surfaced across a number of media outlets today suggesting that Monk – who is loved by all loyal Swansea fans – hadn’t turned up for first team training due to ‘personal reasons’.
Fans will have undoubtedly been alarmed by the news that Monk was on the brink with the club and Swansea’s official Twitter account decided to put an end to all the nonsense with the greatest tweet you’ll see today:
‘Garry Monk was 28/1 this morning and has been steadily backed all day, he is currently now 3/1. We think punters are viewing Saturdays fixture between Aston Villa and Swansea at Villa Park as a sack race decider,’ said Sky Bet’s Sandro Di Michele.
‘Tim Sherwood is 1/2 favourite in the Next Premier League Manager To Leave market and punters are speculating that a poor result for Swansea on Saturday heaps even more pressure on Monk and takes the pressure of Tactics Tim a bit.’


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An article yesterday in the Washington Post disclosed the NSA’s massive cell phone location program. The program, codenamed CO-TRAVELER, is designed to track who meets with whom and covers everyone who carries a cell phone, all around the world.
With neither public debate nor court authorization, CO-TRAVELER collects billions of records daily of cell phone user location information. It maps the relationships of cell phone users across global mobile network cables, gathering data about who you are physically with and how often your movements intersect with other cell phone users. The program even tracks when your phone is turned on or off.
The trillions of collected records, which add up to twice the amount of data in the Library of Congress’ print collection, are saved and stored in the NSA’s mammoth database called FASCIA. While allegedly aimed at foreigners and mobile phones overseas, the NSA admits that it has “incidentally” collected location information on U.S. persons.
CO-TRAVELER ignores fundamental values in the Constitution the NSA has sworn to uphold, including the right against unreasonable search and seizure as well as freedom of association. Thinking globally, the program disregards international human rights law, which is currently in the process of being reaffirmed in a draft resolution by the UN General Assembly.
The Fourth Amendment Protects Cell Phone Location Data
EFF has been working for years to get the courts to recognize that the government must get a warrant before seizing cell phone location records. The court decisions are split. In 2008 the Third Circuit federal appeals court correctly held that federal magistrates have the discretion to require the government to get a search warrant based on probable cause before obtaining cell phone location records. But the Fifth and Sixth Circuit have approved the seizure of cell phone location records without a warrant. The Supreme Court has yet to rule on cell phone location, but did hold that planting a GPS device on a car requires a warrant, without reaching a decision on whether the warrantless tracking itself would violate the Fourth Amendment.
CO-TRAVELER does not simply collect location information. It creates a portrait of travel times and people who crossed paths, revealing our physical interactions and relationships. The cell site information goes beyond email and phone calls and ordinary telephony data, allowing the U.S. government to know who we are with in-person and where. This is information that would be impossible to collect using traditional law enforcement methods.
An NSA official said that the agency’s collection methods are “tuned to be looking outside the United States.” This appears to be an attempt to assert that U.S. law does not apply because they are not “targeting” U.S. persons. Without the protections of U.S. law, the spying is regulated only by Executive Orders–orders by the President that are not subject to substantive oversight, and can modified at any time. It’s likely that this program falls under Executive Order 12333. EO 12333 has few limits on surveillance overseas, even if it is a U.S. person.
CO-TRAVELER Violates the First Amendment
The CO-TRAVELER program is based on guilt by association, tracking location to determine our relationships and where we meet. The First Amendment protects our right to associate with individuals and groups without disclosing that information to the government. This is an essential right because it allows people to discuss their ideas, concerns, and feelings with others without the shadow of government surveillance. And this is not just a right recognized in the United States: the right to freely associate with individuals or groups has also been recognized in the UN Universal Declaration of Human Rights, the European Convention on Human Rights, and in countless other human rights charters.
EFF is currently representing 22 organizations from across the political spectrum who sued the NSA for violating their First Amendment right of association by illegally collecting their call records. The case, First Unitarian v. NSA, brings to light the real implications of mass surveillance–people are afraid to associate and meet based on likeminded interests.
Equally threatening to the rights guaranteed by the First Amendment are the speech-chilling effects of cell phone location tracking. Even if you use encryption online, when you meet someone in person and aren’t even on the phone, your movements may be tracked and recorded and stored. The Washington Post article reports that the NSA tracks when a cell phone has been turned off, for how long, and what nearby devices are also being used and shut off. The NSA provides further scrutiny of people who switch their phones on and off for brief periods or use throw-away phones.
Yet these security practices are common methods that journalists (or anyone else who might be privacy conscious) use to ensure security and trust when they meet with confidential sources and conduct investigations. Under this program, it is harder than ever for a journalist to guarantee a reasonable degree of privacy and security to their sources.
Privacy is an Internationally Recognized Human Right
While the NSA likes to claim it takes great care in not collecting the data of U.S. persons, the billions of people tracked by their programs have a basic human right to privacy. Right now the United Nations General Assembly is discussing a resolution that reaffirms that the human right to privacy is carried over and effective in the digital age.
EFF is part of the global movement demanding the protection of our most basic right to privacy, no matter the country or citizenship of a person. We signed on to a list of thirteen principles that a state should use to determine whether or not a surveillance program will encroach on fundamental human rights. Join us by adding your name to the global petition for privacy today.
We will continue to fight against the NSA’s unconstitutional and over-broad surveillance programs in the courts and in Congress, and advocate for deeper oversight of the NSA from all branches of government.
Over the past few months, I’ve certainly wondered quite a bit about just how bad the NSA seems to be at recognizing how the public feels concerning what it’s doing. This week’s revelations about tracking mobile phone locations was incredible because folks at the NSA must have known that information about this program was in Snowden’s collection, and yet when they were asked about collecting location info a few months ago, they made statements that would clearly look bad, when put next to the truth:
“We don’t get any cell site or location information as to where any of these phones were located.” — Keith Alexander
These phones. Under this program. But under this other program we collect pretty much everything. Beyond that, the various “code names” the NSA uses are somewhat revealing as well. Lots of people commented on the insanity of calling the giant database FASCIA. But, at the very least, you could argue that the NSA never expected those code names to be made public. And with the misleading statements, they were still holding out hope that maybe, just maybe, a meteor would magically flatten Glenn Greenwald, Barton Gellman and Laura Poitras before the info got out.
But… how about when the US intelligence community actually does something publicly. Like live tweeting the launch of a new spy satellite. Apparently, they slap the most unsubtle logo on it that you can imagine.
Yes, it’s an octopus, with tentacles reaching all over the globe. And the tagline is “Nothing is Beyond Our Reach.”
Sure. They’re spies. This is what they do. But, somehow, you’d think that maybe, just maybe, someone with a tiny bit of sense back there at the office of the director of national intelligence would think that, “gee, a lot of people around the globe are pretty fucking angry at us for all the spying we’re doing right now. maybe we shouldn’t be spitting in their faces, mocking their concerns, and reminding them that we’re blatantly evil people who really don’t give two shits about their privacy.”
Of course, that would take some actual recognition of what anyone thinks of them, and that doesn’t seem to be part of the way that the US intelligence community operates.
The UK Parliament is presenting itself as a complete joke. Rather than looking into controlling the GCHQ (the UK’s equivalent to the NSA), it has instead held a hearing to interrogate and threaten Guardian editor Alan Rusbridger for actually reporting on the Snowden leak documents and revealing the widespread abuses of the intelligence community. The hearing included the insulting and ridiculous question: “do you love this country?”
Committee chair, Keith Vaz: Some of the criticisms against you and the Guardian have been very, very personal. You and I were both born outside this country, but I love this country. Do you love this country?
Alan Rusbridger: We live in a democracy and most of the people working on this story are British people who have families in this country, who love this country. I’m slightly surprised to be asked the question but, yes, we are patriots and one of the things we are patriotic about is the nature of democracy, the nature of a free press and the fact that one can, in this country, discuss and report these things.
Perhaps equally ridiculous: after UK Prime Minister David Cameron ordered the destruction of Guardian hard drives, urged the Parliament to start this very investigation and flat out threatened news publications for reporting on government abuse, folks in Parliament have the gall to suggest that it’s Rusbridger who broke the law in sharing some of the Snowden docs with the NY Times? Maybe if Cameron hadn’t done everything he could to try to stifle a free UK press, the Guardian wouldn’t have felt the need to share documents with a competitor.
Conservative MP Michael Ellis: Mr Rusbridger, you authorised files stolen by [National Security Agency contractor Edward] Snowden which contained the names of intelligence staff to be communicated elsewhere. Yes or no?
Rusbridger: Well I think I’ve already dealt with that.
Ellis: Well if you could just answer the question.
Rusbridger: I think it’s been known for six months that these documents contained names and that I shared them with the New York Times.
Ellis: Do you accept that that is a criminal offence under section 58(a) of the Terrorism Act, 2000?
Rusbridger: You may be a lawyer, Mr Ellis, I’m not.
And from there it took a turn to the bizarre as Ellis started talking about how Rusbridger might reveal that GCHQ agents were gay. I’m not kidding.
Ellis: Secret and top-secret documents. And do you accept that the information contained personal information that could lead to the identity even of the sexual orientation of persons working within GCHQ?
Rusbridger: The sexual orientation thing is completely new to me. If you could explain how we’ve done that then I’d be most interested.
Ellis: In part, from your own newspaper on 2 August, which is still available online, because you refer to the fact that GCHQ has its own Pride group for staff and I suggest to you that the data contained within the 58,000 documents also contained data that allowed your newspaper to report that information. It is therefore information now that is not any longer protected under the laws and that jeopardises those individuals, does it not?
Rusbridger: You’ve completely lost me Mr Ellis. There are gay members of GCHQ, is that a surprise?
Ellis: It’s not amusing Mr Rusbridger. They shouldn’t be outed by you and your newspaper.
[Brief inaudible exchange in which both men are talking]
Rusbridger: The notion of the existence of a Pride group within GCHQ, actually if you go to the Stonewall website you can find the same information there. I fail to see how that outs a single member of GCHQ.
Ellis: You said it was news to you, so you know about the Stonewall website, so it’s not news to you. It was in your newspaper. What about the fact that GCHQ organised trips to Disneyland in Paris, that’s also been printed in your newspaper, does that mean if you knew that, information including the family details of members of GCHQ is also within the 58,000 documents – the security of which you have seriously jeopardised?
Rusbridger: Again, your references are lost to me. The fact that there was a family outing from GCHQ to Disneyland … [CUT OFF]
There was much more in the hearing, with multiple UK members of parliament making statements that suggest that they are ignorant of a variety of things, including how encryption works and the nature of a free and open press.
But, really, just the fact that they’re spending time investigating Rusbridger in the first place, rather than looking more closely at what the GCHQ is doing, makes a complete mockery of the UK Parliament.
The United Nations is set to carry out an investigation into the spying activities of the US and UK, a senior judge has said. The probe will examine the espionage programs and assess whether they conform to UN regulations.
UN special rapporteur Ben Emmerson QC told British newspaper The Guardian that the UN will conduct an inquiry into the NSA and the GCHQ’s spying antics. Following Edward Snowden’s revelations, which blew the whistle on both agencies’ intelligence gathering programs, Emmerson said the issue was at “the very apex of public interest and concerns.”
The report will broach a number of contentious issues, said Emmerson, including whether Snowden should be granted the legal protection afforded to a whistleblower, whether the data he handed over to the media did significant harm to national security, whether intelligence agencies need to scale down their surveillance programs and whether the UK government was misled about the extent of intelligence gathering.
“When it comes to assessing the balance that must be struck between maintaining secrecy and exposing information in the public interest, there are often borderline cases,” Emmerson told The Guardian.
Emmerson also mentioned the raid this summer on The Guardian’s London offices in search of hard drives containing data from Snowden. Addressing the allegations made by the chiefs of British spy agencies MI5, GCHQ and MI6, that publishing Snowden’s material was “a gift to terrorists,” Emmerson said it was the media’s job to hold governments to account for their actions.
“The astonishing suggestion that this sort of responsible journalism can somehow be equated with aiding and abetting terrorism needs to be scotched decisively,” said Emmerson, who will present the conclusions of his inquiry to the UN General Assembly next autumn.
Guardian editor-in-chief Alan Rusbridger is set to appear before a Commons home affairs committee in a hearing about the newspaper publishing of Snowden’s security leaks. British Prime Minister David Cameron issued a statement in September, warning of a possible crackdown if media continued to publish information on covert intelligence gathering programs.
He said the government had not yet been “heavy-handed” in its dealings with the press, but it would be difficult not to act if the press does not “demonstrate some social responsibility.” Cameron added that the UK was a more dangerous place after the Guardian published Snowden’s material.
Snowden’s revelations of the international spying activities of the UK and US have embarrassed the White House and Downing Street. Recent leaks show that the NSA and GCHQ not only monitored millions of civilian communications using programs such as PRISM and Tempora, but also eavesdropped on high-profile businessmen and politicians. Moreover, it was revealed that the NSA also spied on the UN’s headquarters in New York.
Both nations have sought to justify their intelligence gathering programs as being in the interests of national security.
It seems that the NSA’s “talking points” keep on leaking. The latest is a two pager it sent home with employees prior to Thanksgiving, so they’d have substance-free pablum to say in response to any family and friends who might actually have been paying attention to the news lately, and have some concerns to raise about the NSA violating our privacy and the Constitution. The document is broadly split into five sections, with sub talking points within each section. Here are the key points (underlines in the original):
- NSA’s mission is of great value to the Nation”
- NSA performs its mission the right way—lawful, compliant and in a way that protects civil liberties and privacy
- NSA performs its mission exceptionally well. We strive to be the best that we can be, because that’s what America requires as part of its defense in a dangerous world
- The people who work for NSA are loyal Americans with expert skills who make sacrifices to help protect the freedoms we all cherish
- NSA is committed to increased transparency, public dialog and faithful implementation of any changes required by our overseers.
Almost all of the talking points are misleading, with some clearly being outright lies. Kevin Gosztola at Firedoglake, who first obtained and published these talking points, does an incredibly thorough demolishing of the talking points, so I highly recommend reading that. Here’s a short snippet:
“NSA programs protect Americans and our Allies,” the document reads. “As an example, they have helped to understand and disrupt 54 terrorist events since 9/11: 25 in Europe, 11 in Asia and 5 in Africa. Thirteen of those had a homeland nexus.”
Deputy Director John Inglis admitted in August during a Senate hearing, when pressed by Sen. Patrick Leahy, that US bulk records phone spying had been “critical” in stopping just one terrorist plot. He clarified that the spying on phone records had only “made a contribution” to discovering the 13 plots.
Sens. Ron Wyden, Mark Udall & Martin Heinrich, who filed a brief in support of an American Civil Liberties Union (ACLU) lawsuit challenging the collection of phone records of all Americans, explained the Executive Branch has defended the program by conflating it with “other foreign intelligence authorities.” The senators highlighted the fact that the collection under Section 215 of the PATRIOT Act had played “little or no role in most of these disruptions.”
“Indeed of the original fifty-four that the government pointed to, officials have only been able to describe two that involved materially useful information obtained through the bulk call-records program,” the senators added. “Even the two supposed success stories involved information that [the senators] believe—after repeated requests to the government for evidence to the contrary—could readily have been obtained without a database of all Americans’ call records.”
At this point, any intelligence agency leader, member of Congress or government official who highlights 54 “thwarted” plots is advancing propaganda to save the NSA from being forced into giving up this power to collect the phone records of all Americans.
There’s much, much more at the original. Go read it. Most of these talking points are pretty much what you’d expect, and the standard doublespeak we’ve been hearing from the NSA and its defenders ever since the Snowden revelations began. At best they’re setting up strawmen to knock down. No one has argued that NSA employees aren’t American citizens. We just question what they’re doing. Furthermore, the whole “lawful, compliant” thing is kind of laughable, given the numerous examples of abuses, and the regular discussions from the courts about how the NSA has abused its mandate. Even more to the point, many of these programs simply have not been challenged in court in an actual trial, so claiming that they’re legal is a huge stretch.
Maybe it’s time that someone put together a list of “talking points” for friends and family of NSA employees to read back to them the next time they spew these kinds of bogus claims.
Bonus: The folks at Gawker worked the talking points into a script. Here’s a snippet:
DAD: So, Ted, how’s work lately?
UNCLE TED: NSA’s mission is of great value to the Nation.
DAD: Oh, for sure. I was just thinking since it’s been in the news a lot…
UNCLE TED: NSA performs timely, actionable intelligence to political and military customers who use that information in a range of activities from decisionmaking to military operations.
MOM: Honey, maybe Ted doesn’t want to talk abou—
UNCLE TED: NSA performs its mission the right way—lawful, compliant, and in a way that protects civil liberties and privacy.
KEITH ALEXANDER: Pass the salt?
It appears that the heads of the Senate and House Intelligence Committees, Senator Dianne Feinstein and Rep. Mike Rogers, are recognizing that their strategy for keeping their co-dependent relationship with the NSA going is failing and that the American public and an increasingly large segment of Congress no longer believes their bogus claims. Perhaps that’s because every time they open their mouths, it takes all of about an hour before many of their claims are completely debunked, if not outright mocked for obviously being bogus. So their latest strategy? To basically yell “Ooga Booga Terrorists!” as loud as they can to try to scare people based on absolutely nothing.
Feinstein and Rogers did a little dance on Sunday political TV shows insisting that “the terrorism threat is increasing” and we’re all going to die if we stop trying to make sure the NSA actually, you know, respects the Constitution. Asked if we were “safer” now than a year or two years ago, Feinstein kicked off the FUD:
“I don’t think so,” Feinstein replied. “I think terror is up worldwide, the statistics indicate that. The fatalities are way up. The numbers are way up. There are new bombs, very big bombs. Trucks being reinforced for those bombs. There are bombs that go through magnetometers. The bomb maker is still alive. There are more groups than ever. And there is huge malevolence out there.”
And Rogers quickly followed:
“I absolutely agree that we’re not safer today for the same very reasons,” he said. “So the pressure on our intelligence services to get it right to prevent an attack are enormous. And it’s getting more difficult.”
Of course, Feinstein’s claim that “terror is up worldwide” is — as is so often the case with her (and Rogers’) claims about terrorism — sorta true, but highly misleading. Yes, recent stats show an uptick in terrorist attacks and fatalities in 2012 — but you can also see that it’s highly variable. Earlier in the year, before the 2012 numbers came out, people were commenting on the fact that terror attacks and fatalities around the globe had been on the decline since 2007. Terrorism is highly variable and dependent on a few big successful attacks. Furthermore, if we look at attacks on the US, we find that there have basically been next to none in the US since 2001. You could make the case that 16 people have died in US “terrorist” attacks since 2001 (including the 13 soldiers killed by Army psychiatrist Maj. Nidal Hasan at Fort Hood), but you have to have a very broad definition of terrorism to do so.
Nearly all of the “terrorist” attacks in that original report that Feinstein is obviously relying on, appear to take place in areas that are considered war zones: Iraq, Afghanistan, etc. And, um, I hate to bring this part up, but part of the reason why those are war zones is because, you know, the US invaded both places. This isn’t to say that there aren’t terrorists out there who would like to attack the US. There clearly are. But it seems highly misleading to make the claims that both Feinstein and Rogers are making here, as the “data” they’re talking about don’t show any heightened risk in the US at all.
Either way, this whole thing — having both appear together, both making vague “we’re all going to die” statements without any details to back it up combined with an exceptionally misleading use of statistics — suggests that this is the typical FUD. It’s Feinstein and Rogers shouting “terror” in a crowded theater, because they know that they’ve already lost public opinion on this, and are quickly losing Congress as well.
Anita Kumar, a reporter at McClatchy, has a good article highlighting how, for all the talk by the Obama administration about how it needs to be more open and transparent about what the NSA is doing, in actuality, the administration has built up the walls even higher, increasing the levels of secrecy… including secrecy about how he’s responded to everything:
Obama has been gradually tweaking his vast government surveillance policies. But he is not disclosing those changes to the public. Has he stopped spying on friendly world leaders? He won’t say. Has he stopped eavesdropping on the United Nations, the World Bank and the International Monetary Fund? He won’t say.
Even the report by the group Obama created to review and recommend changes to his surveillance programs has been kept secret.
As is noted in the article, the administration, which likes to pretend it’s the most transparent in history, is actually one of the most secretive. Its attempts at transparency have almost exclusively been focused on where it can get the most political bang, not for what areas people expect the government to be transparent about — such as how it interprets the laws that allow the government to spy on everyone…
What’s incredible is that it appears that no one high up in the administration seems to recognize how this is a strategy that will almost certainly make things worse, not better. It may be how the administration is used to functioning, but it makes it much more difficult to believe anything that is said about a supposed “vigorous public debate” being held on the surveillance activities. It also means that as more leaks come out revealing more questionable practices, the constant backtracking and excuses will just destroy whatever credibility the administration has left on this issue. If, instead, it were to actually be transparent and simply reveal things like how it interprets the law, and allow for a real public discussion on these matters, that would actually result in some frank discussions that the administration seems terrified of actually having.
Extreme secrecy may seem like the easier short-term strategy, but it’s just digging an ever deeper hole that the administration is going to have to try to climb out of in the long-term. Hiding reality from a public that’s going to find out eventually is just making the problem worse.
The National Security Agency conducted widespread surveillance during the 2010 G8 and G20 summits with the blessing of host country Canada’s government.
Documents supplied by former NSA contractor Edward Snowden show the US converted its Ottawa embassy into a security command for six days in June 2010 as world leaders met in Toronto. The covert operation was known to Canadian authorities, CBC News reported.
The documents do not reveal targets of the espionage by the NSA – and possibly by its counterpart, the Communications Security Establishment of Canada (CSEC). The NSA briefing notes say the operation was “closely co-ordinated with the Canadian partner.”
Ultimately, the documents obtained by the CBC do not give exact specifications of CSEC’s role, if any, in the Toronto spying. Former Guardian reporter and Snowden’s chosen journalist to receive the NSA documents, Glenn Greenwald, co-wrote the story for CBC.
But the documents do spell out that CSEC’s cooperation in the venture was crucial to ensuring access to telecommunications systems needed to spy on targets during the summits.
Both NSA and CSEC were implicated, along with British counterpart GCHQ, for monitoring phone calls and email of foreign leaders and diplomats at the 2009 G20 summit in London. In addition, it was recently reported that CSEC hacked into phones and computers at the Brazilian government’s department of mines. These revelations also came via documents from Snowden, who has received asylum in Russia.
The revelations also contradict a statement made by an NSA spokesman to The Washington Post on August 30, which said that the US Department of Defense – of which the NSA is is part of – “does not engage in economic espionage in any domain, including cyber.”
The NSA briefing document says the operational plan at the 2010 summit included “providing support to policymakers.”
The Toronto summit was chock full of major economic issues following the 2008 recession. Measures like the eventually-nixed global bank tax were strongly opposed by the US and Canadian governments. Further banking reform, international development, countering trade protectionism and other issues were on the docket – and on NSA’s list of main agenda items in the aim of supporting “US policy goals.”
The partnerships by some Western spying arms at the Toronto and London summits, not to mention other stories that have come out based on the Snowden documents, call attention once again to the “Five Eyes” surveillance coalition among Australia, Canada, New Zealand, the UK and the US.
Wall Street Journal columnist L. Gordon Crovitz wrote a misleading and error-filled column on NSA surveillance Monday, based on documents obtained by EFF through our Freedom of Information Act lawsuit. Since we’ve been poring over the documents for the last week, we felt it was important to set the record straight about what they actually reveal.
Edward Snowden thought he was exposing the National Security Agency’s lawless spying on Americans. But the more information emerges about how the NSA conducts surveillance, the clearer it becomes that this is an agency obsessed with complying with the complex rules limiting its authority.
That’s an interesting interpretation of the recently released documents, given that one of the two main FISA court opinions released says the NSA was engaged in “systemic overcollection” of American Internet data for years, and committed “longstanding and pervasive violations of the prior orders in this matter.” The court summarized what it called the government’s “frequent failures to comply with the [surveillance program’s] terms” and their “apparent widespread disregard of [FISA court imposed] restrictions.”
[The documents] portray an agency acting under the watchful eye of hundreds of lawyers and compliance officers.
Again, this is not what the actual FISA court opinions portray. “NSA’s record of compliance with these rules has been poor,” and “those responsible for conducting oversight failed to do so effectively,” FISA court Judge Bates wrote in the key opinion released last week. In another FISA court opinion from 2009, released two months ago, the NSA admitted that not a single person in the entire agency accurately understood or could describe the NSA’s whole surveillance system to the court.
It’s true that the number of compliance officers at the NSA has increased in recent years, but as the Washington Post reported, so has the number of privacy violations.
These documents disprove one of Mr. Snowden’s central claims: “I, sitting at my desk, certainly had the authority to wiretap anyone, from you or your accountant, to a federal judge, to even the president if I had a personal email,” he told the Guardian, a British newspaper.
Here, Crovitz is setting up a strawman. Snowden wasn’t talking about the NSA’s legal authority, but their technical authority to conduct such searches. Snowden was likely referring to XKeyScore, which the Guardian reported allowed NSA analysts to “search with no prior authorization through vast databases containing emails, online chats and the browsing histories of millions of individuals.”
We actually have a specific example that proves Snowden’s point. As the New York Times reported in 2009, an NSA analyst “improperly accessed” former President Bill Clinton’s personal email. More recently, we’ve learned that the NSA analysts abused the agency vast surveillance powers to spying on ex-spouses or former lovers.
The NSA also released the legal arguments the Justice Department used in 2006 to justify collection of phone metadata-the telephone number of the calling and called parties and the date, time and duration of the call.
Metadata collection is about connecting the dots linking potential terrorist accomplices. The Clinton administration created barriers to the use of metadata, which the 9/11 Commission concluded let the terrorists avoid detection. Since then, metadata has helped stop dozens of plots, including an Islamist plan to blow up the New York Stock Exchange in 2008.
Again, not true. As Intelligence Committee members Sen. Ron Wyden and Sen. Mark Udall have continually emphasized, there is “no evidence” that the phone metadata program is effective at stopping terrorists. Independent analyses have come to the same conclusion. When called out on that number in a Congressional hearing, even NSA Director Keith Alexander admitted the number was exaggerated.
The only “disrupted plot” the NSA can point to that was solely the work of the phone metadata program was a case where a man from San Diego sent a few thousand dollars to the al-Shabaab organization in Africa in 2008. In other words, the metadata did not disrupt an active terrorist plot inside the US at all.
The declassified brief from 2006 made clear that such metadata “would never even be seen by any human being unless a terrorist connection were first established,” estimating that “0.000025% or one in four million” of the call records “actually would be seen by a trained analyst.”
The major 2009 FISA court opinion released in September, that apparently Mr. Crovitz either didn’t read or conveniently left out of his piece, showed that the NSA had been systematically querying part of this phone records database for years for numbers that the agency did not have a “reasonable articulable suspicion” were involved in terrorism—as they were required to have by the FISA court. Of the more than 17,000 numbers that the NSA was querying everyday, the agency only had “reasonable articulable suspicion” for approximately 1,800 of them.
The FISA court concluded, five years after the metadata program was brought under a legal framework, that it had been “so frequently and systematically violated that it can fairly be said that this critical element of the overall…regime has never functioned effectively.”
These documents clearly do not paint a picture of an agency with a clean privacy record and a reputation for following court rules, as Mr. Crovitz claims, and in fact, they show why it is vital Congress passes substantive NSA reform immediately. You can go here to take action.
- How NSA Mass Surveillance is Hurting the US Economy (alethonews.wordpress.com)
- Obama administration defends NSA against civil liberties lawsuit (counterinformation.wordpress.com)
In the five months since the world first learned of Edward Snowden, story after story based on documents disclosed by the young whistleblower have filled out a picture of the National Security Agency (NSA) as an organization with a limitless — and almost indiscriminate — hunger for information. Today, Glenn Greenwald, Ryan Gallagher, and Ryan Grim add a startling new dimension to that portrait by revealing that the agency has contemplated ways to use its troves of data to discredit and undermine individuals who the agency believes are “radicalizing others through incendiary speeches” but who lack any ties to actual criminality. The government is apparently seeking out “personal vulnerabilities” of these individuals, including their online sexual activity, hoping to expose them as hypocrites to their followers. While all of the targets are outside the United States, at least one of them is a U.S. person — meaning, either a citizen or a permanent resident.
As Greenwald notes, it’s a story that’s eerily reminiscent of past abuses of government surveillance authority. Greenwald’s new report does not provide evidence of the NSA marshaling its vast databases to influence individuals or events within the United States. But you need not be a conspiracy theorist or a novelist with a knack for bending history to imagine how granting the NSA the power to “collect it all” might have seriously chilling and destructive repercussions here at home.
In fact, the NSA appears to be taking this effort right out of the shameful playbook of our not-so-distant history. Most infamously, as part of the COINTELPRO program, J. Edgar Hoover’s Federal Bureau of Investigation (FBI) obsessively monitored the activities of Martin Luther King, Jr., picking and choosing from the results to produce a report chock full of insinuations about King’s role in an evolving Communist conspiracy against the United States. Never mind that King unwaveringly espoused non-violence. It was King’s rising public stature and broadly influential political ideas that led the government to see him as a threat.
The FBI viewed no space as off limits. The agency consistently bugged King’s hotel rooms to monitor his planning of the 1963 March on Washington and to keep tabs on his strategic partnerships with other civil-rights leaders. But it also sought to compile a dossier of embarrassing information about King’s private sex life that the government could (and did) employ to discredit King and obstruct his political efforts.
King was not alone on the government’s long list of targets; he shared marquee billing with boxer Muhammed Ali, humorist Art Buchwald, author Norman Mailer, and even Senator Howard Baker. But the greater scandal was that — as the Church Committee revealed in 1976 — these big names appeared alongside more than one million other Americans, including half a million so-called “subversives.”
That is why, as disturbing as it is to read about the FBI’s sordid history of targeting domestic political “enemies,” the potential of the NSA to revive those tactics today (as exposed by Greenwald’s article) is alarming on a profoundly different scale. In the age of mass call-tracking and XKeyScore, hotel-room bugs seem almost quaint.
Indeed, Greenwald’s new story is a warning shot to those of us who have thus far ignored the Snowden revelations on the basis of having “nothing to hide.” As Greenwald makes clear, the subjects of the NSA’s newly exposed effort to target individuals with influence on social media have tangential (if any) ties to real terrorists or violent extremists. And as the ACLU has explained, the entire premise of the NSA’s focus on so-called “radicalizers” — the theory that a person’s adoption of what the government views as “radical” ideas is a step to terrorism — has been debunked. Intelligence programs based on that discredited theory are not just wrong, they’re ineffective. But they do very real damage to belief communities and political activists singled out for surveillance based on their views.
The efforts reported by Greenwald cut to the heart of the zone of expression and association that must remain free from intrusive, dragnet surveillance, both abroad and at home. In his very first public words, Snowden himself addressed the alarming consequences of the NSA’s hunger for obtaining and storing an incomprehensibly vast record of our lives:
Even if you’re not doing anything wrong, you’re being watched and recorded…[T]hey can use the system to go back in time and scrutinize every decision you’ve ever made, every friend you’ve ever discussed something with, and attack you on that basis, to sort of derive suspicion from an innocent life and paint anyone in the context of a wrong-doer.
In the months since the first Snowden revelations, few have managed to evoke the existential threat presented by unhinged NSA surveillance with such plain, direct force. In an instant, Greenwald’s new story has brought this surveillance nightmare— “collect it all” meets COINTELPRO — jarringly close to the here and now.
Privacy may not be the only casualty of the National Security Agency’s massive surveillance program. Major sectors of the US economy are reporting financial damage as the recent revelations shake consumer confidence and US trade partners distance themselves from companies that may have been compromised by the NSA or, worse, are secretly collaborating with the spy agency. Members of Congress, especially those who champion America’s competitiveness in the global marketplace, should take note and rein in the NSA now if they want to stem the damage.
The Wall Street Journal recently reported that AT&T’s desired acquisition of the European company Vodafone is in danger due to the company’s well-documented involvement in the NSA’s data-collection programs. European officials said the telecommunications giant would face “intense scrutiny” in its bid to purchase a major cell phone carrier. The Journal went on to say:
“Resistance to such a deal, voiced by officials in interviews across Europe, suggests the impact of the NSA affair could extend beyond the diplomatic sphere and damage US economic interests in key markets.”
In September, analysts at Cisco Systems reported that the fallout “reached another level,” when the National Institute of Standards and Technology (NIST) told companies not to use cryptographic standards that may have been undermined by the NSA’s BULLRUN program. The Cisco analysts said that if cryptography was compromised “it would be a critical blow to trust required across the Internet and the security community.”
This forecast was proven true in mid-November, when Cisco reported a 12 percent slump in its sales in the developing world due to the NSA revelations. As the Financial Times reported, new orders fell by 25 percent in Brazil and 30 percent in Russia and Cisco predicts its overall sales could drop by as much 10 percent this quarter. Cisco executives were quoted saying the NSA’s activities have created “a level of uncertainty or concern” that will have a deleterious impact on a wide-range of tech companies.
It is hard for civil libertarians to shed tears over AT&T losing business because of NSA spying, considering the company allowed the NSA to directly tap into its fiber optic cables to copy vast amounts of innocent Americans’ Internet traffic. AT&T was also recently revealed as having partnered with both the DEA and the CIA on separate mass surveillance programs. It is also hard to feel sorry for Cisco, which stands accused of helping China spy on dissidents and religious minorities. But the fact that the spying is hurting these major companies is indicative of the size of the problem.
This summer, European Parliament’s civil liberties committee was presented with a proposal to require every American website to place surveillance notices to EU citizens in order to force the US government to reverse course:
“The users should be made aware that the data may be subject to surveillance (under FISA 702) by the US government for any purpose which furthers US foreign policy. A consent requirement will raise EU citizen awareness and favour growth of services solely within EU jurisdiction. This will thus have economic impact on US business and increase pressure on the US government to reach a settlement.” [emphasis ours]
Meanwhile, Telenor, Norway’s largest telecom provider has reportedly halted its plans to move its customers to a US-based cloud provider. Brazil seems to be moving ahead to create its own email service and require US companies locate an office there if they wish to do business with Brazilian customers.
Laws like this mean that companies like Google “could be barred from doing business in one of the world’s most significant markets,” according to Google’s director for law enforcement and information security at Google, Richard Selgado. Google has been warning of this as far back as July, when in FISA court documents it argued that the continued secrecy surrounding government surveillance demands would harm its business.
Many commentators have been warning about the economic ramifications for months. Princeton technologist Ed Felten, who previously at the Federal Trade Commission, best explained why the NSA revelations could end up hurting US businesses:
“This is going to put US companies at a competitive disadvantage, because people will believe that U.S. companies lack the ability to protect their customers—and people will suspect that U.S. companies may feel compelled to lie to their customers about security.”
The fallout may worsen. One study released shortly after the first Edward Snowden leaks said the economy would lose $22 to $35 billion in the next three years. Another study by Forrester said the $35 billion estimate was too low and pegged the real loss figure around $180 billion for the US tech industry by 2016.
Much of the economic problem stems for the US government’s view that it’s open season when it comes to spying on non-U.S. persons. As Mark Zuckerberg said in September, the government’s position is“don’t worry, we’re not spying on any Americans. Wonderful, that’s really helpful for companies trying to work with people around the world.” Google’s Chief Legal Officer David Drummond echoed this sentiment last week, saying:
“The justification has been couched as ‘Don’t worry. We’re only snooping on foreigners.’ For a company like ours, where most of our business and most of our users are non-American, that’s not very helpful.”
Members of Congress who care about the US economy should take note: the companies losing their competitive edge due to NSA surveillance are mainstream economic drivers. Just as their constituents are paying attention, so are the customers who vote with their dollars. As Sen. Ron Wyden remarked last month, “If a foreign enemy was doing this much damage to the economy, people would be in the streets with pitchforks.”
The American intelligence service – NSA – infected more than 50,000 computer networks worldwide with malicious software designed to steal sensitive information. Documents provided by former NSA-employee Edward Snowden and seen by this newspaper, prove this.
A management presentation dating from 2012 explains how the NSA collects information worldwide. In addition, the presentation shows that the intelligence service uses ‘Computer Network Exploitation’ (CNE) in more than 50,000 locations. CNE is the secret infiltration of computer systems achieved by installing malware, malicious software.
One example of this type of hacking was discovered in September 2013 at the Belgium telecom provider Belgacom. For a number of years the British intelligence service – GCHQ – has been installing this malicious software in the Belgacom network in order to tap their customers’ telephone and data traffic. The Belgacom network was infiltrated by GCHQ through a process of luring employees to a false Linkedin page.
NSA special department employs more than a thousand hackers
The NSA computer attacks are performed by a special department called TAO (Tailored Access Operations). Public sources show that this department employs more than a thousand hackers. As recently as August 2013, the Washington Post published articles about these NSA-TAO cyber operations. In these articles The Washington Post reported that the NSA installed an estimated 20,000 ‘implants’ as early as 2008. These articles were based on a secret budget report of the American intelligence services. By mid-2012 this number had more than doubled to 50,000, as is shown in the presentation NRC Handelsblad laid eyes on.
Cyber operations are increasingly important for the NSA. Computer hacks are relatively inexpensive and provide the NSA with opportunities to obtain information that they otherwise would not have access to. The NSA-presentation shows their CNE-operations in countries such as Venezuela and Brazil. The malware installed in these countries can remain active for years without being detected.
‘Sleeper cells’ can be activated with a single push of a button
The malware can be controlled remotely and be turned on and off at will. The ‘implants’ act as digital ‘sleeper cells’ that can be activated with a single push of a button. According to the Washington Post, the NSA has been carrying out this type of cyber operation since 1998.
The Dutch intelligence services – AIVD and MIVD – have displayed interest in hacking. The Joint Sigint Cyber Unit – JSCU – was created early in 2013. The JSCU is an inter-agency unit drawing on experts with a range of IT skills. This new unit is prohibited by law from performing the type of operations carried out by the NSA as Dutch law does not allow this type of internet searches.
The NSA declined to comment and referred to the US Government. A government spokesperson states that any disclosure of classified material is harmful to our national security.


text:
Access to Chinese Games (Français). Mah-jong. Chinese tile games Mah Jongg: Free Majong Tiles Game · Blue Mahjong · Mahjong Connect: play while the. Mahjong is known by many other names, including Mahjongg, Majong, Mah-jong, Mahjong Solitaire, Chinese tile games, and Shanghai Games. No matter what. Mah Jong Play Solitaire Mahjongg Free, A traditional Chinese Tiles Game.
Chinese game: How to play mahjong? Fun, fun, fun...
Chinese tile game - Definition von
The dealer is chosen by various means, either by throwing dice the highest total takes the east wind , by placing one of each wind face down and having each player randomly select one of these tiles or other house rule variations. Mind sport Board game. HOW TO PLAY The aim of the game is to match pairs of identical tiles and remove them from the board, revealing the tiles underneath and making them available for play. Introduction Mah Jong is a game for four players although two, three or five may play played at a table with a set of tiles, During the game the players hold 13 tiles. The game and its regional variants are widely played throughout Eastern and South Eastern Asia and have a small following in Western countries. This continues until all four players have been East dealer. In Western Classical variants, this is known as creating a Mahjong , and the process of winning is called going Mahjong. Even though both skill and chance play a fundamental role in the game, there is no shortage of superstitions in which players believe where they sit, how they hold their pieces or objects they have on their person will somehow affect the outcome. Some people call the game Shanghai or Mahjongg Solitaire. Many variations jacks or better poker differ only by scoring:. Player has 1 and 9 of each simple suit, one of each wind, one of each dragon and in addition one extra piece of any of those thirteen elements. On December 30, at 7: Depending on the game, there are multiple copies of each card.

domain: entertainment


text:
Opioid analgesics with restricted access to the central nervous system represent a new approach to the treatment of severe pain with an improved safety profile. The objective of this study was to investigate the peripheral and central components of the antinociceptive actions of the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared with those of the centrally penetrating μ-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. In the tail-flick test in rats, the 6-amino acid conjugates were 45- to 1170-fold more potent than morphine after i.c.v. administration and 19- to 209-fold after s.c. administration. They showed potencies similar to fentanyl after s.c. administration and were more potent after i.c.v. application. The time course of action was different between s.c. and i.c.v. administration, with significant long-lasting effects after i.c.v. administration. Systemic administration of the peripherally selective opioid antagonist naloxone methiodide antagonized the effects after s.c. but not after i.c.v. administration in the tail-flick test. Subcutaneous 6-amino acid derivatives also elicited antihyperalgesic effects in the formalin test in rats, which were reversed by systemically administered naloxone methiodide. Although morphine exerts its analgesic effects by central and peripheral mechanisms, the investigated new opioids interact primarily with peripheral opioid receptors after s.c. administration. The present data indicate that the 6-amino acid conjugates of 14-O-methyloxymorphone have limited access to the central nervous system and can mediate antinociception at peripheral sites. Also, they might find clinical application when the central actions of opioids are unwanted.
The potent antinociceptive actions of classical opioids such as morphine are traditionally considered to be mediated centrally through an action at the supraspinal or spinal level (for reviews, see Fürst, 1999; Gutstein and Akil, 2001; Przewlocki and Przewlocka, 2001). Antinociceptive effects have also been demonstrated to result after local application of opioids in the periphery, for example, in mouse writhing (Kolesnikov et al., 1996; Reichert et al., 2001) and in rat models of inflammation (Stein et al., 1989; Perrot et al., 2001) or neuropathic pain (Obara et al., 2004). These effects have been attributed to opioid induced actions mediated by peripheral opioid receptors (Fields et al., 1980; Stein et al., 1995). Neuroanatomical, molecular and electro-physiological studies have shown that such receptors are expressed on peripheral terminals of sensory neurons where they can modulate both afferent and efferent neuronal functions, resulting in antinociception (Schäfer et al., 1995; Stein et al., 1996).
Opioids interacting with peripheral opioid receptors without crossing the blood-brain barrier might be used as potent analgesics and should be devoid of centrally mediated side effects. Strategies to restrict the access of opioids to the central nervous system include quaternization and incorporation of highly polar hydrophilic substituents (Brown and Goldberg, 1985; Botros et al., 1989; Portoghese et al., 1995). Generally, it has been found that quaternary compounds have reduced access into the central nervous system, but they have considerably lower affinity and potency to opioid receptors (Herz and Teschemacher, 1971; Brown and Goldberg, 1985). To avoid this problem, opioids with hydrophilic groups attached at the C-6 position of the morphinan structure were synthesized (Botros et al., 1989, Portoghese et al., 1995; Schütz et al., 2003). Loperamide, asimadoline, morphine-6-glucoronide (M6G), and several peptidic κ-opioid agonists are examples of peripherally restricted opioids that have been investigated in experimental and clinical studies (for review, see Stein et al., 2003).
Since the numerous side effects (e.g., respiratory depression, sedation, and constipation) and tolerance to morphine, fentanyl, or oxycodone strongly limit their clinical use, there is a continuous search for analgesic drugs with an improved side effect profile (for reviews, see Nicholson, 2003; Stein et al., 2003). Efforts to eliminate or minimize the undesired side effects of morphine led to the synthesis of a significant large number of compounds (for reviews, see Schmidhammer, 1993; Fürst et al., 1995). A derivative of oxymorphone, 14-O-methyloxymorphone, was developed by our group and reported to be about 400- and 40-fold more potent than morphine and oxymorphone, respectively, in the hot-plate test in mice (Schmidhammer et al., 1984; Fig. 1). Further chemical optimization led to 14-methoxymetopon (Schmidhammer et al., 1990; Fig. 1), a highly selective μ-opioid receptor agonist (Fürst et al., 1993; Spetea et al., 2003). This opioid was described as an extremely potent centrally acting analgesic, being 300- to 20,000-fold more potent than morphine, depending upon the analgesic paradigm used (Schmidhammer et al., 1990; Fürst et al., 1993; Zernig et al., 2000; King et al., 2003).
Our research efforts in the morphinan series have shifted from the development of highly potent and selective μ-opioid receptor agonists with a central site of action (Fürst et al., 1993; Schmidhammer, 1993) to the development of opioid analgesics that would have limited access to the central nervous system. A family of 6-amino acid-substituted (glycine, alanine, and phenylalanine) derivatives of 14-O-methyloxymorphone (Fig. 2) was developed to obtain opioid agonists that are more hydrophilic than the parent compound and that have peripheral selectivity (Schütz et al., 2003; Spetea et al., 2004). Binding studies revealed that these 6-amino acid conjugates displayed very high affinities to the μ-opioid receptor and were effective in inhibiting the electrically evoked contractions of the mouse vas deferens through the μ-opioid receptor (Spetea et al., 2004). Based on the calculation of blood-brain distribution coefficients, these derivatives were predicted to have restricted access to the central nervous system after systemic administration (Schütz et al., 2003).
In the present study, we aimed to investigate the peripheral and central components of the antinociceptive action of the 6-amino acid conjugates of 14-O-methyloxymorphone after subcutaneous and intracerebroventricular administration in the tail-flick test in rats. In addition, we have examined the dose-response correlations and the site of action of the 6-amino acid derivatives after subcutaneous administration in the formalin test in rats.
Materials and Methods
Materials. The 6-amino acid-substituted derivatives of 14-O-methyloxymorphone, HS-730, HS-731, HS-935, HS-936, HS-937, and HS-938, were prepared as recently described (Schütz et al., 2003; Fig. 2). 14-O-Methyloxymorphone was synthesized as described previously (Schmidhammer et al., 1984; Fig. 1). Morphine hydrochloride, fentanyl, and naloxone hydrochloride were obtained from Sigma-Aldrich (St. Louis, MO) or from Polfa, Kutno, Poland (morphine). Naloxone methiodide (N-methylnaloxonium iodide; quaternary naloxone) was kindly provided by Dr. S. Hosztafi (Alkaloida-ICN, Tiszavasvari, Hungary) or obtained from Sigma-Aldrich. Formaldehyde was obtained from Odczynniki SA (Lublin, Poland).
All drugs were dissolved in physiological saline and administered to 5 to 10 rats/group. Rats received s.c. injections under the skin of the neck, in a volume of 5 ml/kg body weight in the tail-flick test, or in a volume of 4 ml/kg in the formalin test. Intracerebroventricular (i.c.v.) injections were given directly into the cerebral ventricles in a volume of 5 μl. Control animals received the same volume of s.c. or i.c.v. saline.
Animals. Male Wistar rats (120–150 g) used in the tail-flick test were purchased from Charles River (Budapest, Hungary). Male Wistar rats (250–270 g) used in the formalin test were obtained from the Institute of Pharmacology, Polish Academy of Sciences (Krakow, Poland). Animals were housed in Macrolon cages (six animals per cage) with food and water ad libitum, in a temperature-controlled room (22 ± 2°C), maintained on a 12-h light/dark cycle (the light on at 8:00 AM). Experiments were carried out in accordance to the Declaration of Helsinki and the Guide for Care and Use of Laboratory Animals. The experimental protocols were approved by the Semmelweis University (Budapest, Hungary) and the Institute of Experimental Animal Care Committee (Institute of Pharmacology, Krakow, Poland).
Tail-Flick Test. The tail-flick test in the rat was performed according to the described procedure (Fürst et al., 1993). A beam light was focused on the tip of the tail, and the latency required for the rat to remove its tail was determined before (baseline) and after drug administration, using an arbitrary cut off time of twice the control reaction time and expressed as percentages. The antinociceptive activity was assessed 30, 60, 120, and 180 min after s.c. drug administration, and 10, 20, 30, 60, 120, 180, 240, 300, 360, 420, and 480 min after i.c.v. administration.
To evaluate the site of action (peripheral or central) of the opioid agonists, the effect of naloxone, the tertiary opioid antagonist that readily crosses the blood-brain barrier, and that of the peripherally selective opioid antagonist naloxone methiodide on the antinociceptive action in the tail-flick test was assessed after s.c. and i.c.v. administration. In experiments when the antagonist effect was assessed, i.c.v. naloxone or naloxone methiodide was given 10 min before the s.c. administration of the opioid agonist. Antagonists were coadministered with the respective agonist, when they were given by the same route of administration, s.c. or i.c.v. Measurements were performed 30 min after s.c. and 20 min after i.c.v. administration of the opioid agonists.
Formalin Test. The formalin test was used as a model of tonic inflammatory pain. Pain-related behavior induced by local administration of formalin is characterized by the occurrence of two characteristic phases of increased pain sensitivity in rats. The first phase is related to a direct stimulation of nociceptors, primarily owing to the increased secretion of substance P, bradykinin, and stimulatory amino acids. In the second phase, there is an increase in the levels of histamine, prostaglandins, 5-hydroxytriptamine, and bradykinin, which leads to the development of a localized inflammatory response and progressive functional changes in the dorsal horn and the central nervous system.
Fifteen minutes after s.c. administration of the opioid agonists, rats were lightly anesthetized by inhalation of halothane [2–3% (v/v/oxygen mixture), 5 l/min] for 2 to 3 min in a Plexiglas chamber. Rats were then s.c. injected with 100 μl of 12% formalin into the dorsal part of the right hind paw as described previously (Dorazil-Dudzik et al., 2004). After formalin injection, rats were placed in a single wire cage for observation. Pain-related behavior was quantified by counting the incidence of spontaneous flinches, shakes, and jerks of the formalin-injected paw. Pain reactions were continuously counted for 90 min for each animal and then totaled over two characteristic periods: 5 to 15 min (first phase) and 35 to 40, 40 to 45, 45 to 50, 75 to 80, 80 to 85, and 85 to 90 min (second phase) after formalin administration. Naloxone methiodide (2131 nmol/kg s.c.) was injected simultaneously with the highest dose of each opioid agonist, 15 min before formalin injection.
Data Analysis. The differences between the results obtained both by the tail-flick test or the formalin test were statistically determined by analysis of variance (ANOVA). For the significant differences between the groups, we used Student's t test with Bonferroni correction as post hoc test. The ED50 values and 95% confidence limits were given in nanomoles. A p value <0.05 was considered statistically significant.
Antinociceptive Effects in the Tail-Flick Test in the Rat
Subcutaneous Administration. In the tail-flick test in the rat, morphine, fentanyl, 14-O-methyloxymorphone, and five of the six 6-amino acid-substituted derivatives of 14-O-methyloxymorphone elicited dose- and time-dependent antinociceptive effects after s.c. administration. The values of ED50 are listed in Table 1. The peak ED50 values of the amino acid conjugates were ranging between 29 and 315 nmol/kg. One compound, HS-938, failed to produce 50% antinociception between 30 and 120 min after s.c. administration of 3600 nmol/kg (Table 1). The calculated ED50 values of morphine, fentanyl, and 14-O-methyloxymorphone at the peak of action (30 min) were 6053, 38.6, and 14.9 nmol/kg, respectively.
As shown in Table 1, morphine, fentanyl, and 14-O-methyloxymorphone produced their maximum antinociceptive effect 30 min after s.c. administration, whereas the new opioid agonists reached their peak of action at 60 min. The antinociceptive action of morphine, fentanyl, 14-O-methyloxymorphone, HS-731, and HS-935 lasted about 120 min, whereas the effect of HS-730, HS-936, and HS-937 lasted for 3 h after a single s.c. administration. A 2-fold higher dose of morphine was required to produce the same effect at 2 h after s.c. administration compared with the ED50 dose at the peak of action. In the case of HS-731, HS-935, and HS-937, only a 1.0- to 1.5-fold ED50 dose, as determined at 60 min, was required to produce antinociception at 120 min after s.c. administration. Notably, dose-dependent antinociceptive effects were still observed at 3 h after s.c. HS-730, HS-936, and HS-937. The shortest duration of action was elicited by fentanyl, and a 10-fold higher dose was required to induce 50% analgesia at 120 min after s.c. administration than the dose determined at the peak effect (Table 1).
Antinociceptive potencies in the tail-flick test of α-versus β-epimers (Table 1; Fig. 2) did not differ significantly. The ratios are between 1.3 and 2.0 except for HS-938, the 6β-phenylalanine derivative, which proved to be ineffective up to 3600 nmol/kg, whereas its α-counterpart HS-937 showed a dose-dependent effect after s.c. administration (ED50 = 315 nmol/kg, at 60 min; Table 1).
Intracerebroventricular Administration. All tested opioid agonists produced dose- and time-related antinociceptive effects in the tail-flick test in rats after i.c.v. administration (Table 2). The time-response curves of higher i.c.v. doses corresponding to the calculated ED95 of the test opioids are shown in Fig. 3. The onset of the antinociceptive response elicited by fentanyl, morphine, and 14-O-methyloxymorphone was rapid, with a peak of action at 10 and 20 min, respectively (Fig. 3A). This effect rapidly declined and returned to the preinjection value about 1 to 2 h after i.c.v. drug injection. In contrast, the 6-amino acid conjugates of 14-O-methyloxymorphone exhibited a significantly increased duration of the antinociceptive effect (Fig. 3B). Their antinociceptive action showed a somewhat slower onset of action, which peaked at 30 to 120 min and lasted about 4 to 7 h. Whereas HS-938 failed to induce antinociception by s.c. administration up to 3600 nmol/kg, it produced a time- and dose-dependent response when applied i.c.v. (Table 2; Fig. 3B).
Relative Antinociceptive Potency after s.c. and i.c.v. Administration in the Tail-Flick Test
The peak antinociceptive potencies of the 6-amino acid derivatives of 14-O-methyloxymorphone relative to morphine and fentanyl are shown in Table 3. The differences in potency of the novel opioid agonists compared with morphine and fentanyl were much more remarkable after i.c.v. than after s.c. administration. Although they were slightly less potent or equipotent compared with fentanyl, they were about 19- to 209-fold more potent than morphine when administered s.c. (Table 3). However, the 14-O-methyloxymorphone derivatives proved to be 45- to 1170-fold more potent than morphine when given i.c.v. Furthermore, HS-938, which failed to produce antinociception by s.c. administration, was 45-fold more potent than morphine after i.c.v. injection (Tables 2 and 3). In contrast to s.c. administration, whereby the difference observed between the new opioids and fentanyl was negligible, the 6-amino acid derivatives of 14-O-methyloxymorphone were about 2- to 55-fold more potent analgesics than fentanyl after i.c.v. administration.
Antinociceptive s.c./i.c.v. Potency Ratios in the Tail-Flick Test
As shown in Table 4, the difference between the doses required to elicit 50% antinociceptive effect after peripheral systemic (s.c.) versus central (i.c.v.) administration (ED50 nanomoles per kilogram, s.c./ED50 nanomoles per rat, i.c.v.) was 23 in the case of fentanyl, 172 for morphine, and 87 for 14-O-methyloxymorphone, the parent molecule. The s.c./i.c.v. potency ratios of the 6-amino acid conjugates were found to be much higher compared with morphine, fentanyl, and 14-O-methyloxymorphone, 569, 651, 967, 1887, >4600, and 5000 for HS-935, HS-936, HS-731, HS-730, HS-938, and HS-937, respectively. These ratios were observed to be remarkably high in the case of HS-938 and HS-937, the phenylalanine-substituted β- and α-epimers, respectively (s.c./i.c.v. ED50 ratios >4600 and 5000, respectively) (Table 4).
Antagonist Effect on the Antinociceptive Action in the Tail-Flick Test
Among the new opioid agonists, HS-731 was selected for a more detailed investigation of the site of action and compared with the action of morphine (Fig. 4). Although systemically (s.c.) administered naloxone methiodide did not alter the effect of s.c. morphine (7769 nmol/kg), except in a very high dose (21,308 nmol/kg), it antagonized the s.c. antinociceptive effect of HS-731 (183 nmol/kg) (Fig. 4, A and B). A similar degree of antagonism (34–42%), as determined for HS-731, was observed in rats after s.c. coadministration of equipotent antinociceptive doses of HS-730, HS-935, HS-936, and HS-937, with 320 nmol/kg naloxone methiodide (data not shown). Subcutaneous administration of 2131 and 21,308 nmol/kg naloxone methiodide failed to antagonize the antinociceptive effects of i.c.v. HS-731 (0.18 nmol/rat) and i.c.v. morphine (78 nmol/rat) (Fig. 4, C and D). Both naloxone methiodide (21.3 nmol/rat) and naloxone (2.75 nmol/rat) injected i.c.v. blocked the antinociception produced by HS-731 (0.18 nmol/rat) and morphine (78 nmol/rat) after i.c.v. administration (Fig. 4, C and D). However, although i.c.v. injected naloxone (27.5 nmol/rat) completely antagonized the antinociceptive effectof s.c. morphine (7769 nmol/kg), it was ineffective to influence the action of s.c. HS-731 (183 nmol/kg) (Fig. 4, A and B). The same experiments were performed with HS-730, HS-935, HS-936, HS-937, and HS-938, and similar results were obtained (data not shown).
Antinociceptive Effects in the Formalin Test in the Rat after Subcutaneous Administration
Subcutaneous administration of morphine and 6-amino acid conjugates of 14-O-methyloxymorphone, HS-730, HS-731, HS-937, and HS-938, produce a dose-dependent antinociceptive action in both phases of the formalin test in rats (Figs. 5A, left, and 6). The ED50 values of the 6-amino acid derivatives in the first and second phase of the formalin response were ranging between 72 and 171 nmol/kg and 110 and 292 nmol/kg, respectively (Table 5). The antinociceptive potencies of the new opioid agonists in the formalin test were 10- to 22- and 5- to 13-fold higher in the first and second phase, respectively, compared with morphine (Fig. 6). Their inhibition of pain behavior seems to be somewhat higher in the first phase than in the second phase, whereas morphine produced comparable inhibition of formalin-induced behavior in both phases. Although s.c.-administered 6β-phenylalanine epimer HS-938 was ineffective in eliciting antinociception in the tail-flick test up to 3600 nmol/kg (Table 1), it produced antihyperalgesic effects in the formalin-injected paw after s.c. administration (ED50 first phase 79 nmol/kg and second phase 109 nmol/kg; Table 5).
To establish the site of action of the 6-amino acid derivatives and morphine, the peripherally selective opioid antagonist naloxone methiodide was s.c. coadministered with the opioid agonists, and the response in the formalin-injected paw was assessed. As shown in Fig. 5B (right), the antihyperalgesic effects of s.c. 366 nmol/kg HS-730 or HS-731 were significantly antagonized by s.c. 2131 nmol/kg naloxone methiodide. Similar inhibitory effects of naloxone methiodide were observed after coinjection with the other tested amino acid derivatives (data not shown). The antinociceptive activity of s.c. 5278 nmol/kg morphine in the formalin test was also significantly reversed by s.c. naloxone methiodide (Fig. 5B, right).
The major finding of the present study is that the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone produce potent antinociceptive effects in acute nociceptive and inflammatory pain in rats. These effects were demonstrated to be mediated preferentially via activation of opioid receptors located in the periphery after systemic (s.c.) administration.
The 6-amino acid derivatives elicited antinociception in a dose-dependent manner after s.c. administration. The peripherally selective opioid antagonist naloxone methiodide reversed the antinociceptive effects of these opioid agonists. Typically, the pain ceased very rapidly upon s.c. and i.c.v. administration of morphine, fentanyl, and 14-O-methyloxymorphone, but in the case of the new opioids, there was some delay in the onset of the effect after s.c. administration. Extremely long-lasting effects were measured in the tail-flick test after i.c.v. administration. In the tail-flick test, potencies of the 6-amino acid derivatives did not significantly differ between the α- and β-epimers, in agreement with in vitro biological data whereby also no major changes in opioid binding and agonist activity were detected (Spetea et al., 2004). In the case of the phenylalanine conjugates, the β-epimer HS-938 failed to elicit antinociception up to 3600 nmol/kg after s.c. administration. However, its α-counterpart HS-937 produced dose- and time-dependent antinociceptive action. In contrast to the inactivity of the β-epimer HS-938 determined after s.c. administration, it proved to be a potent antinociceptive agent after i.c.v. administration. The 6β-phenylalanine derivative was reported to have some preference for δ-over μ-opioid receptors in binding and δ-opioid agonism in mouse vas deferens bioassays (Spetea et al., 2004). The increased activity at δ-opioid receptors might explain the virtual ineffectiveness detected in the tail-flick test after systemic administration. However, a potent antihyperalgesic effect of s.c. HS-938 was also found in the formalin pain model. These observations corroborate with earlier reports on the lack of antinociceptive effects of other δ-opioid agonists after s.c. application in the tail-flick test, which are, however, more active in visceral pain models such as the writhing test (Quock et al., 1999). Antinociceptive effects of δ-opioid agonists are enhanced in hyperalgesia and allodynia after spinal and supraspinal administration (Desmeules et al., 1993; Mika et al., 2001).
The potent antinociceptive effect of this class of opioids might be attributed to the substitution pattern in position C-6 of the morphinan skeleton. It was reported that numerous opioids bearing various substituents in position C-6, e.g., azido (Knoll et al., 1975) and 6-O-glucuronide in morphine (Abbott and Palmour, 1988; Frances et al., 1992), or amino in oxymorphamine (Botros et al., 1989), induce strong analgesic actions. As recently established in structure-activity relationship studies, the substitution at position C-6 with ionizable groups such as amino acid residues does not have any detrimental effect on opioid activity at the receptor level (Spetea et al., 2004) and on antinociceptive potency as described here. The parent molecule 14-O-methyloxymorphone proved to be a more potent antinociceptive agent after s.c. administration than the new 6-amino acid-substituted derivatives, whereas it was observed to produce similar potency after i.c.v. administration.
Characteristic differences occurred in the time course of the antinociceptive action of the new opioids depending on the route of application, s.c. or i.c.v., in the tail-flick test. The rapid onset with a maximum effect early, which waned very shortly after drug administration, is a typical characteristic of the time course of action of opioid agonists (e.g., morphine, fentanyl, and etorphine) that mediate analgesia via central mechanisms and were described under both normal and inflammatory conditions (Millan et al., 1987; Aceto et al., 1997). In contrast, the new opioids administered s.c. acted longer with some delay in onset. Intracerebroventricular administration of the 6-amino acid conjugates produced a different time course of action in the tail-flick test than the centrally acting opioids, with extremely prolonged effects. Our observations are consistent with previous findings on the effect of i.c.v. morphine and its active metabolite M6G in different pain tests (Abbott and Palmour, 1988; Frances et al., 1992). Significantly long-lasting analgesia was reported for i.c.v. M6G, a hydrophilic molecule, which poorly penetrates the blood-brain barrier (Abbott and Palmour, 1988; Frances et al., 1992; Tegeder et al., 2003). One possible explanation of the long-lasting action might be a slow elimination of opioids containing hydrophilic groups from the brain based upon their reduced lipid solubility. It was observed that the differences in the duration of action of various opioids, after i.c.v. administration, are largely determined by their hydrophilic/lipophilic character and the time that the compound remains in the ventricular system (Herz and Teschemacher, 1971).
That the presence of hydrophilic groups is indeed important in limiting penetration into the central nervous system was demonstrated by comparing the activity ratios of the peripheral (s.c.) versus central (i.c.v.) potencies in the tail-flick test of the 6-amino acid conjugates with those of centrally penetrating μ-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. There was a marked enhancement of potency of the new agonists after i.c.v. in comparison with s.c. administration. Very good correlations between hydrophilicity and the i.v./i.c.v. activity quotients were earlier described for various opioids (Herz and Teschemacher, 1971; Botros et al., 1989; Frances et al., 1992; Portoghese et al., 1995).
To further explore the peripheral and central components of antinociceptive actions of the 6-amino acid conjugates of 14-O-methyloxymorphone after s.c. and i.c.v. administration, the antagonist effects of naloxone methiodide, which has restricted access to the central nervous system, were investigated in the tail-flick test. Antinociceptive effects of peripherally administered HS-731 were dose dependently antagonized by s.c. naloxone methiodide. However, an approximately 10-fold higher dose of antagonist was required to antagonize the effects of morphine to the same extent as the s.c. HS-731. A low dose of naloxone methiodide (320 nmol/kg s.c.) also significantly attenuated the s.c. action of the other 6-amino acid conjugates, in contrast to s.c. morphine, indicating that these ionizable opioids have a peripheral site of action. The lack of antagonism by low doses of naloxone methiodide on the antinociception elicited by s.c. morphine, and the attenuation in nociception with significantly higher antagonist dose in the tail-flick test corroborate with previous findings in hyperalgesia and inflammation (Kayser et al., 1991; Perrot et al., 2001; Reichert et al., 2001; Shannon and Lutz, 2002). Subcutaneous naloxone methiodide was ineffective in antagonizing the effects of the i.c.v. administered agonists. In addition, even a 10-fold higher dose of naloxone methiodide failed to block the antinociceptive effects of i.c.v. HS-731.
On the other hand, antinociceptive effects of HS-731 after i.c.v. administration were antagonized by i.c.v. naloxone, demonstrating an opioid mechanism of action. Although i.c.v.-injected naloxone inhibited almost completely the effects of systemically administered morphine, it failed to antagonize s.c. HS-731. Moreover, i.c.v. coadministration of the agonists with naloxone methiodide also resulted in significant antagonism. Naloxone was about 10-fold more potent than naloxone methiodide in antagonizing HS-731 and morphine. This is in agreement with observations that much higher doses of quaternary opioid antagonists compared with their tertiary congeners are required for equivalent antagonism (Brown and Goldberg, 1985; Shannon and Lutz, 2002). Together, these data are consistent with the interpretation that systemically administered morphine exerts its analgesic effects by interacting with both central and peripheral opioid receptors (Perrot et al., 2001; Shannon and Lutz, 2002), whereas the 6-amino acid derivatives of 14-O-methyloxymorphone interact primarily with peripheral opioid receptors after s.c. administration.
Several studies demonstrated that opioids can produce analgesia through peripheral mechanisms after inflammation of peripheral tissues (Stein et al., 1995, 2003). The new opioid agonists produced potent antihyperalgesic effect in the formalin test in rats after s.c. administration, being more potent than morphine. These effects were inhibited by s.c. naloxone methiodide, indicating that such opioids produce antihyperalgesia by activating peripheral opioid receptors. The present findings are in agreement with other studies where antihyperalgesic effects of a peripherally acting μ-opioid agonist, loperamide, were detected in the formalin test after s.c. administration (Shannon and Lutz, 2002).
The 6-amino acid conjugates of 14-O-methyloxymorphone possess groups that should be highly ionizable at physiological pH. The presence of these ionized groups increases hydrophilicity and thus reduces the penetration into the central nervous system by having greater selectivity than the nonionized molecules toward peripheral tissues upon peripheral administration. The peripheral nature of antinociception produced by the new opioids is supported by the calculated blood-brain distribution coefficients (Schütz et al., 2003), which indicate that they have a limited ability to enter the central nervous system after systemic administration. In most of the published experimental and clinical reports, peripheral analgesic effects were achieved after local injection of opioids (Stein et al., 2003). Systemic rather than local administration of opioids with exclusive or predominant peripheral action would be more convenient in many cases.
In conclusion, the pharmacological profile described for the 6-amino acid conjugates of 14-O-methyloxymorphone indicate that such opioids have limited access to the central nervous system and can mediate antinociception at peripheral sites. Opioid agonists in this series can find clinical application where the central actions of opioids are unwanted.
We acknowledge the excellent technical assistance of I. Wachtl and K. Parina.
- Received July 28, 2004.
- Accepted September 21, 2004.
This work was supported by a grant from the European Community (EPILA, QLK6-1999-02334), Hungarian grants (ETT 024/2003; A-12/03 Austrian-Hungarian S&T Intergovernmental Cooperation) and the Hungarian Academy of Sciences-SE Group of Neuropsychopharmacology). Parts of this work were presented at the 2003 International Narcotics Research Conference and at the 2004 European Opioid Conference.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: M6G, morphine-6-glucoronide; HS-730, 2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-yl)amino]acetic acid bis(tetrafluoroborate); HS-731, 2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic acid bis(tetrafluoroborate); HS-935, (2S)-2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-yl)amino]propanoic acid bis(tetrafluoroborate); HS-936, (2S)-2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]propanoic acid bis(tetrafluoroborate); HS-937, (2S)-2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6α-yl)amino]-3-phenylpropanoic acid bis(tetrafluoroborate); HS-938, (2S)-2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]-3-phenylpropanoic acid bis(tetrafluoroborate); ANOVA, analysis of variance.
- The American Society for Pharmacology and Experimental Therapeutics

domain: chemistry


Man accused of cutting wife with knife
Updated On: Sep 13 2012 08:03:00 AM EDT
A man is in jail after he was accused of assaulting his wife on Tuesday.
Deputies were dispatched to a report of a domestic violence and stabbing at 1717 Maple Grove Road in Mt. Orab just after 4:30 p.m.
The victim, identified as Holly High, 57, suffered two superficial knife wounds to her chest and was transported to the Southwest Regional Hospital in Georgetown, where she was treated and released.
The suspect, identified as Steven High, 58, was not home when deputies arrived, but returned later and was arrested for domestic violence and felonious assault.
High remains incarcerated at the Brown County Adult Detention Center on $100,000 bond.
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