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I don't get these wars. I see people write "Oh XBOX 360 is better. It has Halo!", " Noo! PS3 is better. We have better exclusives!" or " COD sucks! Battlefield 3 will kill MW3!", " COD rules! Battlefield 3 is boring!" Why do people write these comments? For me, I like both the Battlefield franchise and the COD franchise. I have a PS3 and love it, but I'm jealous of some features and games that the XBOX 360 has. So why do people do this? I'll see you guys later and on my next blog. Bye!
Sorry, I haven't made any new blog posts in a while and I do mean a while. I've been busy with things and had no time to do them. Ok, in 2011 and 2012 there are going to be some big games coming out. Here are my top 5 of my most anticipated games:
1. Call of Duty Modern Warfare 3- Well I love the CoD franchise and have been playing it since my PS2 days. Infinity Ward, Sledgehammer games, and Raven Software are all working on this new CoD game. From what I have seen, the campaign is going to be like a hollywood type action movie. Explosions, choppers, and gunfights.
2. Battlefield 3- This game is developed by DICE and uses the Frostbite 2.0 engine. I have never played any battlefield games except for Bad Company 1 and 2. I don't have enough money to buy a gaming PC. Although I love that you can destroy almost anything and alter the battlefield. The graphics are also amazing!
3. Uncharted 3: Drake's Deception- This game is developed by Naughty Dog. I have played Uncharted 2 but not the first one. It got tons of awards and got the best award of all, Game of the Year. I downloaded the multiplayer beta and though it was fun and good. I liked the buddy system in which you can spawn on your buddy. The graphics are nice and the controls are easy and fluid.
4. Batman: Arkham City- This game is developed by Rocksteady Studios. I played Batman: Arkham Asylum and loved every second of it. The graphics are nice and the combat is awesome and fluid. The stealth sections make you think about what to do to take down all the enemies and it is just plain awesome.
5. The Elder Scrolls V: Skyrim- I have never played RPG's although they seem interesting. I have never also played the Elder Scrolls series or franchise. The gameplay I have seen looks awesome. Combat is good, magical powers, and fighting dragons!
Now I know there are more great games such as Gears of War 3, Halo 4 , Bioshock Infinite, Mass Effect 3, and The Last Guardian but this are just my opinions. Tell me what games are you looking forward too.
Can Kaos Studios compete with other FPS shooters?
Homefront is developed by Kaos Studios and published by THQ. Homefront takes place in the future in the year 2025 as Robert Jacobs, a former Marine helicopter pilot. America has been taken over by North Korea. The atmosphere and feel of the campaign actually makes you feel like it is happening right in front of you. Some of parts of the campaign actually make you cry and makes you want to kill those North Korea soldiers. The AI is good. The graphics are not as bad as they say. It's like Borderlands.
The controls are like CoD and is easy to learn. Now, the campaign will last around 5 hours. Onto multiplayer. In multiplayer there are 3 modes basically, Ground Control[ Domination], Team Deathmatch, and Skirmish[ Both GC and TDM]. All of them have Battle Commander variants. A match can hold up to 32 players. There is an ingame currecncy called Battle Points. You can get them for getting a kill, destroying vehicles, death streak, and more. With that you can purchase vehicles at the loadout screen.
Before you buy it, you need a battle code to access the full multiplayer. It only comes with a new copy or $9.99 on the PSN Store. Without it, you can only level up to 5. Homefront is a great game with a good campaign and an awesome multiplayer. If you're looking for a game just for multiplayer, look no further.
Score: 8.8 out of 10
The PSN is down, due to for some maintenance. Looking to play online Co-op for Portal 2 or play Black Ops zombies with some friends? Too bad. Here is an article about it.http://www.joystiq.com/2011/04/21/psn-down-for-maintenance-in-north-america-and-europe/. It's from Joystiq. What are you planning to do while the PSN is down?
Test Drive Unlimited 2[TDU2] is developed by Eden Games and is published by Atari. It was released on February 8, 2011. It is a racing game and is the sequel of Test Drive Unlimited. The game starts of at a house in Ibiza, one of the two islands. It is your birthday and as a present Tess, one of the main characters and the host of a show named Solar Crown, gives you a new Ferrari California. After driving about 20 miles, you wake up as a valet and is being yelled at by Tess. Tess calls her dadStuart Wintory, one of the competitors in Solar Crown, and gets you fired. But instead Tess tells you she will get you a spot on Solar Crown if you drive her to the filming spot at a club.
After you get there, you are driven to a used car dealer where you get to buy one of the three cars. The used car dealer named Jude installs this machine called F.R.I.M. which you can make money if you drift, dodge, or jump. The game has 4 categories which are competition, social, collection, and discovery. The game has a nice amount of cars and are greatly detailed. The game has great graphics and has great car sounds. The AI is pretty dumb. You will win most of the time. But they can catch up of you crash or miss a checkpoint and they do get harder as you finish championships. There are two islands Ibiza and the island from the first game, Oahu.
The game has multiplayer, but sometimes you can't connect online because of the servers. There are clubs which you can join and race. The multiplayer is a blast and you will have fun! You can customize you character with clothes, shoes, pants, and more. You can also put vinyls on your car and upgrade them. This game has some issues though, the environment pops in and i wish there were more events since the championships are so easy to defeat.
Overall, 9.0 out of 10.


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Na Smetance Apartment
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- Room service
- Restaurant
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... U Tri Ruzi (The Three Roses in English). I ordered a beer called Dark Special which they brew on the premises. The menu described it as "bottom-fermented dark beer prepared by five kinds of malt and well known hops from Zatec. Strong chocolate colour, delicate hop flavour". If I was a beer aficionado I would probably have said the same thing, but I'm not so I'll just say that it tasted like Guinness to me.
I wasn't that hungry so I ordered something from the ...
Two Praha tourist specials coming up!
... 8226; The lookout tower- built to resemble the Eiffel Tower in Paris. • We took a boat tour and it rained. Fortunately, we were covered. • We did lots of walking through old town and all around the city- Wenceslas Square, etc • Went to The Bed Cafe and had shisha (hookah) • Took a shot of absinthe and Chris taught the waitress how they do it in her country. • The St. Vitus Cathedral, but only on the ...
Prague - a fairytale
... quarter, concert hall and a number of famous churches.
One of the best things about the tour was that I met a lovely girl, Stephanie from Canada.
After enjoying the walking tour we both decided to make the most of the sunshine and hop onboard the castle tour - the biggest ancient castle in the world. This was another brilliant tour that took us up the hill starting with the castle guards then moving to the oldest building St ...
... more of the country after our small taster of Berlin.
The train to Prague took 5 hours and was pretty comfortable for the first 3 hours of the journey. We nabbed a 6 seat compartment which 2 Spanish? girls joined us in. The girls immediately settled in to sleep whilst Steven and I occupied ourselves with our devices and ate lunch. The sleeping girls were quiet and acted as a solid deterance for ...
Vietnam? ... Vietnam!
Hi guys,
this is the first blog post I'm writing to this trip... Welcome here :) I hope you will like the blog.
It's 07/26 and I'm receiving message from my friend Filip: "Don't you want to go to Vietnam? There are some cheep fly tickets." Hmm... Vietnam, it doesn't sound bad, but I already had plans to go to South America again or to North America. Let's check if there aren't any cheaper ticket to this places (Filip is flexible ...

subset: commoncrawl


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iOS 9.3 Displays Exact Wi-Fi Assist Data Usage Numbers
Tuesday January 12, 2016 1:39 pm PST by Juli Clover
Apple's iOS 9.3 beta introduces major new features like Night Shift, but there are also dozens of little tweaks to be discovered in the operating system update. It appears that one of those minor changes applies to Wi-Fi Assist, adding a much-needed feature that allows users to see just how much data it's using. Wi-Fi Assist data usage can be checked within the Settings app by choosing the Cellular section and scrolling down to the Wi-Fi Assist option. Next to the toggle that turns the feature on and off, there's now a data usage number that displays how much data has been consumed when it is in use. Wi-Fi Assist was first introduced with iOS 9. It's a feature that allows an iPhone to seamlessly switch over to a cellular connection whenever a local Wi-Fi connection is weak. Enabled automatically when updating to iOS 9, Wi-Fi Assist proved to be unpopular with users who claimed it was eating up a lot of data. One recent news story even accused Wi-Fi Assist of causing a teenager to receive a cell phone bill for upwards of $2,000. Concerns about Wi-Fi Assist led Apple to publish a support document on the feature, explaining how it works and assuring users that data usage should only be a "small percentage higher" than previous usage. Wi-Fi Assist only turns on in a limited number of circumstances and won't activate when data roaming, when apps are downloading background content, or when using third-party apps that stream audio or video. Despite Apple's reassurances about Wi-Fi Assist, unhappy customers filed a $5 million class action lawsuit over the feature,


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Long Station Necklace
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HideDetails & Care
Commanding curb links connect rows of faux-pearl, crystalline and semiprecious stations around a super-long necklace.
- Fold-over closure.
- Approx. length: 42".
- Hematite plate/glass pearl/black agate/glass/cubic zirconia/smoky quartz/plastic elastic.
- By Givenchy; imported.


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Inter midfielder Ricky Alvarez has conceded that the Derby della Madonnina is a 'unique game'.
The Nerazzurri host Milan this Sunday, and the Argentine playmaker has admitted he can't wait to play at San Siro against the city rivals.
"It's an incredible game – unique," he told Inter Channel. "Playing a derby is the best feeling.
"With the stadium full of fans, the atmosphere – it will be a great occasion. We really hope to win the match and give some joy to the supporters.
"Maybe we have not played as well in the League as we'd have liked, but I have confidence in this team and I believe we can win the match."
Keep up to date with the latest news and action from Spain's Primera Division with Football Espana - from the team behind Football Italia.


text:
My Philosophy and Approach to Wellness...I am available at all times to help you stay HEALTHY and HAPPY.
Physician Profile
- Undergraduate
- Western Kentucky University
- Bowling Green, KY
- Bachelor of Arts, Mass Media Communications, Magna Cum Laude 1969
- University of Louisville
- Louisville, KY
- Pre-Medical with Honors 1972
- Medical School
- University of Louisville School of Medicine
- Louisville, KY
- Doctorate of Medicine with Honors 1976
- Internship
- University of Louisville Affiliated Hospitals
- Louisville, KY
- 1976-1977
- Residency
- University of Louisville Affiliated Hospitals
- Louisville, KY
- Internal Medicine 1977-1979
Professional Society Memberships
- Greater Louisville Medical Society 1979-2008
- Kentucky Medical Association 1979-2008
- President, Louisville Society of Internists 1990-1991
- Sigma Alpha Epsilon National Fraternity
Hospital Affiliations
- Baptist Hospital East
Military Service
- 1st Lieutenant, U.S. Army, Signal Corps, Fort Bragg, NC andCamRahn Bay, South Vietnam, 1969-1971
Honors and Awards
- Alpha Omega Alpha Medical Honor Society
- Outstanding Civic Contributions, Millennium Maker Award 2000
- Kentucky Quality of Care Award, Pfizer, Inc. 2000
- Distinguished Military Student, Western Kentucky University 1969
- ROTC Scholarship Award, Western Kentucky University 1969
CertificationsAmerican Board of Internal Medicine
Patient Testimonials
Member: Jane
Dr. Veal is patient and interested in me when I am at his office. For this attitude, I am thankful and trust his judgment. Thank...
Member: Don
How's this for an opening line: WE ARE STILL ALIVE!! My wife and I are both diabetics. She is a juvenile diabetic (since 13), I...
Member: ALAN
Dr Veal instils such a close relationship and understanding, that a visit to his office is commensurate to a visit to a close rela...
Member: PERVEZ
I have been Dr Veal's patient for over 27 years and I have never regreted from the 1st day I met him. He is a soft spoken, genuine...


text:
From Wikipedia, the free encyclopedia
|This article is of interest to the following WikiProjects:
Greatest Ever Racemare[edit]
Perhaps this needs to be reconsidered as now Makybe Diva is probably considered the greatest ever racemare. Kearney6 16:22, 8 August 2006 (UTC)
- What about Kincsem? We are too concerned with earnings and not performances. Also, Allez France has a Timeform rating of 136, against Sunline's much lower 129 and Makybe Diva's 125. Wallie (talk) 06:41, 10 May 2009 (UTC)
Removing hype[edit]
This is a New Zealand racehorse. Let her record speak for itself. No hype required. Wallie (talk) 06:07, 30 April 2009 (UTC)
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Web site logo.
This project received 37 bids from talented freelancers with an average bid price of $55 USD.Get free quotes for a project like this
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I want learning related website logo.
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How to turn Music Player off and on?
I am sure these are silly questions. Thanks in advance for the help.
1. How do I turn off Music app once it is on? I don't see it under settings on the phone or in the app? Once it is on, the only way I can stop it is via task manager? That cannot be right can it?
2. I have Bluetooth in my car. As soon as it sees my phone, it turns on the music app to play music. (Also, goes to lockscreen - see 3.) I do not want it do that? I thought it was the bluetooth autoplay feature in my car but I have turned that off and on multiple times to see if that was the problem and it keeps happening?
3. How do I keep music player off my lockscreen? Once I hit play, it goes to the lockscreen. I do want it to do this sometimes but I cannot find where to control it?
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|Government & Organizations
Keep up with all of President Obama's remarks, town halls, and press conferences in this comprehensive podcast. This feed will occasionally include remarks from other principals like Vice President Biden and First Lady Michelle Obama.
June 2nd, 2015
Episode 277 of 668 episodes
President Obama presents the Medal of Honor posthumously to Private Henry Johnson and Sergeant William Shemin, both of whom served courageously in World War I. June 2, 2015.
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Welcome to the daily audio workout for your head.


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Market pullbacks can be unnerving. That is why investors should have a plan for managing pullbacks that is informed by historical perspective, not emotion. While pullbacks can be emotionally unsettling, they will not generally undermine a well-diversified portfolio and are not necessarily signals for panic. The benefit of gaining reliable market and economic perspective is essential in preparing for market pullbacks.
Note: We may use your contact information in future marketing campaigns. We will never share your contact information with third-party entities. View our Privacy Policy.
Read the fund's prospectus and summary prospectus (if available) carefully before investing. It contains the fund's investment objectives, risks, charges, expenses and other information, which should be considered carefully before investing. To obtain a prospectus and summary prospectus (if available), click here.
There can be no assurance that any investment product will achieve its investment objective(s). There are risks associated with investing, including the entire loss of principal invested. Investing involves market risk. The investment return and principal amount of any investment product will fluctuate with changes in market conditions. Shares of the funds are not deposits of, or guaranteed or endorsed by, any financial institution; are not insured by the Federal Deposit Insurance Corporation (FDIC), the federal reserve board, or any other agency.
The referenced funds are distributed by Guggenheim Funds Distributors, LLC. Guggenheim Investments represents the investment management businesses of Guggenheim Partners, LLC ("Guggenheim"), which include Security Investors, LLC, ("SI"), the Investment advisor to the referenced funds. Guggenheim Funds Distributors, LLC is affiliated with Guggenheim and SI.
©2017 Guggenheim Investments. All Rights Reserved.
• Not FDIC Insured • No Bank Guarantee • May Lose Value
#22527 0516 x0517


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Bob's Red Mill Milk Powder Buttermilk can be used in recipes that call for buttermilk. It is a 100% natural product produced from pure sweet cream buttermilk dehydrated. You can easily rehydrate it and get the freshness which your recipe needs. Plus you also get two great recipes on the pack to treat the family with a surprise.
This premium quality buttermilk powder lasts longer than the liquid and can be used in all baked goods as a substitute for buttermilk. To make quart of this powder just mix half cup Milk Powder Buttermilk with three and a half cups of water and it'll be ready to be used.
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Comments about Milk Powder Buttermilk, 24 oz:
I live overseas, so needless to say it is hard to find certain things, particularly the staples for good southern cooking! I decided to give the Bob's red mill buttermilk a try after reading an article that claimed powdered buttermilk was indistinguishable from fresh in recipes, and boy am I glad I did! It is WONDERFUL! I make it 1/2 or 1 cup at a time when I need it - my lavender buttermilk scones are the talk of the office, and my biscuits taste just like my grandmother's!
Because it tastes so good, and works so well in recipes, I think it will become my staple even when I'm back in a place where I can get fresh buttermilk - I've always struggled with buying a carton and not using all of it before it goes bad! now I can have it whenever I need it, no running to the store, no waste, and no funny flavor from substituting regular milk with vinegar!


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Robert Talbott
Classic Fit Dress Shirt
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Finely lined checks pattern a classic dress shirt featuring a narrow spread collar and mitered, single-button cuffs.
- French placket.
- Chest pocket.
- Curved hem.
- Split back yoke.
- Cotton; machine wash.
- By Robert Talbott; made in the USA of imported fabric.
- Men's Furnishings.


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Up to 8 hours per pad; Includes 5 Vicks refill scent pads; The Comforting Vapors vapouriser works by heat activating the soothing vapours in the Vicks VapoPad and releasing them in the air. Guiding slots make it easy to insert and remove scent pads. Simply plug unit in for up to 8 hours of soothing comfort. Soft Glowing night light.
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Is this a pub?
Are the prices at this restaurant mid-range / moderate?
Is this restaurant good for bar scene?
Is this restaurant good for business meetings?
Does this restaurant serve Bar / Pub food?
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Thanks for helping!
Stopped by with my girlfriend for some live music. She ordered the Crab cakes and I the Rack of lamb!!! Amazing evening ****
We had been driving all day and were moderately hungry. With only three places to eat in Sheffield, we picked the TripAdvisor #1 place which was right next to the Race Brook Lodge, our accommodations for the night.
The Stagecoach Inn is very dark in a very old building. But, it doesn't have to smell. Nearly gagged when we came...
Dear Chip,
Thanks so much for your review! I'm glad you thought the food was fairly good and I'm so sorry that you didn't enjoy the atmosphere. Most people really love the feeling of the old tavern. It takes a lot to maintain an old building like that and we really appreciate all the feedback! Can you elaborate on the...
we loved the atmosphere in the tavern -- draws on the age of the building combined with eclectic antique fixtures; cozy and dark. Food was very good - well prepared and interesting flavors. only bad mark was that the steak was significantly underdone
Stopped by with some friends on the way to NY. Was blown away!! Great start, middle and end! The waitress was happy and helpful.
This country style pub located in an old house on a scenic, rural road between Sheffield and Great Barrington has a warm, rustic feel. In the summer, if it's a hot night avoid sitting in the windowed front room which has no air conditioning. A fan might help or just sit outside until the mosquitoes come out. The food is...
We've always heard about this place, built in the 1700s, but have never made it there until today! I can't believe we did not go sooner!!!! It's simply amazing if you love history, architect and food!!! The staff were very inviting and warm. We took the little booth off the bar which was so romantic and comfy!!!! Decent selection of...
Eat by candlelight and enjoy the very quaint atmosphere. It is a bit off the beaten track but that adds to the charm. Our food was very good.
We came from all over and met for a candlelight dinner in such a cozy restaurant. We had roast chicken and it was divine. All the wines around the table were good, but our cab was exceptional. The waiter was exceptional and talked us into the strawberry rhubarb crumble and we LOVED that. The best word for this place is...
Waitstaff could not have been friendlier. The food was fantastic. It was a bit pricey but it was a special dining experience.
I've been coming hear for years, since the early 1970s and have seen many owners and changes. Food is very good and the wine is excellent. Wait staff is friendly and courteous. It's not perfect but all the details come together for a truly unique destination dining experience in an inn that is filled with history.
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Japanese Kitchen Knives by Hiromitsu Nozaki, teaches knife cutting techniques like Ken Needle Cut: Cutting Daikon Needle Strips, Chasen-giri Tea-whisk Cut (for Eggplant), and Dividing Fish Heads; and includes recipes like Needle-cut Vegetable Salad with Sesame Dressing, Simmered Eggplant and Chicken Breast, and Braised Tai Sea Bream Head with Turnips.
The bamboo whisk used to whip powdered green tea and hot water into froth during the tea ceremony is called a chasen. Since eggplant cut in this style resembles a tea whisk, the cut became known as chasen-giri. Used almost exclusively on nasu Japanese eggplant, chasen-giri serves two purposes. Not only does it give the eggplant an attractive appearance, but it also serves to help the eggplant soak up the stock in which it is simmered.
Here the skin of the eggplant is scored at approximately 1/4 inch (6 mm) intervals. The skin may also be scored at closer intervals, which creates a beautiful effect when cooked.
1. Remove the leaves of the eggplant by scoring them shallowly at the base and pulling them off. The stem should be left intact.
2, 3, 4. Insert the heel of the blade at the bottom of the eggplant and slide the knife slowly along the natural curve of the fruit. It helps to hold the base of the blade firmly between your thumb and index finger. Take care to maintain an even depth when scoring from the bottom to the top of the eggplant, and be sure not to cut all the way to the center of the fruit. Repeat this cut at regular intervals around the eggplant.
See the recipe for Simmered Eggplant and Chicken Breast.
More about Japan and Japanese Recipes
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Hotel Villa Conti
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TripAdvisor Reviews Hotel Villa Conti Pisek
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You haven't seen a castle til you've seen this one
... ve seen in all of Cesky, this road quickly turned into a popular small bike path. It took us through a massive amount of ovals and recreation areas and ended up taking us all the way into the centre of České Budêjovice. České Budêjovice is a big town with 100000 people, but the centre is a beautiful little area, full of old baroque buildings, it has a big square in the middle and our accommodation ...
Pisek - a nice place to spend some time
... all been very helpful and eager to make your stay enjoyable. Pisek is a really impressive town, and we were lucky that we got in early enough to enjoy the sites. Pisek has charming cafes, lots of beautiful old buildings in the centrum, and especially baroque houses that are very ornate and well maintained. Most of the centre is cobblestones and no cars, giving it that small town, European friendly appeal, just what we like to see. We headed out through ...
Cobblestone paths make you go ouch
... d see for a while, so although we headed out on the main road, it soon turned to lovely farming country which reminded us a lot of some of our France journey and the lovely back roads 2 years previously. The first three hours saw us continue along the backroads and through tiny little villages in glorious riding weather and thank God, smooth roads. It's pretty undulating, so lots of hill practices but also lots of rolling down the other side. Hooray. On the way in ...
Day 10 - Prague to Orlik (46 miles)
We were impressed with Camp Matyas where we stayed near Prague and would recommend it to other travellers - close to the station, clean facilities, good restaurant with cheap, home cooked and good quality food and lots of little extra touches throughout including one free return train journey to Prague. Our short journey to Orlik was uneventful and the only thing of note was the road FROM ...
Ceske Budejovice
Today is a quiet day. We head to Ceske Budejovice in the Czech Republic for a mini tournament to help us get prepared for the Hockey Challenge Cup which starts Tuesday. The Cowboys played good hockey in the first two periods. Lots of chances, crisp passes and excitement for fans on both sides. The third was terrible. Unfortunately Cashe took a penalty for charging with 5 ...


text:
It's gotten so cold
No hearth can warm me to the bone
Shadows dancing in the silence
Past regrets gathering in my head
All the things I wish I would have said
Walking this winding road
You've left me so alone
How can I,
How can I recover from when the cancer took you from me?
Every time I pass your bed,
I see the empty side where you're supposed to be.
Why'd you leave me like this?
You promised me,
That you would protect me
From the tides of life
Where are you now?
In Heaven or Hell?
All that I have left, now,
Are remnants of you.
© Copyright 2017 Tyler Benjamin. All rights reserved.
Status: Finished
Genre: Poetry
Oh, it is so touching directly written from the depth of heart, I am sorry for the emotions you go through, I wish almighty bless you with the power of tolerance and fighting attitude for tides of life. Very well done, keep writing :)
Sad poem. Someone in my family had chemo therapy too, and it was a horrible experience. Its a good poem of course, but its sad.
wow... i just realised that i'm not the only one who has lost their mother from breast cancer... this poem really touched my heart which is somewhat hard to do it made me cry a bit.
You are very very lucky to get her back. Now you should take care of her and make her happy and with your excellent poems. Be happy:)
Short Story / Literary Fiction
Poem / Poetry
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Is Customwood Flooring incorrect or missing key business information? Update your Hotfrog listing today.
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Hotfrog Canada provides information regarding Customwood Flooring in Cumberland. Customwood Flooring is located at 6215 Garlandside Rd, Cumberland K4B 1S7 and provides home improvement services. Contact them on (613) 443-7779.
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text: There's No Cloning in Quantum Mechanics, So the Star Trek Transporter Really Is a Suicide BoxJennifer Ouellette3/16/16 9:00pm69834EditPromoteGo to permalinkRemember last week's video about the trouble with Star Trek's transporter (a.k.a. a "suicide box") by CGP Grey, delving into whether the teleported version of yourself would really be, well, you? Henry Reich of Minute Physics has posted a video response with his own resolution to the logical paradox.


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Is Poorna Chandra D T incorrect or missing key business information? Update your Hotfrog listing today.
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Hotfrog INDIA provides information regarding Poorna Chandra D T in Mysore Karnataka. Poorna Chandra D T is located at 162 1st Floor, Mysore Karnataka 570024 and provides Financial services. Contact them on 0821 242 2872.
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463th Main, 1stage, Vijay Nagar, Mysore Karnataka 400 60
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Has Akron found a dominant running back?
Certainly, that must have been the question as fans left Stile Field House for Akron's Spring Game on Saturday.
Freshman Jawon Chisholm sliced, dashed and plowed his way through the Zips' defense for 124 yards and two touchdowns on 14 carries. The stats don't show that another long run was called back because of a penalty.
"He's a very talented back," coach Rob Ianello said. "I think Jawon's got tremendous upside. He showed today he can make a big play. He did a very nice job. We are pleased with that. All three tailbacks ran very well today."
Akron only brought three running backs to spring camp with only a combined five games and one season of collegiate experience. But that trio of Broderick Alexander, Marvin Staten and Chisholm have each looked good this camp.
Chisholm was the Offensive MVP of the Spring Game. Nico Caponi took the defensive honors (5 tackles, 2 sacks).
The offense "won" the Spring Game based on the convoluted scoring by a 82-36 count, but fans might remember today as the first time they saw Jawon Chisholm run the ball.
Notes on today's game and spring practice as well:
The game was originally scheduled to be played at InfoCision Stadium. It was a gameday decision to move the game indoors. "I just felt for as much positive things have come out of spring practice, we should have a positive environment for our players. I think our players enjoyed it," Ianello said. Fans weren't completely immune from the weather, though. There were some leaks coming from the field house roof. The band was in midseason form, albeit perhaps too loud for an indoor performance.
The offense played a clean game, committing no turnovers. There were a total of 550 offensive yards in 69 plays. The Zips had 13 offensive drives, and Patrick Nicely and Clayton Moore piloted five each. Zach D'Orazio ran the offense for the other three series. "I thought all three quarterbacks were very efficient," Ianello said. "We are heading in the right direction. No interceptions. Took care of the ball. Managed the team. Percentages are good. I thought they were very efficient."
You didn't see the defense at full strength. Four potential starters sat out with injuries: defensive back Anthony Holmes, lineman Oren Wilson, and linebackers Matt Little and Troy Gilmer. Ianello also limited his blitzes and kept it to the base package, in part, because it's an open practice where opposing coaches could watch. "I did handcuff the defense," Ianello said. "I think the spring games are about running your base offense and base defense, because if you can't run your base offense and base defense, you're in trouble anyway." Despite those limitations, Ianello told his players to focus on hitting hard in the Spring Game. "I want people in the stands to know they were at a football game today," the coach said.
Ianello has said he's looking forward to "reinforcements" coming in August. "We have 10 defensive players coming. Those 10 defensive players are going to have to help us on defense," he said. Last year, there were eight true freshmen starting at various times. Ianello said that depth has improved since 2010 such that he's like to see about that many freshmen playing in the two-deep.
Several players emerged as key members of the program in the past few weeks. The two freshmen running backs perhaps top the list. Also included are defensive backs Seth Cunningham and L.T. Smith, receiver Marquelo Suel, and linebackers ShelDon Miller and Jamar Williams. "We're certainly a much-improved football team from where we were a year ago and from the Buffalo game," Ianello said.
There are now 109 days until fall camp opens, and the coaching staff is hoping that the team's leaders encourages players to spend significant time in the weight room.
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Sports Betting
The California Bears host the 6th ranked Oregon Ducks in a Pac 12 game that will take place at the Haas Pavilion in Berkeley, California at 9 PM ET. The betting odds for this game opened with the visiting Read more
The California Bears host the 6th ranked Oregon Ducks in a Pac 12 game that will take place at the Haas Pavilion in Berkeley, California at 9 PM ET. The betting odds for this game opened with the visiting Read more
David Schwab takes a look at some of this year's Super Bowl proposition wager. Super Bowl Bets
Sports Database: Research past team game results using variables such as versus opponent, home or away, grass or artificial turf, month, as a favorite or dog, point spread odds, by division and more! Start improving your bottom line today!
Offshore Sportsbooks versus Corner Bookie
We take a look at the advantages of placing your wagers at internet sports books versus laying your action with a corner bookie.
High Betting Limits?
Pinnacle Sportsbook's withdrawal from the US market left many big bettors looking for a reputable sportsbook to place their action.
Betting Math - ROI
Return on your money invested is one concept that many gamblers do not consider when they wager on sports.
Sports Betting Primer
To profit in sports wagering you need to follow strict money management rules. Beginners and novice bettors should not vary their wager size.
How to Successfully Bet Parlays
Betting on parlays can lead to big payouts, but it doesn't come without risk. Learn how to you can increase your chances of cashing.
If you are new to wagering online or sports gambling in general then you could probably benefit from reading our articles below. Learn why not all sportsbooks are the same and why you should choose a bookmaker that suites your style of wagering.
That you can bet over or under on how many yards a QB wil through for in the 2016 NFL regular season? Do you think Aaron Rodgers will pass for more than 4270.50 yards? How about Ben Roethlisberger and the 4,952 yards the oddsmaker has listed his O/U line at? Check out our cappers' take on what QB passing props that are worth betting on.
2016 NFL QB Over/Under Prop Bets
Check this site out for tons of free sports picks against the point spread and betting advice from their team of prognosticators!


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Motton: Plays Two
"Looking at You (Revived) Again", "Message for the Broken Hearted", "Terrible Voice of Satan", "Lazy Brien" v. 2
By (author) Gregory Motton
Format: Paperback
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Motton: Plays Two by Gregory Motton
Book DescriptionIncludes the plays Looking at You (Revived) Again, A Message for the Broken Hearted, The Terrible Voice of Satan and Lazy Brien "An Irish Peer Gynt...Motton's use of language gives sheer delight" - The Times "An eerie mixture of needling precision and shambling incoherence...every line is taught and precise...mysterious, provoking and uncomfortably comic." - Time Out "A masterpiece...A writer of the first importance" - La Liberation
Buy Motton: Plays Two book by Gregory Motton from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9781840020205
(210mm x 130mm x 13mm)
Pages: 224
Imprint: Oberon Books Ltd
Publisher: Oberon Books Ltd
Publish Date: 1-Sep-1998
Country of Publication: United Kingdom
Books By Author Gregory Motton
World's Biggest Diamond, Paperback (October 2005)
Two old lovers re-unite for a weekend after 30 years. He has an appointment with death, and she has left her husband upstairs. Both think the other has betrayed their love. They fight it out as a storm grows out at sea.
Strindberg, Paperback (June 2004)
This is a fantastic collection of plays from the renowned Swedish playwright August Strindberg. This version is translated by Gregory Motton and includes: The Chamber Plays (The Storm, The Burned Site, The Ghost Sonata, The Pelican, The Black Glove) and The Great Highway
Plays One, Paperback (August 2002)
A collection of plays from one of Europe's most produced and translated playwrights. This is Plays One. One of the many collections which are published by Oberon Books. Includes the plays Someone is Going to Come, The Guitar Man, The Name and The Child
Nightsongs, Paperback (February 2002)» View all books by Gregory Motton
A play by the poet and playwright Jon Fosse. This version is translated for the stage by playwright Gregory Motton. Two lovers have conflicting interests when they have a child together.
» Have you read this book? We'd like to know what you think about it - write a review about Motton: Plays Two book by Gregory Motton and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a member - it's free to sign up!)
Author Biography - Gregory Motton
Gregory Motton's plays include "A Message for the Broken Hearted", "The Terrible VOice of Satan", "Looking at You (revived) Again", "Lazy Brien", "Ambulance" and "Downfall", all published by Oberon.
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Features December 2007 Issue
Practical Sailor Editors Pick the Best Sailing Gear of the Year 2007
From wind generators to winch handles, this year�s roundup of standouts represents the best of the best.
Over the last year, we�ve reviewed everything from thermo-electric coolers to snatch blocks, navigation software, PBO rigging, and even sunscreens. The 2007 Practical Sailor Gear of the Year winners list is no less varied. The general gear winners include the Superwind 350 wind generator, the Fujinon TS 1040 Techno-Stabi and Bushnell Stableview image-stabilized binoculars, the Mercury Big Foot 9.9-horsepower outboard engine, the Force 10 propane galley stove, Digital Antenna�s 3-dB VHF antenna, Harken�s 1609 snatch block, the Kestrel 4000 and Speedtech Skymaster handheld weather instruments, the Norcold 60-quart and Engel 35-quart thermoelectric coolers, and both the Lewmar and Dax Onetouch winch handles. The marine safety gear standouts included the Elliot SOLAS-6 life raft, Mustang�s automatic inflatable PFD/harness combo (MD 3184), West Marine�s Basic harness, the Mustang Integrity float coat, and the Mustang Ocean Commander survival suit. The marine maintenance products that topped our list include Interlux�s Micron 66 bottom paint, West Marine�s CorrosionPro Lube metal protectant, the TC-11 corrosion-inhibiting spray, and the Star brite One-Step Cleaner Wax.


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Blogs // 1 Articles
News // 2 Articles
John McLaughlin, Zakir Hussain: Remember Shakti: The Way of Beauty [DVD]
29 Apr 2008 // 4:59 PM
A dreamy, explosive collaborative effort steeped in a mystical past but forward-looking in its execution -- human music fueled by a touch of the sacred.
Zakir Hussain: 13.Mar.2010 - New York
12 Apr 2010 // 1:17 AM
Thanks to a teenage history of fighting for embarrassing '90s alt-rock bands on the car stereo, I don't know my way around North Indian classical music as well as I might. Another thing I didn't realize? You can't show up late.
Indian classical music duo combats 'Ravi Shankar syndrome'
31 Mar 2009 // 12:30 AM
For well over three decades, Americans have viewed Zakir Hussain as one of the world's most prominent ambassadors of Indian classical music. When you have
Indian tabla master Zakir Hussain says he never stops learning
5 May 2008 // 10:21 PM
He has jammed with George Harrison, laid down tracks with Van Morrison and collaborated with everyone from jazz guitarist John McLaughlin and Grateful Dead drummer


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Does anyone know predictions or can you predict the science paper? I will cover the full corse just want to know what to focus on? Also any study tip? Thanks
im not sure but just go over the questions from the mocks as i think that they might appear in the exam again.If you have a revision book make sure that you all of the course revised.hope i helped


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Christopher Hitchens doesn't strike Pandora as the most nostalgic of chaps, but perhaps we had him all wrong.
We're told that the hard-hitting writer – described by George Galloway as a "drink-soaked former Trotskyist popinjay" – was among an assortment of Leys School alumni to attend a reunion held at the Cambridge institution over the weekend, apparently seeking material for his forthcoming memoirs.
Curiously, given his reputation as a hard-boiled atheist, Hitchens, chose to pay a quick visit to the school's Methodist chapel. "It made quite a change from back in his day," says our man under the pews.
"When he was a pupil, he would refuse to engage in anything to do with religion. He wouldn't even stand up during the prayers like you were supposed to – he just refused to take part in it."
As for the reunion, we're assured it was suitably jovial. We only hope the barman had some Bells to hand – it's said to be the only tipple Hitchens will accept, since, he claims, "they're the only ones who don't give money to the Tory party". Bottoms up!
No favours for Dame Viv's son
"What a load of rubbish!" exclaims Dame Vivienne Westwood of her son Ben's forthcoming "Celebrity Spawn" exhibition, which pleads the case for Peaches Geldof et al's innate, ahem, "disadvantage". "The children of the famous are helped by their parents' fame, not bound by it," insists the designer. Naturally, Pandora couldn't agree with her more, although we can't see Ben being too thrilled with the review. Marks out of 10, Dame Viv?
Clarke rules himself out as Speaker
With all horses rushing to the starting line, Pandora's mind turns to the intriguing prospect of Ken Clarke running for Speaker (we think he'd be rather good). Last year it was rumoured that he might go for it, had Michael Martin stepped down then, following tales of his wife's taxi rides around London. Of course, Clarke is now battling it out with Lord Mandelson as David Cameron's Shadow Business Secretary, but could he be tempted once again into Martin's role? Apparently not, judging from comments to friends. "I couldn't sit there listening to speeches and not argue with them," he is said to have insisted.
Neville sells his 'gaudy' pad – at long last
Tremendous news! Everton's perennially expectation-routing midfielder Phil Neville has finally managed to sell his house, a full year-and-a-bit after putting it on the market.
The development is all the more delightful – as chroniclers of such things may recall – given the humiliation meted out by Channel 4's property "guru" Phil Spencer, who claimed the mansion was "too gaudy" to sell. (He had a point: the dining room was decked out almost entirely in Versace accessories, replete with gold ceiling and fitted bar.)
Apparently, all Phil had to do to convince the buyers was knock an extra £500,000 off the asking price. Now if that's not the clearest sign of green shoots so far, we don't know what is.
Burley takes on her ex – on camera
Lastly, Sky news pulled out all the stops for their coverage of the Michael Martin affair, sending Kay "hurly" Burley out of the studio to cover it (a brave move; last time she ventured out, she ended up with a black eye and rumours of a fight with a cameraman). Even braver, however, was the presenter's lengthy on-air interview with none other than her ex-partner, the Sun's George Pascoe-Watson.
- More about:
- Everton
- George Galloway
- Peaches Geldof
- Phil Neville


text: Some people like the creamier, denser consistency of frozen custard (due to the eggs in the recipe), but I prefer ice cream because the flavors seems to shine through more. When I treat myself I want what I want, so this isn't for me - although it is quite good. It's also a little pricey for the serving size.


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Riner, VA Rent to Own Homes
|1 Listings Found
This 1828 square ft Property has 3 Beds(s) and 1 bathrooms(s). The Monthly payment estimated Balance/Default amount is $110,800.00....
$110,800 - Foreclosure
Riner, VA 24149Details »
RentUntilYouOwn.com is the #1 provider of Riner, Virginia rent to own homes listings.
Our goal is to offer the highest quality results, along with helpful Riner resources and support. We understand that finding genuine rent to own homes in Riner can be very difficult. Even more challenging is trying to search Riner, VA listings for free.
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If the initial results in Riner, Virginia did not provide any listings of interest, or you just want more selections, click any of the blue tabs just above the search results for more.
Thanks for visiting and good luck!


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Here is a teaser from the Longevity Cookbook project.
The first chapter is on pharmacologic enhancement of lifespan. This chapter includes different ways of trying to develop pharmaceuticals to combat aging.
Full Story...
What would you say if I told you that aging happens not because of accumulation of stresses, but rather because of the intrinsic properties of the gene network of the organism? I'm guessing you'd be like: o_0.
So, here's the deal. My biohacker friends led by Peter Fedichev and Sergey Filonov in collaboration with my old friend and the longevity record holder Robert Shmookler Reis published a very cool paper.
There is something important going on in the fight against baldness.
As in the majority of tissues, the hair follicle has stem cells. There are two types of stem cells that are responsible for the continuous renewal of the follicles. The first type is called active stem cells and they start dividing quite easily. Stem cells of the second type are called quiescent and in case of the new hair growth they don't start dividing as easily. At the same time, the new hair is based primarily on quiescent cells, which attracted close attention of researchers to these cells. At first people thought that baldness was due to this type of cells.
I have mentioned mTOR as one of the main aging genes on multiple occasions. It's about time I tell you what it is, what it does and why it is so important in aging.
mTOR has a little m in front of TOR, which means I am speaking about mammals. It technically means «mechanistic» TOR, but think of it as the molecule that mice and all of us have, whereas in worms is it just TOR.
When I hear that the conversation is about an ethical problem I anticipate that right now the people are going to put everything upside down and end with common sense. Appealing to ethics has always been the weapon of conservatism, the last resort of imbecility.
The most significant event in a person's life is death. It changes everything. More precisely, it takes everything that a person had. If he was in love, he no longer is. If he was aspiring to pleasures, there will be none any longer. The world will be gone for the person.
Every single neuron will disappear that was responsible for the wishes, desires, and feelings. We don't realize this, but everything single thing we accomplish, we do so looking in the face of inevitable death. Death takes away the sense of a person's life.
First of all, let's draw a line between a strategy and wishful thinking. There are plenty of wonderful transhumanist projects. A viral video, a global portal, attracting celebrities, proof that aging is a disease, convincing billionaires, educational programs, letters to politicians, civil actions, participating in elections, creating a strong community, clinical trials of combinations of existing age delaying drugs on animals, TV shows, Hollywood blockbusters, creating a political committee, conferences on transhumanist topics, scientific megaproject on life extension, cryonics company, crowdfunding, a lot of startups relevant to transhumanist topics, active use of AI elements in all areas and so on .
We've put together the survey on transhumanism strategy to reveal the inner discussion inside the transhumanist movement. Our goal is to inspire the people to act. We believe the greatest sin in our field is wishful thinking. It's when a person is saying that it would be good to do something, like for instance, to shoot a viral video, but at the same time this person is not doing anything. His or hers advice has to be implemented in real life somehow on its own.
Accumulating evidence suggests that microbiota plays an important role in modulating lifespan. This makes possible to use symbiotic bacteria as "living drugs", which live in the host organism and promote its longevity. We propose to create bacteria, which dramatically extend lifespan of its host. Such bacteria have to produce not one, but a set of longevity-promoting substances with optimal concentrations and dynamics of secretion. To obtain such bacteria we propose to use directed evolution, a process that mimics Darwinian selection on a laboratory scale.
While discussing the longevity gene therapy project we encountered various questions and observations that prompted us to broaden the project and slightly change it. Generally, all the comments can be reduced into 5 main points…
Maria Konovalenko and team put together a list of popular science video lectures on gene therapy – one of the most promising molecular medicine directions. What makes this approach different is that nucleic acid molecules, DNA and RNA, are used as therapeutic agents.
Dr. Valter Longo hold the record of yeast lifespan extension. He was able to increase longevity of this species 10 fold. This a one of the most remarkable results in longevity science. Here Dr. Longo is giving us a lecture on yeast genetics. Let me summarize what he told us.
There are tree lectures about the mitochondria in my course. Dr. Pinchas Cohen, the Dean of Davis School of Gerontology, talked about the role of mitochondria in disease and pathology. Mitochondria have essentially three major functions. They are responsible for cellular respiration, integration of apoptotic signals, which means they control cell death, and production of reactive oxygen species (ROS). Mitochondrial function declines with age as a result of accumulated mutations in the mitochondrial DNA. Mitochondrial disfunction is common in diseases, such as diabetes, neurodegenerative pathologies and cancer.
$1,000,000 is the recently announced prize by Joon Yun, a Palo Alto-based entrepreneur, who is willing to donate this amount of money as an incentive to end aging. Half of the million will be given to the team of researchers who are able to extend lifespan by 50% in a model animal, and the other half – to those who manage to "demonstrate that it can restore homeostatic capacity (using heart rate variability as the surrogate measure) of an aging reference mammal to that of a young adult."
Gene engineering is the most powerful existing tool for life extension. Mutations in certain genes result in up to 10-fold increase in nematode lifespan and in up to 2-fold increase in a mouse life expectancy. Gene therapy represents a unique tool to transfer achievements of gene engineering into medicine. This approach has already been proven successful for treatment of numerous diseases, in particular those of genetic and multigenic nature. More than 2000 clinical trials have been launched to date.
Today was an amazing lecture by Dr. David Lee about mitochondria and its role in aging. Dr. Lee started with an overview of what mitochondria is and what it does. You may have heard that the origin of mitochondria is bacteria that was engulfed by the cell early in the course of evolution.
This attention-worthy article in The Hollywood Reporter signals that Hollywood people are ready and willing to do something about their longevity. The article mentions hormone replacement therapy, different check-ups and other things available in California, however completely misses 99% of what actually can be done about aging – science.
We have prepared a list of resources that can help understand biology of aging. We tried to find easy to grasp information sources and compiled a list of lectures, audio courses, popular science books and articles on biology in general and biology of aging in particular. The selected resources probably don't exhaust the whole picture of aging science, but they shed light on the main ideas and research directions in this area.
Let's make a bet? I will propose something incredibly effective in the area of life extension and no one will be able to suggest a better strategy. Deal?
Maria Konovalenko discusses personalized medicine services, why you should participate in clinical trials of geroprotector drug candidates, Personalized science, Why scientific research should be organized, why you should be friends with people with no harmful habits, "Create crowdfunding campaigns in the area of longevity", why you should increase your own competence, promote the value of human longevity, and neuropreservation.
Theoretically the problem is already solved. It is now quite obvious what kind of research should be done for life extension. For example, testing various combinations of different things that extend lifespan in old mice. Particularly important is longevity gene therapy development.
More than 200 participants from North America, Europe and Asia met in post-Olympic Sochi for five days this April, as world-famous anti-aging researchers exchanged ideas at the third International Conference on Genetics of Aging and Longevity. They discussed progress and remaining obstacles, in their efforts to deepen our understanding of this complex phenomenon and develop strategies for interventions.
Maria Konovalenko presents us with 3 beautiful images of important life extension sciences. They include topics such as evaluating drug efficacy based on aging and longevity makers, studying our genetic makeup, genomics, genetic mathematical models, growing new bodies, stem cells, hematopoiesis, stimulating nerve tissue, better brain to computer interfaces, computer models of working nervous systems, full map of the human brain, to uploading ones mind to a computer platform.
Sooner or later the human life extension problem, the task of achieving immortality will become the main issue of government policies in developed countries of the world. This will happen on its own because of the exponential growth of technologies. At some point of time immortality will become the main political question. This is inevitable.
The study, conducted by a team of scientists and clinicians from JCVI and WCHN, will focus on two groups of elderly individuals aged 65 to 85 years by correlating genetics with a variety of human genomic, gut microbiome and other "omics" profiles and integrating these data with the individuals' health record. One group will consist of healthy individuals, and the other will have individuals with a variety of diagnosed health conditions.
I've heard you are interested in the topics of aging and longevity. This is very cool, because fighting for radical life extension is the wisest and most humanitarian strategy. I would like to tell you what needs to be done, but, unfortunately, I haven't got your email address, or any other way to be heard.
One of the best art galleries in Moscow is going to host the first art exhibition about radical life extension – "You may not die". This message is addressed primarily to the artistic community, and is a proposal for cooperation – let's stand together and convince people that we have the opportunity to stay alive.
I don't want to die, but apparently Daniel Callahan wants me to. He wants me to say nothing, do nothing about aging and just wait until I am 75 and die quietly. Well, that's not going to happen, mister. Bioethicisits like Callahan are the ones responsible for our suffering from the horrors of aging-related diseases and death. And here's why. The opinion of bioethicists prevents the progress from being fast enough to cure aging. The decision-makers rely upon what senior "thinkers" like Callahan have in mind on the problem of life extension.
On September 18 Google announced their crusade against death via the Time journal cover. Calico company was created specifically to fight aging. Larry page made it clear for the shareholders that Google is an innovative company and that they can afford the most courageous projects, while the investments won't be too large and won't undermine the foundations of the company.
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Executive Director, Dr. James J. Hughes,
35 Harbor Point Blvd, #404, Boston, MA 02125-3242 USA
Email: director @ ieet.org


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|Table of Contents
|Vol. 69, No. 2, 2008
Issue release date: January 2008
|Section title: Mini Review
Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH ActionChan L.F. · Clark A.J.L. · Metherell L.A.
Centre for Endocrinology, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, UK Corresponding Author
Dr. L.A. Metherell
Centre for Endocrinology, John Vane Science Centre
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Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15–20%. MRAP encodes a small single transmembrane domain protein, which is essential in the trafficking of the MC2R to the cell surface. In this review, we will firstly summarize the clinical presentation and genetic aetiology of this condition. Secondly, we will discuss how the discovery of MRAP has enhanced our understanding of the mechanisms of ACTH/MC2R action. Finally, we will explore future developments in this field.
© 2007 S. Karger AG, Basel
Over the past 15 years significant advances have been made in the understanding of the genetic basis of adrenal disease with regard to primary and secondary causes of adrenal insufficiency. The discovery of individual gene defects has contributed to understanding the mechanisms controlling adrenal gland development and steroidogenesis pathways (some examples are shown in table 1). The study of adrenal resistance syndromes, namely triple A syndrome and in particular familial glucocorticoid deficiency (FGD), has provided insight into the mechanism of ACTH action.
We searched PubMed for articles published between 1970 and 2006 using the search terms 'familial glucocorticoid deficiency', 'ACTH resistance' and 'adrenal unresponsiveness'. We also searched the reference lists of identified articles for further papers.
The triple A syndrome is a complex multisystem disorder characterized by adrenal failure, alacrima and achalasia. Not all patients have adrenal involvement, but of those with adrenal insufficiency approximately 80% will have isolated glucocorticoid deficiency. This condition has been reviewed elsewhere and will not be covered here [1].
FGD (OMIM 202200) was first described by Shepard et al.[ 2] in 1959. The report of two siblings with what was called 'familial Addison's disease' prompted subsequent papers describing patients with isolated glucocorticoid deficiency [3,4,5]. It took a further 30 years before the identification of the first inactivating ACTH receptor mutation in a patient with FGD [6]. Since then a large number of mutations have been found which are summarized in figure 1. The ACTH receptor was the second melanocortin receptor to be cloned hence the alternative nomenclature of MC2R [7].
FGD is characterized by glucocorticoid deficiency in the presence of normal plasma renin and aldosterone levels. Nevertheless, mild derangements of the renin-angiotensin system at the time of diagnosis are sometimes seen with this condition [8], and it has been suggested that a partial mineralocorticoid-deficient state exists in those patients with 'severe genotypes' [9]. This may mean that in some cases a diagnosis cannot be made using clinical and biochemical parameters alone. The finding of mutations in the MC2R gene and the more recently described MRAP gene would provide a definitive diagnosis. However, genetic defects in MC2R and MRAP only account for 40–45% of cases, leaving the remaining 55–60% of patients with no identifiable gene defect.
Patients with FGD are usually diagnosed during the neonatal period or by early childhood. They may present with hypoglycaemic seizures, hyperpigmentation, recurrent infections, failure to thrive, collapse and coma. Transient neonatal hepatitis has also been described as a presenting feature [10]. All the symptoms and signs seen in FGD are the result of either hypocortisolaemia or elevated ACTH levels. The long-term neurological consequence of FGD can vary from learning difficulties to spastic quadriplegia, which may reflect the severity and number of hypoglycaemic episodes during childhood [11]. There may be a family history of unexplained neonatal deaths, the presence of another affected family member and/or consanguinity.
FGD can usually be distinguished from other causes of primary adrenal insufficiency by the absence of mineralocorticoid deficiency and associated features seen in such conditions. This would include progressive neurological manifestations (triple A, adrenoleucodystrophy), ambiguous genitalia (congenital adrenal hyperplasia, CAH), other dysmorphic features (IMAGe), hypogonadism, delayed puberty (congenital adrenal hypoplasia), alacrima/achalasia (triple A) and presence of other autoimmune deficiencies (polyglandular autoimmune syndromes). These differential diagnoses should always be considered prior to the diagnosis of FGD and in some instances specific investigations may be required. For example, adrenal antibodies, very-long-chain fatty acid measurement, 17-OHP, Schirmer test of tear production together with a barium swallow could help to differentiate autoimmune cause of adrenal insufficiency, adrenoleucodystrophy, CAH and triple A syndrome, respectively. Monitoring of blood pressure is an essential part of assessment and may diagnose some forms of CAH presenting with hypertension.
Tall Stature
Tall stature is observed in some FGD patients with MC2R mutations [12, 13]. In addition, a proportion of these patients have been shown to have advanced or dissociated bone age, e.g. advanced bone maturation in the radius and phalanges with delay seen in the carpal bones. This excessive growth is more noticeable prior to the initiation of treatment, and although hydrocortisone replacement appears to bring the height back towards the mid-parental target, children remain tall as adults [8]. The rather limited data available suggests that the insulin-like growth factor I-growth hormone axis is normal in these patients [12]. It has been proposed that the excessive growth is due to high plasma ACTH levels [13]. The presence of all five melanocortin receptors in bone and the ability of ACTH to stimulate cAMP production and gene expression in bone cells provide a plausible mechanism [12, 14, 15]. However, not all FGD patients with inactivating mutations of the MC2R are tall, short stature has also been described [16].
Absent Adrenarche
ACTH is required in the regulation of adrenarche in normal children and absent adrenarche is a feature seen in children with FGD. Clinically this presents as delayed or absent pubic hair development associated with extremely low/undetectable adrenal androgen levels in children >7 years of age and those in puberty [17]. Ishii et al.[ 18] report a FGD patient with sparse pubic hair in adulthood despite normal progression in puberty and regular menses, demonstrating the importance of ACTH in the induction and subsequent maintenance of adrenarche and pubic hair attainment. In contrast, true puberty defined as breast development and subsequent ovarian development, controlled by the hypothalamic-pituitary-gonadal axis, is unaffected in FGD.
Markedly High Plasma ACTH
Most FGD patients have markedly raised plasma ACTH levels reflecting the extent of resistance. However, suppression of plasma ACTH levels in FGD can be very difficult despite treatment with high doses of hydrocortisone. The reason for this apparent lack of suppression is unclear. There is some suggestion of the existence of a short ACTH negative feedback loop at the level of the pituitary/hypothalamus. Hence, patients with mutations which render the MC2R inactive would lack negative inhibition of ACTH release at this level [19,20,21,22].
Hyperpigmentation is almost always observed in FGD. The child often develops pigmentation by the 1st month of life and usually remains pigmented despite treatment. Pigmentation is generally thought to be due to the high ACTH levels which act on the melanocortin-1 receptors in melanocytes.
The typical biochemical results in FGD are a combination of low cortisol levels paired with extremely high plasma ACTH levels, in the presence of normal plasma renin and aldosterone. ACTH levels of above 1,000 pg/ml (normal range <80 pg/ml by RIA; <50 pg/ml by IRMA) are commonly found [8, 23]. Occasionally, children may have minor impairment of the renin-angiotensin-aldosterone axis at the time of initial presentation [8, 24]. The physiological explanation of this observation is unclear. Two factors may play a part. Firstly, there is evidence that ACTH directly activates the production of aldosterone in the zona glomerulosa (ZG). It has been found that MC2R mRNA localizes to the ZG and administration of synthetic ACTH to normal human subjects results in a rise in plasma aldosterone levels [5,24,25,26,27]. The physiological importance of ACTH-dependent regulation of aldosterone in normal physiology and disease is undetermined. Interestingly, the ability of ACTH to stimulate aldosterone production may stem from the role of ACTH in the normal organization of the ZG during development of the adrenal gland, as suggested by the abnormal ZG histology seen in patients with FGD (see later). Secondly, during periods of illness and acute stress, changes in the renin-angiotensin-aldosterone axis are seen [8, 28]. The difficulties in dissecting the biochemical results in a sick child and the potential of misdiagnosing patients presenting with adrenal insufficiency and mild renin-angiotensin-aldosterone disturbance were exemplified by Lin et al. [9]. They identified 7 children diagnosed with probable primary adrenal hypoplasia who on genetic evaluation were found to have FGD with MC2R mutations. This enabled the withdrawal of fludrocortisone treatment in a number of patients. However, there was a suggestion that a partial mineralocorticoid-deficient state might exist in some 'MC2R severe loss of function mutations'. Patients with minor changes in renin/aldosterone levels would benefit from re-evaluation as this would have significant implications on their long-term management and genetic counselling [8, 9].
Blood glucose monitoring is essential in any child who is unwell and in FGD hypoglycaemia may result in a number of symptoms ranging from failure to thrive to coma. Dynamic testing with the short ACTH stimulation test (Synacthen® = 1–24 ACTH) will confirm a diagnosis of primary adrenal insufficiency. A normal response is defined as a peak plasma cortisol level of more than 550 nmol/l. There is evidence that some patients with FGD have a normal response to a short Synacthen test initially which on re-testing in later life becomes abnormal (unpubl. observation). Additional investigations may help with differentiating FGD from other causes of primary adrenal insufficiency. For example, detectable adrenal autoantibodies can indicate autoimmune Addison's disease. Elevated levels of very-long-chain fatty acids would suggest adrenoleucodystrophy. Adrenal androgen levels including 17-OHP and urinary steroid chromatography would help to differentiate CAH.
Despite careful clinical and biochemical evaluation some patients may not easily fall into a diagnostic category. In such patients diagnosed with 'primary adrenal insufficiency', mutational analysis of genes such as those listed in table 1 has proved successful [29].
Adrenal Imaging
Adrenal imaging in the form of MRI/CT scanning can be helpful. In FGD the glands are usually small in size [8]. This is in contrast to tuberculosis (calcified adrenal glands), CAH (enlargement), storage disorders and infiltrative disorders (enlargement of the gland).
There are several histopathology studies from cases where a sibling has died prior to the diagnosis being made on the index child. These report the absence of fasciculata or reticularis cells together with disorganization of granulosa cells [2, 8, 30, 31].
The treatment is by replacement with hydrocortisone. An oral dose of 10–12 mg/m2/day in three divided doses in children and 20–30 mg/day in adults is usually sufficient. The suppression of plasma ACTH levels in FGD can be very difficult and should not be used as the goal of treatment. Educating parents and patients on the need to increase hydrocortisone dosages during illness and the emergency management with intramuscular hydrocortisone is vital. Recently, Crown et al.[ 32] reviewed the management of glucocorticoid deficiency, highlighting controversies that still exist in the 'optimal' treatment regime of such patients. Medic alert bracelet, 'steroid card' and handheld summaries should be given to all patients.
The cloning of the MC2R by Mountjoy et al. [33] in 1992 enabled researchers to identify point mutations in the ACTH receptor in patients with FGD [34,35,36,37,38,39]. The MC2R gene, located on chromosome 18q11, encodes a 297-amino acid G-protein-coupled receptor. More than 30 mutations have been described in the MC2R (fig. 1), the majority of which are homozygous missense or compound heterozygous mutations. In comparison, homozygous nonsense mutations are rare. The functional consequence of various MC2R mutations has been demonstrated by a number of groups [36,40,41,42,43,44]. To date there is no strong evidence to suggest that heterozygous carriers, i.e. parents or siblings of FGD patients, have abnormal cortisol secretion or response. On detailed investigation, Tsigos et al. [34 ]found that the mother and grandmother of an affected child with the R201X (substitution of an arginine residue at amino acid position 201 with a stop codon) and S120R (serine → arginine at position 120) mutations had exaggerated and prolonged ACTH responses to administration of corticotropin-releasing hormone (CRH). This suggests subclinical resistance to ACTH in heterozygous carriers; however, an investigation into 4 patients heterozygous for 4 different MC2R mutations revealed normal responses to CRH in 3/4 carriers. The 4th carrier heterozygous for the L192fs (frameshift at the leucine residue, position 192) mutation had an exaggerated increase in plasma ACTH combined with an elevated serum cortisol response to CRH. The findings in this patient were believed to be a stress response to human CRH administration as a previous ovine CRH test was reportedly normal [36]. CRH responses have been shown to vary according to ethnic background [45, 46]. The family studied by Tsigos et al.[ 35] were of black ethnicity which may account for the elevated ACTH response after CRH.
Mutational screening of the MC2R revealed that MC2R defects could only account for approximately 25% of cases [47, 48]. Linkage studies provided evidence of a second FGD locus [49] and, in parallel with this, evidence accumulated of the existence of an 'MC2R' accessory factor [50, 51]. Homozygosity mapping, utilizing SNP (single nucleotide polymorphisms) microarrays across the whole genome, identified a third locus on chromosome 21 in some families with FGD. Fine mapping of the region together with mRNA expression studies of genes within this region revealed a candidate gene, now known as MRAP (melanocortin-2 receptor accessory protein). This gene was found to encode a single transmembrane protein with 2 isoforms of 19 and 11.5 kDa in size derived from alternative splicing of exons 5 and 6 (fig. 2). Functional analysis of the protein revealed four key findings: (1) direct interaction with MC2R, (2) requirement for MC2R function, (3) co-localization with the MC2R and (4) requirement for MC2R cell surface expression [52]. So far our group has identified 8 different mutations of MRAP in FGD patients (publ. and unpubl. data). Modan-Moses et al.[ 11] identified a further mutation consisting of a 7-nucleotide deletion in exon 3, resulting in a frame shift and a premature stop codon, L31X. These mutations are summarized in figure 3. In contrast to the MC2R mutations, these mutations would all result in either the complete absence of the protein or a severely truncated product.
FGD type 1 and type 2 refer to patients with MC2R and MRAP mutations, respectively. In clinical samples over 50% of FGD patients have no identifiable mutation in either gene – this group of patients are referred to as having FGD type 3. Linkage to chromosome 8 has been found in a minority of families with FGD type 3, although a candidate gene has yet to be identified [49], but not all families segregate to chromosome 8 suggesting the involvement of additional genes.
The discovery of MRAP has provided a new mechanism of melanocortin receptor regulation which was previously unknown. Small single transmembrane proteins such as the RAMPs, RTPs and REEPs are a growing number of receptor accessory proteins which interact with G protein-coupled receptors [53,54,55]. These accessory proteins assist receptor trafficking to the cell surface and may be able to determine ligand specificity. MRAP may also have functions in the folding and translocation of the MC2R through the endoplasmic reticulum hence acting as a molecular chaperone. The molecular properties of MRAP are being investigated by a number of groups including our own. Roy et al. [56 ]recently reported their work looking at the differential regulation of the human MC2R by MRAP isoforms.
Single gene defects in rare diseases have been crucial to the understanding of a variety of signalling pathways. At the molecular level, CUL-7 in 3-M syndrome [57], P450 oxidoreductase deficiency in Antley-Bixler syndrome [58], and POMC in the syndrome of adrenal insufficiency and red hair [59] are just some of the examples in which the study of rare diseases has provided insight into the respective signalling mechanisms. Homozygosity mapping in consanguineous families has proved to be a highly successful strategy in the mapping of rare recessive traits. One may argue that the identification of such genes in rare diseases may be of limited benefit to the population at large. However, it is difficult to quantify the benefit from improvement in the understanding of the molecular biology of the cell. Moreover, it may be that aetiological genes in rare disorders can also play a role in conditions of high relevance to the population at large. An example of this success is the study of the melanocortin-4 receptor (MC4R) in obesity. MC4R mutations, identified initially as a rare cause of severe obesity in childhood, are now believed to be the most common monogenic cause of obesity in the general population [60, 61].
The discovery of mutations in genes that cause FGD now enables a definitive genetic diagnosis of FGD in some cases. Such a diagnostic test not only has relevance for diagnosing new cases of FGD but also revisiting of patients thought to have adrenal failure of unknown cause. Isolated glucocorticoid deficiency should still be considered the norm. However, in cases where there may have been derangements of renin-aldosterone levels at the time of diagnosis and those who may have slight derangements, these children may benefit from review of their mineralocorticoid status and genotyping of the MC2R/MRAP genes.
At present a genetic diagnosis is not possible for a large proportion of patients and the aetiology of FGD type 3 patients needs to be elucidated. It is hoped that such discoveries will shed more light on the ACTH signalling pathway and the diseases which arise when regulation of this pathway fails in underactive and overactive states.
L.F.C. is supported by a Clinical Research Training Fellowship from the Medical Research Centre, and L.A.M. by the Wellcome Trust.
Dr. L.A. Metherell
Centre for Endocrinology, John Vane Science Centre
Charterhouse Square
London EC1M 6BQ (UK)
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Received: December 15, 2006
Accepted: July 31, 2007
Published online: December 05, 2007
Issue release date: January 2008
Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 1
ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)
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