text:
Recaps Note: Parts of this post is linking back to BULLDOG SECURITY UPDATES also a TUESDAY afternoon post LINK
Bulldog75: OK; LETS CONCENTRATE ON SOME LAST MINUTE PREPARATIONS THAT ARE URGENT/PERTINENT. BRING IT.
Bulldog75: QUESTIONS (NO RATE OR DATE PLS) THANKS.
Brian to undefined Bulldog75: can we get ready for tomorrow?
Bulldog75: BRIAN; I WAS READY TODAY.
Snoopy to Bulldog75: I know that you are going to cash some dinar for other currency, but then you'll do two trust, my question is what % of each of these? Thanks
Bulldog75: SNOOPY: ONLY ONE TRUST IS OK. AFTER CASHIN , THEN SWITCH TO FOREIGN. IMHO.
Bulldog75: CURRENCY
Bulldog75: HAVE TWO COMPUTERS. ONE TO THE INTERNET AND ONE THAT IS NOT. OBVIOUS REASON WHY.
Spoofs: I live in South Texas and my husband and I are wanting to purchase a new home. I know you say nothing over a million but here in Texas, should we aim to keep it under $400K?
Read More Link on Right
Bulldog75: SPOOFS ; HI. GREAT NEIGHBORHOODS ALL OVER USA FOR UNDER ONE MILLION. CHOOSE WHAT BEST FITS ONE PEACE OF MIND. TY.
Bulldog75: PLS USE ONLY ONE COMPUTER ON INTERNET. WOLVES WILL BE LOOKING FOR BANK ACCT INFO AND HACKING.TY.
Bulldog75: SEEK COMPETENT COMPUTER ADVICE. ONE CAN EVEN BE HACKED THRU PRINTERS NOW. PLS TAKE HEED.
Bulldog75: [13:34:03] Jesusloves:
Bulldog75 do we have to have the trust set up before we cash -in Thanks
Bulldog75: JESUSLOVES: ANSWER: MUST LEGALLY SET UP TRUST PRIOR TO OPENING A BANK ACCT. THIS IS A MUST. THANKS.
Bulldog75: [13:27:34] Bulldog75: THIS TRUST WILL AFFECT EVERYONE THE REST OF ONE'S LIFE. ASSUME NOTHING. STUDY AND KNOW DETAILS. THIS WILL PROTECT U AND YOUR ASSESTS. OR PAY HEAVY TAXES. YOUR CHOICE.
Bulldog75: BENNY; BEST TO HAVE TRUST ACCOUNT SET UP IN BANK NEAR BY ONE'S HOME BASE. GET TO KNOW ONE'S BANKER VERY, VERY WELL. ITS EASIER THAT WAY. NO QUESTIONS ON BIG TRANSACTIONS.
Bulldog75: THE GOAL HERE IS: TO BE A GHOST TO THE GENERAL PUBLIC AND THE WOLVES.
Texasslot to Bulldog75: What if we cant afford to set up a trust prior to cash in?
Bulldog75: TREXAS: SET UP TRUST AFTER CASH IN. TY.
Bulldog75: MONI; IMPT DATA THAT COULD BE TRANSFERRED OVER TO OTHER ONE. VITAL STATS. TY.
Moni101101 to Bulldog75: the second computer what would you use it for... Are saying never have it connected to the Internet and do not do any banking on the Internet through our computers?
Bulldog75: MONI; IMPT DATA THAT COULD BE TRANSFERRED OVER TO OTHER ONE. VITAL STATS. TY.
Chmission to undefined Barb: you can do your banking paperless now in most banks, I believe...I just like paper as well....
Bulldog75: BARB; VERY WISE. BEST NOT TO HAVE STATEMENTS MAILED .
Bulldog75: CAN U IMAGINE THE HOURLY EEMPLOYEES SEEING YOUR 100 MILLION BALANCE.
Mountaingirl47 to LoveMyKids: BULLDOG........If one does not have the money to set up trust before RV, is it ok to cash-in and immediately set up trust and move monies to Trust/LLC's? Thanks for helping.
Bulldog75: MOUNTAINGIRL ANSWER: CASH IN MINIMUM. FORM TRUST. CASH BALANCE LATER , IMHO. TAKE SOME BUT NOT ALL. U FILTER. GET ADVICE.
Mamabird to Bulldog75: And I checked over and over and over... There is 'no way' to deposit your money and 'no one in the bank' to be prevented from seeing your balance. Bothers me!
Bulldog75: MAMABIRD; EXACTLY. THIS IS WHY KEEP A LOW PROFILE IN AND OUTSIDE THE BANK.
Scooby80 to Bulldog75: What are we supposed to tell people when they ask what we do? Gonna be kinda weird when someone askes what we do.
Bulldog75: SCOOBY80; GOOD Q; EVERYONE LISTEN UP TO THIS. WHAT KIND OF WORK DO U DO???? (POST RV)......ANSWER: (COULD BE)I AM IN OIL PARTNERSHIPS & INVESTMENTS. (GIVE NO DETAILS. CHANGE SUBJECT).
Snuggs101 to Bulldog75: I have a trust we set up 7 yrs ago. We lost everything and are trying to start over. Would our old trust still be valid?
Bulldog75: SNUGGS; GOOD Q; CONSULT ATTORNEY. VERIFY. DO U HAVE EIN# STILL VALID AND TAX RETURNS. CHECK WITH CPA.
LSUTIGER to Bulldog75: Bulldog75: can you explain about the black debit card please
Bulldog75: LSUTIGER: GREAT Q: ITS A CASH DEBIT CARD. JUST LOAD IT UP WITH CASH. THAT WAY NO CHECKS NEED TO BE WRITTEN AND NO HEAVY CASH ON HAND.
Bulldog75: [13:20:23] BlessedinAZ: Bulldog Good afternoon. Have you seen the copu of the US Postal form in recaps regarding a PO Box being your address? On line #3 it specifically states if you use the PO Box as your address on legal forms, the P.O. Box may be closed and it may be a violation of civil and criminal laws. Your thoughts please, sir?
[13:24:16] Bulldog75: BLESSEDIN; DO WHAT ONE NEEDS TO DO SO AS TO PROTECT YOUR INTERESTS. THIS IS FOR FED EX, UPS, TYPE DELIVERIES ALSO.
Bulldog75: I SEE YOU ALL HAVE STUDIED AND GAINED TREMENDOUS KNOWLEDGE OVER THE LAST FEW WEEKS. TRAIN THE OTHERS. SOMETIMES WE ARE TEACHERS AND SOMETIMES WE ARE STUDENTS.
browneyes to Bulldog75: You said no co-mingling trust to another but if you are a family put all in to one then u want to distribute and all have trust's??
Bulldog75: BROWNEYES BLUE: HI. DISCUSS WITH FAMILY. LOTS OF OPTIONS. GOOD Q.
moreagles to Bulldog75: How much do you think Maliki is the hold up?
Bulldog75: MOREAGLES; HE IS GONE WITH THE WIND.
cman13 to Bulldog75: do you think the banks will have the proper forms when cashing out? and what forms do we need?
Bulldog75: CMAN; BANK HAS ALL FORMS
Bulldog75: THAT RELATE TO BANKS ONLY.
dimples1943: I do not have a receipt for my dinars. Will I have a problem cashing out?
Bulldog75: DIMPLES; NO PROB., IMHO;
Bulldog75: [13:18:10] praiseRus to Bulldog75: I have a Down's syndrome daughter. I am a single mother. Do I make a seperate trust for her and her care after I leave this world/
[13:19:05] Bulldog75: PRAISE; IMHO, I WOULD HAVE TWO TRUSTS. SEEK CPA, ATTORNEY ADVICE FOR YOUR STATE. THANKS.
Bulldog75: TRUSTS CAN TAKE ONE WEEK TO ONE MONTH ; DEPENDING ON YOUR CIRCUMSTANCES.
Chefmom: No a 508 is NOT REGUL:ATED if you wish I will send you the info
vic1 to undefined Chefmom: Are you a LAWYER?
vic1 to dinarmama7: Giving ADVICE as a LAWYER is ACCEPTABLE...outside of That...an OPINION? ASK the PRO'S...A 508 is somrthing YOU REALLy need to KNOW..what your Doping With! Please do NOt accept or Give ADVICE...unless your LICENSED to DO SO!
Bulldog75: [13:15:47] mazzie to Bulldog75: Sir, you have mentioned using POD - payable on death to avoid problems for your family. Is this something that is written into the trust? Can it also be included in your regular NIBA's?
[13:18:29] Bulldog75: MAZZIE: JUST HAVE POD PLACED ON YOUR ACCOUNTS WHERE IT IS LEGAL. YOUR BANKER WILL ASSIST YOU. THANKS.
Bulldog75: [13:16:54] 123 to Bulldog75: Bulldog75 Do you have separate trustee's or are you the trustee on your trust? TIA
[13:17:34] Bulldog75: 123: ANSWER: I AM THE TRUSTEE OF BOTH OF MY TRUSTS. I OWN NOTHING , BUT CONTROL EVERYTHING. TY.
Bulldog75: [13:16:35] Bulldog75: I WILL GIVE NO INFORMATION ON RATES & DATES TODAY. MOST SHOULD BE AWARE THIS CAN HAPPEN ANY MINUTE OR HOUR. ALL SHOULD BE PREPARED FROM EVERY ANGLE.
Bulldog75: [13:14:56] Frenchy to Bulldog75: Question for someone Else. Does a Single Person with no property or Dependents Benefit from a Trust?
[13:15:48] Bulldog75: FRENCHY: YES, DRAMATICALLY. FOR EVERYONE. BIG BUCKS NEEDS TAX PROTECTION.
Bulldog75: [13:11:36] mikesbabe to Bulldog75: when you say no joint accounts does that go for married couples also ?
[13:13:38] Bulldog75: MIKE ANSWER: COUPLES JOINT ARE OK. SOME BOUND BY MARITAL LAWS OF STATE.
[13:14:34] Bulldog75: TRUSTS CAN BE NAMED ANYTHING REASONABLE: THE TRUST WILL HAVE AN 'EIN NUMBER' REGISTERED WITH THE GOVT.THESE RULES ARE TO PLAY THE GAME SMART. CONTROL EVERYTHING BUT OWN NOTHING. AND NO ONE CAN FIND YOU, YOUR FAMILY UNLESS YOU WANT THEM TO. ITS UP TO YOU. U FILTER, U DECIDE. THANKS.
Bulldog75: [13:12:29] Bulldog75: TWO RECOMMENDED TRUSTS: Irrevocable, Discretionary, Non Grantor, Complex, Spendthrift Trust : IS A GOOD ONE. YOU FILTER. YOU DECIDE. I ALSO HAVE A SECOND TRUST: CALLED A BUSINESS TRUST .
[13:13:24] Bulldog75: THESE TWO TRUSTS ARE IRREVOCABLE.
Bulldog75: [13:05:26] mawdot to Bulldog75: what about a irrevocable trust
[13:08:02] Bulldog75: MAWDOT: BOTH TRUSTS ARE IRREVOCABLE.!!!
[13:09:26] mpryde49 to Bulldog75: Sir we are sisters in this equally - are we going to run into trouble with trusts etc???
[13:10:13] Bulldog75: MPRYDE ANSWER: NO JOINT ACCTS. MAKE SEPARATE.
Bulldog75: [13:00:30] Bulldog75: ALWAYS USE YOUR PASSPORT, NEVER YOUR DRIVERS LICENSE EVER AGAIN.
[13:01:30] Bulldog75: IF THERE IS ONE THING LEFT UNDONE, THE WOLVES WILL FIND IT.
Bulldog75: [12:57:25] Bulldog75: TAKE NOTHING FOR GRANTED EVER AGAIN. ONE CAN BE TRACED EASILY. YOUR ADDRESS AND PRIVATE DATA CAN BE 'CAMERA DONE' IN 3 SECONDS FROM A CELL PHONE.
[12:58:01] Bulldog75: WE HAVE TO BE PREPARED FOR EVERYTHING. ALL ANGLES.
Bulldog75: INSPIRED ANSWER: TAKES AT LEAST A WEEK TO FORM A LEGIT TRUST. CANNOT OPEN A BANK ACCT PRIOR. MUST HAVE TRUST FIRST. THANKS.
Bulldog75: 2 TRUSTS FOR TWO MAJOR DIFFERENT INTERESTS. TY.
Bulldog75: ALWAYS USE PASSPORT. PLEASE.
Bulldog75: [12:52:25] Frenchy to Bulldog75: IMHO I have only one question.. You are Not suppose to Take any Money out of a Trust to a Personal Account, What is the Best way or % we should have in Personal account for general Living, Or What is the Best Plan there. Also Business Trust for Business Expenses, Then Income from Business is Just That INCOME Right?
[12:53:29] Bulldog75: FRENCHY; SIMPLE. TAKE A LOAN OUT OF THE TRUST AT 1% FOR 10, 20 YEARS.
vic1 to Chefmom: I have a 508...I know what they are and HOW they WORK! However, Since MTT ..I have said I will NOt talk about anything TILL after RV...With my Lawyer at MY side to HELP TEACH the NEXT....STEP! he was and is QUALIFIED to Speak...see many will NOT understand...and use wrong protection for certain needs! Referring to the Licensed PROFESSIONALS is The Best help you can give...NOt ADVICE!!! IMHO!
Bulldog75: SOME RULES VARY DEPENDING ON CIRCUMSTANCES. THESE ARE IMHO. SEEK ATTORNEY AND CPA AND STATE/FED LAWS FOR CLARIFICATION. THANKS.
Bulldog75: ALABAMASUN; NO ANNUITIES. THATS AN INSURANCE PRODUCT. COSTLY. ITS NOT LIQUID. TIES YOUR MONEY UP. PLS STAY AWAY FROM THAT PRODUCT.
Blinkster to undefined Bulldog75: and repay that loan as???
Bulldog75: BLINKSTER; BINGO
Bulldog75: STUDY THE TRUSTS AND ASK QUESTIONS FROM THE TWO SITES I GAVE PREVIOUSLY FOR LEGAL CLARIFICATIONS . THANKS.
Bulldog75: [12:48:13] Bulldog75: HERE IS THE LINK TO MANY SECURITY ISSUES; IF YOU HAVE ANY LAST MINUTE QUESTIONS, PLEASE ASK THEM NOW: EVERYONE SHOULD HAVE THEIR PASSPORTS IN POSSESSION, HOME ADDRESSES CHANGED TO PO BOXES, CAR TAGS CHANGED TO PO BOXES, NAMES/HOMES REMOVED FROM TAX PUBLIC VIEW, VOTING CERTIFICATE ADDRESSES CHANGED TO PO BOXES AND HAVE THEIR TRUSTS IN PLACE. ANY QUESTIONS THAT HAVE NOT BEEN ADDRESSED? REVIEW THIS FIRST: http://www.dinarrecaps.com/1/post/2012/01/bulldog-security-updates-post-by-bulldog-oom-forum.html
Bulldog75: [12:59:41] Bulldog75: OUR LIVES ARE ABOUT TO BE CHANGED FOR DECADES. YOU ARE MY FRIENDS. I KNOW THERE IS UNFINISHED BUSINESS BY MANY. TAKE NOTHING FOR GRANTED. I AM MOVING, HOME WILL BE IN THE TRUST'S NAME.
Bulldog75: EVERYTHING I LEGALLY CAN PLACE IN THE TRUST'S NAME WILL BE DONE THAT WAY. WE WANT TO STAY ANONYMOUS.
Bulldog75: YOU ALL ARE WONDERFUL. GREAT QUESTIONS. AND I SAW SOME OF YOU HELPING OTHERS.. MARVELOUS. WE ARE SUPER CLOSE TO THIS DOMINO. WE ARE FAMILY. I LOVE U ALL.
Bulldog75: LET US REMEMBER THE MOST VALUABLE ISSUE AT STAKE HERE ON TRUSTS: [13:26:22] Bulldog75:
Bulldog75: WE BLESS AMERICA AND OUR PLANET. WE BLESS EVERY MAN, WOMAN, CHILD ON THIS EARTH. MAY OUR HEAVENLY FATHER SEND OUR MANNA AS WE HAVE DECLARED AND PRAYED. GOD BLESS OUR MILITARY AND ALLIES. AMEN.
Bulldog75: PLEASE NO CO-MINGLING OF FUNDS ON OR SHORTLY AFTER CASHIN. DO EVERYTHING LEGAL. NO GUESS WORK.
Bulldog75: WE ARE BLESSED AND HIGHLY FAVORED. WE ARE CHOSEN TO BE HERE. YOU ARE LEADERS AND WILL GAIN GREAT MANY MORE POWERS BY ONE'S WEALTH. WE WILL USE IT WISELY. WE WILL REMOVE THE 'INCUMBENTS' FROM OFFICE AND TAKE BACK OUR COUNTRY.
Bulldog75: MAY THE HEAVENS BLESS MANKIND AND THIS NEW FRUITION OF ECONOMIC BLESSINGS AROUND THE WORLD . WE ARE THANKFUL IN ADVANCE. WE KNOW OUR BLESSINGS COME NOW. AMEN.
Comments are closed.


text:
- 52" Blade Span
- UL Indoor listed
- 14.5" Height, Top to Bottom
- Standard or Angled Mount
- Pull Chain Control
- No Light Included
The Barclay family is a stunning example of refined design. The uniquely shaped blade holders add distinctive style, while the walnut blades add a touch of elegance. Choose from three finishes to give any room a fresh look.
The Quorum 76525-65 Barclay collection 52" indoor ceiling fan (with pull chain control) in Satin Nickel brings Traditional style. This fan includes Five Rosewood / Walnut Blades and the hanging height is 14.5". The voltage is 120 volts. Additional Information: Control - Three-speed pull chain with manual reversing switch on motor; Downrod - Includes 4" and 6" (1/2" Exterior Diameter) Poles
By Selecting the Options above you can view all of these Quorum Ceiling Fan Products in this Barclay Collection: 76525-44, 76525-65, 76525-70, 76525-86

subset: commoncrawl


text:
A Good Egg Easter Mini Cakes
Additional Information
Step 1
Make mini cakes. Prepare batter following recipe directions. Bake and cool mini cakes. Use knife to trim off details.
Step 2
Decorate mini cakes. Prepare buttercream icing following recipe directions. Tint light violet, yellow, rose and green. Use spatula and light violet icing to ice mini cakes smooth.
Use tip 48, cut disposable decorating bag and yellow icing to pipe three lines across mini cakes. Use tip 4, cut disposable decorating bags, and rose, green and yellow icing to pipe dots on mini cakes.
Favorite cake recipe or mix
Violet Icing Color ((Combine Violet with Rose for Violet Shown))
Rose Icing Color
Lemon Yellow Icing Color
Leaf Green Icing Color
9 in. Angled Spatula
In Stock (ships in 1-2 business days)
Out Of Season
12-Pc. Easter Treat Decorating Set ((tip 4, tip 48 and disposable bags used))
Paring Knife
food-safe scissors
Pipe dots for flower centers, faces, figure piping and border effects. When making large dots, lift the tip as you squeeze to allow icing to fill out completely.
Characters or designs are often outlined first, then piped in with stars or zigzags. Outlines can also be used for facial features.


text:
FREE SHIPPING on orders of $85 or more
An excerpt from www.HouseOfNames.com archives copyright © 2000 - 2017
Anglo-Saxon name Kerrige comes from the family having resided in the village of Kerridge found in the parish of Prestbury in the county of Cheshire.
Kerrige Early Origins
Cheshire, in the village of Kerridge. The place name was derived from "key ridge." However, we must look to Suffolk for the earliest record of the family as John Kerrage was registered there in 1297. Two years later, the family "occurs in the records of Dunwich for 1299." [1]CITATION[CLOSE]
Guppy, Henry Brougham, Homes of Family Names in Great Britain. 1890. Print.
Kerrige Spelling Variations
Kerrige Spelling Variations
Kerrige has been spelled many different ways. Before English spelling became standardized over the last few hundred years, spelling variations in names were a common occurrence. As the English language changed in the Middle Ages, absorbing pieces of Latin and French, as well as other languages, the spelling of people's names also changed considerably, even over a single lifetime. Spelling variants included: Kerridge, Kerrage, Kerrich, Kerriche, Kerysche and others.
Kerrige Early History
Kerrige Early History
This web page shows only a small excerpt of our Kerrige research. Another 179 words (13 lines of text) covering the years 1327, 1524, 1631, 1308, 1616, 1628, 1748 and 1828 are included under the topic Early Kerrige History in all our PDF Extended History products and printed products wherever possible.
Kerrige Early Notables (pre 1700)
Kerrige Early Notables (pre 1700)
Another 34 words (2 lines of text) are included under the topic Early Kerrige Notables in all our PDF Extended History products and printed products wherever possible.
Kerrige In Ireland
Kerrige In Ireland
Some of the Kerrige family moved to Ireland, but this topic is not covered in this excerpt. Another 78 words (6 lines of text) about their life in Ireland is included in all our PDF Extended History products and printed products wherever possible.
The Great Migration
The Great Migration
In an attempt to escape the chaos experienced in England, many English families boarded overcrowded and diseased ships sailing for the shores of North America and other British colonies. Those families hardy enough, and lucky enough, to make the passage intact were rewarded with land and a social environment less prone to religious and political persecution. Many of these families became important contributors to the young colonies in which they settled. Early immigration and passenger lists have documented some of the first Kerriges to arrive on North American shores: John Kerridge, who was living in Haldimand County, Ontario in 1877; and Frederick John Kerridge, who was on record in Minneapolis in 1875.
The motto was originally a war cry or slogan. Mottoes first began to be shown with arms in the 14th and 15th centuries, but were not in general use until the 17th century. Thus the oldest coats of arms generally do not include a motto. Mottoes seldom form part of the grant of arms: Under most heraldic authorities, a motto is an optional component of the coat of arms, and can be added to or changed at will; many families have chosen not to display a motto.
Motto: Nunquam Non Paratus
Motto Translation: Never unprepared.
Kerrige Family Crest Products
Kerrige Family Crest Products
See Also
See Also
Other References
The Kerrige Family Crest was acquired from the Houseofnames.com archives. The Kerrige Family Crest was drawn according to heraldic standards based on published blazons. We generally include the oldest published family crest once associated with each surname.
This page was last modified on 19 January 2017 at 16:18.
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text:
ATLANTA -- A few thoughts on the Atlanta Falcons' 21-20 loss to the Carolina Panthers on Sunday at the Georgia Dome.
What it means: A miserable season finally ended, although the Falcons went down swinging. A team that finished 13-3 a year ago and was within one game of the Super Bowl suddenly plummeted to 4-12. At least the Falcons will have a high draft pick in order to address noticeable weaknesses along the offensive and defensive lines. They entered Sunday sixth in the draft order.
End of an era: Sunday marked the final game in the illustrious career of Tony Gonzalez. The Falcons tight end caught a pass to open the game, closing his career with 211 consecutive games with a catch. The Falcons sent Gonzalez out as the only captain for the coin toss, and they honored him with a special video-board tribute and presentation at halftime. The 37-year-old Gonzalez will leave as the best tight end to play the game. Panthers receiver Steve Smith said it best pregame: "Is he a guy who has changed the game? Absolutely."
Stock watch: The stock of the offensive line, as a group, continued to fall, as it allowed quarterback Matt Ryan to get beat up the entire day. The line's inability to block contributed to Panthers defensive end Greg Hardy setting a franchise record with four sacks. And every member of the offensive line had issues, from steady left guard Justin Blalock to surprising center Joe Hawley to struggling left tackle Lamar Holmes. Ryan got sacked a season-high nine times and appeared to be hobbled after each one. The Falcons probably should have pulled Ryan in favor of Dominique Davis, based on the beating Ryan absorbed. It emphasized how much the Falcons need to address the offensive line in the offseason either via free agency or through the draft.
Dropping the ball: Roddy White stepped up his game late in the season, as he finally recovered from some early injuries. But White would be the first to say he took a step back after dropping at least three passes on Sunday. It was an uncharacteristic performance for the sure-handed White.
What's next: The Falcons will go through their evaluations this week to figure out what type of coaching and personnel changes are needed going into next season. It wouldn't be a surprise to see a change at defensive coordinator, although Mike Nolan has tried to do the best with the group he has. Offensive line coach Pat Hill might be under fire, too, although he doesn't have much to work with, either. Whatever happens in the coming weeks, the Falcons have significant strides to make in order to become a contender once again, especially with Gonzalez no longer in the fold.


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Hogan Lovells has taken its counselling service on-site, joining a growing number of UK law firms pushing for better mental health among its staff.
The firm has decided to bring its counselling service in-house in order to make it, "more accessible and convenient" for staff, who can now access a counsellor two days a week.
London managing partner Susan Bright said: "The health and well-being of our people is a key priority for us and we are always reviewing what more we can provide. As part of this, in addition to our already wide range of benefits, such as our in-house gym, GP service, onsite occupational health service, on-site physiotherapist and employee assistance programme, in January we introduced an on-site counselling service.
"Our counsellor is available two days per week on a completely confidential self-referral basis. We recently held a well-being awareness week which included free health checks, healthcare advice and a number of seminars on topics such as emotional wellbeing and healthy eating."
Last year the firm pledged to examine its policies and procedures around workplace stress and mental health in the wake of the death of IP partner David Latham (13 September 2013). A spokesperson said the move to bring counselling on-site was not related to Latham's death.
The issues also impact working in-house. In November, Barclays' head of compliance and regulatory relations Hector Sants resigned from the post after taking a temporary leave of absence due to stress and exhaustion (13 November 2013). According to UK mental health charity Mind, one in four people in the UK will experience a mental health problem each year.
A number of firms have introduced programmes to help its staff deal with work-related stress. In September 2009 legacy Herbert Smith launched an internal training programme to help its staff recognise the symptoms of stress and deal with mental illness (28 September 2009).
|2.6 in 100 people
|4.7 in 100 people
|Mixed anxiety and depression
|9.7 in 100 people
|2.6 in 100 people
|1.3 in 100 people
|Panic disorder
|1.2 in 100 people
|Post traumatic stress disorder
|3.0 in 100 people
|Eating disorders
|1.6 in 100 people
Source: Mind


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Life is not about existing, it's about living. Life is not about waiting, it's about going. Life is not about the future, it's about the present. And that is what Dang Travelers is all about. Inspire and be inspired to indulge in all that this wonderful world has to offer! Welcome and thanks for visiting!
Who We Are
We are Dang Travelers, David and Angela, a married couple in our late-thirties who have an obsession with travel. We kissed for the first time in Denmark, decided to move in together while hot tubbing in Hawaii, got engaged on the Eiffel Tower in France and married on a beach in Mexico. Throughout our ten year marriage, we have continued our love affair with wanderlust by exploring new places and challenging the normal 9-5 life.
The Dang Travelers mission is to highlight amazing locations, pass along budget-friendly tips, share our favorite travel resources, and to post about our journey from part-time to full-time travel.
Where It All Began
David was raised by missionary parents in a converted school bus for the first five years of his life, and was exposed to location independence at an early age. Wanderlust has been part of his DNA since then. His family traveled a considerable amount growing up, but always on a budget, and usually camping.
He chose a career in aviation after high school, lured by the expectation of a flexible schedule and travel benefits. After graduating college he joined the Air National Guard, where he met his now wife, Angela.
Angela grew up in Chicago taking limited vacations as a child. Her aunt and uncle would take her on some of their family trips and that is where her excitement for travel began.
Right after high school graduation, she joined the Air National Guard to pay for college. It opened doors on traveling to exotic places and meeting new people, including David.
Together they maintained a long distance relationship, then marriage, for a total of 11 years. Angela was working 60+ hours a week as a CPA while David commuted back and forth from the St. Louis area to Chicago (600 miles round trip). By year 12, both Angela and David were tired of the distance and ready for a change.
In 2014, they made the BIG decision for Angela to quit her full-time position. Then in 2015, Dave transitioned into a part-time position allowing them to travel on a more long-term basis like our three month summer road trip driving 11,000 miles, visiting thirteen national parks.
Where We Are Going
Angela's goal is to visit all 50 states by the time she turns forty in a few years. David has already explored every state across America, but some were when he was young so he is just as excited to jump on this journey. While David is working part-time (a few months out of the year), Dang Travelers will travel throughout the states. During long breaks, Dang Travelers will adventure to other parts of the world.
Some of our future goals include hiking the El Camino in Spain, trekking to Machu Picchu, biking along the Rhine, taking an African Safari and seeing the butterfly migration in Mexico.
We love nature and the great outdoors. Even when visiting cities, we tend to find parks and botanical gardens to navigate like in St. Louis or Kotor. We also enjoy getting off the beaten path and finding unpopular things to do like seeing the cherry blossoms bloom in Macon, the arts scene in Kansas City or Brown County's hidden gem.
Visiting breweries is always on our list of things to do, along with some adventure like when we went swimming with manatees and boating in the Everglades.
How We Travel
We strongly believe in budget travel. We find ourselves in the middle of the road on spending except when we are truck camping which is a little extreme. We rarely book on the luxury side except when it involves using hotel loyalty programs or if we are getting luxury accommodations for a budget price.
With that in mind, we don't go for the cheapest option either. We don't typically stay in hostels or couchsurf. We usually stay in hotels during short-term travel and camp and rent apartments for long-term trips.
What Our Website Can Do For You
We share everything we know and everything we learn as we go like how to reduce hotel expenses with BRGs, the best free apps to use on a road trip or what is Ebates and why you should be using it in the hopes that it will help you with future travel plans.
We also pass along vital information on each location we visit like Best Side Trips from Myrtle Beach and Kansas City Highlights. We like to tell you what we enjoyed and didn't enjoy, so when you travel to the area you can use our posts as a guide.
We like to share the good, the bad and the ugly. There's always some mishaps along the way like on our Adult Only Day in Gatlinburg and the B&B Blunder that ruined us probably for life.
We are glad you stopped by and hope you come along on our journey so we can share what we are learning and inspire you along the way!
David & Angela (DANG)
Be Part of the Adventure.


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No Name-Womens
When the toy store burned and didn't return to the same location it was a sad time. Then a place opened up – a bar with no name. A place where I almost had too much fun and I met my wife there, 29 years and still going!
Comes in navy short sleeve and available in ladies


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Public Information MeetingConstruction of Interstate 40/Casey Jones and North Highland in Jackson
September 14, 2017, from 5:00 pm to 7:00 pm CST
JACKSON, Tenn. – The Tennessee Department of Transportation will host a Public Information Meeting Thursday, September 14, 2017, from 5:00 p.m. to 7:00 p.m. at the Region 4 TDOT Office to discuss a major construction project that is about to get underway.
TDOT officials will provide detailed information on the I-40 widening from west of SR 186 (US45 By-Pass) to east of SR 5 (US45) and SR 186 (US45 By-Pass) from I-40 to Old Hickory Boulevard. There will be a formal presentation with a question and answer period following.
WHAT: Public Information Meeting
WHEN: Thursday, September 14, 2017
5:00 p.m. – 7:00 p.m.
WHERE: Tennessee Department of Transportation
300 Benchmark Place
Jackson, Tennessee 38301


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The Kensington was very nice and had a variety of activities. They were perfectly adequate for what we are probably going to need. The garden areas were very nice and had gardening opportunities for people outside.
The Kensington Assisted Living
Top Nearby Assisted Living Facilities
Reviews of The Kensington | Assisted Living
Overview of Ratings
December 27, 2016
I visited this facility
May 12, 2016
I visited this facility
I wasn't completely impressed with The Kensington as we didn't get to see inside the rooms and just got a floor plan of what they looked like. The place was very nice and clean, though, and looked like it would be a pleasant place in which to spend time. The staff was very polite, nice, and cordial. It was a one-bedroom apartment, approximately 800 to 1,000 sq. ft.
September 26, 2014
I am a friend or relative of a resident
My sister-in-law works at the church with many residents from Kensington, so we went on a tour. We liked the layout of it and everything so we just took mom there to check it out and she really liked it. Our experience was very positive. Mom and Dad are in a 1-bedrom. They widened the shower door a little bit more because my father has a walker so it's cozy and perfect for them. I've eaten there many times and the food is excellent. The chef does an incredible job and the specials always taste great. Dad does the exercise classes and mom sometimes goes with him. I haven't had any problem with the staff, and they've been able to answer our questions and do things that we needed.
May 20, 2014
I am a friend or relative of a resident
My aunt was at The Kensington a little over two years. It's a very good facility. They had a good staff, and they took very good care of her. They had a courtyard, which was very pleasant and beautiful yet still enclosed within their buildings. My aunt found a boyfriend while she was there. They had excellent food, and they also had an excellent chef.
April 30, 2014
I visited this facility
We loved Vintage Senior Living. It was an older facility, but it was very nicely appointed. It was very warm from the minute you walked in. Everyone was very friendly. The dining area had just been remodeled, and it was very nice. We had lunch there, and the food was great. They had crab night once a week, which was really out of the ordinary. I liked that it was very oriented to the people who lived there. They had wonderful amenities and great activities.
April 30, 2014
I am a friend or relative of a resident
My mom was at Vintage Senior Living. She was in the independent living. At the time, my dad was living also, and they'd used several different facilities, and that was the one that they liked the best. Also, it was conveniently located in relation to where my sister works and lives. We thought it was very nice; it was very homey. The staff was very cordial, and they offered a variety of activities. They had bingo, exercise, movie nights. They had an on-site beauty salon. They had a game room with pool table. They had a library where people would play cards and do puzzles. When my mom first moved, the food was good, but it was bought out by a company, and the quality of the food went down. There were a lot of complaints by the residents about the food. The apartment had a 1-bedroom, which was large enough to accommodate the king-sized bed. The bathroom was located in the bedroom. There was a small kitchen area with a full-sized refrigerator and a pantry, and then there was a living room area.
August 09, 2013
I visited this facility
This is the nicest facility of the three we have visited in our search for a two-bedroom unit within a community offering independent and assisted living and memory care. The building is very nice, the grounds are lovely, the staff appears to be dedicated and competent, and the activity schedule offers something for everyone. The residents we met while on our tour all appeared to be happy here.
July 25, 2013
I visited this facility
My experience during my visit at The Kensington with what I have seen was very good. Everything was nice. It was a beautiful facility. They have excellent food. However, their dining room was pretty formal. People have to dress up to go to the dining room and that was a little intimidating for my mother. Also this facility was too expensive for us.
July 24, 2013
I am a friend or relative of a resident
The Kensington seemed like a pretty nice place. It's very clean, it smelled good, and the landscaping was very nice. The management and their worker seemed to be pretty nice, too. But it's not cheap. My friend's room was okay. It wasn't cramped and he had a little kitchen. They have a little theater room where they could go down and watch movies. They also have a very nice lobby with a grand piano, and they would have a piano player come in 1 or 2 hours a day. And sometimes they'd have a little group come in and they have a concert. They had a library and an exercise room as well.
May 31, 2013
I visited this facility
Vintage Senior Living was very nice. It seemed like the people and their services were very integrated. It was very pleasant. The staff was helpful and personable. They sat down with us and tried to do a breakdown of the cost, which was difficult for my sister because if she was inside, she would need to have a caregiver with her there. So, we were going to work out some more details and right now, things are kind of on hold. But, yes, I was very, very impressed. They sat us down, gave us lunch, we talked, and it was just very impressive. They have a supreme chef who will be able to accommodate my sister's special needs because she's a diabetic, and he could do this for her on a daily basis. The rooms are all nice and I would prefer my sister to be on the first level because she'd have a patio.
October 25, 2012
I am a friend or relative of a resident
My grandmother has had severe dementia, which progressed to stage 4 Alzheimer's.In the last 5 years, our family was unable to give her the total support and medical attention she deserved/needed. When we took her to Vintage Senior Living, we felt completely supported in a very emotionally traumatizing time. Their staff is incredibly well trained, constantly checking in on her and being transparent with our family, whom visit every week. The program and activities look very engaging, and when my grandmother was more cognitive, she enjoyed exercising with the groups there and taking dance lessons. The facility itself is very big and the outdoor area is beautiful, as it is facing the hills on the East Side of the Bay. The food is great, tasting restaurant quality and open to all residents, as well as visitors. My grandmother is always smelling fresh, well groomed, and any open wound/rash is taken care of right away, due to their beauty salon and medical staff. Overall, Vintage Senior Living is a fantastic facility that I feel safe and secure that my grandmother stays there.
June 24, 2012
I visited this facility
The Kensington is extremely a clean facility. The staff members were very accommodating and highly helpful when they gave me a tour of the facility. The chef even came out and talked to me and asked about my mother. A resident spoke to me as well and said that she's very happy in Kensington. The apartments were great. I saw one that hadn't been renovated and I saw one that had been. The way that they had it renovated is just perfect They made it clean and made look like brand new.
June 09, 2011
This used to be an independent living facility. Now it's assisted living, and it's very good. Some of the residents from the old independent living days still drive and have cars. They also have a new memory care unit, which is geared to those with more advanced dementia. I have a client there and have visited many times (to see other clients too). It's a large facility""very nice and recently renovated. But it's near a busy intersection, close to the freeway. There's nowhere to walk except for a garden area in back of the facility. The apartments in the independent and assisted living are small but with good natural lighting. There are one bedroom and studio apartments. The food seems superior. The staff are a plus. They're tolerant of dementia behaviors, and they're caring and attentive. Medications management""one of the keys to dementia care""is also good. They have a large hall and a wide-open hall, which is good for walking and activities. One of the things I like is that even though the memory unit has a separate entrance, there's some supervised interaction between the memory unit residents and the other parts of the facility.
Photos of The Kensington
Features of The Kensington
- Minimum Rate: $4095/month
- Minimum Memory Cost: $5955/month
- Rent Plus Care Fees
- Entry Fee
- Fee Structure Extra: We Offer A Month To Month Rental
Room and housing options
- 1-bedroom apartments
- 2-bedroom apartments
- Companion Suites: We Do Not Offer Companion Suites
Dining options
- In Room Kitchenette
- Dining Room Shared Meals
- Room Service For Meals
- Beauty Barber Shop
- Resident Transportation
- Party Space
- Tv Room
- Garden And Patio
- Resident Parking
- Features Extra: Library, 24/7 Front Desk/Concierge
Cleaning services
- Private Cleaning Services
- Housekeeping
- Laundry For Clothing
Technology and entertainment
- Wifi
- Technology Extra: Emergency Call System
Health services
- Hospice Care
- Medication Management
- Offsite Activities
- Games
- Stories
- Religious Services
- Lectures Discussions
- Wii Sports
- Tai Chi
- Fitness Room
- Gardening
- Arts And Crafts
Financial guidance
- Home Sale Assistance
- Va Benefits Consultation
- Financing Advice
Guest services
- Guest Parking
- Guests At Mealtime
- Overnight Guests
- Minimum Age: 60
- Pets: Small Pets Allowed
- State Licenses: 75601405
About The Kensington
Assisted Living, Memory Care and Independent Senior Living in Walnut Creek, California.
Make yourself at home at The Kensington in Walnut Creek, California. It's a friendly, flexible environment that celebrates your individuality and nurtures your soul. We recognize that each new resident has a unique lifestyle. So we've tailored solutions to match:
- Independent Living, for our most active seniors
- Assisted Living, when you need a helping hand
- Memory Care, special care for those with memory challenges e.g. Alzheimer's and dementia
- Short Term Care, for a respite or recovery period
- Diabetes management
- Selected skilled nursing services
- Serving Walnut Creek, Woodborough, Walden, Pleasant Hill, Lafayette, Danville, Concord and other neighboring towns in Contra Costa County
All options include:
- A safe, secure environment
- Compassionate, capable staff
- Busy days, rewarding activities
- 3 chef prepared meals daily
- Scheduled transportation for errands, medical appointments and field trips
- Friendly people and a sense of community
Shopping and Dining:
- Extensive fine dining nearby
- Three major shopping malls minutes away
- Just 23 miles north east of San Francisco
- John Muir Hospital
- Mt. Diablo Hospital
- Kaiser Permanente
- The Kensington, a Vintage Senior Living retirement community, offers Independent and Assisted Living starting at $4,100 per month, depending on availability and floor plan.
- The Kensington also offers compassionate Memory Care services and accommodations starting at $5,450 per month, depending on floor plan and availability.
Map of The Kensington
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text:
Opened an account, deposited 100 Euros and accepted the bonus off of 100% match.
Played for around 15 minutes and account was then locked out.
Spoke with casino who said that I had previously self excluded from a casino called spin to win as I felt my gambling was getting out of control.
Feeling more under control I opened an account with Magical Vegas but as stated they have closed my account and withheld about 160 euros stating that I had breached their terms, I still had to play through the funds I had deposited.
I have never had an account with Magical Vegas before and used made no attempt to hide my identity as I had no reason to.
They are stating that I used different details to open this account and have point blank refused to return my deposit.
I have got no idea if these casinos are connected but if indeed they are then I should never have been allowed to open an account. It's not as if I lost the money and complained, they just took my money and closed the account.
This is not right
Opened an account, deposited 100 Euros and accepted the bonus off of 100% match.
Hi Razorreay,
Magical Vegas is a responsible gaming company which adheres to strict gaming policies through its License from the UK Gambling Commission (UKGC). We support the work of Gamcare and we make it our duty to encourage our players to gamble responsibly.
While we have measures in place to protect them, the terms and conditions of the site are valid for all players. Any successful registration is possible only if a player has agreed to the terms of the site which clearly mentions that they warrant and represent they are not classified as compulsive gamblers.
As much as we understand your current situation, the decision taken regarding your account is in accordance with our terms and we invite you to contact our customer support team if you wish to discuss this matter further.
Dear sir / madam
Thank you for your prompt response.
Your terms and conditions written by your legal team are very worthy but you omit the key issues which the online gambling industry brings:
Your controls are poor and allowed a self confessed addict to open an account. I made no attempt to hide my identity.
If I had of won I would have been unable to withdraw any winnings but you also don't allow my original deposit to be credited back to me.
A gambling addiction has no logic, it is an addiction and thus there is a duty for you as a casino to assist and help keep the fun in gambling.
Think about it, what as a casino have you lost, nothing, as a user I have lost some money. Money that I was actively playing when you detected my account.
Fair play that you did detect my account although I did not know that you were affiliated with the other casino which I self excluded from.
Your response to my issue is disappointing and I had hoped you would see the logic. This is to say that I can never win and you just close the account and don't return the funds.
Online gaming requires trust and good controls and I do believe a refund is due to me.
It is clear from your stance that you see things differently, a win win for the casino. I am not confident that a resolution will be found on this forum and I seek advice as to where I should take my complaint.
Ask Gamblers
Please advise on how I should proceed with my complaint.
Do you have an email address of the regulator?
The complaint has been reopened as per Magical Vegas Casino request and AskGamblers Complaints Team would like to give this case one more try and help both parties involved to reach to a satisfactory resolution.
Hi Razorreay,
So that we can look further into your complaint, could you please provide us with your username?
AskGamblers Complaints Team send required information directly to the Magical Vegas management.
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Magical Vegas Casino - Delayed withdrawal payment
I won big on one of the slots on Monday 6th Nov and I chose to withdraw my money that day through paypal. The website states that there is a 36 hour ...Read more
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Woah well where do i start... i complained about this casino before silly me for giving it another go right? well i felt it was due to a third party ...Read more
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Magical Vegas Casino - Stalling my payment
I am sad to say this is my first experience with a casino that hasn't been a good one (registered at all over 20 + casinos) I managed to cashout on at ...Read more
Magical Vegas Casino - Getting the runaround with account closureResolved
Magical Vegas Casino - Getting the runaround with account closure
I would like to submit a complaint about magical vegas casino and their constant dileberate delay, ackward and dismissive attitude when requesting the ...Read more
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text:
Assessment of Heart and Heart-Lung Transplant Patient Outcomes Following Pulmonary Rehabilitation
The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified August 2005 by Royal Brompton & Harefield NHS Foundation Trust.
Recruitment status was: Recruiting
Recruitment status was: Recruiting
Royal Brompton & Harefield NHS Foundation Trust
ClinicalTrials.gov Identifier:
First Posted: August 11, 2005
Last Update Posted: December 9, 2005
Information provided by:
Royal Brompton & Harefield NHS Foundation Trust
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
No Study Results Posted on ClinicalTrials.gov for this Study
|Study Status:
|This study is currently recruiting participants.
|Estimated Study Completion Date:
|February 2008
|Primary Completion Date:
|No date given


text:
No substitute for player needing toilet break: MCC
The International Cricket Council (ICC), in its new rules, has not only put a ban on runners for injured batsmen, but the "comfort breaks" for fielders have also been prohibited.
Fraser Stewart, the Laws & Universities Manager for the Marylebone Cricket Club (MCC), the custodian for the laws of the game, said: "A substitute fielder shall not be allowed when a fielder leaves the field to go to the
Stewart said the ICC has included an additional paragraph in its regulations as well. It states: "Under Law 2.2.3, substitute fielders shall only be permitted in cases of injury, illness or other wholly acceptable reasons.
'Wholly acceptable reasons' should be limited to extreme circumstances and should not include what is commonly referred to as a 'comfort break'." The MCC law expert said substitutes would not be allowed at any cost. "Even if a player wants to change his shirt, boots, etc, he will not be provided a substitute,"
Stewart added.


text:
Latest Navigator Insight Article
It all seemed so simple, not so very long ago
The introduction of Microsoft's new mobile operating system, the Windows Phone 7 Series has really complicated things. It seemed so simple not long ago - iPhone was the front runner, Android was the up and coming underdog, Blackberry was the old fighter with the new style, and Windows Mobile was down and out in the smartphone ring. But now that has all changed. Microsoft has unveiled a new Smartphone OS, and for once it is good. Really good.
What's in store for the iPad in South Africa?
Brian Neilson
As Steve Jobs said at the launch, the team at Apple have pondered for years over whether there really is room in the market for a third form factor, and the iPad would have to be very good at some applications. Judging from the launch, it is difficult to say that they have focused on a few specific apps, because it seems to do just about everything, and the swarms of developers out there will make certain of that.
Misunderstandings about Technology Neutrality
Broadband and Universal Access/Service – Not By Wireless Alone
Mobile Operators – How to be lean and not mean
The making and sustaining of a good, effective regulator
Evidence and justification for major reductions in South Africa's mobile interconnection rates (MTR)
Digital Strategies and the Value and Limitations of Wireless Access
"Net Neutrality": In the crossfire of politics, social values and disruptive technologies
VoIP over Mobile Networks: A Curse or a Mixed Blessing for Operators?
History of the 2.6GHz Band
International Mobile Price Comparisons – Limitations of the OECD's Methodology


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Mercer (consulting firm)
|Subsidiary (LLC)
|Professional services
|New York City, United States
Number of locations
|180 cities in 40 countries
Key people
|Julio Portalatin (Chairman and CEO)
|Human resource consulting services, including retirement, health & benefits, human capital, surveys & products, communication, investments, outsourcing, and mergers & acquisitions
|$4.2 billion
Number of employees
|~20,500+ (2014)[1]
|Marsh & McLennan Companies
Mercer is the world's largest human resources consulting firm.[2] Headquartered in New York City, Mercer has more than 20,500 employees, is based in more than 40 countries, and operates internationally in more than 130 countries.[1] Mercer is a subsidiary of global professional services firm Marsh & McLennan.
Started in the United States in 1937 as the employee benefits department of Marsh & McLennan, Inc., the company took the name of "William M. Mercer" in 1959, when Marsh & McLennan acquired William M. Mercer Limited, a Canadian firm founded by William Manson Mercer in Vancouver in 1945.[3] In 1959, Mercer became a wholly owned subsidiary of Marsh & McLennan Companies, Inc. In 2002, its name was changed to Mercer Human Resource Consulting.[4]
In 2004, the company acquired Houston, TX-based Synhrgy HR Technologies, a human resources technology and outsourcing services company.[2] Also in 2004, Mercer admitted giving the NYSE board a compensation report that contained "omissions and inaccuracies" that led to a $139.5 million pay package for former NYSE Chairman Richard Grasso. Mercer had been brought in to advise the stock exchange on Grasso's 2003 contract and his request for $139.5 million. The consultancy returned $440,000 in fees it collected from the NYSE and provided key documents in the lawsuit.[5]
In 2007, the company became simply "Mercer."[6] Also in 2007, Mercer acquired Höfer Vorsorge-Management, a German actuarial and retirement consulting firm. At the time, the acquisition reportedly gave Mercer the top market position in Germany.[7]
In 2008, Mercer's Italian human capital consulting business merged with Tesi, an Italian competitor. The combined business, Mercer Tesi was noted at the time to be the largest HR consultancy in Italy.[8]
In 2010, Mercer acquired ORC Worldwide, an expert in international work assignments.[9] Also in 2010, Mercer acquired Brecksville, Ohio-based Innovative Process Administration LLC (IPA), a health benefits and technology provider.
In 2011, Mercer acquired Fort Lauderdale, FL-based Mahoney & Associates, a defined contribution plan provider.[10] Also in 2011, Mercer acquired Alicia Smith & Associates, a Washington DC-based Medicaid policy consulting firm.[11]
In 2013, Mercer acquired British Columbia-based Hall Consulting Limited (HCL), an HR consultant and salary surveyor focusing on the mining and energy business.[12] Also in 2013, Mercer acquired PricewaterhouseCoopers' pension windup (termination) administration business in Canada.[13] Also in 2013, Mercer acquired Global Remuneration Solutions (GRS), a South African compensation and benefits survey data and rewards information provider.[14]
In 2014, Mercer acquired Norwell, MA-based Transition Assist, a private health care exchange specializing in coverage for Medicare-eligible retirees.[15] Also in 2014, Mercer acquired Jeitosa Group International, a business and technology consultancy,[16] and acquired a 34% stake in South Africa-based employee benefits specialist Alexander Forbes.[17] Later that year, Mercer acquired Swiss private markets manager and consultant SCM,[18] and Denarius, a Santiago, Chile-based consulting firm focused on compensation and benefits survey and information products.[19]
In 2015, Mercer made two acquisitions. It acquired Hopkinton, MA-based Comptryx, a workforce metrics company offering surveying, modeling and analytics services, [20] and also acquired HRBS, a provider of career and talent consulting and information services to clients across Asia, with concentrated strength in Hong Kong, Singapore and mainland China.[21]
Lines of business
Mercer offers consulting and research services in the areas of health, retirement, investments and talent.[22] Additionally, Mercer has an M&A business segment that provides consulting services regarding human capital and related issues in financial transactions. The company helps clients with global HR issues, balance sheet risk and post-acquisition integration.[23] In certain markets around the world, Mercer provides localized employee benefit services under the Mercer Marsh Benefits name in partnership with sister operating company, Marsh.
Mercer's Health & Benefits business assists employers with the design, management and administration of employee health care programs, and offers support managing related compliance issues. Mercer also provides a private benefits exchange called Mercer Marketplace.[24]
Mercer's Retirement group provides strategic and compliance-related retirement services and solutions, including assistance in the design, governance and risk management of defined benefit, defined contribution and hybrid retirement plans.
Mercer's Investments group provides investment consulting and other services for wealth management companies including pension fund sponsors, foundations and endowments. These institutional investment services range from strategy and implementation to portfolio management. Investment services include manager of managers funds offered to institutional investors such as retirement plans, endowments and foundations and wealth managers. As of December 31, 2014, Mercer had assets under management of $116 billion worldwide.[22]
The Mercer Pension Risk Exchange helps companies move their pension liabilities to an annuity insurer. The platform allows pension plan sponsors to execute group annuity buyouts more quickly, with competitive pricing.[25]
Mercer's Retirement, Health and Investments businesses also provide outsourced benefits administration services.
Mercer's Talent businesses offer advisory services in the areas of improving employee engagement, management and employee compensation, including improving the effectiveness of their clients' human resource operations.
Within the Talent group, the Information Products Solutions business provides clients with human capital information and analytical capabilities to improve strategic human capital decision making. The Communications business helps clients plan and implement HR programs and other organizational changes designed to maximize employee engagement, drive desired employee behaviors and achieve improvements in business performance.
The Talent group offers proprietary survey data and decision support tools to provide clients with information to improve decisions related to talent management.
Survey data
The Mercer Quality of Living Survey is designed to help companies create compensation packages for executives living overseas.[26]
The Mercer National Survey of Employer-Sponsored Benefits shows trends in employer-sponsored benefits.[27]
Decision support tools
The Mercer Mobile Housing Solution allows HR managers to calculate expatriate living expenses.[28]
Mercer's Mergers and Acquisitions Transactions Services group supports clients with issues related to cross-border transactions, divestitures, mergers, and related HR integration services.[29]
Since January 2013 Mercer has been organized into three geographic regions, each with a regional president: North America, EuroPac (Europe + Pacific markets of Australia and New Zealand) and Growth Markets (Asia, Africa and Latin America). Headquarters for the North American region are in New York City, for EuroPac in London, and for Growth Markets in Singapore. Less than half of the organization's employees are based in North America.[22]
See also
- 1 2 "About Us". mercer.com. Retrieved 2015-11-06.
- 1 2 "Acquisition by Mercer to give new energy to high-flying Synhrgy". Houston Business Journals. 2004-01-18. Retrieved 2015-11-06.
- ↑ "Acing the Mercer Interview – An Overview of the Firm". managementconsulted.com. 2013-04-08. Retrieved 2015-11-06.
- ↑ "William Mercer changes name". indiatimes.com. 2002-04-18. Retrieved 2015-11-06.
- ↑ "HR Figures Prominently in Stock Exchange Scandal". hr.blr.com. 2004-05-26. Archived from the original on July 22, 2012. Retrieved 2015-11-06.
- ↑ "Mercer HR Consulting rebrands as Mercer". professionalpensions.com. 2007-09-12. Retrieved 2015-11-06.
- ↑ "Mercer acquires Höfer Vorsorge-Management in Germany". news.top-consultant.com. 2007-12-19. Retrieved 2015-11-06.
- ↑ "Mercer & Tesi deal creates Italian market leader". growthbusiness.co.uk. 2008-10-16. Retrieved 2015-11-06.
- ↑ "Mercer acquires ORC Worldwide to strengthen its capabilities in global workforce management". hrmagazine.co.uk. 2010-06-24. Retrieved 2015-11-06.
- ↑ "Mercer buys Mahoney & Associates' practices". southfloridabusinessjournal.com. 2011-07-20. Retrieved 2015-11-06.
- ↑ "Mercer acquires Alicia Smith & Associates in D.C.". Washington Business Journal. 2011-11-16. Retrieved 2015-11-06.
- ↑ "Mercer acquires Hall Consulting". growthbusiness.co.uk. 2008-10-16. Retrieved 2015-11-06.
- ↑ "Mercer to buy PwC's Canadian pension windup business". businessinsurance.com. 2013-08-08. Retrieved 2015-11-06.
- ↑ "Mercer in deal for Global Remuneration Solutions". mindbench.com. 2013-09-03. Retrieved 2015-11-06.
- ↑ "Mercer expands health care exchange offerings with acquisition". businessinsurance.com. 2014-03-03. Retrieved 2015-11-06.
- ↑ "Mercer Acquires Jeitosa Group International". workforce.com. 2014-10-27. Retrieved 2015-11-06.
- ↑ "Mercer to buy Alexander Forbes stake". bdlive.co.za. 2014-06-24. Retrieved 2015-11-07.
- ↑ "Mercer acquires Swiss private markets manager/consultant". Pensions & Investments Online. 2014-06-24. Retrieved 2015-11-07.
- ↑ "Marsh & McLennan Unit Mercer Buys Denarius". rttnews.com. 2014-12-15. Retrieved 2015-11-07.
- ↑ "Mercer Acquires Workforce Metrics Company Comptryx". workforce.com. 2015-09-30. Retrieved 2015-11-07.
- ↑ "Mercer acquires HRBS". Retrieved 20 August 2016.
- 1 2 3 "Marsh & Mclennan 2015 10-K". EDGAR online. 2015-02-26. Retrieved 2015-11-06.
- ↑ "Mercer Strengthens M&A Consulting with Two Appointments". ABFjournal.com. 2013-10-04. Retrieved 2015-11-06.
- ↑ "Mercer Signs First Group of Insurance Carriers to Mercer Marketplace Private Exchange". theihcc.com. Retrieved 2015-11-06.
- ↑ "Exchange helps pension sponsors shop annuity insurers". businessinsurance.com. 2015-06-09. Retrieved 2015-11-05.
- ↑ "Vienna Tops 2015 List Of The Most Livable Cities On Earth". Forbes.com. 2015-03-05. Retrieved 2015-11-05.
- ↑ "Health benefits costs back on the rise: Mercer survey". businessinsurance.com. 2014-09-11. Retrieved 2015-11-05.
- ↑ "Mercer introduces expatriate housing portal for mobility managers". relocatemagazine.com. 2013-06-26. Retrieved 2015-11-05.
- ↑ "M&A Transaction Services". mercer.com. Retrieved 2015-11-05.
External links


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Robert Downey Jr. is too cool for school. Here he is delivering a real bionic arm to a special boy.
Robert Downey Jr. and Albert Manero, a #CollectiveProject student who founded Limbitless, surprised a very special child with a new bionic 3D printed arm at no cost to the family.


text:
A 5-day exposure to morphine exerts a profound cardioprotective phenotype in murine hearts. In the present study, we examined mechanisms by which morphine generates this effect, exploring the roles of Gi and Gs proteins, PKA, PKC, and β-adrenergic receptors (β-AR) in acute and chronic opioid preconditioning. Langendorff-perfused hearts from placebo, acute morphine (AM; 10 μmol/l)-, or chronic morphine (CM)-treated mice (75-mg pellet, 5 days) underwent 25-min ischemia and 45-min reperfusion. After reperfusion, placebo-treated hearts exhibited marked contractile and diastolic dysfunction [rate-pressure product (RPP), 40 ± 4% baseline; end-diastolic pressure (EDP), 33 ± 3 mmHg], whereas AM hearts showed significant improvement in recovery of RPP and EDP (60 ± 3% and 23 ± 4 mmHg, respectively; P < 0.05 vs. placebo). Furthermore, CM hearts demonstrated a complete return of diastolic function and significantly greater recovery of contractile function (83 ± 3%, P < 0.05 vs. both placebo and AM). Pretreatment with Gi protein inhibitor pertussis toxin abolished AM protection while partially attenuating CM recovery (P < 0.05 vs. placebo). Treatment with Gs inhibitor NF-449 did not affect AM preconditioning yet completely abrogated CM preconditioning. Similarly, PKA inhibition significantly attenuated the ischemia-tolerant state afforded by CM, whereas it was ineffective in AM hearts. PKC inhibition with chelerythrine was ineffective in CM hearts while completely abrogating AM preconditioning. Moreover, whereas β1-AR blockade with CGP-20712A failed to alter recovery in CM hearts, the β2-AR antagonist ICI-118,551 significantly attenuated postischemic recovery. These data describe novel findings whereby CM preconditioning is mediated by a PKC-independent pathway involving PKA, β2-AR, and Gs proteins, whereas AM preconditioning is mediated via Gi proteins and PKC.
- ischemia-reperfusion
- G protein-coupled receptors
- rate-pressure product
- end-diastolic pressure
- morphine
opioid receptors have been shown to regulate cardiovascular function in both normal and diseased myocardium. These receptors have been localized to the central nervous system and peripherally to autonomic presynaptic nerve endings and on cardiac myocytes. Importantly, myocardial cells are sites of opioid peptide synthesis, storage, and release (4), which are elevated during episodes of stress, such as ischemia (11).
The opioid receptor family comprises three primary subtypes, μ, κ, and δ. The opioid receptors are guanine nucleotide binding protein (G protein)-coupled receptors, inhibiting adenylyl cyclase (Gi coupled). Opioid receptor activation has been implicated in ischemic preconditioning (IPC), and, indeed, exogenous activation of opioid receptors has been well documented to afford both acute and delayed cardioprotection against ischemia-reperfusion (16). The mechanisms by which opioid receptor activation affords cardioprotection are typically thought to involve the phosphatidylinositol 3-kinase (PI3K), MAPK, and GSK3-β pathways (15, 16) as well as both the sarcolemmal and mitochondrial ATP-sensitive K+ (mitoKATP) channels (16). Opioid-mediated delayed preconditioning also involves cyclooxygenase-2 and inducible nitric oxide synthase (34, 45). We recently described a cardioprotective phenotype that occurred after prolonged exposure (5 days) to the opioid agonist morphine (35). This phenotype persists for at least 48 h after complete opioid withdrawal and still exists in the aged myocardium (36).
The opioid receptor family is known to have functional cross talk with other G protein-coupled receptor families, including both adenosine (37) and β-adrenergic receptors (β-AR) (38). The β-AR system exerts various effects on the myocardium via three β-AR subtypes, β1-AR, β2-AR, and β3-AR. β1-AR is coupled to the stimulatory G protein (Gs), whereas β2-AR can couple to both Gi and Gs proteins. β3-AR primarily associates with Gi proteins. The Gs protein coupling is associated with adenylyl cyclase activation and a resultant increase in cAMP production. This increased cAMP subsequently results in the activation of cAMP-dependent PKA, which is responsible for downstream signaling (for review, see Ref. 10). Moreover, β2-AR activation via isoproterenol administration has been demonstrated to mimic IPC (12, 30).
In light of this, we sought to investigate the mechanisms responsible for chronic opioid-mediated preconditioning while examining the potential roles of both Gi and Gs proteins in the genesis of chronic preconditioning and to determine whether the protection afforded by prolonged morphine exposure is, in part, mediated by β-AR and PKA.
The following investigations conformed to the guidelines of and were approved by the Animal Care Committee of the Medical College of Wisconsin (Milwaukee), which is accredited by the American Association of Laboratory Animal Care. Hearts were isolated from fed male wild-type C57/BL6 mice (22.7 ± 0.3 g body wt).
Perfused heart preparation.
Mice were anesthetized with 60 mg/kg pentobarbital sodium administered intraperitoneally and perfused as described previously (17). After anesthesia, a thoracotomy was performed, and hearts were rapidly excised into ice-cold perfusion fluid. The aorta was cannulated, and the coronary circulation of all hearts was perfused in a Langendorff mode and maintained at a constant pressure of 80 mmHg with modified Krebs-Henseleit buffer containing (in mmol/l) 120 NaCl, 25 NaHCO3, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 1.2 KH2PO4, 15 d-glucose, and 0.5 EDTA. Perfusate was equilibrated with 95% O2-5% CO2 at 37°C to give a pH of 7.40 and Po2 of ∼600 mmHg at the tip of the aortic cannula over a 1–5 ml/min range. All perfusate delivered to the heart was passed through an in-line 0.22-μm Sterivex-HV filter cartridge (Millipore, Bedford, MA) to continuously remove microparticulates. The left ventricle was vented with a polyethylene apical drain, and hearts were instrumented for functional measurements as described below. They were then immersed in warmed perfusate inside a water-jacketed bath maintained at 37°C. The temperature of the perfusion fluid was monitored by a needle thermistor at the entry into the aortic cannula, and the temperature of the water bath was assessed with a second thermistor probe. Temperature was recorded using a three-channel Physitemp TH-8 digital thermometer (Physitemp Instruments, Clifton, NJ).
Hearts were excluded from the study after the initial 25-min stabilization period if they met one of the following functional criteria: 1) coronary flow >5 ml/min (near maximal dilation or an aortic tear), 2) unstable (fluctuating) contractile function, 3) left ventricular systolic pressure below 100 mmHg, or 4) significant cardiac arrhythmias.
Experimental protocol.
After a 20-min stabilization period, hearts were switched to ventricular pacing at a rate of 420 beats/min (Grass S9 stimulator, Quincy, MA). Those hearts receiving acute morphine and antagonist drug treatment were then treated for 10 min before induction of global normothermic ischemia. Baseline measurements were then made and 25 min of ischemia was initiated, followed by 45 min of reperfusion. Pacing was terminated on initiation of ischemia and resumed after 1.5 min of reperfusion. Drug infusion resumed at the onset of reperfusion and continued throughout the reperfusion period. Pertussis toxin (PTX)-treated hearts received 100 μg/kg intraperitoneally 24 h before heart isolation.
Chronic model.
To induce chronic preconditioning, mice were briefly anesthetized with halothane, and a small incision was made at the base of the neck. Placebo or morphine (75 mg) pellets (National Institute of Drug Abuse) were inserted in the dorsal subcutaneous space before the site was closed with 9-mm wound clips. Pellets were left in place for 5 days.
PTX, NF-449, H-89, ICI-118,551, and CGP-20712A were purchased from Sigma-RBI (St. Louis, MO). The PKA inhibitor (PKI) 14-22 amide was obtained from Calbiochem (La Jolla, CA). All drugs were infused through a 0.22 μm filter at not more than 1% of coronary flow to achieve the final concentrations indicated. Inhibitor concentrations were based on previous literature reports, concentration-response experiments, or prior work performed by the authors' laboratory.
Statistical analysis.
Data are expressed as means ± SE. For all groups, n ≥ 6. Functional responses to ischemia-reperfusion were analyzed by multiway analysis of variance with repeated measures. When significance was detected, a Newman-Keuls post hoc test was employed for individual comparisons. For all tests, significance was accepted for P < 0.05.
Baseline hemodynamics and ischemic tolerance.
After pellet implantation for the allotted time, hearts were rapidly excised and perfused. After 20-min equilibration, baseline measurements were taken. No baseline differences were noted between placebo and morphine-treated mice. Global ischemia was induced for 25 min, followed by 45 min reperfusion. On termination of reperfusion, placebo-treated hearts exhibited a poor recovery of left ventricular contractile function [40 ± 4% baseline function, rate-pressure product (RPP)] and an elevated EDP (33 ± 3 mmHg) (Fig. 1). In contrast, mice receiving acute morphine (10 μM) infusion before ischemia and throughout reperfusion exhibited a significant improvement in recovery of both RPP (60 ± 3% baseline, P < 0.05 vs. placebo) and EDP (23 ± 4 mmHg, P < 0.05 vs. placebo). Additionally, mice implanted with morphine pellet for 5 days demonstrated a further improvement in ischemic tolerance and EDP returned to baseline, whereas left-ventricular contractile function returned to 83 ± 3% of baseline (RPP) after 45-min reperfusion (P < 0.05 vs. placebo and vs. acute morphine treatment; Fig. 1).
Archetypal mediators of preconditioning.
In a preliminary study, we set out to investigate the role of previously described mediators implicated in the preconditioning phenotype (15, 16, 45). To this end, we employed the nonselective opioid antagonist naloxone (10 μmol/l), the nonselective KATP channel inhibitor glibenclamide (300 nmol/l), the general nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (100 μmol/l), the inhibitor of the mammalian target of rapamycin, rapamycin (1 nmol/l), and GW-5074 (5 μmol/l), an inhibitor of cRaf1 kinase, an upstream mediator of the MEK/MAPK pathway, including ERK1/2. These antagonists/inhibitors were administered pre- and postischemia, after isolation and perfusion of the heart. As demonstrated in Fig. 1, these compounds failed to antagonize the cardioprotective effects of chronic opioid preconditioning, suggesting that the pathways involved in the mediation of this protection may be dissimilar to that of "acute" preconditioning. On the basis of these observations, we sought to investigate in more depth an alternate receptor-mediated pathway in the genesis of this cardioprotective phenotype.
G proteins.
To determine the relative contributions of both the Gi (inhibitory) and Gs (stimulatory) proteins in the phenotype generated with prolonged opioid receptor activation, we utilized selective inhibitors for both proteins. The Gi protein inhibitor PTX was administered intraperitoneally (100 μg/kg) 24 h before excision of the heart, whereas NF-449 (1 μmol/l), a selective Gs protein inhibitor that blocks the binding of GTP to Gsα, was administered 10 min preischemia and throughout reperfusion, as were the remainder of the inhibitors.
When administered to placebo-treated hearts, PTX failed to afford any shift in recovery, whereas NF-449 led to an improvement in recovery of EDP but not RPP. The NF-449 effects are likely due to the limitation of catecholamine-mediated damage (41). As expected, PTX pretreatment abolished the cardioprotective effects of acute morphine treatment, whereas NF-449 failed to exert any effect (Fig. 2).
Despite the dependency of opioid receptors on Gi protein coupling, pretreatment with PTX, although partially limiting postischemic functional recovery in chronic morphine-treated hearts (P < 0.05 vs. chronic morphine alone), failed to completely abolish the cardioprotective phenotype (P < 0.05 vs. placebo; Fig. 2). Conversely, NF-449 treatment completely abrogated the protective response observed with chronic morphine treatment against postischemic dysfunction, as measured by the recovery of RPP and EDP (Fig. 2), implicating a major effect of Gs proteins in the genesis of the chronic morphine preconditioning phenotype.
PKA, PKB, and PKC.
Preconditioning is typically thought to be mediated via a PKC-dependent pathway, being downstream of Gi protein coupling. Here we sought to determine the role of PKC in our model of chronic preconditioning with a comparison to that of PKA. Blockade of PKC with the inhibitor chelerythrine (3 μmol/l), with or without the tyrosine kinase inhibitor lavendustin A (1 μmol/l), infused both preischemia and throughout reperfusion completely abrogated the protection afforded by acute morphine, yet it failed to modify the substantial protection afforded by chronic opioid exposure (EDP, 8 ± 1 mmHg; %RPP, 78 ± 5%; P < 0.05 vs. placebo, for both parameters; Fig. 3).
To further verify the results obtained with the PKC inhibitor, we further interrogated the involvement of the PI3K/protein kinase B (Akt) pathway in both acute and chronic opioid preconditioning. To this end, wortmannin (100 nmol/l) was infused pre- and postischemia. Wortmannin failed to significantly alter the ischemic tolerance in the placebo heart; however, it abolished the protection produced by acute morphine preconditioning. Moreover, Akt blockade, although attenuating postischemic recovery, failed to completely abolish the chronic morphine-mediated phenotype. (P < 0.05 vs. chronic morphine alone, P < 0.05 vs. placebo; Fig. 3).
Coupling to Gs activates adenylyl cyclase, increasing cAMP production with resultant cAMP-dependent PKA activation. On the basis of the findings with NF-449, we sought to examine a potential dependency between chronic morphine preconditioning and PKA. To this end, we treated hearts with H-89 (3 μmol/l), a cell-permeable PKA inhibitor, or PKI (14-22) amide (300 nmol/l), an alternate PKA inhibitor with enhanced cell permeability due to myristoylation at the NH2 terminus.
Neither inhibitor significantly altered baseline hemodynamics. In contrast to PKC inhibition, chronic preconditioning failed to limit postischemic diastolic dysfunction (26 ± 2 mmHg, not significant vs. placebo) nor improve contractile recovery (26 ± 2 %RPP, Fig. 3) in the presence of H-89.
Similarly, at the termination of reperfusion, PKI reduced the recovery of %RPP observed in chronically preconditioned hearts (48 ± 2 %RPP) while significantly attenuating the preconditioning-mediated improvement in postischemic diastolic dysfunction (15 ± 2 mmHg, P < 0.05 vs. placebo, P < 0.05 vs. morphine; Fig. 3), further suggesting an important role for PKA in the preconditioning phenotype generated after prolonged morphine exposure. In contrast, PKI failed to alter the improvement in postischemic recovery of acute morphine-treated hearts. However, H-89 abolished the preconditioning effect of acute morphine treatment, although this effect may be due to nonspecific actions of H-89 as a general kinase inhibitor (29).
The β-ARs, primarily β1-AR and β2-AR, are representative Gs-coupled receptors. As such, the next series of experiments explored the potential role for β-AR in both acute and chronic morphine preconditioning. Administration of the β1-AR antagonist CGP-20712A (300 nmol/l) or 1 μmol/l of the β2-AR antagonist ICI-118,551 had no effect on hearts preconditioned with acute morphine treatment. Interestingly, both CGP-20712A and ICI-118,551 appear to induce an ischemia-tolerant state in placebo hearts (Fig. 4). Similarly, CGP-20712A failed to alter the postischemic recoveries of hearts from chronic morphine-preconditioned mice (EDP, 7 ± 2 mmHg; %RPP, 74 ± 1% not significant vs. chronic morphine; Fig. 4). On the contrary, the ischemia-tolerant phenotype observed in hearts after prolonged opioid exposure was significantly attenuated in the presence of 1 μM of the β2-AR antagonist ICI-118,551 (EDP, 16 ± 2 mmHg; %RPP, 53 ± 1%; P < 0.05 vs. placebo, P < 0.05 vs. chronic morphine, for both parameters; Fig. 4). These data suggest a potential role for β2-AR, as opposed to β1-AR, in chronic opioid preconditioning.
Interestingly, concentration-response curves to isoproterenol failed to discern a difference in inotropic or chronotropic responses between either placebo or chronic morphine-treated hearts (data not shown), suggesting a maintenance in the β-AR status quo.
MitoKATP channel.
To further dissociate the respective pathways involved in acute and chronic opioid preconditioning, we examined the function of the mitoKATP channel, often considered an integral component of both acute and delayed preconditioning. Here, with 300 μmol/l 5-hydroxydecanoate acid (5-HD) infusion bracketing the ischemic episode, the cardioprotective effects of acute opioid treatment were abolished, whereas those of chronic morphine preconditioning were unaltered (Fig. 4), adding further credence to the hypothesis that chronic and acute opioid preconditioning is mediated via distinctly different pathways (Fig. 5).
We have previously reported a profound and persistent ischemic-tolerant state observed in mice after a chronic (5 day) exposure to morphine. Classical preconditioning is typically thought to be a receptor-mediated process transduced via Gi proteins with PKC activation as a common intermediate effector. Here we demonstrate that our model of chronic opioid preconditioning, being distinctly different from that of acute preconditioning, is mediated via Gs proteins, as evidenced by NF-449 treatment. Furthermore, this Gs-mediated protection is also PKA dependent and may involve activation of β2-AR.
Involvement of β-AR system.
The role of β-AR in preconditioning is controversial. Historically, it was thought that the activation of β-AR by catecholamines released during ischemia and reperfusion is partially responsible for the propagation of ischemic cell damage (41). Regardless, our observation that β2-AR inhibition limits the cytoprotective effects of chronic opioid exposure is supported by previous studies. Lochner et al. (27) demonstrated that IPC was associated with increases in cAMP during the trigger phase. Ablation of the increases in cAMP abrogated the IPC-mediated myocardial protection. Additionally, numerous studies (12, 30) have reported that preischemic β-AR stimulation with isoproterenol mimics preconditioning. Marais et al. (30) suggested that β-AR preconditioning is mediated via p38 MAPK and heat shock protein 27. Preconditioning may also reduce β-AR internalization (21).
The correlation between the β-AR system and opioid-mediated preconditioning is unclear. However, there is a well-reported "cross talk" interaction between both the β-AR and opioid receptor systems. Endogenous opioid peptides are released concomitantly with catecholamines from sympathetic neuronal terminals in the heart, presumably as an inhibitory control mechanism. These effects are thought to occur as a result of an interaction between the δ-opioid and β1-AR, because β2-AR responses were not reversed by a δ-opioid peptide, and this effect appeared to be mediated via a PTX-sensitive Gi protein (38). Interestingly, Jordan et al. (22) reported a robust hetero-oligomerization between the β2-AR and both the κ- and δ-opioid receptors leading to differential modulation of receptor trafficking and signal transduction. Furthermore, Shan et al. (42) show a decreased Gs protein-dependent cross talk between β-AR and κ-opioid receptors after chronic hypoxia.
Chronic morphine exposure may also modify the β-AR system in the central nervous system. Chronic morphine treatment significantly increases extracellular norepinephrine (13) and leads to an upregulation of β2-AR (1). Although Genade et al. (14) reported a significant reduction in β-AR responses to isoproterenol in the presence of acute opioid receptor stimulation, the lack of change in our isoproterenol concentration-response curve in chronically treated hearts suggests that the tonic balance of β-ARs remains unchanged in our model.
Moreover, chronic morphine exposure confers a Gi protein-dependent adenylyl cyclase superactivation (3). This increase in adenylyl cyclase is consistent with PKA activation.
Role of PKA.
The results of our current study demonstrate that the enhanced ischemia-tolerant state provided by prolonged exposure to morphine was abolished via two structurally distinct PKA inhibitors but was unaffected by PKC blockade, suggesting that this protection is mediated via a PKA-dependent mechanism, independent of PKC. In support of our data, Lou and Pei (28) reported that, whereas acute δ-opioid receptor activation activated PKC in a dose-dependent manner with no effect on PKA, prolonged (24 h) δ-opioid receptor activation led to a significant increase in PKA activity with subsequent reduction in the basal activity of PKC.
PKA activation, which has been implicated in tolerance to opioid stimulation (44, 49), has also been previously shown to limit ischemia-reperfusion injury (24, 46). Moreover, PKA has also been implicated in IPC (20). Indeed, IPC mediation by PKA is independent of PKC (40), supporting our findings. However, there is controversy regarding the role of PKA in IPC. Makaula et al. (29) reported that PKA blockade, via H-89, elicited an improvement in postischemic function and reduced infarct size in the isolated rat heart and augmented postischemic function induced by IPC, whereas Tong et al. (47) reported that both H-89 and PKI attenuated IPC-derived cardioprotection in the isolated mouse heart. Indeed, Inserte et al. (20) suggested that transient activation of PKA acts as an IPC mimetic and, moreover, that H-89 blocked the effects of IPC. These results are supported by those of Robinet et al. (39), who reported that preconditioning, induced by β1-AR activation, is inhibited by H-89, and by Sanada et al. (40), whereby PKA blockade with H-89 blunted IPC in a canine model of myocardial infarction. Additionally, in this model, PKA activation mimicked IPC. The downstream kinase signaling mediated via PKA may include PI3K and Akt (2), p42/p44 MAPK (6), p38 MAPK (18), and GSK3-β (25), all of which have previously been shown to be involved in opioid-mediated cardioprotection (15, 16).
Relative roles of Gi/Gs proteins.
Our current data implicate a role for both inhibitory and stimulatory G proteins in the mediation of chronic preconditioning, with an apparently greater role for the Gs protein, as evidenced by a complete abrogation of myocardial protection after blockade of Gs. This would seem to be counterintuitive because Gs activation is typically considered detrimental to the ischemic myocardium. Indeed, β-AR blockade is a widely used therapeutic modality for heart failure and mice overexpressing Gs-α develop cardiomyopathy with age (23). Additionally, β-AR overexpressing mice also develop cardiomyopathy (9, 26).
Regardless, there is little evidence to support a protective role of Gs protein activation in cardioprotection. However, a recent study by Meino et al. (31) reported that the loss of IPC-mediated protection in postmyocardial infarcted hearts was restored in the presence of adenylyl cyclase, suggesting a role for Gs and β-AR.
After chronic activation of opioid receptors, the opioid receptors may convert from inhibitory (Gi coupled) to excitatory (Gs coupled) (7). There is considerable evidence to support opioid-mediated Gs stimulation (75, 48, 50), regardless of mechanism. Although Gs stimulation may potentially exist as a downstream effect, there are studies that support conformational changes from Gi to Gs. Wu et al. (51) reported that cloned δ-opioid receptors transfected in Chinese hamster ovary cells do indeed undergo a conformational change, or at least undergo some change resulting in increases in cAMP. Moreover, in line with the prolonged protective state that we have reported previously (35), Crain and Shen (8) reveal that chronic morphine-treated, dorsal-root ganglion neurons exhibit an opioid excitatory supersensitivity for up to 3 mo after return to control culture medium.
MitoKATP channel.
The mitoKATP channel has long been touted as one of the primary mediators of both acute and delayed preconditioning. Indeed, it is considered by many to be the "end-effector" of myocardial preconditioning. In support, there is a vast body of literature describing an integral role for mitoKATP channels in many previously described models of preconditioning. Moreover, there are numerous reports of a tight link between KATP channels and the physiological actions of opioids (2, 19, 33, 43, 52). Although our current data fail to discern an association between the mediation phase of chronic opioid preconditioning and the mitoKATP, there exists the possibility of a tangible relationship between mitoKATP and the "trigger" phase of chronic preconditioning. Nonetheless, the data regarding the mitoKATP channel presented herein further support the notion that the mediation of chronic opioid preconditioning is markedly different from the acute and delayed modes of preconditioning.
Study limitations.
An alternative hypothesis for the apparent inability of the "classic-pathway" inhibitors, administered acutely, to block the chronic morphine-mediated "preconditioning" may be due to a combination of enhanced PKC and PI3 activation after chronic morphine and, consequently, suboptimal dosing of the inhibitors, rather than a lack of activation of these pathways. However, Lou and Pei (28) report that, in NG 108-15 cells, acute treatment with a δ-opioid agonist [δ-pen2,5enkephalin (DPDPE)] activated PKC with no effect on PKA, whereas prolonged exposure (24 h) to DPDPE reduced the basal activity of PKC while increasing the activity of PKA. Moreover, some of our more recent data, incorporating a coinfusion (from implanted osmotic minipumps) of PKI failed to block the development of chronic morphine-mediated protection, despite the acute effects of PKI, whereas the same coinfusion of wortmannin completely abolished the onset of preconditioning. These unpublished results suggest a differential involvement on both PKA and PI3K/PKC, where PI3K/PKC is involved in the trigger, but not mediation, phase and the opposite is true for PKA. This differential involvement may also support a crucial "upstream" role for these signaling intermediates. Indeed, there is a high likelihood that the mediators that failed during the "mediation" phase of chronic morphine preconditioning protection are integral components of the early onset/trigger phase of the phenotype.
Additionally, our examination of the mitoKATP channel with 5-HD, which is often cited as being the end-effector in myocardial preconditioning, also considered distal to or the converging point/s of multiple upstream pathways, leads to the presumption that the tolerance observed is unlikely due to a suboptimal dosing of the upstream inhibitors.
We also cannot discount the possibility that, as the mice are still absorbing morphine up until the point of euthanasia, circulating morphine may be having an acute effect. However, there are numerous factors suggesting that this is not the case. First, after excision, the heart is perfused for 30 min before the onset of ischemia, allowing for the complete washout of any circulating morphine. Second, our previous study (35) shows that the protected state is still present at least 48 h after complete opiate withdrawal. Finally, the current study demonstrates that acute and chronic opioid protection is mediated via distinct pathways, namely, PKC dependent and PKA dependent, respectively. As such, we are confident that any potential acute effect of morphine is negligible in this model.
In summary, chronic preconditioning with morphine, which leads to both a persistent and profound cardioprotective phenotype (35) in the murine heart, occurs via a pathway independent of that described for both classical acute and delayed preconditioning. Although the exact mechanisms remain unknown, the protection appears to be mediated by both Gi and Gs proteins, with a greater emphasis on the activation of the Gs protein, a PKA-dependent/PKC-independent pathway, and activation of the β2-AR. The resolution of these protective pathways elicited by chronic opioid exposure may provide novel therapeutic approaches to myocardial protection, particularly in light of our previous observation that chronic morphine exposure rescues the protective effects of opioid stimulation that is lost in aged hearts (36).
This work was supported by National Heart, Lung, and Blood Institute Grant HL-08311 (to G. J. Gross), an National Health and Medical Research Council of Australia Howard Florey Centenary Research Fellowship (to J. N. Peart), and National Heart Foundation of Australia Grant-in-Aid G 05B 2029 (to J. N. Peart).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 by the American Physiological Society


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2013 External Evaluation Report
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"Everything that can be counted does not necessarily count;
everything that counts cannot necessarily be counted." - Albert Einstein
Tuesday, March 09, 1982
On March 10 - tomorrow - our solar system is about to become perilously unbalanced!
All of the nine planets - and a yet-to-be discovered comet named C/2010 X1 (Elenin) - are going to line up on one side of the Sun. The resulting disbalancement can and will be catastrophic for our planet! See for yourself by viewing the attached "graphic" image file (I apologize in advance for its size, and realize that it will take several hours to download over a 2600-baud modem, but this is important!)
As you can see, the planets and undiscovered comet are all on the same side of the Sun, a most dangerous form of syzygy. According to Dr. John Gribbin, author of The Jupiter Effect, the effects of this inbalanced gravity on our planet will be a veritable smorgasbord of natural disasters. Hurricanes, typhoons, earthquakes, volcanoes, tsunamis, you name it - one of these will happen tomorrow.
My prediction - and mind you, I could be wrong, as I tend to make my natural disaster predictions while drunk on grain alcohol and Clamato - is that there will be Magnitude 6 earthquake somewhere on our planet in the next 48 hours. Though I cannot say where with absolute certainty, my mind's eye is being drawn to Indonesia. Specifically, the Sumbawa Island region.
I could be wrong. I hope I am. But if not, I do hope the good people of Sumbawa will heed my warning and take cover!
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