text: SALT LAKE CITY and AMSTERDAM, Jan. 21, 2014 /PRNewswire/ -- ClearOne (NASDAQ: CLRO), a global provider of voice and visual communication solutions, launches yet another innovation for enterprise video collaboration and conferencing. ClearOne's revolutionary Beamforming Microphone Array has become wildly popular among professional AV distributors, integrators, contractors, and the enterprise customers they serve. Now, ClearOne's recent technology enhancements allow the Beamforming Microphone Array to connect directly to the COLLABORATE Room Pro system without the need for a DSP mixer by using a standard USB connection. This new, ground-breaking, integrated COLLABORATE Room Pro SKU will be showcased at Integrated Systems Europe in Amsterdam's RAI Exhibition Centre, Stand 3-A129. "This powerful video collaboration system fulfills our commitment to supply innovative solutions to professional AV and IT practitioners and their enterprise customers," said Zee Hakimoglu, Chairman and CEO of ClearOne. "We will continue to bring highly differentiated solutions to the market to help drive the industry forward, grow the business of our partners, and promote better collaboration and productivity for end-users of our products." The unique, standards-based COLLABORATE Room video conferencing solution from ClearOne enables up to nine locations to be easily and inexpensively bridged together with built-in video streaming, recording, and multicasting – all without the need for expensive infrastructure or media servers. Since COLLABORATE Room is software-based, it offers a higher level of flexibility with software feature upgrades, incremental licensing, and guarantees a higher return on investment as a future-proof solution when compared with hardware-based room conferencing systems. ClearOne's industry-leading Beamforming Microphone Array is the first professional-grade microphone system with focused acoustic beams, digital signal processing, adaptive steering, and next generation acoustic echo canceling to produce the clearest and most intelligible conferencing sound possible. The Beamforming Microphone Array virtually disappears into the background when flush-mounted into a ceiling, wall, or tabletop and blends in with even the most sophisticated corporate conferencing environments and interior designs. As an example, when wall-mounted directly below a video display in its glossy black format, the array appears to simply be a part of the monitor.


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24 September 2015
Optional Practical Training is training facility provided by the USA government to the International Students for certain duration along and after their graduation. Majority of all the international students are eligible for this kiread more..
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❯ Hadoop : What is it? Hadoop is an open-source software framework for storing Big Data and running applications on clusters of commodity hardware. It is a free, Java-based programming framework. It supports storing and processing large data-sets in a parallel distributed coread more..
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SAP Testing is an integrated effort that requires skills and expertise of various resources like ABAP developers, SMEs, business analysts and functional configuration resources. It is a complex and esoteric module. It uses applications like SAP EP and R/3 for testing. It allows two paths: SIT (syread more..
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Peel and mince 3 shallots and saute in 1 tablespoon butter until soft and fragrant. Add 2 tablespoons minced fresh sage, stir, and remove from the heat. Add to the polenta with the pepper, butter, and cheese.
Prepare the sage-shallot polenta several hours in advance. When it is done, pour it onto a baking sheet rinsed in cold water and use a rubber spatula to spread it 3/4-inch thick. Let it cool slightly and then place it in the refrigerator, covered, until it is very firm. Remove it from the refrigerator, cut it into small cubes, and place the cubes in a medium mixing bowl. Add the minced sage and the pancetta, toss lightly, and set aside.
Preheat the oven to 350 degrees. Rinse the game hens inside and out, dry them thoroughly with a clean tea towel, and set them on end, central cavity down, on absorbent paper or toweling so that excess moisture can drain out. Let them sit for 5 minutes. Stuff the hens one by one. Turn the hen on end, with the cavity facing you. Season the inside with salt and one or two turns of black pepper, and then fill the cavity with about 1 cup polenta mixture. When all the hens have been stuffed, loosen the breast skin by extending your finger under the skin to loosen the membrane. Insert 2 sage leaves under each side of the breast skin of each hen and then truss or tie the hens tightly with string to close the cavities. Pour a little olive oil in the palm of one hand and rub the olive oil over the surface of the hen's skin. Season each with several turns of black pepper and a little salt. Set the hens on a roasting rack, place in a baking pan, and roast for approximately 1 hour. Remove from the oven, remove the string, and serve immediately.
Recipe courtesy of Gourmet Magazine
Count down through our top 50 most-saved recipes, like Tyler's Chicken Parmesan.


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Fresh Lime Margaritas RecipeRead Reviews Be the first to add a review
5 5 5
A handful of ingredients make it easy to experiment with this classic margarita recipe. Stir in any fruit or herbs you like! —Tina Bellows, Racine, Wisconsin
Featured In: Margarita Recipes
- 1/2 cup tequila
- 1/4 cup Triple Sec
- 1/4 cup lime juice
- 1/4 cup lemon juice
- 2 tablespoons superfine sugar
- 4 lime wedges
- 1 tablespoon kosher salt
- 1-1/3 cups crushed ice
- In a pitcher, combine first five ingredients; stir until sugar is dissolved. Moisten rims of four margarita or cocktail glasses with lime wedges. Sprinkle salt on a plate; dip rims in salt. Serve in prepared glasses over crushed ice. Yield: 4 servings.
For Frozen Lime Margaritas: Reduce lime and lemon juices to 2 tablespoons each. Increase superfine sugar to 1/4 cup and crushed ice to 4 cups. Add 3/4 cup limeade concentrate. Prepare glasses as directed. In a blender, combine tequila, Triple Sec, lime juice, lemon juice, superfine sugar, limeade concentrate and crushed ice; cover and process until smooth. Yield: 5 cups. For Frozen Strawberry Margaritas: Follow directions for Frozen Lime Margaritas, except add 2 cups frozen unsweetened strawberries and reduce crushed ice to 2 cups. Yield: 4 cups.
Originally published as Fresh Lime Margaritas in The Taste of Home Cookbook 2006, p46
Reviews for Fresh Lime Margaritas
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Reviewed Apr. 22, 2017
"Loved these, they taste so fresh and simple to make~thank u!!"
Reviewed Mar. 30, 2014
"I made the Frozen Lime Margarita and it was excellent! Instead of superfine sugar I used Domino Light Sugar and Stevia Blend. This is so much better than buying a Margarita mix. So worth it."
Reviewed Jan. 25, 2014
"Yummy. Used agave instead of sf sugar. Added orange juice as well."
Reviewed May. 7, 2012
"Excellent and refreshing. I did the frozen strawberry version. I did not use the frozen lime-aid since I forgot to buy it and it was great. Love it!"
Reviewed Feb. 12, 2011 Edited Sep. 27, 2016
"These were awesome- thanks for the great recipe!!"


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Staff members at the Minnesota School of Business in Moorhead took a 13-mile bicycle ride along the red river in Fargo-Moorhead all while helping raise funds for a great cause.
The campus was a sponsor of the 12th Annual 'Ride the Red', a fundraiser for Hospice of the Red River Valley. Staff members Jared Bledsoe, Dana Bultema, Lisa Roesch, and Brian Shawn all participated in the ride from Trefoil Park to Lindenwood Park in south Fargo.
"It was a beautiful day outside and I am glad the campus could play a role in helping such a worthy cause," Bultema said. "It was also a lot of fun to hit the trail and meet new people."
Hospice of the Red River Valley is an independent, not-for-profit hospice serving all or portions of 29 counties through offices in Fargo, Grand Forks, Valley City, Lisbon and Mayville in North Dakota and Crookston, Detroit Lakes and Thief River Falls in Minnesota. Hospice care is intensive comfort care that alleviates pain and suffering, enhancing quality of life for terminally ill patients and families by addressing their medical, emotional, spiritual and grief needs.
"Special thanks to Minnesota School of Business-Moorhead, one of Ride the Red's platinum sponsors!" said Hospice of the RRV Public Relations Specialist Bonnie Oelschlager. "With the support of Minnesota School of Business, this annual bike ride and walk for charity raised more than $3,000 to advance the mission of Hospice of the Red River Valley—to provide comfort at the end of life's journey."


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Launch of 'Guardian Cities' website channel
By Staff
28th January 2014
Guardian Online has launched website channel 'Guardian Cities' at theguardian.com/cities.
Aiming to highlight worldwide urbanisation, the channel will feature news, comment, analysis and online discussions as well as contributions from experts including the paper's architecture and design critic Oliver Wainwright.
'Guardian Cities' is produced in association with the Rockefeller Foundation and is edited by Mike Herd.


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Carriagehouseoffices.com is a 1 year old domain, situated in United States. The domain is linked to the IP address 126.96.36.199 which is provided by the hosting company Go Daddy.
It was registered by Richard Baird . The site is owned by BAIRD Design. Registration details show that it was registered on 08 Jan 2016 through Go Daddy and will expire on 08 Jan 2019.
The site returns a status code of 200. The site is being served through Apache.


text: Beauprez joins crowded field in guv's race By Ernest Luning on March 9, 2014 Former U.S. Rep. Bob Beauprez formally entered the governor's race this week, making it eight Republicans hoping to take on incumbent Democratic Gov. John Hickenlooper. "I've been watching this race and thinking that this was an opportunity to maybe take some turf back for the GOP side, especially given the governor's record of late," Beauprez […]This content is only available to subscribers. Login or Subscribe Share this:EmailTwitterFacebook Ernest Luning, Legislative News, The Colorado Statesman, Title Item


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Surabi Bharathi Nagar is located in Papampatti exactly 4km
from Chettipalayam on Cochi Bye-Pass Road 5 Km from Trichy Road,Papampatti Pirivu
Units and Interiors:
Readily available housing choices here consist of 1BHK homes of different dimensions.
Surabi Bharathi Nagar floor plan provides best use of the space. From stylish floor to
roomy balconies, modular kitchen and high-quality fixtures, every little thing here
gives it an attractive appearance.
Facilities and Security:
The master plan of the project includes a large quantity of and desirable facilities
that together guarantee a serene lifestyle. Safe playground has already been provided
for children. Complete power supply has already been guaranteed here with full safety
via high-quality cable and PVC conduits. Protection is one of the biggest issues while
purchasing an apartment. Owing to its safety functions this project is a secure haven
for you and your family members.


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Queen Millani
The room was exquisite; long, twisted roots formed a throne in the centre of the back wall blooming with vivid golden flowers and dancing the sunlight off onto the walls in criss-cross patterns. Attached to the other walls were paintings from our most famous artists and rolling bunches of colourful flowers creating a natural atmosphere. No matter how beautiful the hall might have been, I could no longer feel comfortable in its surroundings. Guards sloped around the room, subtly readjusting their positions so they could be closer to our queen and keep me in their line of sight.
Queen Millani sat upon the throne, her posture straight and acute to the biological shape of her body. Her golden hair had lost most of its radiance, soon to turn grey I was sure, but her blue eyes were still intensely aware of everything that was going on. Fluidly, she rose so her sky blue dress fell to pool at her feet as she silently floated towards us, her gaze fixed upon Elendil. Her nobility comforted him, he was more at ease with women than he was men, especially the one holding him. Only too happily, he went to her outstretched arms and settled comfortably on her hip.
Something stabbed my heart as I realised the picture was not dissimilar to those I had of Elwyn. I gasped and stumbled.
Queen Millani's guards were instantly upon me. One twisted his hand into my stomach and I fell down as one forced my shoulders forward so I was pressed against the floor and two more yanked my arms backwards and above my head. I screamed in pain as fire seared up my limbs. They yanked me to my knees, holding my arms behind me and Lorcan had his thick fingers holding my chin still. Elendil was struggling against Queen Millani so a guard took him, restraining my son though it pained him to do so.
"Stop it!" I gasped, "Elendil, peace, my son!"
Another hand made contact with my stomach.
"Stop the violence!" Queen Millani roared, her voice shaking.
I spat out a mouthful of blood from my broken teeth. My son kept still, his perfect face creased in utter pain at the sight of me. A sob escaped me. The door behind me opened.
"Please-" I began, then Lorcan towered over me and raised his other hand, I cringed from the action.
Then a shadow appeared before me so I looked up to see a small woman holding Lorcan's hand where it had started to fall; I could see the terror and awe in his eyes. Who the woman was I had no idea, but she had stopped him from hitting me.
"You would not dare to go against my mother's wishes, would you Theron Lorcan?" Her voice was sweet, musical, knowing.
"No, Princess Eddia." He lowered his arm.
"I thought not." She bounced lightly over to stand beside her mother where she looked at me.
Princess Eddia? My she had changed so much since I was last in the Palace of Branches. She was no longer the child I had once shadowed, training her when her mother would not allow it. Sympathetically, she smiled at me. My heart thudded in response. I did not know what to do about it, Elwyn was the only one who had ever gotten that reaction out of me. She was wearing a very light green dress with golden embroidery over the waist and neck line, her hair, golden like her mothers, hung in ringlets to her waist.


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Spring 2010 Open House Featured Fun, Facts and Food
The Conservatory of Recording Arts & Sciences hosted its spring open house on Satruday March 27th 2010. The event featured an opportunity for anyone to learn more about the Conservatory and a career in pro audio. Attendees were able to interface with instructors, current students, as well as product representatives from major manufactutrers who were showing the latest in audio technology. A live band played and a catered lunch was served during the after party and gear giveaway. Prospective students were also able to meet with housing and financial aid representatives. For more information about the Conservatory, please visit www.audiorecordingschool.com. See photos from the open house here.


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Currency Displayed in
Higgins Protein Red Egg Food provides your red factor canary with an excellent source of protein derived from both animal and plant proteins. Companion bird foods that do not contain animal proteins can be deficient in the necessary amino acids methionine and lysine. Protein Egg Food is made with baked whole eggs, whole grain bread crumbs and pure honey. In addition, we add Beta-Carotene to assist in maintaining your red factor canary's unique color. Feeding Higgins Protein Egg Food as part of your bird's diet will not only add variety but will supplement its dietary intake with Vitamin A for immunity, Vitamins B12 & E for cell development, Vitamin D for bone and muscular development and Biotin for improved feathering. Feeding InstructionsHiggins Protein Egg Food can be fed dry or moist. DRY - Sprinkle approximately 2 tablespoons (1oz) per bird of Protein Egg Food over your bird's existing regular dry food or serve in a separate treat cup. MOIST – In a small cup, moisten approximately 2 tablespoons (1oz) per bird of Protein Egg Food with about a teaspoon of purified water or just enough to moisten the egg food. Feed in a separate treat cup. For added variety, you can mix in fresh chopped soft fruits or add Sunburst Leafy Greens & Herbs. Remove any uneaten food from your bird's cage daily and discard.
Guaranteed Analysis Crude Protein (Min.) … 13.5% Crude Fat (Min.) … 4.0% Crude Fiber (Max.) … 3.0% Moisture (Max.)… 9.0% Vitamin E (min) ... Min. 100 IU/kg Asorbic Acid (min) ... Min.100.0 mg/kg Omega 6 Fatty Acid ... Min.0.90% Omega 3 Fatty Acid ... Min.0.30% DHA (Doxosahexaenoic Acid) ... Min.0.03%* Total Lactic acid bacteria ... Min.2 x 105 cfu/g (Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei) Ingredients Wheat Flour, Eggs, Corn Flour, Turmeric, Wheat Gluten, German Millet, Steel Cut Oats, Niger Seed, Poppy Seed, Cane Sugar, Honey, Cinnamon, Dried Whey, Dicalcium Phosphate, Calcium Carbonate, Casein, Brewer's Dried Yeast,
This product hasn't received any reviews yet. Be the first to review this product!
All Parrot Products is dedicated to providing the best parrot supplies, parrot food, parrot vitamins, for pet birds. We have a great rewards program and offer fast & free shipping within the 48 states including Puerto Rico.
All Parrot Products carries all of the top brands of organic parrot food and healthy foods, along with the best treats, parrot perches, and parrot toys all in one location for easy access access to the world's best parrot nutrition providers.
We offer a a large selection of safe parrot toys from small bird toys to large parrot toys fun for all type of birds. We also offer toys so you can enjoy making your own bird toys.
All Parrot Products offers the largest selection of parrot vitamins & parrot supplements from The Birdcare Company, Avitech, Vetafarm and Nekton.
If you choose to feed an organic parrot food we offer Harrision's & Top's Parrot Food.
All Parrot Products carries Goldenfeast which is a great favorite of mine offering a seed based diet with greens, grains, fruit, and vegatables. With no dyes, or added vitamins.
We also carry the leading brands of parrot seed from Hagen, Higgins, Kaytee, Abba, Crazy Corn, and Volkman Seed.
All Parrot Products also offers the brand names parrot pellets from Lafeber, Zupreem, Pretty Bird, Roudybush, Scenic, and Oven Fresh Bites.
Parrots require fresh foods to stay healthy and active. Organic, human grade, and food that is not repackaged is the best way to provide optimal care and keep your parrots healthy.
Feeding your parrot right is much more in depth then just feeding a parrot seed or parrot pellet diet. Trusting leading brands is also not enough either. It's up to you, you need to read labels, and know what your feeding. All bird food is not created equal. You will find that all ingredients are listed, on all brands of food that we sell so you can make the best choice for your type of parrot.
Because of the special needs of the Eclectus we have also labeled the foods that are safe for the Eclectus.
Please contact All Parrot Products if you have any questions or if I can be of any help.
Thank you for stopping bye.
All prices are in USD.


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Photo by PoPville flickr user Harry
"Dear PoPville,
I was hoping you could help settle a dispute among my friends and I. We all grew up in/around DC (I live in Mt. Pleasant now), and we would like to settle what the best fast-casual burger/cheeseburger is in DC? I deliberately left places like McDonald's out because that's definitely just fast food and not fast casual."


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Need a PTH Test in Lexington, NC? Simply order online 24/7 and get a fast, affordable PTH Test at a lab near you (Find More Locations):
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text: Newborn Babies How to Make Pear Puree for Babies Share Pin Email Newborn Babies Homemade Baby Food Health and Safety Welcoming Baby Home Baby Names Baby Milestones Sleeping Living With Baby Feeding Growth and Development Formula Feeding Car Seat Safety Holidays with Baby Photography Tips Baby's First Birthday View All Updated April 06, 2016 Pears make an amazing first food for babies! Watch and learn how to prepare them for a simple pear puree for your baby. Up Next Up Next Video How to Make Baby Applesauce Up Next Video How to Make Carrot Puree for Babies Up Next Video How to Make Quinoa with Carrot and Pears Up Next Video How to Make Beets Puree


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Will Tim Lincecum melt in the sweltering DC heat? Is Sandy Alderson trying to pick a fight with the Giants and their fans? Insider Andrew Baggarly chats LIVE from Washington, DC before tonight's series opener between the Giants and Nats -- 12 p.m.!
Giants get blanked by Braves, now have lowest-scoring team in majors
Giants get blanked by Braves, now have lowest-scoring team in majors
SAN FRANCISCO — Over in Cleveland earlier Friday, Brandon Moss hit a three-run homer for the visiting team and five other players chipped in a pair of hits. The Royals had six runs, which meant that when Jim Johnson closed the Giants out a few hours later, what has seemed true all season became officially true. The Giants have the lowest-scoring lineup in the majors.
At 3.32 runs per game, they have dipped below the equally-disappointing Royals (3.38). They are capable at the moment of making any pitching staff look dominant. A 2-0 shutout was the first of the year for the Braves, who previously had just two games this season where they allowed fewer than two runs.
"Six runs in (the last) four games … I thought we would come home and get some rips in tonight, but it didn't happen," Bruce Bochy said.
The manager's frustration showed late in this one. After the only rally of the game — a two-run single by opposing pitcher Jaime Garcia — Bochy took his cap off and rubbed his forehead. He dipped his head and briefly stood as if he was going to fall asleep on the rail. The bats were equally still.
The Giants had just four hits, all of them singles against Garcia, who is a nice pitcher but hardly one of the league's best. One was an infield single by Eduardo Nuñez, another a single through Garcia's five-hole, and a third a generous ruling by the official scorekeeper.
"It comes down to, you've got to get some hits and create opportunities, and we're not doing it very often," Bochy said. "It's just a matter of guys getting somewhat hot. We did, we had some success, and we won some games. The thing you like to see is some good cuts and I didn't think we got enough of those tonight."
That run, which spanned the last homestand and small parts of two road trips, has come to a screeching halt. The Giants have lost five of six. It seems silly to scoreboard-watch in May, especially when a team is playing like this, but it's worth noting that the teams the Giants eventually need to catch keep winning. They fell 12 games back of the Rockies and 11 back of the streaking Diamondbacks. They are 9 1/2 back of the Dodgers, who might be the best team in the whole league.
Matt Cain did his part to allow the Giants to keep pace. He got beat just once in seven sharp innings. The Giants intentionally walked Dansby Swanson to get to Garcia, who bounced a single into left. Brandon Belt had a play at the plate, but his throw was short and hit the runner. A second run scored.
"That's tough," Cain said. "(Garcia) was throwing the ball really good and that's what it comes down to, you're looking for that one hit and he did it. He's a good hitter. We've seen it in St. Louis. But it definitely is tough when the pitcher does that … it just stinks on my part to give up a hit to the opposing pitcher."
Instant Analysis: Giants bats silenced, losing streak now at four games
Instant Analysis: Giants bats silenced, losing streak now at four games
SAN FRANCISCO — The return to AT&T Park was a huge boost to Matt Cain, who has wild home-road splits this season, but it did predictable things to an already-limp Giants offense.
The Giants entered the night as the lowest-scoring team in the National League and they got blanked 2-0 by Jaime Garcia and the Braves. Garcia out-dueled Cain and provided the only offense of the night, as well. The Giants have dropped five of six.
Here are five things to know from AT&T Park, where they keep having Star Wars Night but they've never once celebrated Super Troopers …
--- Cain entered the seventh with a 0.94 ERA at home this season, but the opposing pitcher busted him. With one on and two outs, the Giants intentionally walked Dansby Swanson to get to Garcia, a career .145 hitter. He bounced a single into shallow left and it looked like Brandon Belt had a play at the plate, but his throw home hit the runner. That allowed Swanson to race home for a 2-0 lead.
--- Cain's final line: seven innings, one earned run, one walk, three strikeouts. Yep, that's a Caining.
--- Justin Ruggiano is here for the opportunity he was given in the sixth. Ruggiano has always crushed lefties, and Bruce Bochy put him behind Buster Posey on Friday night. The Braves intentionally walked Posey to load the bases for Ruggiano, who grounded out to third. Even the platoon splits are failing the Giants.
--- If you need a little perspective on Christian Arroyo's struggles, look across the field. Swanson, the former No. 1 overall pick, is batting .198. The shortstop slashed .302/.361/.442 as a rookie but his numbers are way down across the board, and he's nearly two years older than Arroyo. These things take time. Having said that, Arroyo's hole is pretty deep. He's hitless in his last 21 at-bats after an 0 for 3.
--- There were three no-pitch intentional walks. I hope you used the extra ninety seconds wisely.


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Zuckerberg: I'm the Last to Ask About Smooth IPO (Video)
Sept. 12 (Bloomberg) -- Facebook CEO Mark Zuckerberg speaks about the company's IPO at the TechCrunch Disrupt conference in San Francisco. He speaks on Bloomberg Television's "Bloomberg West." (Source: Bloomberg)
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Addictive Genes and the Relationship to Obesity and Inflammation
- First Online:
- Received:
- Accepted:
DOI: 10.1007/s12035-011-8180-6
- Cite this article as:
- Heber, D. & Carpenter, C.L. Mol Neurobiol (2011) 44: 160. doi:10.1007/s12035-011-8180-6
- Citations
- 1.6k Downloads
There is increasing evidence that the same brain reward circuits involved in perpetuating drug abuse are involved in the hedonic urges and food cravings observed clinically in overweight and obese subjects. A polymorphism of the D2 dopamine receptor which renders it less sensitive to dopamine stimulation has been proposed to promote self-stimulatory behavior such as consuming alcohol, abusing drugs, or binging on foods. It is important to determine how this polymorphism may interact with other well-known candidate genes for obesity including polymorphisms of the leptin receptor gene and the opiomelanocortin gene. Leptin is a proinflammatory cytokine as well as a long-term signal maintaining body fat. Upper-body obesity stimulates systemic inflammation through the action of multiple cytokines including leptin throughout many organs including the brain. The association of numerous diseases including diabetes mellitus, heart disease, as well as depression with chronic low-grade inflammation due to abdominal obesity has raised the possibility that obesity-associated inflammation affecting the brain may promote addictive behaviors leading to a self-perpetuating cycle that may affect not only foods but addictions to drugs, alcohol, and gambling. This new area of interdisciplinary research holds the promise of developing new approaches to treating drug abuse and obesity.
KeywordsFood addiction Genetics Dopamine Obesity Drug abuse Inflammation
Addiction is an acquired, chronic relapsing disorder that begins with some experimentation and pleasurable responses and, for subgroups of individuals, is followed by preoccupation, escalation, tolerance, denial, and a series of medical, psychological, and social consequences that relate directly to the continued addictive behaviors. Discoveries over the last 20 years have clearly defined a relationship between obesity and systemic inflammation. The association of numerous diseases including diabetes mellitus, heart disease, common forms of cancer, as well as depression and Alzheimer's disease with chronic low-grade systemic inflammation due to abdominal obesity has raised the possibility that obesity-associated inflammation affecting the brain may promote addictive behaviors leading to a self-perpetuating cycle that may affect not only foods but addictions to drugs, alcohol, and gambling.
A key element of chronic addictions is continued addictive behavior in the face of clear knowledge of the expected consequences. Many obese individuals identify specific foods that promote continued consumption in the face of the known consequences of obesity. Yet they feel powerless to control these urges. While for many individuals, these are simply bad habits that can be changed; there is increasing evidence suggesting that genes implicated in other addictive behaviors may also be associated with food addiction, most commonly to sweet and fat foods. Specific associations of genetic polymorphisms of the dopamine, opiomelanocortin, and leptin receptor have been hypothesized to increase the risk of food addiction. Exercise and regular physical activity can entrain some of the same reward pathways and its efficacy in maintaining body weight after weight loss may be due to the activation of neural pathways involved in the initiation of overeating. Insights into the genetics of addictive behaviors associated with obesity may both lead to improved therapies of obesity and at same time may provide insights into adjunctive therapies useful in treating drug addiction, alcoholism, and other addictions.
Food Urges, Addiction, and Eating Behavior
Humans eat even when they are not physically hungry as psychological, environmental, and hedonic influences affect food urges. The peripheral and central pathways which regulate food intake are geared toward the storage of calories when food is eaten in excess of metabolic needs, leading to obesity in situations of high fat and sugar food availability coupled with sedentary lifestyles.
Dopamine increases the motivation for food intake in animals and humans as demonstrated by imaging studies carried out using food images [1]. It has also been demonstrated that obese individuals have reduced levels of dopamine D2 receptors and that these are inversely related to body weight [2]. Presentation of desirable foods increases metabolism in the orbitofrontal cortex (OFC), the area of the brain that programs chewing and salivation, in proportion to the subjective perception of hunger and the desire to eat [3]. Obese subjects studied with functional magnetic resonance imaging (fMRI), which detects changes in blood flow, had evidence of activated striatum and OFC as well as the insula while viewing pictures of high-caloric food [4]. Wang and co-workers used positron emission tomography imaging which detects uptake of 2-deoxy-2[18F]fluoro-d-glucose (18FDG) to assess the ability of men and women to inhibit the activation of brain metabolism following presentation of images of favorite foods. In men food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insula, orbitofrontal cortex, and striatum, but this did not occur in women [5]. The regions studied are integral to emotional regulation, conditioning, and motivation of food intake and in men suppressed activation of the orbitofrontal cortex with inhibition was associated with decreased self-reports of hunger. These observations suggest that hormonal mechanisms may underlie a gender difference in the ability to suppress hunger, and may contribute to the greater incidence of obesity in women compared to men.
The repeated stimulation of DA (dopamine) reward pathways has been proposed by Volkow to trigger adaptations in other neurotransmitters and in brain reward circuitry that may lead to increases in compulsive behaviors affecting both food and drug intake [6]. Moreover, exposure to drugs that elicit dependence alters gene expression profiles throughout the reward circuitry of the brain [7]. Drugs of abuse induce repeated profound dopamine stimulation which, with chronic use, may induce changes in neuronal plasticity resulting in increased emotional reactions to drugs and reduced ability to inhibit drug consumption leading to compulsive chronic drug abuse [6]. Sugar-induced dependence in rats has been shown to promote increased consumption of ethanol, suggesting that food-related dependence may influence drug addiction [8]. As reviewed above, repeated exposure to favorite foods, especially those that are calorie dense due to excess sugar and fat could lead to binge eating disorder, and poor inhibitory control of food intake [9]. The increased usage of high fructose corn syrup in the American diet has been further suggested to reduce satiety that would have normally been satisfied with consumption of natural sugars [10]. Studies of rats show that excessive binging on sugar followed by deprivation creates a state of anxiety and suggested opiate-like withdrawal [11]. While both pathways have similarities, there is a need for more research to assess whether they are also interacting. That is, whether addictive drugs affect the emotional reaction to foods and vice versa. Such an interaction could have significance for efforts to combat drug abuse as well as obesity. A possible mechanism for such an interaction is the systemic inflammation associated with obesity which could affect the brain and promote changes that make individuals more susceptible to dopamine-related rewards.
Genetic Polymorphisms Associated with Obesity and Food Addiction
Consumption of favorite foods increases dopamine concentrations in the nucleus accumbens, activating the mesocorticolimbic dopaminergic reward pathways of the brain, resulting in the reinforcing effects of euphoria or pleasure. These discoveries have been the result of advances in brain imaging including positron emission tomography scan and fMRI that enables visualization of brain activation on simply seeing images of favorite foods.
Since consuming food is critical to survival, it is perfectly reasonable that this activity would be highly valued within our inherited biological control mechanisms that evolved over eons of food scarcity and insecurity. Only in recent times has there been a surplus of calories available to all Americans including those in the lower socioeconomic strata. While these foods are inexpensive, they also have limited nutritional value and excess amounts of sugar and fat. Pleasurable responses to sugar and fat linked to activation of reward circuits in the brain activated by dopamine and other neurotransmitters can lead to food addiction and obesity in susceptible individuals as has been documented for drugs, alcohol, tobacco, sexual activity, and gambling.
Dopamine Receptor DRD2 Gene
The D2 dopamine receptor (DRD2) gene has most commonly been linked to alcoholism, although the gene has been associated with other addictive behaviors such as smoking, illicit drug use, gambling, and overeating. The Taq1A polymorphism, the most frequently studied polymorphism, is located more than 10 kilobase-pairs downstream from the coding region of the DRD2 gene at chromosome 11q23. Recent studies have further localized the coding region of Taq1A within the coding region of a neighboring gene, ANKK1 [12].
The D2 dopamine receptor, a G-protein-coupled receptor located on postsynaptic dopaminergic neurons, is centrally involved in reward-mediating and reward-deficiency pathways [13]. The DRD2 gene encodes two molecularly distinct isoforms with distinct functions [14]. Signaling through dopamine D2 receptors governs physiologic functions related to locomotion, hormone production, and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia.
By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms, D2S and D2L [15]. They are coexpressed in a ratio favoring the long isoform, D2L. D2L differs from D2S by the presence of an additional 29 amino acids within the third intracellular loop. Usiello et al. demonstrated that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions [14].
There is evidence of a direct association in Taq1A A1 allele carriers with increased body fat and co-morbid substance use disorders. A clinical study found increased prevalence of Taq1A A1 allele in obese patients with other drug dependencies compared to non-abusing obese patients [16]. Among Taq1A A1 allele carriers, D2 receptor stimulation could potentially be effective in reducing craving and reward-seeking [17]. Individualized custom formulations of neutraceuticals have been proposed to "treat" individuals with known genetic deficiencies such as Taq1A A1 allele carriers [18].
Consumption of sweet or fat foods increases dopamine concentrations in the nucleus accumbens [19], activating the mesocorticolimbic dopaminergic reward pathways of the brain [20], resulting in the reinforcing effects of euphoria or pleasure. The A1 allele of the Taq1A polymorphism (rs1800497), located ≈ 10 kb downstream of the DRD2 gene [12] has been investigated for possible associations with habitual use of alcohol [21, 22], cocaine [23], nicotine [24, 25, 26, 27], and opioids [28]. Evidence indicates that individuals carrying this allele have reduced brain D2 receptor density compared with other individuals [29, 30, 31, 32]. Adolescent girls shown with pictures of palatable food had weaker activation of the frontal operculum, lateral orbitofrontal cortex, and striatum if they are carriers of the DRD2 Taq1A A1 allele or the DRD4-7R allele. These girls were also at risk for future weight gain [33].
Persistent substance abuse in individuals with the A1 allele may be a form of self-stimulatory behavior that compensates for insufficient dopamine activity [34]. The A1 allele has also been observed to be associated with obesity [35, 36, 37]. More research is needed to determine whether the Taq1A genetic polymorphism interacts with other well-known candidate genes for obesity including polymorphisms of the leptin receptor gene and others, and whether these interactive genetic effects could promote the development of obesity-associated inflammation. In turn, systemic inflammation could affect the brain leading to mild depression or other effects which promote continued addictive behaviors.
Leptin Receptor LEP-R Gene
Other candidate genes for appetite control may interact with the DRD2 A1 allele to increase the likelihood of overeating and obesity. The leptin receptor gene has polymorphisms that affect binding of leptin to the leptin receptor [38]. The leptin receptor gene (LEP-R, formerly OB-R) identified in 1995, is expressed in the hypothalamus and other organs, binds to free-circulating leptin released from adipose tissue, and plays a major role in metabolism and appetite signaling [39]. Genetic variants potentially affecting receptor structure, function, and binding to leptin include three single-nucleotide polymorphisms (SNPs) that result in amino acid substitutions (Lys109Arg (K109R) rs1137100; Gln223Arg (Q223R) rs1137101; and Lys656Asn (K656N) rs8179187) [40, 41, 42] located at highly conserved positions in the extra-cellular domain of the receptor protein.
Research from our group demonstrated an association between percent body fat and the LEP-R variant Lys109Arg [43]. Other studies reported linkage of Lys109Arg with fat mass [44], association with serum leptin levels in young Dutch men [45], an interaction between Lys109Arg and menopause with body mass index (BMI) [46], and fat mass loss in a caloric restriction intervention [47]. While the DRD2 gene increases the likelihood of food addiction and obesity [36, 37], the LEP-R gene influences appetite control and has been associated with elevated levels of body fat and body composition [43, 44, 45, 46, 47]. The joint influence of DRD2 and LEP-R could therefore predispose individuals to weight gain and obesity if risk alleles are carried from both genes.
Evidence for potential DRD2 and LEP-R interaction has been demonstrated in mice lacking D2 receptors [48]. D2 receptor knock-out mice demonstrated leptin sensitivity, while wild-type mice had heavier body weights and were leptin resistant. Further studies are needed to characterize the interplay between genes that encode for reward/pleasure neurotransmitters and energy balance regulation.
Mu-Opiod Receptor Gene (OPRM1)
The mu-opioid receptor gene (OPRM1, located on chromosome 6q24) is one of four genes whose protein products bind to endogenous opioids. OPRM1 is a member of the large family of transmembrane G-protein-coupled receptors. It is widely expressed in both brain and periphery [49]. The mu-opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing, DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol dependence, five different SNPs in the coding region of the mu-opioid receptor gene were identified. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in the study population. Significant differences in allele distribution were observed among ethnic groups studied [50]. In a targeted study of food addiction, the functional A118G polymorphism of the mu-opioid receptor gene was found to be associated with binge eating disorders [51].
Human Diets, Obesity, and Inflammation
Over the last 200 years, changes in the human diet and lifestyle have outstripped the ability of the genome to adjust to a changing environment and billions of people around the world are now overfat as a result [52, 53, 54, 55, 56, 57, 58]. While studies demonstrate that hunter–gatherers ate over 800 varieties of plant foods [59], Americans eat only about three servings per day which fail to provide the naturally occurring antioxidants, phytochemicals, vitamins, and minerals essential to good health. Highly processed foods with refined starches, sugars, fats, and oils often fail to contain essential nutrients found in nutrient-dense foods [60]. At the same time, labor-saving devices of all kinds and advances in transportation have made a highly sedentary lifestyle possible in just the last 30 years [61]. A global epidemic of obesity and chronic disease that is underestimated using the BMI is sweeping the globe as industrialization and improved standards of living are spreading to urban centers. Certain ethnic groups including African–Americans, Asians, Asian Indians, Latinos, Native Americans, and Eastern Europeans are genetically susceptible to Metabolic Syndrome resulting from the accumulation of visceral fat with resulting inflammation [62]. It is estimated that in the next 10 years, the majority of all heart disease will be associated with type 2 diabetes mellitus [63].
The metabolic syndrome has emerged as an important cluster of risk factors for atherosclerotic disease. Common features are central (abdominal) obesity, insulin resistance, hypertension, and dyslipidemia, with high triglycerides and low high-density lipoprotein cholesterol. According to the clinical criteria developed by ATP III, it has been estimated that about one of every four adults living in the USA merits the diagnosis. The presence of the metabolic syndrome is highly prognostic of future cardiovascular events.
Chronic inflammation may represent a triggering factor in the origin of the metabolic syndrome: stimuli such as overnutrition, physical inactivity, and aging would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. Alternatively, resistance to the anti-inflammatory actions of insulin would result in enhanced circulating levels of proinflammatory cytokines resulting in persistent low-grade inflammation. A generally enhanced adipose tissue-derived cytokine expression may be another plausible mechanism for the inflammation/metabolic syndrome relationship. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, may play a pathogenic role in metabolic syndrome. Although the precise role of adipokines in the metabolic syndrome is still debated, an imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may be an intriguing working hypothesis. The chronic inflammatory state that accompanies the metabolic syndrome associates with both insulin resistance and endothelial dysfunction, providing a connection between inflammation and metabolic processes which is highly deleterious for vascular function. However, small amounts of weight loss which relieve the pressure for abdominal adipocytes to proliferate have been shown to reduce inflammation in patients with type 2 diabetes [64], and in two large trials to reduce the incidence of new cases of diabetes over 5 years by 58% in individuals with glucose intolerance and insulin resistance [65].
Our brains are programmed to activate the pleasure centers of the brain on visualizing food and then eating it, to remember the food that was eaten in specialized memory neurons, and to activate our digestive processes including chewing and hormone secretion in preparation for digesting a delicious meal. Eating food is a life-giving event in the wild and so it is perfectly reasonable that this activity would be highly valued within our inherited biological control mechanisms. However, when the stimuli are linked in susceptible individuals to increases in reward circuitry activity as detected in changes in dopamine and glucose metabolism, then neuronal plasticity could be altered in ways that both increase the tendency to eating disorders and obesity as well as drug addiction. Whether these pathways interact in susceptible individuals is unknown but has potential significance for efforts to prevent or treat chronic drug abuse through changes in diet and lifestyle including the treatment of obesity which may reduce brain inflammation.
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Re: [KWChoir] Spoken words for last two foreign-language pieces done and posted
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- Hi Svea,Good question!Hence Stars will be SSATB. That's why I have two soprano parts for people to select. So First sopranos, please learn the Cantus part, and Second sopranos, please learn the Quintus part. Everyone else should learn their appropriate line - Altus, Tenor or Bassus.That said, Altos, I know your part on Hence Stars is VERY low in a few spots. If you're more comfortable with the high F than the low D, feel free to switch to the Cantus part. If neither of those notes is in your range, don't worry about it - that low D is the 5th of the chord and thus not vital, plus the Cantus has a D two octaves above that, so it won't be a big deal if it's not very loud. Of course, by the time the concert rolls around, the combination of the smoky Pennsic air and fatigue from too much partying may give some of us low notes we don't normally have. :-)Thanks!Arianna
On Thu, 7/2/09, Constance Swanson <ladysvea@...> wrote:
Great! Now for one more question: How do you foresee dividing the voices on Hence Stars? SSATB? Soprano, 1st Alto, 2nd alto/female tenor,male Tenor, Bass? We'll know when you see what you have? As a female tenor, I have been going over both possible parts.
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