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Select or modify your travel plan
Update date, no of rooms or guest info
Update date, no of rooms or guest info
The hotel is ideal for hosting large scale business conferences and events with well-equipped business facilities, a business centre and Internet access. Furthermore, professional in-house services at this hotel will certainly meet the 5-star hotel standard such as a concierge service, laundry service, room service, car park, baby sitting and car hire. The air-conditioned establishment also features a lobby with 24-hour reception, lift access and a breakfast room.


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Men Of UK
Do As I Say (Damien Crosse, Paddy O'Brian and Theo Ford)
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Theo Ford will do what Damien Crosse tells him. For starters, he can get fucked by Paddy O'Brian! This hot new scene from men.com is the latest from subsite MenOfUK.com.
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1957 Ford Custom 300 for Sale
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Selected Filters:Year: 1957 Type of Ad: Vehicles for Sale Make: Ford Model: Custom 300 Remove All
1957 Ford Custom 300
Lithia Springs, GA
Believe it or not, Ford outsold Chevrolet in 1957 but today you don't see nearly as many '57 Fords. That's a shame, because this... More
Offered By: Streetside Classics - Atlanta
Advertiser since 2008
Advertiser since 2008
1957 Ford Custom 300
Wendell, NC
Museum Collection car, like new in and out. NO RUST-NO DENTS. Mileage is not documented but believed to be accurate. New brake cylinders, hoses,... More
Offered By: Private Seller


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text: An Educational Journey: Heading Down the Co-op Path a New Experience for Sacramento Students SACRAMENTO, CA, February 6, 2014 As an undergraduate student at Drexel University Sacramento, Jeremy Labelle has friends who have already graduated from college and accepted jobs in their career path. Yet the excitement and high expectations many of his friends felt when the jobs began has been replaced by discontent; it turns out the field they chose in college isn't what they thought it would be. Labelle vows not to make the same mistake and have a misguided college career. "My generation all seems to be looking for that dream job when they get out of college," Labelle explained. "But some of my friends have graduated and gotten jobs that they hate. They found out that it isn't the type of work they want to do. That's not going to happen to me." Labelle, 24, chose Drexel's new Bachelor in Business Administration degree program in Sacramento for many reasons. But the primary one was its cooperative education (co-op) program. "The co-op aspect sealed the deal for me. It's similar to an internship, but it's in your chosen field and you get paid to do it for six months," Labelle said. "Drexel gives you a lot of help in lining up the job and it's very major specific. It's a great way to find out if this is what you really want to do." That's sound logic to Amanda Miller as well. She excelled at Sierra Community College in Rocklin, east of Sacramento, leaving with associate degrees in both natural science and liberal arts. Miller, 30, was accepted and ready to attend California State University, Sacramento before hearing a Sierra College presentation by Olivia Stelte, Drexel's Assistant Director of Admissions. "Olivia's presentation blew me away and had a huge impact," Miller recalls. "I couldn't stop thinking about Drexel. The thought of going there really intrigued me. It made so much sense, being in Drexel's co-op program and getting real-world experience for six months. Getting that experience is very relevant and something you can't receive sitting in a classroom." Miller and Labelle are among the inaugural class of students enrolled in the new program, which is designed for students who have finished at least the first two years of their undergraduate education. Thanks to Drexel's main campus in Philadelphia and the vigilant efforts of John Carvana, the Manager of Career Services in Sacramento, Drexel has developed an enormous network of business relationships for their co-op students. Each term, 98 percent of Drexel students applying for a co-op have found a placement, and in 2012-13 earned an average of $16,593 for the six-month period. There are 3,329 jobs openings available to the students in the U.S. Drexel offers co-op placements in 33 states and 40 countries worldwide. There are currently six Sacramento employers participating in the co-op program, including the NBA's Sacramento Kings. Among the employment choices Sacramento students are considering for their April-September 2014 co-op include: Accounting firm in New York City Pharmaceutical company in Philadelphia Boston-based foundation, sponsored by the Boston Red Sox Leading PR firm that's branding the City of Sacramento New York fashion showroom Sacramento non-profit located next door to the home of one Drexel student "This first group of BSBA students are the 'pioneers' of our undergraduate program," Carvana said. "They chose Drexel University Sacramento because they understand that having a degree isn't enough. They know that today's students need to graduate having practical experience along with a solid academic foundation in order to remain competitive in the job market. Our BSBA program is unique in that respect." Drexel-Philadelphia has been nationally recognized as a co-op education leader for many years. The co-op program, which is available to every Sacramento undergraduate student, is an aspect that Dr. Sandra Kirschenmann, Associate Vice Provost and Executive Director of Drexel University Sacramento, is proud to discuss. "I think that's the most exciting part of what we're doing," Kirschenmann said. "Providing our students with on-the-job experience gives them a much better chance of competing in the job market. The added benefit is students receive good wages while they are working and that money can be used to offset their educational costs." Unlike many students at California universities and colleges who struggle to get classes and frequently don't graduate on time, the Drexel model is set up for students to graduate in two years. Labelle, who lives with his wife in Sacramento, is taking 16 units in his first quarter and will have an even heavier load in the second one with 20 units. He welcomes the challenge. "I don't have to worry about not getting the classes I need; I'm assured of that at Drexel," he said. "Being about to finish in two years was another big reason that I chose Drexel." One year after graduating from high school, Labelle enlisted in the Air Force and served four years. During his two deployments, he spent considerable time aboard cargo planes, which were frequently the target of ground fire in Iraq and Afghanistan. At Drexel, Labelle is not only getting his education paid for under the Yellow Ribbon Program, he's also receiving a monthly stipend. Labelle is already considering remaining at Drexel and getting his MBA. After graduating high school in Idaho, Miller spent one year at Boise State. However, the cost was an issue, so she relocated to Sacramento and lived with her mother. Miller has worked ever since, juggling a full-time job at Costco and pursuing her education. Although she has nothing but praise for Costco, Miller is eying an accounting job after graduating from Drexel. "I'm very excited at the prospect of having a co-op job that's in my career field," Miller said Miller. "The business administration field is very broad and there are tons of different options to take. I love anything with numbers, so I think accounting is my calling." Besides an array of intriguing business courses, both Miller and Labelle have been impressed by the Co-op 101 class taught by Carvana. Among the goals are producing a flawless resume and getting students totally prepared for interview situations. They practice online in "InterviewStream," where mock interview questions are answered and recorded on a webcam. Carvana critiques every aspect of the interviews and provides insightful feedback. "John is amazing. He's extremely knowledgeable and totally approachable. He's a huge help," Labelle said. Miller also lauds the efforts of Carvana and has enjoyed the cohort aspect of a Drexel education. The intimate class of students will be together for two years. "We've really been able to build strong relationships and we hang out together. We're almost like family now," Miller said. "I love the small class size and all the one-on-one attention we receive." Miller and Labelle both agree that graduation in spring 2015 will be a prideful day, picking up their diplomas as the first group of Business Administration degree programs students. "Being able to say I was part of that first class will be great," Labelle said. "I'll be very proud of that. I love talking about Drexel to other people that I know. Drexel has become a special place for me."


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I am happy to announce that we have now launched our wordpress blogging network. This means that you can now register a FREE blog using our registration page. We would, of course, approve all the blogs according to our standards but blogs created through our website will have the full power of a self-hosted blog.
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Alison Krauss helped bring bluegrass to a new audience in the �90s. Blending bluegrass with folk, Krauss was instantly acclaimed from the start of her career, but it wasn�t until her platinum-selling 1995 compilation Now That I�ve Found You that she became a mainstream star. Between her 1987 debut Too Late to Cry and Now That I�ve Found You, she matured from a child prodigy to a versatile, ambitious, and diverse musician and, in the process, made some of the freshest bluegrass of the late �80s and early �90s.
When she was five years old, Krauss began playing the violin, taking classical lessons. She soon tired of the regiments of classical playing and began performing country and bluegrass licks. At the age of eight, she began entering talent contests in and around her native Champaign, Illinois. Two years later, she had her own band. In 1983, when she was twelve years old, she won the Illinois State Fiddle Championship and the Society for the Preservation of Bluegrass in America named her the Most Promising Fiddler in the Midwest. In 1985, Krauss made her recording debut on an album, playing on a record made by her brother Viktor, Jim Hoiles, and Bruce Weiss. The album was called Different Strokes and appeared on the independent Fiddle Tunes label. Later that year, she signed to Rounder Records. She was fourteen years old at the time.
Too Late to Cry, Krauss� debut album, appeared in 1987 to very positive reviews. The album was recorded with Krauss� backup band, the Union Station, which featured guitarist Jeff White, banjoist Alison Brown, and bassist Viktor Krauss; the following year, the group won the Society for the Preservation of Bluegrass in America�s National Band Championship contest. In 1989, Krauss and Union Station released Two Highways, which was nominated for the Grammy Award for Best Bluegrass Recording. Although the album didn�t win the award, her next album, 1990�s I�ve Got That Old Feeling, did. The success of I�ve Got That Old Feeling was unprecedented for bluegrass acts in the �80s and it laid the groundwork for Krauss� breakthrough in the �90s. By this time, Union Station�s lineup had more or less settled. It now featured mandolinist Adam Steffey, banjoist/guitarist Ron Block, bassist Barry Bales, and guitarist Tim Stafford; Stafford later left the group and was replaced by Dan Tyminski.
In 1992, Alison Krauss & Union Station released Every Time You Say Goodbye, which featured a typically eclectic array of material. The album appeared in the country charts and Krauss� videos were shown on Country Music Television. I Know Who Holds Tomorrow was released in 1994 and was even more successful. But it was the 1995 compilation Now That I�ve Found You: A Collection that made Krauss a star. The album reached number two on the country charts and - even more remarkably - went into the pop Top Ten and sold over a million copies. Its success confirmed her status as bluegrass� leading light in the �90s.
Krauss & Union Station followed the unexpected success of Now That I�ve Found You with So Long, So Wrong in spring 1997. Forget About It followed in mid-1999. A year later, Krauss & Union Station joined the likes of John Hartford, Ralph Stanley, and others for the multi-million-selling soundtrack O Brother, Where Art Thou? A North American tour showcasing some of the album�s stellar musicians followed in summer 2002, allowing Krauss and her band�s popularity to soar. New Favorite appeared in November and went gold within four months. A live album followed soon after, and in 2004 Krauss released Lonely Runs Both Ways. A Hundred Miles or More, a collection drawn from Krauss� Rounder albums, along with sides recorded for various soundtrack projects and five previously unreleased tracks, appeared in 2007.
Alison Krauss and Union Station features the talents of Krauss (fiddle and lead vocals), Dan Tyminski (guitar, mandolin and lead vocals), Barry Bales (bass and harmony vocals), Ron Block (banjo, guitar and harmony vocals), and Jerry Douglas (Dobro and harmony vocals). Paper Airplane was produced by the band and recorded in Nashville with engineer Mike Shipley (Maroon 5, The Cars, Def Leppard, Joni Mitchell). As bluegrass virtuosos the members of Union Station are beyond compare, and the music they create together transcends all genres. Their work on films such as �Cold Mountain� and �O Brother, Where Art Thou?� has contributed immeasurably to a renaissance of American roots music.


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Considering the animated world of Rick and Morty is full of vibrant, peculiar galaxies and an assortment of fascinating creatures, you'd be forgiven for thinking it looks like the perfect backdrop to a kid's TV show. But make no mistake: the cult cartoon created by Justin Roiland and Dan Harmon is far, far away from being child-friendly.
Based around the dysfunctional but ultimately tender relationship between Rick (a mad-cap scientist, raging alcoholic and habitual belcher) and his grandson Morty (a socially awkward 14-year-old and hesitant sidekick), the show deals with both the metaphysical and the mundane in perfect synchrony.
The narrative centers around Rick and Morty and their adventures, led by Rick's crazy interdimensional travels and oddball creations. This essentially gives Roiland and Harmon a blank canvas to let their creative synapses go wild, with equally hilarious and controversial results.
See Also:
- Master Rick And Morty Theory Reveals The Relationship Between Rick and Evil Morty
- It's Time To Get Schwifty With This Theory: Is Rick And Morty Based In The Saints Row Universe?
- Throw Up Thursday: Rick And Morty Parodied The Purge Once, But Will They Again In Season 3?
Such controversy has encouraged entertainment rating website Common Sense Media to rate the show suitable for those aged 16+, and it'd be hard to disagree. Let's look at some of the most outrageous moments from the first two seasons to put the show into context.
1. The Biggest Controversy
From the offset, profanity, sex and violence runs through the core of Rick and Morty. While it's general approached in a jocular, off-the-cuff manner, "Meeseeks and Destroy" (Season 1, Episode 5) takes things to a much darker, shocking place.
Having complained their adventures are too dangerous, Rick allows Morty to take control. This leads the plucky protagonists to the Thirty Steps Tavern, where Morty encounters King Jellybean, an anthropomorphic version of the popular candy (obviously, duh!). Seemingly friendly on the outside, King Jellybean approaches Morty in the Tavern and attempts to rape him, before Morty fights him off and escapes, clearly traumatized.
Although shocking, Roiland and Harmon treat the assault with the seriousness it deserves, using the scene as a device that serves the plot and not glorifying the incident. It also illustrates how the show doesn't shy away from taking on dark themes.
2. On To Violence, And Lots Of It
As mentioned above, violence is a common theme throughout the show. Species from all kinds of galaxies are often maimed and killed in a graphic nature. A good example of the extremes the cartoon violence can escalate to occurs in "Look Who's Purging Now," a parody on the 2013 horror movie, The Purge.
See our Rick and Morty / Purge mashup trailer below:
Rick and Morty arrive on a planet that celebrates an annual purge, where all crime — including murder — is legalized for a set period of time. In its satirical take on the themes of the movie, the episode unleashes obscene amounts of gratuitous violence, including one particular scene where the planet's elite are slaughtered by Rick and one of the planet's inhabitants, before they both jubilantly dance through the bloody mess.
3. Strong Sexual Themes (See: Sex Robots)
The subject of sex features heavily throughout the show, to varying degrees of absurdity. Like most topics, Roiland and Harmon balance the mundane (such as Morty being caught masterbating by his parents or being in the midst of hormonal lust for his classmate, Jessica) and the bizarre (Morty falling in love with a special sex robot he finds in a souvenir shop in another galaxy — yeah, really).
4. As Well As Some Intergalactic Drug Taking
There's no denying Rick is a bit of a party animal who still manages to find time during his galaxy hopping misadventures to fit in a couple of (extra) drinks or even drugs.
In "Ricksy Business" (Season 1, Episode 11), while in another universe, Rick sends Morty on a mission to find Kalaxian Crystals, claiming they are of significant importance but not telling him for what reason. When Morty returns, Rick then cuts up the crystals and snorts them, instigating a powerful drug trip.
5. And Then There's The Simply Disturbing
Working in the realm of animation with a concept that is really unlimited in its scope allows for all sorts of messed up storylines that aren't for kids. A prime example of the deranged improvization occurs during a commercial for Strawberry Smiggles, shown during "Rixty Minutes" (Season 1, Episode 8). Without giving anything away, check out the commercial below:
Not to mention "Rick Potion #9" (Season 1, Episode 6) where Rick and Morty find an alternate universe where identical versions of themselves die, so they can replace them and assume their places. They even have to bury their own bodies. Yikes.
Final Thoughts
Rick and Morty definitely isn't for kids, but it's still one of the smartest animations created in recent years. While there is an abundance of profanity, violence and sexual content, the show generally handles such themes with a wink to the viewer, rarely relying on them purely for cheap laughs. For those slightly older, make sure you watch it. It's unlike anything you would've seen before.
At what age do you think it is appropriate to watch Rick and Morty?
(Source: Common Sense Media)


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shawnwrote a review of Gravis Carter Shoe - Men's on July 12, 2011
Soles cracked through in less than a month
A waste of money.
The bottoms of the soles developed U shaped cracks right under the heels of my feet in less than one month of wear. I emailed Gravis support to see if they would make-good, but never even heard a reply. Weak!
And I had previously owned a pair of Gravis that held up for almost 8 years. It seems they have gone south as a company. So sad.


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Physician allocation system in Quebec inhibits recruitment
Related Articles
- Quebec reports C. difficile mortality statistics. Eggertson, Laura // CMAJ: Canadian Medical Association Journal;7/19/2005, Vol. 173 Issue 2, p139
Focuses on the third surveillance report on Clostridium difficile, released by the Ministry of Health of Quebec in June 2005. Total number of deaths caused by Clostridium difficile from August to December 2004; Mortality rate of Clostridium difficile cases; Percentage decline in Clostridium...
- Quebec extends free drug coverage to 300 000. Pindera, Loreen // CMAJ: Canadian Medical Association Journal;3/27/2007, Vol. 176 Issue 7, p917
The article reports on an initiative undertaken by the Quebec Ministry of Health and Social Services to extend free drug coverage to 300,000 citizens, including the seniors, those with limited income and citizens on welfare programs. The initiative was announced on February 1, 2007 together with...
- Some conference resolutions. // British Medical Journal;7/29/1978, Vol. 2 Issue 6133, p378
Presents several conference resolutions on community health services in England. Urgency toward the amendment of the constitution of the central committee; Alteration on the terms of reference of the Review Body; Discussion on the problem of recruiting community physicians.
- HUDSON VALLEY NEWSMAKERS. // Hudson Valley Business Journal;4/5/2004, Vol. 15 Issue 7, p22
This article focuses on professionals of Hudson Valley who made news recently. St. Luke's Cornwall Hospital has promoted Joanne Sturans from manager of recruitment services to manager of employee and labor relations. Amy Finnegan, has been promoted to manager of the hospital's Unity Center in...
- New visa laws to boost graduate employment. // Australian Nursing & Midwifery Journal;Dec2013/Jan2014, Vol. 21 Issue 6, p12
The article discusses Australian visa laws which became effective in November of 2013 and may increase the chance of Australian graduate nurses finding jobs, and discusses reaction to the laws which was voiced by Lee Thomas, the federal secretary of the Australian Nursing and Midwifery Federation.
- Global view: SNCH opens doors to nurses of the world. Solnik, Claude // Long Island Business News (7/1993 to 5/2009);5/19/2006, Vol. 53 Issue 21, p13B
The article reports that Oceanside, California's South Nassau Communities Hospital is recruiting nurses from around the world. The hospital is constructing housing for nurses and other health-care professionals specifically recruited from abroad. It is an effort to avoid a potential shortage of...
- Diary from a Week in Practice. Larimore, Walter L.; Hartman, John R.; Wohlever, Amaryllis Sanchez; Littell, John T. // American Family Physician;8/1/2001, Vol. 64 Issue 3, p413
Relates the events encountered by physicians in a week's work. Experiences of a doctor in rural family practice; Weight loss program prescribed to a woman patient; Problems encountered in practice while performing newborn nursery rounds.
- Local doctors' group takes on `virtual integration.' Markley, Jennifer // Inside Tucson Business;12/25/95, Vol. 5 Issue 39, p11
Presents information on the Arizona Community Physicians medical group in Tucson. Membership; Expected growth in membership; ACP run by doctors; How the organization came about; Major issue in formation of ACP; Comments from officials.
- Trust between managers and physicians in community hospitals: The effects of power over hospital... Succi, Melissa J.; Lee, Shoou-Yih D. // Journal of Healthcare Management;Sep/Oct1998, Vol. 43 Issue 5, p397
Examines whether manager and physician power over hospital decisions fosters manager-physician trust. Key element of effective work relationships between managers and physicians; Relation of power of managers and physicians over hospital decisions to manager-physician trust; Professional...


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Croatia : Car Rental 20% Discount!
Events and Car Rental in Croatia
Looking for entertainment in the destination you are planning to visit and still did not find suitable tips? Welcome to Economy Car Rentals and its information about events, happenings and festivals in Croatia which will definitely make your holidays more than pleasant. Read and enjoy all festivals for 2015! Explore Croatia on your trip through various regions, car rental will give you the flexibility you need to enjoy everything and take the best memories with you. Economy Car Rentals has also selected the latest car rental news for Croatia, make the best out of your trip. Rent a car in Croatia and enjoy your trip!
A comfortable car rental such as SUV 4WD, Full Size, Full Size, Full Size is just the right way to make your stay in Croatia even more enjoyable. Whichever car brand Nissan Pixo, Fiat Panda, Fiat Panda New, Opel Corsa, Ford Fiesta, Nissan Note, Skoda Octavia, Opel Astra, VW Polo, VW Up will be provided for your car rental in Croatia, you can be sure that you will spend memorable moments. Make a visual tour in Croatia on our Videos Page to get an idea of what you are going to see when you travel there.
*Economy Car Rentals wants to keep up to date its customers about all festivals, events and happenings! Soon all latest events will be online!
Upcoming events during 2015 for:
Last Updated 2015-02-19


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Gleneagles Kota Kinabalu, a newly-built hospital stands tall in the heart of Kota Kinabalu; the capital city of Sabah. The hospital offers diverse range of healthcare services and patient care from our compassionate and highly trained medical professionals. A branch of Pantai Medical Centre Sdn Bhd under Parkway Pantai Limited, Gleneagles Kota Kinabalu is assimilated with regionally well-established premium Gleneagles brand inculcating a facility with high-quality amenities / comforts, service levels to match, be infused with modern technology and have a highly-trained team of consultants and staffs. Our name is synonymous with dedicated commitment to always provide the highest level of healthcare experience staying true to our tagline of "In the Arms of One Who Cares".
Gleneagles Kota Kinabalu will be a new leading hospital providing excellence in Healthcare Quality, Service & Safety. It is built to comply with all content of local and national regulations. We also aim to be the new referral center in East Malaysia and target international patients from Indonesia, Brunei, Korea and Japan seeking quality and reliable medical care.
Gleneagles Kota Kinabalu has total capacity of 200 inpatient beds, 73 Medical Suites, 6 Operating Theatres, 15 Intensive Care Units, 7 Neonatal Intensive Care Units and 6 Labour & Delivery Suites. It has ample of indoor parking spaces for visitors.
Gleneagles Kota Kinabalu is strategically located along the coastal highway of Kota Kinabalu, close to the heart of the city, just 10 kilometres away from Kota Kinabalu International Airport. The hospital poised in-line with its neighbouring notable landmarks like the Sutera Harbour Golf & Country Club, KK Times Square, the upcoming transport-interchange station, Wawasan Plaza, Harbour City, Ming Garden Hotel – together they will form the new KK Southern City Hub.


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A few weeks ago, I purchased a box sugar cones. I made my kids ice cream cones with Talenti ice cream and I noticed that the texture of sugar cone tasted funny. I looked at the box and it said it's gluten free sugar cones. Last night I bought a box of Tate's chocolate chip cookies to make ice cream sandwich for my kids. The cookies were tasty but I noticed the familiar grainy texture and I knew right away I bought gluten free cookies.
ughhh..I feel like such an idiot. Am I the only one who's keeping buying gluten free foods not by choice?


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OK ladies, looking for the perfect person to do your brows and lashes? Wait, haven't had your lashes tinted? Beauty secret number two, indeed. Careful, you'll be hooked. Dana ...
All reviews seem positive
Salon services including cuts, coloring and waxing are combined with facials, a specialty jelly bath and nine different massage options.
From family friendly trips with kid friendly activities to local plumbers lawyers, spas, and contractors. Judy's Book has millions of listings and reviews for the best and not so great. Whether you're looking for a specific business or just trying to discover great places we make it easy. We're a family oriented site focusing on bringing trusted reviews and recommendations to moms and others. Green and Sustainable places are becoming more relevant to Judy's Book users, have a favorite place? Write a review and tell users why it's Green!


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Hey Lefties!
My youngest is a lefty. She used to use her right hand when mimicking me and her sister, but she now she only uses her left hand to color or write with. My husband thinks only one of his brothers is a lefty (one out of 9) and my aunt is a lefty.
She's only 4 y/o, but I am wondering how difficult it might be for me to teach her how to write correctly.
If there a certain way I should teach her or is it pretty much straight forward like when teaching a righty?
My little guy is a lefty. The Handwriting Without Tears teachers manual I think had how a lefty and righty should be holding a penicl which helped me since I'm so left hand incompetent lol. After I got the hang of how to help him hold his pencil correctly (which was super easy), I haven't had any other issues.
A tip I learned though when it comes to cutting, you always hold your work with the opposite hand you cut with, so a righty typically cuts counter clockwise while a lefty cuts clockwise (i think I got the directions correct...I may have flipped them...)
I am a lefty and never had a problem. If anything it "should" be easier since in earlychildhood she will want to mimick your mirror image when you show her stuff .
Also, for letter formation he often does things differently. If the curriculum says start the letter at the top and bump the line down he may reverse it or draw the circle on the a clockwise instead of counterclockwise. I set a certain standard on letter formation. If it's easier for him to make the letter neatly his way I leave it alone. He does about half his way and have according to the book. I love handwriting without tears. I love the two line paper approach. My son is 7 doing kindergarten to first grade work. He is dyslexic so his learning is staggeringly uneven grade level wise.
We'll have to see how cursive goes in 2-3 years.
I'm a lefty. The only thing to keep in mind is that the page can't be straight up and down, tilt it slightly to the right, almost to a 45 degree angle, otherwise I've seen lefties write with their wrists bent at weird angles in order to see what they were writing. Otherwise teach like she's a righty.
Home Educators Toolbox / Articles / Kicbuttmama's Crazy Lapbooks / KBM Creations / Pintrest / ETSY
Albert Einstein --
"It is, in fact nothing short a miracle that modern methods of instruction have not yet entirely strangled the holy curiosity of inquiry; for this delicate little plant, aside from stimulation, stands mainly in need of freedom."
"Everybody is a Genius. But if you judge a fish by its ability to climb a tree, it will spend its whole life believing it is stupid."
Haley is left handed. :) I had to help her tilt her paper enough so she wouldn't smear her words as she wrote. We also worked together to make sure she didn't 'hook' her hand as she writes.
One of the supervisors at work was left-handed, and he showed me what not to do when she was in kindergarten. The hook was the main thing he did that compromised his writing the most.


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Contact Info / Websites
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If you all are not watching the videos from my new Facebook buddy — and fellow Navy Veteran — John Bridevaux, you need to be. John's the kind of guy I would love to sit around with, having a bunch of beers and talking politics.
He is out of the Corpus Christi area and I have no idea if he has a Master's Degree or never finished high school — and it doesn't matter because the man is highly informed, incisive and smart as hell.
And as much as I dislike the ongoing trend of people getting their news solely from comedy shows and web videos, people will learn important stuff from John's five to 10-minute productions. That's because when he goes on a self-described "rant" it is based on the current news of the day. And, after watching many of his videos, I have yet to see him be incorrect or make assertions not based on fact.
He's also fun to listen to and I often find myself saying out loud "damn right!"
If we all stay as informed and involved as John Bridevaux, Trump doesn't stand a chance. Check him out below. You can also find him on Facebook here.


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Early Differential Resolution of Right and Left Ventricular Obliteration in Löffler Endocarditis After Chemotherapy and Anticoagulation
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A 27-year-old woman diagnosed of T-cell non-Hodgkin lymphoma was referred to our hospital for allogenic hemopoietic stem cell transplantation. In childhood, the patient was diagnosed with hypereosinophilic syndrome. One week before admission, the patient started to develop progressive dyspnea. On chest x-ray, there were signs consistent with congestive heart failure. Her white cell count was 5990/mm3 with 59% eosinophils. A transthoracic echocardiogram disclosed a complete obliteration of the apexes of both ventricles, which were filled with a mildly echogenic material consistent with fibrosis or thrombosis. The right and left atria were enlarged, and pulsed wave Doppler examination showed a restrictive left ventricular (LV) filling pattern (Figure 1A through 1C). All of these findings were compatible with the diagnosis of Löffler endocarditis. The patient was anticoagulated and received conventional treatment for heart failure, resulting in clinical improvement. One week after admission, chemotherapy with fludarabine and melphalan was started, and a nonmyeloablative transplantation was carried out using hematopoietic progenitors from a human leukocyte antigen–compatible brother. Four weeks after chemotherapy, a repeat echocardiogram showed the total disappearance of the LV obliteration and a normal filling flow (Figure 1D through 1F). The right ventricular (RV) obliteration remained unchanged. The patient was discharged in a stable clinical condition with a total white cell count of 3100/mm3 with eosinophils 1%. Six months later, a repeat echocardiogram showed that the LV cavity remained empty, but the RV apex was still obliterated. Cardiovascular magnetic resonance imaging identified the RV occupation (Figure 2A). After administration of a gadolinium-based contrast agent, this occupation presented a delayed enhancement compatible with fibrosis (Figure 2B). The patient remained asymptomatic and her blood cell count was normal; these results continued on ambulatory follow-up.
Hypereosinophilic syndrome is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement.1 Cardiac involvement (Löffler endocarditis) may be present in more than 60% of the patients and may include endocardial thickening; ventricular obliteration by an echogenic material, suggestive of fibrosis or thrombosis; atrial dilation; and a restrictive pattern in echo Doppler.1,2 Before the advent of early diagnosis and management, cardiac disease was the leading cause of both morbidity and mortality. Two-dimensional echocardiography is an essential tool for diagnosis and follow-up.2 Cardiac damage has been attributed to the toxic effects on the myocardium and endocardium of proteins released from the degranulation of eosinophils. This tissue infiltration is responsible for inflammation and later fibrosis.3 The control of blood eosinophil count is considered crucial to limit the extent of cardiac involvement.3 Optimal treatment is not well defined. Apart from anticoagulation and conventional treatment of heart failure, steroids and α-interferon may halt the progression of the disease and improve the survival.1,4 Anticoagulation, by preventing thrombotic apposition, may contribute to long-term positive ventricular-cavity remodeling.4 In our patient, soon after the initiation of anticoagulation and chemotherapy, we observed a rapid resolution of the LV occupation. To the best of our knowledge, such fast, extensive, and unilateral improvement has never been reported before. It is not clear why the RV apical occupation persisted when the LV obliteration had resolved. Magnetic resonance imaging is a promising technique for delineation of ventricles' anatomy and function and for characterizing the composition of the ventricular wall. Gadolinium delayed-enhancement magnetic resonance imaging accurately identifies regions of myocardial fibrosis.5 This technique identified the material occupying the RV of a fibrotic nature. This differential resolution might suggest that the LV occupation was mainly caused by a relatively recent thrombus formation, whereas the material filling the RV apex had a higher fibrotic content. This hypothesis is also consistent with the recent onset of symptoms of heart failure and their rapid resolution. We cannot exclude that chemotherapy also might have contributed to the resolution of the LV occupation. Our findings show that anticoagulation combined with chemotherapy can resolve restrictive heart failure and ventricular obliteration in these patients. It is tempting to suggest that it would be worthwhile to use oral anticoagulation in hypereosinophilic patients before ventricular obliteration develops. Magnetic resonance imaging has become a promising technique in the evaluation and management of such patients.
The online-only Data Supplement, consisting of movie files, is available with this article at http://circ.ahajournals.org/cgi/content/full/114/24/e635/DC1.
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Gottdiener JS, Maron BJ, Schooley RT, Harley JB, Roberts WC, Fauci AS. Two-dimensional echocardiographic assessment of the idiopathic hypereosinophilic syndrome: anatomic basis of mitral regurgitation and peripheral embolization. Circulation. 1983; 67: 572–578.
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Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol. 2005; 45: 98–103.
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- Early Differential Resolution of Right and Left Ventricular Obliteration in Löffler Endocarditis After Chemotherapy and AnticoagulationJuan Benezet-Mazuecos, Pedro Marcos-Alberca, Jerónimo Farré, Miguel Orejas, Adolfo de la Fuente and Elena PrietoCirculation. 2006;114:e635-e637, originally published December 11, 2006https://doi.org/10.1161/CIRCULATIONAHA.106.636753
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- Early Differential Resolution of Right and Left Ventricular Obliteration in Löffler Endocarditis After Chemotherapy and AnticoagulationJuan Benezet-Mazuecos, Pedro Marcos-Alberca, Jerónimo Farré, Miguel Orejas, Adolfo de la Fuente and Elena PrietoCirculation. 2006;114:e635-e637, originally published December 11, 2006https://doi.org/10.1161/CIRCULATIONAHA.106.636753Permalink:


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On July 31st and August 1st, Windsor Pita Pit will be celebrating the first Anniversary of its 4140 Walker Road location and its 12th Anniversary at 6711 Tecumseh Rd. East.
In the spirit of Pita Pit's "Fresh Thinking, Healthy Eating" philosophy they are planning a community event on both days with $2 from every pita sold from both locations generously donated to the Bulimia Anorexia Nervosa Association (BANA) to support local programs and services.
As part of a balanced healthy lifestyle, the event will also include BANA information booths, the opportunity to participate in a fitness bootcamp hosted by Workit! Fitness Inc. (on Saturday at the Walker location); and live broadcasts from the Mix 96.7FM and Cool 100.7FM.
Don't miss out on some amazing raffle prizes including: Swag, Pita platters, free lunches, free smoothies and a grand prize of a BBQ Grill !
On behalf of Pita Pit, BANA and Workit! Fitness Inc. we hope that the Windsor-Essex Community will join us in celebrating the success of a wonder local business and support a great local cause.


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Life hack: remove a pine tree from a room to make it feel spacious
Pro tip: you can avoid the U2 album by never opening iTunes #lifehack
You think people are upset now. Wait until Facebook buys the potato salad.
Oh God, #TheDress has hit Facebook, meaning it will haunt us randomly throughout eternity.


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When you have a ton of weekend plans and the weather calls for rain, you have two choices; you can stay in bed and watch it from the window or you can go out and dance in it... this is the story of a great weekend in the pouring rain:
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This silent protest could have serious consequences.
Wisconsin basketball star Nigel Hayes was invited to attend ESPN's College GameDay, and he used the opportunity to protest the NCAA's policy of not paying college athletes. But his stunt may have serious consequences.
Hayes is a senior for the Wisconsin Badgers and was named the Preseason Big Ten Player of the Year. Last year he made the All-Big Ten's first team and averaged 15.7 points per game. He's considered a strong NBA prospect.
Hayes takes considerable issue with the fact that the NCAA does not pay the student-athletes upon which its built a multimillion-dollar empire. He made his intentions for the GameDay protest known on Twitter.
Then he showed up with a headline-grabbing sign that reads "Broke College Athlete Anything Helps." It includes a screenname for Venmo, the digital payment system.
It's a bold statement that will undoubtedly catch the NCAA's attention. Even before his protest, Hayes' tweets sparked serious discussion on Twitter, and he engaged with many of the people who took issue with his stance.
Hayes likely didn't intend to actually get paid from his protest—he intentionally put the wrong username on his sign—but it's not hard to find him on the platform, and people appear to be sending him money and comments of encouragement.
Hayes appears to be putting himself at considerable risk. According to the NCAA, "The receipt of a benefit not authorized by NCAA regulations by a student-athlete or his parents, relatives or friends will immediately place the student-athlete's eligibility for intercollegiate athletics competition in jeopardy."
This isn't the first time someone has used College GameDay to score some extra cash. Earlier this season, internet hero Sam Crowder's sign for beer money went viral and resulted in more than 400 people sending money.
The NCAA, however, could care less about some random student's beer money. Hayes' protest, on the other hand, will likely be investigated.
H/T BroBible
Pure, uncut internet. Straight to your inbox.


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Was Selena Gomez Drinking Beer
July 30, 2011 by Post Team
Was Selena Gomez Drinking Beer, Gomez made the smuggling of beer Magical World of Harry Potter? Disney star Selena Gomez, 19, was allegedly caught drinking a beer Butterbeer. The photo was uploaded to Facebook. Gomez is too out of control Bieber driving?
On Friday, gossip networks exploded after a photo of Gomez reportedly holding a pitcher of beer with foam mustashe a photo on Facebook. Gomez is known for her Disney family picture and a role model for many children. However, it is what we think it is.
It seems that the pop star of Disney does not really have that kind of beer. Gomez says he was actually making a Harry Potter-inspired soft drink.
The name of the drink is called "Butterbeer." It is a product of the "Harry Potter" series of fantasy novels. It's basically a cream soda that looks sweet beer. I was in the Wizarding World of Harry Potter.
Ugh! We were worried that Gomez. We do not think the type of beer anyway.
Please feel free to send if you have any questions regarding this post , you can contact on
Disclaimer: The views expressed on this site are that of the authors and not necessarily that of U.S.S.POST.


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Minor Girls Softball
Jan 30 - Mar 19
Ages 8-10
Meeting Dates
From Jan 31, 2016 to Mar 20, 2016
About This Activity
For players of age ranges from 1/1/2005 to 12/31/2007.
Minor Girls Softball games are traditionally held on Monday and Wednesday nights.
Minor Girls travel throughout the District 12 area to play games with some games being home games.
Practice dates are determined by coaches, not Fremont Little League, although they must follow FLL and Little League International rules for holding safe practices.
Organizer Info
Fremont Little League


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Russian President Dmitry Medvedev on Monday called for cooperation with North Korea in the building of a gas pipeline, railways and power lines across the heavily fortified border with South Korea.
The call came in a message sent by Medvedev to North Korean leader Kim Jong-Il on the occasion of the anniversary of the end of Japan's 1910-45 colonial rule of the Korean peninsula.
"We have willingness to boost cooperation with the DPRK (North Korea) in all directions of mutual concern including a three-party plan encompassing Russia, the DPRK and (South Korea) in the fields of gasification, energy and railway construction," read the message published by the North's official Korean Central News Agency.
Russia will ship at least 10 billion cubic metres (350 billion cubic feet) of natural gas to South Korea every year from 2017. It wants to build a gas pipeline across North Korea to transport this gas.
Talks are also under way between Russia and North Korea on the laying of power lines and railways.
"They will be of important economic significance and contribute to stabilising the situation in Northeast Asia and denuclearising the Korean Peninsula," the Russian leader said.
Experts say such projects could give North Korea tens of millions of dollars a year in handling charges. But they have yet to be approved by North Korea, despite its chronic need for hard currency..
The two Koreas are still technically at war, but opened their first regular cross-border train service in 2007. The line is presently suspended because of tensions, but the South's long-term plans include connecting the line to Russia and China.


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Investigators how to become a private Star Detective
India, Madhya Pradesh, Agar
Published 1 year ago
Seller did not upload any pictures
20000.00 Rs
Investigators how to become a private Star Detective
India, Madhya Pradesh, Agar,
Published 1 year ago
Detective Agency provides services related to post matrimonial issues, for example, when you feel that your spouse is having an extra marital relation with any one, It is imperative that you verify the facts and obtain as much as evidence are possible. In the long term this will provide you with peace of mind and will clear your doubts Also, if you were to falsely accuse your partner, it may result in an irretrievable breakdown in your relationship.We unearth the truth putting forth a much clearer picture enabling you to take the right decision. We are having our own team of Investigators for handling Post Matrimonial Investigations which means that once the case is assigned to us, we can assured you that you will get the exact picture and evidences as committed to you.
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U.S.: Survey Of Teens Finds No Change In Marijuana Usage Rates For Past 5 Years
The results of an annual survey of U.S. middle and high school students released Wednesday refute claims that reforming marijuana laws and debating legalization will lead to increased marijuana use among teens.
According to the Monitoring the Future Survey sponsored by the National Institute on Drug Abuse (NIDA):
· Rates of daily marijuana use by 8th-, 10th-, and 12th-graders, as well as monthly use by 12th-graders, did not change from 2014 to 2015 and have remained unchanged since 2010.
· The rate of monthly marijuana use by 8th-graders did not change in the past year, but has dropped significantly since 2010.
· The rate of monthly marijuana use by 10th-graders appears to have dropped significantly from 2014 (and 2010) to 2015.
The survey also found a decline in the number of teens who perceive "great risk" in marijuana use, negating the theory that softening perceptions of harm will result in more teens using marijuana.
"Many young people recognize that marijuana is less harmful than alcohol and other drugs," said Mason Tvert, director of communications for the Marijuana Policy Project (MPP). "But they also understand that it is not okay for them to use it.
"For decades, teens had an artificially high perception of risk that stemmed from exaggerations and scare tactics," Tvert said. "Now that there is more information out there and it's not limited to horror stories and propaganda, they are developing a more realistic view.
"The goal of marijuana education should not be to increase teens' perception of risk," Tvert said. "It should be to increase teens' understanding of marijuana.
"A lot of marijuana laws have changed over the past five years, but rates of teen marijuana use have not," Tvert said. "It's becoming harder and harder for our opponents to make the case that rolling back prohibition will lead to increased use by teens.
"The evidence simply does not support the theory that reduced perceptions of risk result in more use among young people," Tvert said. "It's time to stop using teens as a shield to fend off sensible marijuana policy reform efforts."
Photo: Smoking Pagoda
Recent blog posts
- Maine: Prohibitionist Governor Vetoes Cannabis Regulation and Implementation Bill
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- Illinois: High School Newspaper Confiscated For Cannabis Content
- U.S.: Northern Michigan University Offering Cannabis Degree
- Georgia: Atlanta Decriminalizes Marijuana
- U.S.: Support The Marijuana Justice Act of 2017
- Canada: Quebec Sets Minimum Age for Cannabis Consumption at 18
- Georgia: Atlanta City Council Votes To Decriminalize Cannabis
- Lesotho: Kingdom Becomes First African Country to Legalize Cannabis
- U.S.: FBI Reports 653,249 Arrests for Cannabis in 2016


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According to most boxing bookmakers, Sergey Kovalez (26-0-1, 23 KO's) is a solid favorite to defeat Jean Pascal (29-2-1, 17 KO's) when they face off on March 14.
And I tend to agree with them.
In Kovalev, the light heavyweight division hasn't seen this type of frightening punching power in a champion since the great Bob Foster terrorized the division in the late 1960's and early 1970's. He has a long way to go before being in the conversation with Foster, as an all-time great, but his punching power is undeniable.
Just ask the great Bernard Hopkins.
Speaking of Hopkins, he plays a key role in this top-flight matchup between Kovalev and Pascal. He's a common opponent for both boxers.
Pascal drew in his first bout with the Executioner-a fight that most ringside observers (myself included) felt that Pascal had lost. In their rematch, he fought better but still came up short via a narrow points loss.
There is no shame to be had by Pascal in his two highly-competitive, yet unsuccessful attempts against the great Hopkins. But when you compare Pascal's struggles against him while looking at Kovalev's dominance against B-Hop, it does stand out.
But styles make fights. Pascal's awkward style will be like nothing that Kovalez has ever seen. And Kovalev's rare combination of height, reach and power will be unlike anything that Pascal has faced in the ring.
However, when it is all said and done, Kovalev's punching power and "smart" pressure will be too much for Pascal to overcome.
Look for Sergey Kovalev to be the first man to stop Jean Pascal-via a technical knockout, sometime after round eight.


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Is That Your Sister Dancing & Stripping as GoGo Girl ?
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if you want dancing women, here they are!
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Used Benro A-297OF Versatile Transformer Aluminium Tripod
This product is no longer available or has been replaced by a newer model.
Refurbished by manufacturer to original specifications
Refurbished by manufacturer. Item in fair condition and full working order, some of the nuts show signs of rust and has cosmetic marks but item works fine. More
Refurbished by manufacturer. Item in fair condition and full working order, some of the nuts show signs of rust and has cosmetic marks but item works fine.
The Benro A-297OF Versatile Transformer aluminium tripod offers a quick switch from vertical to horizontal centre column positions. The most flexible tripod in the Benro range, the A-297OF FlexPod can be used as an all round tripod, but really comes into its own when you need to get closer to the subject or shoot at awkward angles.Back to top
The Key Features
Adjustable Leg Angles
For an extra measure of flexibility, Benro tripod legs can be independently locked into place at three different angles to enable shooting in cramped quarters, on irregular surface areas, or at ground level.
Column-Locking Setknobs
The angle and position of the adjustable centre-column can be locked into place with a single twist of the centre-column setknob.
Patented Dust & Water Resistant Rubber Lock Grips with Anti-Rotation Leg System
Benro's innovative rubberized locking grips combined with anti-rotation legs enable fast and fumble-free set-up plus weather and dust-resistance not found on other tripods.
Head Mounting Setscrews
Setscrews provide an extra level of security when attaching the head to the tripod's top-plate.
Stainless Steel Spike or Rubber Feet
Benro FlexPod tripods come equipped with a choice of screw-in rubber feet or stainless steel spiked feet.
Centre-Column Hook
A hook, located on the bottom of the centre-column, allows you to hang additional weight from the tripod's centre of gravity for increased stability.
Closed-Cell Foam Grip
A thick layer of closed-cell nitrile butadiene rubber (NBR) provides a comfortable yet firm grip when carrying your Benro tripod.
Shoulder Strap and Carry Case
Benro straps and carrying cases are made of quality, high-durability materials to provide maximum protection for your tripod and head.
Product Specification
|Primary Material
|Weight (g)
|Horizontal centre column
|Leg sections
|Max height
|Max Load
|Min height
|With Head


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Metformin is the first choice drug for the treatment of patients with diabetes, but its use is debated in patients with advanced cardiorenal disease. Epidemiological data suggest that metformin may reduce cardiac events, in patients both with and without heart failure. Experimental evidence suggests that metformin reduces cardiac ischemia-reperfusion injury. It is unknown whether metformin improves cardiac function (remodeling) in a long-term post-MI remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats that were subjected to either myocardial infarction (MI) or sham operation. Animals were randomly allocated to treatment with normal water or metformin-containing water (250 mg·kg−1·day−1). At baseline, 6 wk, and 12 wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) were performed. Echocardiography and hemodynamic parameters were assessed 12 wk after MI. In the MI model, infarct size was significantly smaller after 12-wk metformin treatment (29.6 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P < 0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs. 48.6 ± 5.6%, P < 0.05) compared with MI control. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P < 0.05). Insulin resistance did not occur during cardiac remodeling (as indicated by normal OGTT) and fasting glucose levels and the pattern of the OGTT were not affected by metformin. Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. Altogether our results indicate that metformin may have potential to attenuate heart failure development after myocardial infarction, in the absence of diabetes and independent of systemic glucose levels.
- myocardial infarction
- remodeling
- left ventricular function
- diabetes
the prevalence of patients with diabetes and heart failure (HF) is growing exponentially. Compared with HF patients without diabetes, diabetic HF patients have a poor prognosis and quality of life (5, 22). Moreover, diabetes is an established risk factor for incident episodes of HF (34). According to the HF guidelines metformin should be considered as a first-line agent in overweight HF patients with Type 2 diabetes without significant renal dysfunction (10). This recommendation is based on clinical studies showing that metformin seems the only antidiabetic agent without a harmful cardiac effect in diabetic HF patients (11).
Metformin decreases blood glucose by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose, and decreasing hepatic glucose output while lowering plasma insulin concentrations (17, 33). The cardioprotective effects of metformin can, however, not be attributed to the glucose-lowering effects alone (12). Recent experimental studies suggested ancillary potential mechanisms. More specifically, the protective effects may be conferred via the AMP-activated protein kinase (AMPK) pathway (3, 12, 27, 29, 31, 38), which is activated by metformin. Especially, in ischemia-reperfusion (I/R) models, metformin was shown to decrease the cardiomyocyte apoptosis (16, 29), to improve endothelial function by increasing NO production (12, 29, 39), to maintain myocardial energy production during ischemia (13), and to affect lipid metabolism (15, 32, 37). Clinical studies show that metformin may reduce plasma dipeptidyl peptidase-4 activity and increase circulating levels of glucagon-like peptide 1 (GLP-1), which is an incretin hormone that has protective effects on the heart and the vasculature (4, 23, 28). Experimental studies employing a pressure-overload model in mice and a pacing model in dogs showed that metformin attenuates cardiac fibrosis by inhibiting collagen synthesis (29, 38).
These experimental studies strongly suggest that metformin reduces I/R injury. However, little evidence is available to support the use of metformin in chronic cardiac remodeling, e.g., after myocardial infarction (MI) and in HF.
To further investigate the role of metformin in HF we conducted a long-term study to determine the effects of metformin on cardiac function and metabolic parameters in a post-MI rat model.
Design of the study.
Sprague-Dawley rats (weight 250–260 g, Harlan) were randomly allocated to left coronary artery ligation (MI) or sham surgery. The sham procedure was identical to the MI group except that the ligation was not tied (6). Two days before surgery, rats were fed metformin-containing water (250 mg·kg−1·day−1) or normal water, and this was continued for a period of 12 wk, rendering four experimental groups: sham (n = 7), sham+metformin (n = 7), MI (n = 8), and MI+metformin (n = 9). The animals were further fed ad libitum with a standard rat diet and housed in groups of four to five rats under a 12:12-h light-dark cycle. All animals received standard care, and the experimental protocol was reviewed and approved by the local Animal Ethical Committee of the University Medical Centre Groningen.
At baseline, week 6, and week 12, an oral glucose tolerance test (OGTT) was performed. At week 12, cardiac function was determined by echocardiography. After 12 wk the rats were euthanized after measurement of invasive hemodynamic parameters, and the hearts were rapidly excised, weighed, and prepared for histochemistry and molecular analysis.
Oral glucose tolerance test.
An OGTT was performed in nonanesthetized rats. After 16-h fasting, glucose (2 g/kg as a 50% solution) was given orally to the animal. Blood was obtained from the tail to measure glucose levels at several time points: 0, 5, 15, 30, 60, and 120 min after the glucose administration. Glucose levels were measured with a blood glucose monitor (Accu-Check, Roche).
Echocardiographic measurement.
Echocardiographic measurements were performed by an individual blinded researcher to the treatment groups. Rats were anesthetized with 2.5% isoflurane in a gas mixture of N2O-O2. The M-mode and 2D echocardiography images were obtained with a high-resolution system (Vivid 7, GE, Healthcare, and Chalfont St Giles, UK), by use of a 10 MHz transducer. Diastolic and systolic measurements of left ventricle (LV) internal dimensions (LVIDd and LVIDs, respectively), as well as measurements of the thickness of the interventricular septum (IVSs, IVSd) and posterior wall (LVPWs, LVPWd) were recorded. LV fractional shortening (FS %) was calculated as FS = (LVIDd − LVIDs)/LVIDd × 100%. LV ejection fraction (EF %) was calculated by using the Teichholz method of estimated LV volumes (20).
Hemodynamic measurement.
Before euthanasia, rats were anesthetized and invasive hemodynamics were measured as described (7). Briefly, a microtip catheter with pressure transducer (2-Fr, Millar Instruments, Houston, TX) was inserted into the right carotid artery and advanced into the LV cavity. After 5 min stabilization, the heart rate, LV end-systolic (LVESP) and end-diastolic pressures (LVEDP), and developed LV pressure (dLVP = LVESP − LVEDP) were recorded. The parameters of the maximal rates of increase and decrease in developed LV pressures (dP/dtmax and dP/dtmin, respectively) were determined.
Procurement of heart tissue for infarct size, cardiomyocyte size, and interstitial fibrosis measurement.
After euthanasia, hearts were rapidly excised and arrested in diastole in 2 M ice-cold KCl. The right ventricle and atria were removed. The basal and apical parts of the LV were snap frozen in liquid nitrogen. A midpapillary slice of the LV was fixed in 4% paraformaldehyde overnight and paraffin embedded. The deparaffinized 3-μm sections were stained with picrosirius red/Fast green, as described (35). The infarct size was calculated as percentage of the scar length to the total LV circumference. The images were obtained with a Leica microscope and analyzed by using appropriate software (Image-pro plus, version 220.127.116.11).
Furthermore, sections were stained with a Gomori's silver staining to allow visualization of the cardiomyocytes membranes. We measured cell size from transversally cut cardiomyocytes in the border zone of the infarcted area using image analysis software (Zeiss KS400, Germany). Finally, we examined the collagen volume fraction in sections of the LV free wall, after excluding vessels. Tissue sections were stained with Masson's trichrome stain to evaluate the extent of interstitial fibrosis, modified from previously described methods (7). The area of stained tissue was calculated as a percentage of the total area within a field by using imagescope software.
Biomolecular assays.
Arterial blood was collected with EDTA-coated centrifuge tubes. After centrifugation at 3,000 rpm for 15 min at 4°C the plasma was divided into different tubes, snap frozen in liquid nitrogen, and stored for future additional analysis. Metformin was measured by HPLC in the Pharmacy laboratory of University Medical Centre Groningen. Insulin levels were measured at 12 wk after surgery by use an ELISA kit (rat/mouse insulin 96-well plate assay, Millipore). The plasma active GLP-1 and adiponectin levels were measured with the ELISA kits from Linco Research and Millipore. Myocardial glycogen content was measured by using the EnzyChrom Glycogen Assay Kit (BioAssay Systems, Hayward, CA) according to manufacturer's protocol.
Real-time PCR.
Total RNA from the border zone tissue of infarction was extracted with TRIzol reagent (Invitrogen, Carlsbad, CA) and RNA concentrations were measured with a nano-drop device. First-strand cDNA was prepared by using a random primer mix and thereafter used as a template for quantitative real-time reverse-transcriptase-PCR (25 ng/reaction). mRNA levels are expressed in relative units based on a standard curve obtained by a calibrator cDNA mixture. All measured mRNA expression levels were corrected for 36B4 reference gene expression. Primer sequences can be found in Table 1.
Western blot analysis.
Myocardial tissue samples (75 mg), taken from the area-at-risk portion of the LV, were homogenized in 1 ml RIPA buffer (50 mM Tris pH 8.0, 1% Nonidet P-40, 0.5% deoxycholate, 0.1% SDS, 150 mM NaCl) containing phosphatase inhibitor cocktail 1 (Sigma), protease inhibitor (Roche), and 1 mM PMSF. Protein concentrations were quantified with the DC protein assay (Bio-Rad Laboratories, Veenendaal, the Netherlands) with bovine albumin as a standard. Equal amounts of protein were loaded onto polyacrylamide-SDS gels and, after electrophoresis, proteins were transferred to a PVDF membrane. The membrane was blocked for 1 h with 5% nonfat milk in PBST and probed with primary antibodies overnight at 4°C. The following primary antibodies were used: phospho-AMPKα Thr172 (1:500, Cell Signaling Technology); AMPKα (1:1,000, Cell Signaling Technology); p-Akt Ser473 (1:1,000, Cell Signaling Technology); Akt (1:1,000, Cell Signaling Technology); phospho-eukaryotic elongation factor-2 (eEF2) Thr56 (1:1,000, Cell Signaling Technology); eEF2 (1:1,000, Cell Signaling Technology); phospho-p70S6K Thr389 (1:1,000, B&D Systems); p70S6K (1:1,000, B&D Systems); AMPK α1 and AMPK α2 (1:1,000, Cell Signaling Technology); GLUT4 (1:1,000, Cell Signaling Technology); cleaved caspase-3 (1:1,000, Cell Signaling Technology); GAPDH (1:20,000, Fitzgerald Industries International, Acton, MA). Immunoblots were next processed with secondary antibodies for 1 h at room temperature followed by enhanced chemiluminescence detection using an ECL+Plus chemiluminescence reagent kit (Amersham).
Statistical analysis.
All data are expressed as means ± SE. Differences among groups were tested by one-way analysis of variance with a two-sided Dunnett t-test as post hoc test, taking the MI group as a comparator. Comparison between groups sham and sham+metformin was tested by independent t-tests. P values <0.05 were considered statistically significant. SPSS (PASW, Chicago, IL) version 18.0 was used to perform all statistical analyses.
Effect of metformin on metabolic parameters.
To confirm that metformin was consumed by the rats and entered the blood stream, serum metformin levels were measured. In both treatment groups (sham+metformin and MI+metformin), the serum levels of the drug were ∼3 mg/l, whereas no metformin could be detected in nontreated groups (Fig. 1A, top). Because metformin is an oral antihyperglycemic agent that may lower the blood glucose levels, fasting glucose levels were determined and OGTTs were performed. No differences were found in the fasting glucose levels between the groups at baseline, weeks 6 and 12 after surgery (12-wk results shown in Fig. 1A, middle). Moreover, no differences could be identified in the OGTTs at these intervals (Fig. 1B), suggesting that glucose uptake from the plasma was not altered and that long term remodeling after MI did not generate insulin resistance in these rats. Blood plasma insulin levels were also determined and were significantly decreased in both metformin-treated groups compared with nontreated groups (Fig. 1A, bottom). Since glucose levels were unaltered, this suggests that metformin sensitized insulin responsiveness in metformin-treated animals. Myocardial glycogen content in both metformin-treated groups was significantly decreased compared with nontreated groups (Fig. 1C). We also observed a lower body weight gain in metformin-treated animals (both sham and MI) compared with the untreated animals (Fig. 1D). Food intake was analyzed, but no consistent differences were observed in time, and therefore this lower gain in weight did not appear to be linked to food intake (data not shown). Therefore, we decided to analyze additional plasma parameters controlling metabolism. In particular active GLP-1 and adiponectin plasma levels were determined by ELISA. No differences were, however, observed in these parameters among the groups (Table 2), suggesting that the differences in weight gain are generated at a different level.
Cardiac and hemodynamic parameters.
Infarct size was significantly smaller in the MI+metformin group compared with the MI control group (MI+metformin 29.6 ± 3.2% vs. MI control 38.0 ± 2.2%, P < 0.05) (Table 3 and Fig. 6B). As expected, MI caused significant reduction of blood pressure, LVESP, dP/dtmax and dP/dtmin, but no improvement was observed after a 12-wk treatment with metformin. However, it is of note that sham-operated metformin-treated animals also had significantly lower blood pressure and LV pressure, possibly related to decreased oral (water, food) intake. The LVEDP was increased in the MI group compared with the sham group and was slightly decreased in the MI+metformin group compared with the MI group (Table 3).
The presence of MI was accompanied by wall thinning of the anterior wall (Fig. 2, A and B) as determined by echocardiography. Treatment with metformin significantly attenuated this wall thinning. Furthermore, 12 wk after MI, severe LV dilatation was observed as shown by the increased LVIDd and LVIDs, and this resulted in lower FS and LVEF. Again, metformin significantly attenuated LV dilatation and partially prevented LV dysfunction (Fig. 1, C–F).
Cardiac gene expression.
To assess the molecular changes induced by long-term metformin treatment, we measured cardiac gene expression of atrial natriuretic protein (ANP), endothelial nitric oxide synthase (eNOS), procollagen, and collagen I by RT-PCR (Fig. 3). The ANP mRNA level was significantly increased after MI compared with sham (P < 0.05), but in metformin-treated MI animals this increase in ANP expression was significantly attenuated (Fig. 3A). The eNOS mRNA level was markedly decreased in the MI group compared with sham, and metformin partially prevented this sharp decrease in eNOS mRNA levels in MI animals (Fig. 3B). Similar positive metformin effects were found for procollagen and collagen I expression, which were significantly increased in the MI group compared with sham, and with a trend to a limited increase in the metformin-treated group (Fig. 3, C and D).
Cardiac protein expression.
To study the molecular effects of metformin treatment, the phosphorylation of AMPK, eEf2, and p70S6K were measured in the heart, as well as GLUT-4 protein levels (Fig. 4). Furthermore, the cleaved (active) form of the apoptotic protease caspase-3, AMPK isoforms α1 and α2, and phosphorylated Akt were measured (Fig. 5). Metformin treatment led to a significant increased phosphorylation of AMPK in both treatment groups (Fig. 4A), as well as an increased phosphorylation of eEF2 (Fig. 4B), whereas there was a nonsignificant difference found in the AMPK downstream protein p70S6K phosphorylation (Fig. 4C). GLUT4 expression is decreased in the MI group after 12 wk MI; metformin restored this (Fig. 4D). There were no differences of AMPK α1 and α2 expressions among all the groups (Fig. 5, A and B). No significant differences in Akt phosphorylation were observed among all groups (Fig. 5C). Total caspase-3 levels were equal in all groups, whereas cleaved activated caspase-3 was increased after MI, and this was partially reversed by metformin treatment (Fig. 5D).
LV hypertrophy and interstitial fibrosis.
The cross-sectional area of cardiomyocytes was increased in both MI groups compared with sham groups, and metformin treatment had no effect on the cardiomyocyte hypertrophy in the post-MI heart failure model (Fig. 6A). This contrasts with the ratios of LV weights corrected for body weights reported in Table 3, which probably is explained by differences in body weights rather than LV weight.
Post-MI heart failure is accompanied by increased fibrosis, which was nonsignificantly reduced by metformin (Fig. 6C).
Our study demonstrates that long-term metformin administration is associated with preserved cardiac function in a rat model of post-MI cardiac remodeling. The key findings are that long-term (12 wk) metformin treatment after MI significantly attenuated cardiac remodeling post-MI, evidenced by 1) reduced MI size; 2) improved LV geometry (measured by echocardiography); 3) less increase in molecular correlates of LV remodeling (among others, less ANP and collagen production); and 4) measures of improved glucose and cellular energy metabolism.
Until recently, metformin was contraindicated in HF, mainly because of concerns about lactic acidosis. However, epidemiological data suggest that metformin is safe and may even be the first choice antidiabetic drug in HF patients with diabetes. In a case-control study in patients with diabetes and HF (n = 1.633), metformin was associated with a reduced all cause-mortality (adjusted odds ratio 0.72; P = 0.003) (21). In diabetic patients with newly established HF (n = 1.305), metformin monotherapy was associated with a reduced 1-yr mortality compared with sulfonylurea treatment (25). In HF patients admitted to the hospital (n = 16.417), metformin use was associated with a lower 1-yr mortality compared with treatment with insulin or sulfonylurea (24.7 vs. 36.0%, P < 0.0001) (24). All-cause readmission and HF hospitalization were also less common in diabetic patients treated with metformin than in those not treated with an insulin-sensitizing drug. Although results from prospective randomized placebo-controlled clinical trials are lacking, these data strongly suggest that metformin use is associated with a better outcome in clinical HF in diabetic patients.
It has been shown that metformin exerts cardioprotective effects in various experimental setups, although mostly acute cardiac damage models. First, Solskov et al. (31) reported that metformin exerted a protective effect on the rat heart subjected to cardiac I/R injury in an in vitro Langendorff setup. This study indicated that, at least in vitro, metformin could exert protective effects when administered before a coronary occlusion was inflicted. Another acute study confirmed the cardioprotective effect of metformin in mice subjected to cardiac I/R model in vivo, also when administered during the reperfusion stage (2). This indicated that also in vivo, metformin exerts protective effects after MI, which was confirmed in another study with a longer follow-up, showing improved LV function and survival in mice subjected to I/R injury (12). Moreover, metformin was shown to attenuate cardiac fibrosis induced by pressure overload in a mouse model and inhibited collagen synthesis (38). Interestingly, in dogs in a model of rapid pacing metformin could also prevent progression of HF (29). The precise actions of metformin on the heart are still not fully elucidated, but a central role of activation of AMPK, which is a regulator of cellular energy formation, has been proposed (2, 12, 29, 38).
Our study is unique in that it used a model of chronic (instead of temporary) ligation of a coronary artery, which leads to large myocardial infarction and cardiac remodeling that resembles the human sequel of events. We herein show that chronic metformin treatment is associated with a decreased extent of myocardial damage, possibly due to both necrosis and apoptosis resulting in reduced MI size, which is associated with less remodeling over time. Metformin has been shown to inhibit apoptosis, as reported in a dog model of heart failure (29). We found that cleaved caspase-3 levels were increased post-MI, as reported before (8); however, the use of metformin only nonsignificantly reduced caspase-3 levels. Increased levels of the anti-apoptotic protein Akt are associated with suppression of AMPK phosphorylation, which can be restored by metformin (18). On the other hand, Sasaki et al. (29) showed that metformin treatment causes decreased Akt phosphorylation in failing hearts. In our study, the use of metformin was not associated with meaningful differences in phosphorylated levels of Akt. Therefore we conclude that the beneficial effects of metformin cannot, or can only marginally, be explained by differences in apoptosis. We furthermore confirm the inhibitory effect of metformin on fibrosis, evidenced in multiple experimental models, indicating that this is a general metformin-associated cardiac phenomenon and not only linked to pressure overload model and pacing mode (29, 38). In our study, we observed a decreased expression of collagens and reduced fibrosis.
In support of another study (12), the cardioprotective effects appeared to be independent of antihyperglycemic effects of metformin. In fact, fasting glucose levels and OGTTs were similar in all groups, despite lower insulin levels in the metformin-treated animals. This suggests an insulin sensitizing effect of metformin, resulting in insulin level reductions, lower myocardial glycogen content, and enhanced GLUT4 expression, while maintaining normal plasma glucose levels. These observations suggest an improved myocardial glucose uptake, but we did not measure this. Except for insulin, plasma levels of other metabolic hormones did not change, indicating that metformin did not generate major systemic changes. Nevertheless, weight gain in metformin-treated animals was reduced, and this could not be simply related to changed food uptake. Although, we cannot exclude that nutrient uptake in the intestine has changed, our observation that metformin activates AMPK might point more into the direction of increased cellular metabolism. As described, AMPK is an enzyme that is activated in response to changes in cellular energy metabolism, for instance in muscle contraction, in ischemia, or by pharmacological agents like metformin (26). In our study, metformin treatment led to an increased phosphorylation of AMPK, resulting in an increased phosphorylation of one of its downstream targets, eEF2. Moreover, activated AMPK has a fundamental role in glycogen synthesis and glucolysis (36), which is supported by our study showing that long-term metformin treatment causes a decreased glycogen content in the myocardium, an observation that is common to most antidiabetic drugs (19). All these effects suggest that metformin may restore the cellular energy flux by inhibition of processes that switch off the ATP-consuming pathways to protect the stressed heart (14).
We observed a strong insulin-lowering effect of chronic metformin treatment. It has become apparent that a strong association exists between hyperinsulinemia and incident heart failure. A recent paper provided proof that cardiac insulin signaling itself also exacerbates cardiac remodeling (30). Therefore, part of the beneficial effects that we report herein may be due to low insulin levels and signaling.
AMPK is activated during caloric restriction and stimulates cellular metabolic pathways to maintain energy supply. Interestingly, caloric restriction confers cardioprotective effects, and metformin-treated animals and long-term dietary restriction animals have similar gene expression patterns (9). Together, these effects might suggest that the activation of certain AMPK downstream effectors in the heart, rather than changes in cellular metabolism itself, confers cardioprotective effects.
Limitations of the study.
Sample size and thus power is limited. We started administration of metformin 2 days before MI, so we cannot separate early and late protective effects in this study. The dose of metformin used in this study was comparable to that in other studies in rodents and humans (200–350 mg·kg−1·day−1) (1, 39). We established this dose did not cause side-effects like hypoglycemia and renal dysfunction (data not shown). Since metformin affects various targets, including AMPK and many downstream targets, the study design does not allow to prove causality between the molecular targets and functional outcome.
In summary, our study demonstrated that metformin exerts a protective effect on cardiac remodeling in nondiabetic rats with post-MI heart failure. We postulate that AMPK and low insulin levels are important mediators in the protective effects. These findings underscore the potential beneficial effects of metformin in HF and provide further evidence that metformin should be prospectively tested for its safety and efficacy in HF, e.g., in a post-MI trial. We recently launched such a trial (Metformin to Reduce Heart Failure After Myocardial Infarction; NCT01217307).
This research was supported by the Netherlands Heart Foundation (grant 2007T046) and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VENI, grant 016.106.117), both to Dr. de Boer.
No conflicts of interest, financial or otherwise, are declared by the author(s).
- Copyright © 2011 the American Physiological Society


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Traveling Luck for Marys Chapel, North Carolina, United States
Where is Marys Chapel?What's around Marys Chapel?
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The timezone in Marys Chapel is America/Iqaluit
Sunrise at 07:59 and Sunset at 18:02. It's light
Latitude. 36.0719°, Longitude. -78.5936°
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Geographic features & Photographs around Marys Chapel, in North Carolina, United States
- church;
- a building for public Christian worship.
- Rock Spring Church (1.5km)
- New Rock Spring Church (1.9km)
- Good Hope Baptist Church (5.2km)
- Brassfield Church (6.4km)
- Woodland Church (7.4km)
- New Light Church (8.3km)
- Mount Carmel Church (9.1km)
- Pleasant Grove Church (9.3km)
- Greenfield Church (9.5km)
- Woodland Church (10km)
- New Light Church (10.3km)
- Stony Hill Church (10.5km)
- Fellowship Church (11km)
- Mount Vernon Church (11km)
- Union Zion Church (11.3km)
- school;
- building(s) where instruction in one or more branches of knowledge takes place.
- Brassfield School (historical) (3.8km)
- Reedy Branch School (historical) (5km)
- Bragg School (historical) (6.6km)
- Maple Springs School (historical) (7.3km)
- Sunrise School (historical) (8km)
- New Light School (historical) (8.1km)
- Kinches School (historical) (8.5km)
- Greenfield School (historical) (9.5km)
- Hawley School (10.2km)
- Wilton Elementary School (10.4km)
- Union School (historical) (11.3km)
- Local Feature;
- A Nearby feature worthy of being marked on a map..
- Marys Chapel (0km)
- Medlins Store (historical) (5.1km)
- Wesley Chapel (6.6km)
- Freewill Church (historical) (7.3km)
- Cedar Grove Church (historical) (8km)
- Kinches Chapel (8.5km)
- Popes Chapel (9.9km)
- Poke Chapel (10km)
- Camp Kanata (10.4km)
- stream;
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- West Prong New Light Creek (3.5km)
- Mill Creek (4.4km)
- Reedy Branch (5.8km)
- Buckhorn Creek (6.8km)
- Robertson Creek (8km)
- Smith Creek (8.7km)
- Little Beaverdam Creek (10.5km)
- Cedar Creek (10.6km)
- New Light Creek (10.9km)
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- Wilton (9.9km)
- Popes Crossroads (11km)
Accommodation around Marys Chapel
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- Camp Kanata Lake Number Two Dam (10.8km)
- Masons Pond Dam (11.1km)
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- Lake Hughes (7.8km)
- Camp Kanata Lake Number One (10.7km)
- Camp Kanata Lake Number Two (10.8km)
- Masons Pond (11.1km)
- administrative division;
- an administrative division of a country, undifferentiated as to administrative level.
- New Light, Township of (8km)
- Brassfield, Township of (9.1km)
Wikipedia entries close to
Marys Chapel
- Creedmoor, North Carolina city city o
- Youngsville, North Carolina city city o
- Wake Forest, North Carolina city city o
- Franklinton, North Carolina city city o
- Butner, North Carolina city city o
- Stem, North Carolina city city o
- Rolesville, North Carolina city city o
- Gorman, North Carolina city city o
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- Oxford, North Carolina city city o
- Louisburg, North Carolina city city o
- Flughafen Raleigh/Durham airport airport
- Raleigh (North Carolina) city city d
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- Durham (North Carolina)
Airports close to Marys Chapel
Raleigh durham international(RDU), Raleigh-durham, Usa (34.7km)
Goldsboro wayne muni(GWW), Gotha ost, Germany (111km)
Seymour johnson afb(GSB), Goldsboro, Usa (124.8km)
Pope afb(POB), Fayetteville, Usa (134.3km)
Smith reynolds(INT), Winston-salem, Usa (183.5km)


text:
We caught up with Ms Cosmo during our monthly #UnderdogDay show at Cantare's Phat Thursdays where the September winner Chealex Mpanza was performing that night. She explains very passionately what the underdog feature is all about. It's all about putting new talent on and giving someone an opportunity to grow their brand that much more.
Now, I've been getting questions about how it works exactly. Simple things:
- Submit your music to email@example.com cc email@example.com and firstname.lastname@example.com
- In that email, make sure you have the soundcloud link to your joint, an artwork attached, your twitter handles and all information about the song and artist (a mini bio if you will).
The selection and voting process:
- We'll inform you once your song has been selected to feature and also if it hasn't. We give you feedback on what to improve if your song needs work.
- Since there are 5 songs in a day, we post each one every hour. Don't panic if your song is not up yet.
- There is a poll on each post, vote for your favourite and ALSO "like" the post on Facebook. The Facebook likes are very important too.
- You have until Monday to keep voting, the winner for each week will be announced on the Tuesday, the same day that the new underdogs for that week are announced.
Performing at Cantare:
- After 4 weeks of the weekly voting process, an overall winner from the weekly winners is chosen to perform at the Underdog show at one of Cantare's Phat Thursdays (Details are communicated with the winner).
- In addition to that, your song will feature on Ms Cosmo's "New Heat" during The Stir Up on 5FM.
And that is how it all works!