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There are definitely times when friends and neighbors need a little comfort food. It might be a joyful event--new baby, new house--or it might be in sorrowful times such as a long illness, death, or divorce. Chef Sara Quessenberry and writer Suzanne Schlosberg's The Good Neighbor Cookbook is an excellent source for the family cook who needs some fresh ideas for food to share.
Recipes range from savory (Smoky Corn Chowder) to sweet (Roasted Almond Chocolate Chip Cookies). They are designed to satisfy, to travel well, and to not require a lot of fussing in the kitchen. Although these recipes work great for times of crisis, these same qualities make them great for book club gatherings, church potlucks, or business breakfasts.
Here's a quick look at four cookbooks that offer very different takes on making the most of your food budget and your schedule. From true Brit to vegan to down home Southern, you're likely to find that one of these books for cooks matches your palate and your wallet.
I'm a fan of the Moosewood Collective and own a lot of their cookbooks. Last year, I was given another entry to their line, Cooking for Health. I was pleased to see their fresh and easy philosophy of the 1970s had been updated for modern tastes. Never heard of Moosewood? Not everyone has, yet they were named one of 13 most influential restaurants of the 20th century by Bon Appétit magazine, and our own Sammy T's seems to have drawn on them for vegetarian inspiration.
I love the rich, warm flavors of Mexican food, but trying to create anything more than a simple, kid-pleasing taco or Sundays at Moosewood's tortilla casserole (a family favorite) has left me uncertain as to how to begin.
I liked this book so much I put it on my Amazon.com wish list. (Use Amazon's "Look Inside" feature for a peek at the book.)
It's always a challenge to come up with new and interesting recipes that are quick, easy, and healthy. So Easy: Luscious, Healthy Recipes for Every Meal of the Week by Ellie Krieger is a great resource for fast, nutritious meals, and I can see myself going back again and again to try new recipes or make a favorite. In this clip, featuring some of the recipes from her book, Ellie explains how a pantry stocked with some of her favorite basic ingredients can make a healthy, delicious, quick meal "so easy."
I'm familiar with Ellie Krieger through her "The Good Life" column which appears in each issue of Fine Cooking. I've never seen her Food Network show called "Healthy Appetite," but I'm sure it's good. I love that Ellie embraces the "lusciousness" of food and the enjoyment of eating foremost while gracefully incorporating a nutritonal approach to cooking.


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ArkivMusic Recommendation
Neere: Duparc, Hahn, Chausson / Gens, Manoff
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She is exceptional in this repertoire. Most of the songs are about erotic anticipation and tristesse, and her dark, slightly smoky tone adds to the sensuality of it all. Hahns Néère leaves you open-mouthed with its beauty.

subset: commoncrawl


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Colour in the home: A look at blue
This is the 1st entry in a series that looks at how different colours can be used in the home. Your Christmas might not have been blue, but you can expect to see that colour come in with your New Year. Home decor experts are embracing the calming nature of blue. In fact, you may have already noticed it popping up in designer holiday décor vignettes.
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You could play a part in the creation of A&E's much-anticipated "Psycho" prequel series "Bates Motel," thanks to a contest involving the show's fifteen-second opening title sequence.
The contest begins today on Facebook and continues through Jan. 3, 2013. "Bates Motel" fans can submit their "pitch" as a fifteen-second video submission. Executive producer Carlton Cuse ("Lost") will evaluate the submissions and choose the idea that "best represents the mood, tone, and overall feel of the series."
Whether or not the winning submission ultimately becomes the title sequence for "Bates Motel," the winner will receive a $2,500 prize.
"We want to give fans the chance to participate in the show," Cuse says in a statement. "We're looking for an awesome fifteen-second title sequence that captures the feel of 'Bates Motel' — not as a slasher/horror show, but as a complex, character-based thriller."
The series — premiering in March — stars Freddie Highmore as young Norman Bates and Oscar-nominee Vera Farmiga as his mother, Norma, and follows the pair as they take over ownership of the infamous Bates Motel.


text: Notes from the TED conference, and my conversation with the world's most maniacal polymath, Bill Gates, in which we discuss the economy, his charitable giving, and what happens if he doesn't get enough sleep. READ MORE CNBC's Clueless Mark Haines Calls Me "Clueless" on Morning Joe: I Respond Only people like Mark Haines, their vision limited by Wall Street blinders, don't see the lunacy of allowing stockholders to reap rewards at taxpayers' expense. READ MORE Stimulus Package: If You Jump Halfway Across a Chasm You Fall Into the Abyss If we are going to spend two trillion dollars (and most likely more) trying to deal with the economic crisis, shouldn't we do it right? READ MORE Watch: Arianna On MSNBC, Discussing Obama Admitting His Mistakes: "A Teachable Moment"


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Liu Bolin's photographs
The chameleonic artist that gets camouflage-painted in the environment
From October 21st to November 14th the Fondazione Forma per la Fotografia hosts Hiding in Italy, the personal of the young Chinese artist Liu Bolin, that has already debuted in Italy in 2008 with the exhibition Hide and Seek, at the Boxart Gallery in Verona.
The exhibition contains twenty pieces of the series Hiding in the City, made in his home country and in the rest of the world, between 2006 and 2010, other than unedited pieces that have as a subject Italy.
Born in 1973, Lui Bolin began his career four years ago when he lost his house - in Suojiacun - when Beijin was being redeveloped to hold the Olympics. Since then, as a sign of protest, he has decided to paint and camouflage himself with the surrounding environment.
And the sensitivity to investigate on universal themes, like the relationship between man and nature, thought and power, and the taking of a really creative executing technique - that combines photography, painting and body art - are the keys of Bolin's success. And so he merges with a brick wall, Olympic slogans, theater seats and squares, to report and shout the transparent condition of the most weak.
Once the Milan exhibition is over, the artist's work will once again stop at Verona, at the Boxart Gallery, where they will be exposed for another three weeks, for the 16th of November to December 4th, 2010.
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Successfully Utilizing Military Recruiting Firms in Your Job Search
Recently, Janet Farley updated her book, "Military-to-Civilian Career Transition Guide: The Essential Job Search Handbook for Service Members," for a second edition. As a part of that process, she interviewed Craig Griffin, SVP Operations, Bradley-Morris, Inc. (BMI), regarding what military job seekers should know about working with a military recruiting firm.
The Bradley-Morris, Inc. section is entitled "The Truth About Military Placement Firms" and appears on page 72. An excerpt from the original interview is below:
Janet: What are the benefits to using a military placement firm over conducting a self search?
Craig: There are 3 key benefits to working with a military placement firm: preparation, exposure, and guidance.
- A military placement / recruiting firm should be able to fully prepare you for all aspects of the job search including:
- Professional resume preparation
- Resources to educate you on the different types of jobs available in Corporate America and the ability to match your skill set to the type of jobs that are a fit for you.
- Thorough coaching for the entire interview process
- Military placement firms have deep relationships with companies from all over the world. They are actively marketing the skills of military-experienced talent – your skills – to companies every day. The reputable firms are viewed as solution providers for clients who have the need and desire to acquire military talent.
- The top firms should function as a personal advocate for you. Candidates should not feel as if they are being left to reside in a database wondering if a real person has ever even seen their resume after submitting it through a web portal.
- The sheer volume of opportunities that a leading military placement firm can expose a job seeker to will most likely dwarf what they could produce with only their own efforts. For example, BMI represents over 4,000 clients, and we have our finger on the pulse of their most current position needs, some that are not even being advertised to the public.
- You should expect guidance through the entire process to help you accomplish the ultimate (and only) goal in the job search process: Finding the job that YOU want. Accepting an offer for a job you are not really excited about is a surefire way to ensure you'll be repeating the whole job search process earlier than you would wish. Any agency worth its salt will work until both parties are sure they've found a good fit.
Janet: What should a job seeker understand about the working relationship between him or herself and the placement firm? (i.e. expectations on either side)
- First, ensure you choose a qualified firm that meets the following criteria:
- Track record of success: The firm should have multiple years in business, thousands of successful placements, and testimonials from candidates like you.
- Free: You should not have to pay anything for the job seeker service except potentially to travel to a hiring event or interview.
- No "handcuff" agreements: You should be free to pursue your job search however you choose, including working with more than one military recruiting firm, as well as supplementing this activity with leveraging your personal network.
- You should only expect the agency representing you in your job search to be as committed to the goal as you are. The job search is intense, and requires a firm commitment from the job seeker to be responsive, whether it's in the writing and revising of a resume or in the timely communication with both agency and client corporations. If you're not ready to commit the time necessary to complete the requirements and obligations of your job search, don't start.
- Finally, understand the dynamic between the recruiting firm and their employer clients.
- While the firm is motivated to place a candidate with the employer (the firm typically only gets paid when a successful match is made), don't think that a reputable firm is looking to just put any warm body into a job. If the firm has any hope of winning repeat business, maintaining high client satisfaction and of advancing long-term client relationships, it is not in their interest to make bad matches.
- Your salary is not being reduced in order for the employer to pay the recruiting firm. Understand that employers have different budgets for recruiting and for salaries.
- The recruiting budget: Employers use this budget to attract job seekers through employment advertising and job boards, to pay for employee referral programs, and to pay recruiting firms.
- The employee compensation budget: This includes salary, bonuses and benefits. Your salary is commensurate with others in your position, with your experience and in your city. Employees' compensation is not determined by how they were sourced, no matter if they applied on the company Web site, had their resume on a job board, or if they were found via a civilian or military recruiting firm.
Janet: What about the concept of "handcuff" / exclusionary / exclusive agreements? Is it a good idea for a job seeker to agree to only work with one placement company at a time? Why or why not?
- As I mentioned previously, a handcuff or exclusive relationship with a military recruiting firm should be avoided at all costs. A handcuff agreement never benefits the job seeker. The only benefactor to an exclusive relationship is a placement agency that is not confident in either the number of opportunities they can present to you and / or the quality of opportunities that they can show you.
- You want to give yourself as many options as possible. Applying for jobs with only one company or working with only one transition resource at the exclusion of others is not in your best interests. Take advantage of all of the free services that are available (military placement firms, military job boards, military job fairs, TAP/ACAP, etc) that you have time to invest in.
Janet: Is there anything someone transitioning from the military can or should do, prior to contacting a military placement firm to enhance their chances for a successful placement?
- I'm often questioned by military professionals who are several years out from their separation date about what 'the best thing they can do to prepare themselves' might be as they finish out their military commitment. I've found the best answer is simply this: Perform to your absolute highest level in your current job. Companies in Corporate America are always impressed by a history of excellent performance. And whether through your military evaluations or the references that you provide to prospective employers, that performance will follow you throughout your entire career.
- Don't be afraid to contact military firms far in advance of your transition (even if you haven't positively decided to transition out yet). We recommend at least two years in advance for JMOs / SMOs and six months in advance for NCOs / Enlisted. Reputable firms will record your proposed transition date and if they have opportunities that match your background, will check back in with you to confirm your availability date and begin scheduling you for interviews.


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While we're muddling through the gray depths of winter, our friend Amie Valpone at The Healthy Apple has an idea we just love: a sunshiny smoothie that gives us a tickle from our taste buds to our tummies.
And if you're monitoring your diet for specific ingredients (or even if you're not), this smoothie has you covered: it's dairy-free, gluten-free and vegan, too!
Not to mention delicious.
What more could you ask for?
Oh, the recipe. Here you go. Enjoy!
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Yesterday the internet was alive with discussion about the fact the IeSF had chosen to exclude females from ESports competition specifically for Hearthstone. I was proud to see the discussion come alive and many sites write articles calling for removal of any gender discrimination in competition.
ESports is different in that physical strength is not a factor in competition. There is no real "need" for separating out gender in competition. Today IeSF has responded swiftly by recognizing their mistake publicly. In a statement sent to GamingAngels.com, IeSF General Manager Alex Lim, recognized that the gender separation was part of an old policy that did need to be updated. The organization did not think that they could get female gamers to compete in Hearthstone. Yes, it's an old way of thinking, but it is definitely promising that the organization acted swiftly and responded. Plus I think it's great that Alex actually sent us a statement versus ignoring the issue.
They released this public statement where they have created an Open competition so that genders can compete. Again, it's a start in the right direction.
Here is the statement from Alex:
"My name is Alex Lim, currently in charge of international affairs at IeSF.
For the official stance and decision about this issue as answering to the opinions of gaming communities, please see attached official press release.
To answer your additional question about the rationale of our initial policy to separate the gender division, I hope the following may answer your question:
It could be mistaken in selecting the actual measure to promote women in e-sports, but please note that we tried for good. IeSF did not mean any sexism or gender discrimination, but originally tried to make the scene good for females.
It is important to note the rationale for IeSF's efforts to join the international sports society, and why IeSF initial created a gender division policy. From the very beginning of its establishment, IeSF had noticed that the life cycle of the preferred games and the gamers who are playing competitively is quite short. With this in mind, the structure of a sports society, which is able to support the athletes to live their life related to the sports or even out of the sports, is vital for the long term success of the players. By providing opportunities to continue school through scholarship IeSF can insure the athlete's life, even after their retirement from the competition scene, will continue to be successful. For those reasons IeSF has been putting so much efforts to join the international sports society, or to convince international sports authorities to add e-sports in their multi sports events such as 4th Asian Indoor Martial Arts Games hosted by Olympic Council of Asia.
To achieve this goal, IeSF has been preparing to apply for Sport Accord membership. While applying IeSF found out that it is one of the requirements to have active women promotion to join. Applying such women promotion project to the structure of its event, IeSF approached this matter by following traditional sports. From the tradition sports scene, men were dominating, and international sports society decided to install women division to increase the involvement of women in more easy and efficient way.
Of course in traditional sports there has been the physiological difference between genders that make it necessary to separate the genders in sports. However, it was hard to apply to e-Sports since there has not been any evidence that can be applied to e-Sports. Though some says there is no physiological factor which may affect the performance of men and women, there are others who believe that dynamic visual acuity and precise control may differ by the gender, which may affect the performance.
It is the third year testing women promotion events, and we truly believe that has grown the women player pool in competitive events. We have been testing Starcraft II and Tekken for Female Event for past 2 years. That is why we set those games as the games for women this year, and for other titles such as Hearthstone is the one that we even try for male division for the first time. So, we could not be sure if we could have the female player pool for such game title. IeSF hopes that both men and women will continue to enjoy and compete in e-Sports and e-Sports can be a unique sport that men and women can both compete at an equal level.
IeSF also want to apologize to anyone that got offended by the initial announcement. As we strive to do the best we can to promote e-Sports as a true sports beyond any barriers,
mistakes might happen along the way, but it is our duty as a community of e-Sports fans and enthusiasts to learn from those mistakes and to make sure they remain in the past."


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Aschauerhof Hotel Kitzbuhel
Dorf 33 - Kitzbuhel, Kitzbuhel 6365, Austria
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[hotel-description]The hotel Aschauerhof is located in the landscape area Spertental in the ski and hiking paradise Kitzbühler Alps. The hotel facilities and services include: reception, elevator, lounge with bar, dining room, sauna, steam room, solarium (extra charge), outdoor swimming pool, children's pool, playground and lawn. The rooms are equipped with: shower/WC, TV, telephone and balcony or terrace. Address: Dorf 33, 6365 Aschau in Kirchberg, Tyrol, Austria[/hotel-description]
Dorf 33 - Kitzbuhel Kitzbuhel 6365, Austria


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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This review is from: Acer TimelineU M5-481TG-6814 14" Ultrabook
Pros: High quality, such a solid feel its incredible. Everything from the tactile feel of the keyboard clicking all the way to the solid feeling case. Absolutely no screen wobble, you raise the screen and it just stays right where you put it. The speed is impressive for such a lightweight portable device. Also everyone else is correct about the fan, I have been on this thing for 2 hours surfing the web and what not and I haven't even heard the fan kick on yet. Back lit keyboard is also very nice. I could keep going on about this note book but you really just got to see it to believe, I suggest you do. First impressions are usually the most important thing, and I'm blown away by this impression.
Cons: Only con I can think of isn't really Acer's fault. A lot of people were suggesting upgrading the RAM and I decided to follow suit. Let me tell you though this is not the easiest laptop to upgrade and you have to be EXTREMELY careful. First it doesn't have easy access ports you can remove like normal laptops. The whole back comes off as one piece. Second when removing the back I discovered half the computer is connect to the removable backplate by thin ribbon cables which you could easily tear just by pulling allittle. Being careful though this was a pretty easy upgrade and really I cant complain about how this thing was built. Excellent Quality.
Other Thoughts: I ordered this wednesday night, it shipped out thursday morning I got it friday. That was with normal shipping to NY state. I love Newegg, they are so fast and have great standards and practices. I know these things are circumstantial and are subject to change. But they have an excellent track record, I have used them for almost 10 years and I have never needed to complain, if something wasn't right they make it right no matter what. I've tried the competition and there is a reason why I still use Newegg.READ FULL REVIEW
This review is from: Panasonic SRG06FG Silver/White Automatic 3 Cups (Uncooked)/6 Cups (Cooked) Rice Cooker
Pros: Easy as can be. If you can follow basic instructions this product makes some awesome rice. Quality feels very solid. I bought this for my bachelor pad and it makes so much rice I usually have some left over for another day or two. I have even some of that instant rice like uncle ben's box rice. It still cooked it just as it should. Enjoy!
Cons: I can't think of anything.READ FULL REVIEW
This review is from: EVGA GeForce 8600 GTS DirectX 10 512-P2-N773-AR 512MB 128-Bit GDDR3 PCI Express x16 HDCP Ready SLI Support Video Card
Pros: Beautiful resolution, supported my 1080P HDTV and the software from NVidea has really nice features. Games like Rome: Total War ran at highest reso. highest detail and had no hang ups even in huge battles.
Cons: Make sure you have a plug and play monitor, I spent quite a bit on cords getting my hd hooked up to it, and ontop of that the DVI to HDMI adapter has compatibility issues.
Other Thoughts: It worked on and off with my HDTV but if you have a PnP monitor that you can use to hook up your hd it should work smoothly even if you are using DVI/HDMI converter. Happy playing.READ FULL REVIEW


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Nespresso En520.b Lattissima Coffee Machine By Delonghi, Blue
Save 10%. Was £230, Guide price: £210
Last updated on 2nd Dec 2012
Tags: gifts home coffee makers
Nespresso En520.b Lattissima Coffee Machine By Delonghi, Blue
Savour delicious coffee at home with the easy to use Nespresso EN520.B Latissima coffee maker by DeLonghi. Featuring a refreshing blue and black finish, the DeLonghi EN520.B Latissima was created especially for those who love coffee with fresh milk. And it couldn't be simpler to use: thanks to the patented 'Single Touch' milk carafe and frothing system, you get a real cappuccino or latte straight into your cup or glass.
This machine has a high 19 bar pressure and advanced thermoblock heating system, which is ready to use in approximately 40 seconds for a fast and delicious espresso. The DeLonghi EN520.B uses Nespresso capsules that are available in various blends. Illuminated keys and automatic controls make it easy for you to select the type of coffee you want. The EN520.B can also be personalised to remember the way you like your coffee, every time.
And for completely effortless maintenance, the removable milk carafe can be cleaned at the touch of a button and stored in the fridge when not in use. Delonghi patented 'Single Touch' milk carafe and frothing system offers beautiful coffee straight to your cup or glass 19 bar pump pressure and thermoblock heating for a faster coffee Automatic capsule ejection into collection tray (fits 11 capsules) for seamless use Adjustable drip tray allows you to use your favourite mug or glass for your drink Removable 1L water tank offers easy refilling
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Personal Coffee Maker
Enjoy a hot cup of coffee at home or on the go with the KitchenAid® Personal Coffee Maker. Choose your favorite coffee and brew the right amount just for you of bold, barista style coffee. The sleek, compact design is perfect for your countertop and brews directly into the included 18-ounce thermal mug or into any mug or cup of your choice. Simply add water to the removable tank, add your favorite coffee to the reusable gold-tone filter and press ON to begin brewing. No pods required.


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Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3adenosine receptor expression
- Avivit Ochaion1, 2,
- Sara Bar-Yehuda1,
- Shira Cohn1, 2,
- Luis Del Valle3,
- Georginia Perez-Liz3,
- Lea Madi1,
- Faina Barer1,
- Motti Farbstein1,
- Sari Fishman-Furman1,
- Tatiana Reitblat4,
- Alexander Reitblat4,
- Howard Amital5,
- Yair Levi5,
- Yair Molad6,
- Reuven Mader7,
- Moshe Tishler8,
- Pnina Langevitz9,
- Alexander Zabutti1 and
- Pnina Fishman1Email author
DOI: 10.1186/ar2078
© Ochaion et al; licensee BioMed Central Ltd. 2006
Received: 27 July 2006
Accepted: 13 November 2006
Published: 13 November 2006
Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A3 adenosine receptor (A3AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A3AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A3AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A3AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A3AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A2AAR and A3AR over-expression in paw cells from treated animals. Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A3AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A3AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA.
Low-dose methotrexate (MTX) is the most widely used antirheumatic drug and it is the 'gold standard' against which other systemic medications are compared [1]. It has as its target the enzyme dihydrofolate reductase, which is required for reduction of dihydrofolate to tetrahydrolate. It is presumed that cells exposed to MTX die as a result of reduced folate depletion [2]. Adenosine, an additional active metabolite of MTX, has been found to have potent anti-inflammatory effects, and earlier studies [3, 4] strongly support the notion that the anti-inflammatory effect of MTX is attributed more to adenosine than to tetrahydrolate. MTX increases the extracellular concentration of adenosine, where it is known to exert its anti-inflammatory effect via suppression of inflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin-6, or macrophage inhibitory protein-1α [5–7]. It was further found that the anti-inflammatory effect of adenosine is mediated via A2A and the A3 adenosine receptors [8, 9].
The highly selective A3 adenosine receptor (A3AR) agonist IB-MECA (1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-9-yl]-N-methyl-β-D-ribofura-nuronamide) had an anti-inflammatory effect in collagen-induced arthritis in DBA1 mice and adjuvant-induced arthritis (AIA) in rats [10, 11]. Interestingly, A3AR was found to be over-expressed in the synovial and paw inflammatory tissues as compared with corresponding tissues in normal, healthy animals. Moreover, receptor upregulation was also identified in the peripheral blood mononuclear cells (PBMCs) of AIA rats compared with control animals. Mechanistically, on treatment with IB-MECA, downregulation of A3AR expression level was noted in cells derived from the synovial tissue, most probably due to receptor internalization and degradation. Subsequently, decreased levels of expression of phosphatidylinositol-3 kinase and protein kinase B/Akt were observed. The latter of these proteins is known to control the nuclear factor-κB (NF-κB) signal transduction pathway. The decreased levels of PKB/Akt resulted in failure to phosphorylate IKK, which in turn resulted in inability to release NF-κB from its IκB complex. These events led to decreased expression of NF-κB and TNF-α, resulting in apoptosis of synovial cells. Remarkably, the PBMCs of AIA rats responded to IB-MECA treatment in the same manner as did the synovial cells, namely with receptor downregulation, suggesting that PBMCs reflect the receptor situation in inflammatory tissues and may have utility as a biomarker for monitoring response to IB-MECA [12]. Furthermore, Gessi and coworkers [13] recently noted upregulation of A3AR expression in phytohemagglutinin (PHA)-stimulated PBMCs from healthy individuals. It thus seems that A3AR expression correlates with cell activation or pathogenicity.
Recently, IB-MECA (commercially known as CF101) was tested in phase I clinical trials in healthy individuals. CF101, in single and multiple oral dose studies, was found to be safe and well tolerated, and the pharmacokinetics were linearly proportional to dose [14]. In an early phase II clinical trial of CF101 conducted in patients with rheumatoid arthritis (RA), the drug was well tolerated and conferred benefit as monotherapy [15].
Most biological disease-modifying antirheumatic drugs currently are given in combination with MTX [16]. Therefore, the aim of the present study was to evaluate the efficacy of combined MTX+CF101 treatment. We found that MTX treatment increased expression of A3AR, rendering inflammatory cells more susceptible to CF101. Combined treatment of AIA rats with MTX and CF101 enhanced the anti-inflammatory effect of each drug. In addition, we found A3AR to be over-expressed in PBMCs of MTX-treated patients and in activated cells from healthy individuals. The molecular mechanisms involved are explored.
Materials and methods
The A3AR agonist IB-MECA was synthesized for Can-Fite BioPharma Ltd (Petah-Tikva, Israel) by Albany Molecular Research Inc (Albany, NY, USA) and is referred to as CF101 in the following text. A stock solution of 10 mmol/l was prepared in DMSO and further dilutions were performed. RPMI, foetal bovine serum and antibiotics for cell cultures were obtained from Beit Haemek (Haifa, Israel). The A3AR antagonist MRS1523 was purchased from Sigma (St. Louis, MO, USA) and diluted in the same manner as for CF101. Rabbit polyclonal antibodies against rat and human A3AR as well as rat A2AAR were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). MTX, PHA, adenosine and adenosine deaminase (ADA) were purchased from ABIC (Beit Shemesh, Israel). Dipyridamole was purchased from Sigma.
Effect of CF101 and MTX on development of AIA
Female Lewis rats, aged 9 weeks, were obtained from Harlan Laboratories (Jerusalem, Israel). Rats were maintained on a standardized pellet diet and supplied with tap water. Experiments were performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee at Can-Fite BioPharma, Petach Tikva, Israel. The rats were injected subcutaneously at the tail base with 100 μl suspension composed of incomplete Freund's adjuvant with 10 mg/ml heat killed Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI, USA). Each group included 10 animals.
For the prophylactic treatment study, MTX treatment (0.25 mg/kg intraperitoneally) was administered once weekly, starting 3 days after disease induction. CF101 (100 μg/kg) was orally administered by gavage, twice daily, starting at disease onset. The study also included a group treated with a combination of MTX and CF101. The control group received vehicle only (DMSO at a dilution corresponding to that of CF101).
For the therapeutic treatment study, MTX (0.75 mg/kg intraperitoneally, once weekly) as well as CF101 (100 μg/kg orally, twice daily) were initiated on disease onset. As in the prophylactic study, a group treated with a combination of MTX and CF101 was included.
Clinical disease activity score was assessed as follows. The animals were inspected every day for clinical arthritis. The scoring system ranged from 0 to 4 of each limb: 0 indicates no arthritis, 1 indicates redness or swelling of one toe/finger joint, 2 indicates redness and swelling of more than one toe/finger joints, 3 indicates involvement of ankle and tarsal-metatarsal joints, and 4 indicates redness or swelling of the entire paw. The four individual leg scores were added together to yield a total clinical score.
At the end of the study the legs were removed up to the knees, fixed in 10% formaldehyde, decalcified, dehydrated, paraffin embedded and cut into 4 μm sections. They were then stained by haematoxylin and eosin, and morphopathological assessment was performed.
Pathological assessments were performed using semiquantitative grading scales from 0 to 4 for the following parameters: the extent of inflammatory cell infiltration into the joint tissues, synovial lining cell hyperplasia, pannus formation, joint cartilage layer destruction and bone damage and erosion: 0 indicates normal; 1 indicates minimal loss of cortical bone at a few sites; 2 indicates mild loss of cortical trabecular bone; 3 indicates moderate loss of bone at many sites; 4 indicates marked loss of bone at many sites; and 5 indicates marked loss of bone at many sites, with fragmenting and full thickness penetration of inflammatory process or pannus into the cortical bone. The means of all of the histological parameter scores were summated to yield an overall 'histology score'.
In addition, blood samples were collected and subjected to Ficoll hypaque gradient. The PBMCs were then washed with phosphate-buffered saline (PBS), and protein extracts were prepared as detailed below.
The hind paws were dissected above the ankle joint. The bony tissue was broken into pieces, snap frozen in liquid nitrogen and stored at -80°C until use. The paw tissues were added to RIPA extraction buffer (4 ml/g tissue) contaning 150 mmol/l NaCl, 50 mmol/l Tris, 1% NP40, 0.5% deoxycholate and 0.1% SDS. Tissues were homogenized on ice with a polytron, centrifuged and the supernatants were subjected to Western Blot analysis.
Effect of dipyridamole on the expression of A3AR in PBMCs from naïve rats
Dipyridamole (5 mg/kg intraperitoneally) was administered once to naïve rats and blood samples were drawn 2, 6, 24 and 48 hours after dipyridamole administration and subjected to Ficoll hypaque gradient. The PBMCs were then washed with PBS and protein extracts were prepared as detailed below.
Immunohistochemistry staining of paraffin-embedded slides of paws tissues derived from AIA rats
The paraffin on the slides was melted from the sections, which were placed in xylene three times for 30 min each. The tissues were hydrated with serial dilutions of ethanol and then antigen was retrieved by heating with citrate buffer at 95°C for 30 min. The slides were allowed to cool down and then washed three times in PBS. Endogenous peroxidase quenching was performed by washing the sections with fresh 20% hydrogen peroxide in methanol for 20 min. The sections were then blocked by incubating in 5% normal goat serum in PBS-BSA 0.1% for 2 hours.
The primary antibody (Novus Biologicals Inc., Littleton, CO, USA) was diluted in 0.1% PBS-BSA and incubated overnight at room temperature. After three washes in 1× PBS, the slides were incubated in 0.5% biotinilated secondary antibody in PBS-BSA 0.1% for 1 hour at room temperature and then subjected to an avidin-biotin complex After another wash the slides were incubated with DAB substrate, washed in tap water (to dispose of the DAB) and inactivated with bleach. A light haematoxylin counterstain was performed and the haematoxylin was then removed by quick dip in acid alcohol and the slides were washed in ammonia water, dehydrated and mounted with Permount.
Human blood sample collection and separation
Characteristic of patients newly and chronically treated with MTX
RA patients
Newly MTX treated
Chronically MTX treated
Age (years)
48.5 ± 5.89
59.58 ± 2.42
Disease duration (years)
4.37 ± 2.07
6.6 ± 0.97
CRP (mg/l)
10.75 ± 2.01
9.04 ± 1.65
ESR (mm/hour)
31.75 ± 0.63
33.3 ± 4.39
Swollen joint count
13.25 ± 2.56
3.19 ± 0.88
Tender joint count
10.5 ± 2.63
5 ± 0.86
Patient global assessment (VAS)
32.26 ± 4.41
3.23 ± 0.31
4.11 ± 0.3
To separate PBMCs, heparanized blood (20 ml) was subjected to Ficoll hypaque gradient. The PBMCs were then washed with PBS and subjected to the various assays.
Double immunofluorecence staining of PBMCs of RA patients
PBMCs (1 × 106 cells) were smeared on electrophorized glass slide and fixed with 75% ethanol for 2 min. The slides were then blocked with normal horse serum for 1 hour at room temperature in a humidified chamber, after which a mouse monoclonal CD4 (Santa Cruz Biotechnology; Clone MT310, 1:50 dilution) primary antibody was incubated overnight at room temperature. After rinsing thoroughly with PBS, a rhodamine-tagged secondary antibody (Vector Laboratories, Burlingame, CA, USA; 1:200 dilution) was incubated overnight in the dark. Then the slides were rinsed with PBS, blocked with normal goat serum and incubated with a rabbit polyclonal anti-A3AR antibody (Chemicon International, Temecula, CA, USA; AB9111, 1:100 dilution) overnight. Cells were rinsed with PBS and a second, fluorescein-tagged anti-rabbit antibody was incubated for 1 hour in the dark. Finally, slides were rinsed, coverslipped with an aquous based mounting media (Vectashield; Vector Laboratories) and visualized in a Nikon ultraviolet inverted microscope and processed with a deconvolution software (Slidebook 4.0; Intelligent Imaging, Denver, CO, USA).
Activation of PBMCs
PBMCs (2 × 106 cells/ml) from healthy individuals or from MTX-treated RA patients were incubated in cell cultures with RPMI 1640 supplemented with 10% FBS. PBMCs from healthy individuals were activated with PHA (5 μg/ml) for 24 hours. MTX (1 μmol/l) was added for an additional 27 hours. ADA (1 unit/ml), CF101 (10 nmol/l), or MRS1353 (10 nmol/l) was added to the culture system for the last 3 hours. In another set of experiments PBMCs from healthy individuals were incubated for 27 hours with adenosine (25 μmol/l), and ADA (1 unit/ml) was added to the culture system for the last 3 hours. PBMCs from MTX-treated RA patients were incubated for 1 hour with CF101 (10 nmol/l). At the end of the incubation time in all of the above experiments, the PBMCs were collected from the culture plates and protein extracts were prepared.
Western blot analysis of A3AR and additional signalling proteins in PBMCs
Western blot analyses were carried out according to the following protocol. Samples were rinsed with ice-cold PBS and transferred to ice-cold lysis buffer (TNN buffer: 50 mmol/l Tris buffer [pH 7.5], 150 mmol/l NaCl and NP40). Cell debris was removed by centrifugation for 10 min at 7500 g. Protein concentrations were determined using the BioRad protein assay dye reagent (BioRad Laboratories, Hercules, CA, USA). Equal amounts of the sample (50 μg) were separated by SDS-PAGE, using 12% polyacrylamide gels. The resolved proteins were then electroblotted onto nitrocellulose membranes (Schleicher & Schuell, Keene, NH, USA). Membranes were blocked with 1% BSA and incubated with the desired primary antibody (dilution 1:1000) for 24 hours at 4°C. Blots were then washed and incubated with a secondary antibody for 1 hour at room temperature. Bands were recorded using BCIP/NBT color development kit (Promega, Madison, WI, USA).
Analysis of A3AR protein expression level in patient PBMCs was performed as follows. Samples from each of four RA patients were run in the same gel with a pool of samples from four healthy individuals, designated the standard. The blots were quantified by densitometric analysis and the ratio of RA patient/standard was calculated. Blots of mitogen stimulated cells were quantified against β-actin. The data presented in the figures are representative of at least three different experiments.
RT-PCR analysis of formalin-fixed paraffin-embedded paw tissue slides
Tissue sections of paws derived from AIA rats treated with vehicle, MTX, CF101, or MTX+CF101 were mounted on slides and then deparaffinized in xylen and rehydrated by washing in serial dilutions of ethanol. Slides were used immediately or stored at -80°C until use. After rehydration, 20 μl of solution A (1.25× PCR buffer [200 mmol/l Tris-HCl, 500 mmol/l KCl], 6.25 mmol/l MgCl2, 5 U RNasin [Promega], 2 mmol/l DTT, 1 U RQ1 RNase-free DNase [Promega]) was directly applied to the marked area. The marked area was completely scraped off the slide using a pipette tip, and neoplastic tissue or normal tissue was collected into different microcentrifuge tubes. The samples were treated with proteinase K at a final concentration of 0.1 mg/ml. The samples were incubated at 37°C for 1 hour to allow for DNA digestion. Cells lysate were heated to 95°C for 15 min in order to inactivate DNase and proteinase K. Following centrifugation at 14,000 rpm for 5 min, 17 μl of the supernatant was transferred to a separate tube and 4 μl of RT mixure (5 mmol/l dNTPs, 2.5 μmol/l random hexamer, 5 U RNasin, 100 U SuperScript One Step RT-PCR with Platinum Taq (Invitrogene, San Diago, CA, USA) and the primers for rat A3AR (245 up CTA GCA CTG GCA GAC and 245 down CAG CAG AGG CCC AGG) were added.
The RT reaction was performed at 45°C for 45 min, followed by heating to 99°C for 5 min; then, 50 cycles at 94°C for 30 s, 50°C for 75 s and 73°C for 45 s, and an extension of 73°C for 7 min were performed. Products were electrophoresed on 2% agarose gels, stained with ethidium bromide and visualized with ultraviolet illumination. The specificity of the RT-PCR reaction was confirmed by size determination on agarose gels in comparison with a positive control, from RNA extracted using standard techniques, and by sequencing the RT-PCR product and comparing the sequences with the known sequences (ADORA3-L77729, L77730). The optical density of the bands (Et-Br) was quantified using an image analysis system. This analysis was performed on tissues from three different experiments.
Statistical analysis
To analyze differences in clinical score between the four study groups (CF101, MTX, MTX+CF101 [combined treatment] and control), we used analysis of variance (ANOVA) with repeated measures from days 8 to 25 for prophylactic treatment and from days 14 to 20 for therapeutic treatment. To test differences in trends during the study between the four study groups, we used ANOVA using Dunnet method to evaluate differences between each of the study groups and the control group: for prophylactic treatment this was from days 20 to 25, adjusted to baseline values (day 8); and for therapeutic treatment this was from days 14 to day 20, adjusted to baseline values at day 14. ANOVA using Dunnet method was utilized to evaluate differences between each of the study groups and the combined treatment group (CF101+MTX): for prophylactic treatment this was from days 20 to 25, adjusted to baseline values (day 8); and for therapeutic treatment this was from days 14 to 20, adjusted to baseline values at day 14. The data were analyzed using SAS software (SAS Institute, Cary, NC, USA).
The Student's t-test was used in the Westen blot analysis, and P < 0.05 was considered statistically significant.
Effect of MTX, CF101, and MTX+CF101 treatment on development of AIA in rats
In the therapeutic treatment study, in which all of the treatments were initiated at the onset of disease, clinical score in the MTX and CF101 combined treatment group was found to be statistically significantly lower than that in the control group. Moreover, clinical score in the group receiving combined treatment with MTX and CF101 was always lower than that the other groups. From day 17 the trend becomes statistically significant (Figure 1b).
Histological evaluation of the paws in the vehicle-treated arthritic animals revealed complete distruction of cartilage and bone, which were replaced by granulation tissue. Severe inflammation infiltration was also noted. In the MTX treated group bone destruction was also observed, with a few remnants of bone spicutels seated in the granulation tissue. The degree of inflammatory infiltration was less than that observed in the control group, resulting in a 47% decrease in histological score. CF101 treatment resulted in a 75% decrease in histological score, which was manifested as a mild inflammatory infiltration. The articular space, cartilage, bone and bone marrow appeared normal. Treatment with MTX in combination with CF101 was associated with normal cartilage and bone architecture, and with an histological score that was almost zero (Figure 1c,d).
Effect of MTX, CF101 and MTX+ CF101 treatment on exhibition and expression of A3AR in paw and PBMCs from AIA rats
We further examined the effect of MTX on expression of A3AR protein compared with A2AAR protein in paw extracts. Figure 3d shows that the expression levels of both receptors is increased with MTX treatment.
A3AR expression in PBMCs from RA patients
In addition, we performed double immunofluorecence staining on PBMCs from RA patients to identify A3AR on the cell surface of CD4+ T lymphocytes. Figure 5c shows massive A3AR staining on the CD4+ T cells.
In an additional set of experiments we looked at the in vitro effect of CF101 on A3AR protein level in PBMCs from MTX-treated RA patients. The cells were cultured in the presence and absence of CF101 for 1 hour. Figure 5d shows A3AR over-expression in the RA samples compared with control samples. CF101 treatment induced A3AR downregulation, reflecting the response of PBMCs to the drug; this suggests that receptor expression may have utility as a biological prediction marker.
Effect of MTX+CF101 on A3AR expression level in PHA-stimulated PBMCs from healthy individuals
Introduction of CF101 to MTX-treated, PHA-stimulated cells induced receptor downregulation, which was counteracted by the A3AR antagonist MRS1535 (Figure 6c).
The present study shows that combined treatment with CF101 and MTX has an additive anti-inflammatory effect, which is indicated by a decrease in the clinical and pathological manifestations of AIA. Mechanistically, MTX induced an increase in A3AR expression level in inflamed tissues and in PBMCs, thereby rendering the cells more susceptible to CF101 treatment. Interestingly, MTX given either in prophylactic or therapeutic mode in combination with CF101 resulted in the same additive effect.
To explore the mechanism underlying the efficacy of the combined treatment, we first examined the mode of action of MTX. It acts as an antagonist of folic acid, subsequently inhibiting the synthesis of purines and pyrimidines. It was further suggested that the anti-inflammatory effect of MTX is due to adenosine, which is known to exert potent anti-inflammatory effect [3, 4]. More specifically, MTX polyglutamates inhibit the activity of the enzyme aminoimidazolecarbox-amidoadenosineribonucleotide transformylase [17, 18]. This enzyme has a direct inhibitory effect on two additional enzymes: ADA, which metabolizes adenosine to inosine; and AMP deaminase, which converts adenosine to AMP. This chain of events results in intracellular accumulation of adenosine, which is then released into the extracellular environment [19]. The working hypothesis of the present study was that the increase in adenosine level may act via an autocrine pathway and induce the expression of its own receptors, in this case A3AR. Indeed, MTX treatment increased both mRNA and protein levels of A3AR in the inflammatory tissue (paw) of AIA rats, indicating that increased gene expression and translation took place. An increase in protein A3AR expression was also noted in the PBMCs from the animals. Interestingly, increased A2AAR protein levels were also noted in paw samples from MTX-treated animals. Ravid and coworkers [20] have shown that activation of A2AR increases A3AR promoter activity. It could therefore be suggested that over-expression of A2AAR plays a role in the increased level of A3AR that occurs with MTX treatment. Moreover, A3AR protein level was raised in RA patients treated with MTX. This was attributed to the increase in A3AR expression detected on CD4+ T cells from RA patients compared with CD4+ T cells from healthy individuals.
In this report we present two lines of experimental evidence that support a role for adenosine in modulating A3AR expression in response to MTX treatment. In vitro studies with PBMCs showed that MTX treatment induced an increase in A3AR expression that was reversed on treatment with ADA. Adenosine mimicked the effect of MTX and induced an elevation in A3AR expression. In vivo dipyridamole, an inhibitor of nucleoside transporters, known to increase adenosine levels, induced A3AR over-expression in PBMCs from treated rats. These data led to the conclusion that MTX, via the metabolite adenosine, induces elevation in A3AR expression.
Receptor density was previously reported as an important factor that controls cell response to a given agonist [21–23]. It may be suggested that A3AR upregulation, mediated by MTX, preconditions cells to the effect of CF101, resulting in a more potent anti-inflammatory effect.
An additional important finding of the study is that inflammatory cells and PBMCs from CF101-treated AIA rats, as well as the PBMCs cultured in vitro with CF101, responded to agonist treatment and to combined treatment with receptor downregulation. The A3AR antagonist MRS 1353 counteracted the downregulation induced by the combined treatment. This finding supports the notion presented above that the effect of CF101 alone or in combination with MTX is solely mediated via A3AR, without the involvement of additional receptors. Our earlier studies in tumor cells showed that, on binding of an agonist such as CF101 to tumor cells, receptor is internalized and degraded within the cytoplasm [24, 25]. This is followed by initiation of downstream signal transduction pathways, leading to inhibition of tumor growth. A few hours later receptor is resynthesized and recycled to the cell surface. Recently, we reported a similar chain of events in the synovial cells of AIA rats treated with CF101. A3AR receptor levels were downregulated on agonist treatment, followed by modulation of cell signaling proteins that belong to the NF-κB signal transduction pathway, resulting in decreased expression of TNF-α and inhibition of the inflammatory process [12]. It thus seems that if A3AR upregulation is characteristic of inflammation, then CF101 treatment induces receptor downregulation, which reflects receptor functionality, and modulation of key signaling proteins that control the inflammatory process. Interestingly, introduction of CF101 to in vitro culture of PBMCs derived from MTX-treated RA patients resulted in A3AR downregulation. The ability to assess in vitro the response to CF101 may be utilized in the future to predict the response of individual patients to the drug before treatment.
The mechanism presented in this study by which MTX elevates A3AR expression may also account for the anti-inflammatory effect of this drug when given as a standalone therapy. Under physiological conditions A3AR is not activated because adenosine has the lowest affinity value to this receptor (A2A > A1 > A2B > A3). On MTX treatment the adenosine level goes up, thereby activating A3AR and resulting in an anti-inflammatory effect [3, 4, 26].
High expression levels of A3AR in inflamed or activated cells were previously reported in other inflammatory conditions. A selective, approximately 10-fold upregulation of A3AR mRNA and protein was consistently found in nonpigmented ciliary epithelium of eyes of patients with pseudo-exfoliation syndrome, with and without glaucoma, as compared with normal and glaucomatous control eyes [27]. Blair and coworkers [28] showed that A3AR transcript abundance is greater in lung tissue and eosinophils from individuals with airway inflammation than in normal lung. A3AR elevation was also reflected in eosinophils derived from the peripheral blood of the same patients. Treatment of eosinophils with IB-MECA inhibited platelet-activating factor induced eosinophil chemotaxis [28]. Moreover, Gessi and coworkers [29] reported that A3AR is induced in activated PBMCs from healthy individuals, and further demonstrated that the CD4+ T cells are the subpopulation of cells that over-express the receptor. Taken together, it may be concluded that A3AR upregulation is a characteristic of activated cells, and is noted in cells of inflammatory origin and is reflected in PBMCs.
To summarize, enhanced anti-inflammatory effect takes place on treatment of AIA rats with the combination of MTX and CF101. This effect is mediated via adenosine, which accumulates in cells on MTX treatment, leading to increased levels of A3AR, thereby rendering the cells more sensitive to the effect of CF101. We recently reported a positive response of RA patients to CF101 treatment (as a standalone therapy) in a phase IIa study [15]. The results of the present study provide justification for a phase IIb study combining CF101 with MTX treatment in a population of RA patients.
Using an in vivo model of AIA in rats, we demonstrated that combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect. Mechanistically, we found that MTX induced an increase in the expression level of A3AR, rendering the inflammatory cells more susceptible to CF101 treatment. Adding further support to these findings were data from the MTX-treated RA patients, who exhibited A3AR over-expression in PBMCs.
= A3 adenosine receptor
= adenosine deaminase
= adjuvant-induced arthritis
= bovine serum albumin
= 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-9-yl]-N-methyl-β-d-ribofura-nuronamide
= methotrexate
- NF-κB:
= nuclear factor-κB
= peripheral blood mononuclear cell
= phosphate-buffered saline
= phytohemagglutinin
= rheumatoid arthritis
= reverse transcription polymerase chain reaction
= tumour necrosis factor.
Authors' Affiliations
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Being diagnosed with HIV during pregnancy increases the risk of domestic violence postpartum among women with no history of abuse in their relationship. A few weeks ago during my work as a specialist doctor in infectious diseases at a hospital … more
Why is HIV-related stigma still rife in Uganda?
More than three decades since the first case of HIV was diagnosed in Uganda, it is inexcusable that stigma and discrimination towards people living with HIV still rear their ugly heads among us. In one way or another, many Ugandans … more


text:
b.o.c Acacia Flat Sandal
Sorry, this item is sold out!
Looks like you've got more shoe shopping to do - have fun!
Looks like you've got more shoe shopping to do - have fun!
Item # 235332
You will live in this adorable flat sandal all season long! The Acacia thong sandals from b.o.c are feminine and look great on everyone!
- Leather upper
- Heel strap with adjustable buckle
- Flower detail
- Comfort cushioned footbed
- Flexible rubber sole
- Imported
- View more b.o.c
By: topshorty
Location: Detroit, Michigan
November 17, 2012
So Soft
"This shoe was so soft and comfy for walking. I was really surprised how comfortable this shoe was going to be. I normally have to change from flats to a high heel after a while but I was able to wear them all day without my feet or legs hurting."
By: LauVic
Location: New Jersey
October 27, 2012
"Bought for my mom whom has problems with her feet & ankles often, but the cushioning in this sandal made it comfortable. The only con is that the strap around the back is short. It is on the loosest hole, yet her foot doesn't even hang over the back, so it's not like the sandal is too small for her."
By: 2dieforshoes
Location: buford dr.
October 04, 2012
Love these!!!!!!
"I love these sandals, they are so comfy. Just what I wanted. I am very satisfied."
By: Mmmily
Location: San Antonio, TX
September 20, 2012
Great sandal
"I bought these in champagne & I love them. They have extra padding in the sole which adds to the comfort. No problems with fit. And considering they made my best girl friend drool, I would definitely recommend them."
Click anywhere to close this.


text:
California - In Stock
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A few products do not qualify for free shipping and are designated with "Does Not Ship Free" in the product detail. Those products are charged actual shipping charges. View Details
If you are unsatisfied with any item for any reason you can return the product within 60 days and we will refund your purchase price on that item, excluding shipping charges. View Details
For the fast delivery we ship from CA and PA warehouses! You will see exact arrival dates at checkout. View Details
Phil created this recipe in an effort to stop his long, slow spiral into fruity, phenolic, sour beers that began to populate his fermenters and kegs back in 1998. Honestly, Phil seriously contemplated throwing gummy bears into his brew and realized it was time to step back, look around, sober up, and grab a classic West Coast pale ale.
This beer is dominated by the wonderful Amarillo hop that is known for having a citrus/orange flavor. The Left Coast Pale has been brewed many times over as a house favorite during the Fermentation Frenzy shop era (Los Altos, CA circa 1997-2007). Try it, you'll like it. And, unfortunately, so will your friends.
Phil recommends for an even more pronounced hop nose and flavor you add an additional 1oz of Amarillo to the fermenter as a dry hop addition (not included with kit).
Target OG -- 1.050-1.055
Est. SRM -- 11-14
Est. IBU's -- 50-55
Est. ABV % -- 5-5.5
Yeast Recommended: WLP001 California Ale
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|Beer Style
|Pale Ale & IPA
|Ready to Drink Within
|2-4 Weeks
|Alcohol Content
|Medium (5-7%)
|High (46-70ibu)
|Fermentation Temp Range
|Brewing Method


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Fenwick Island DE Real Estate & Homes For Sale
54 Properties Found
The median home value in Fenwick Island, DE is $510,000. This is higher than the county median home value of $225,400. The national median home value is $177,414. The average price of homes sold in Fenwick Island, DE is $510,000. Approximately 22.37% of Fenwick Island homes are owned, compared to 1.07% rented, while 76.57% are vacant. Fenwick Island real estate listings include condos, townhomes, and single family homes for sale. Commercial properties are also available. If you see a property you're interested in, contact a Fenwick Island real estate agent to arrange a tour today! Learn more about Fenwick Island Real Estate.
1 - 25 of 54 Properties Displayed
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$1,899,999 10 E Essex Street Fenwick Island, DE 19944
$2,290,000 1706 Bunting Avenue Fenwick Island, DE 19944
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text:
136 Colonial Drive,Loveland OH, 45140
Sold Price
3 beds , 2 Full baths
2,822 sq. ft
Status: Sold
Berkshire Hathaway HomeServices Professional Realty
(800) 599-8936
Last Updated: 2/20/2017 5:17 AM
Description for 136 Colonial Drive Loveland, OH 45140
Move right in! One floor living in this gorgeous ranch. 5 years new custom finishes, hardwood floors, exquisite custom kitchen. Open great room with built-ins. Private, wooded setting. Blank slate for future basement design, features 9' foundation.
Listing Information
Public Water Service
Public Sewer
Natural Gas, Cable TV
School Information
Room Information
Floor - Wood, Walk-In Closet
Floor - Wood
Floor - Wood, Formal
Floor - Wood, Eat-In Kitchen, Gourmet Kitchen, Butler Pantry, Island, Walkout
Shower Only, Tub Only, Dual Sinks, Floor - Marble
Interior Features
Range-Oven, Dishwasher, Refrigerator, Microwave
Central Air, Ceiling Fan(s)
Gas Heat
Full, Unfinished Basement, Walkout, Concrete
Insulated, Vinyl Frame
1, Gas Burning, Fireplace
Crown Molding, Cathedral/vaulted Ceiling, French Doors, Recessed Lights
Exterior / Lot Features
3 Garage Spaces, Attached Garage, Driveway
Brick, Stone
Less than .5 Acre
Cul-De-Sac, Wooded
Financial Considerations
Inside AccessTM
Current market conditions for 136 Colonial Drive
Active Market Trends
Source:MLS DATA
Median list price$399,000
Days on market90
Properties for sale25
Sold Market Trends
Source:MLS DATA
Median sold price$154,000
Sales to list price9,752.0%
Properties sold46
Median sq ft price$91
Arrows indicate 90 day trend
Listing Price History for 136 Colonial Drive
Loveland Real Estate
Loveland is located in Ohio. Loveland, Ohio 45140 has a population of 12,171.
The median household income in Loveland, Ohio 45140 is $73,854. The median household income for the surrounding county is $49,104 compared to the national median of $53,046. The median age of people living in Loveland 45140 is 38.5 years.
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text:
A TRAVELERS RESTCosta RicaPuntarenasUvita
About this listing
High Quality Low cost Lodging.Walking Distance to
Rivers and Waterfalls, Mountains and Jungles
Beaches, the Bus Stop, Supermarket and Restaurants, Banks.
Free:Beach shuttle, Coffee, WiFi, Public Kitchen,Smiles!
Bar, Laundry Service
The space
The Tucan Hotel is located in Uvita, Costa Rica, just 100 meters from the Coastal Highway. Getting here by bus, or car is very easy. We have secured parking on premise. You can walk to the grocery store, banks, restaurants as well as the mountains, rivers, beaches, and waterfalls.
Our hotel common area is cozy and comfortable enough to just stay here all day! A large roof means that the you are comfortable in the rainy season!
Our famous full service helps you see and do everything in the area with the best tour companies and at the best prices. We also help you explore the area on your own for free!
Guest access
Free Coffee, Computer, WI-FI, Pool Table, Games, Public kitchen, bicycles.
Surf Board and Snorkel gear Rental!
Library full of books, music, and movies!
Interaction with guests
We are a full service Alberque!
We can arrange your tours, transportation, dinner reservations and more!
The neighborhood
Uvita, Costa Rica - Where the mountains meet the Sea!
Let help you have an inexpensive vacation in Costa Rica with plenty of outdoor activities. We are walking distance to Mountains, Jungles, Rivers, Waterfalls, Ocean, and beaches!
Getting around
The bus stops just 100 meters from the Tucan Hotel. Plenty of taxis. Free beach shuttle from the hotel. But, you can walk to everything!
29 Reviews
Your Host
Tucan Hotel
An oasis in Uvita, Costa Rica - where the Mountains meet the Sea ! We are walking distance to mountains, rivers, and waterfalls - the ocean, beaches, and mangroves. Let us help you have a High Quality, Low Cost Costa Rica Vacation with plenty of outdoor activities!


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More Videos...
1932 Ford Victoria Street Rod of the Year 2012 "Miss Vicky"
A Bobby Alloway built 1932 Ford Victoria.. This car was voted 2012 Street Rod of the year...a very cool Street Rod...Give Miss Vicky a look!!
33 Ford 3 Window Street Rod
A 1933 Ford 3 Window Street Rod..the coolest thing???...It has a 700 HP 427 Ford in it...this car was a Feature Car at Cruising The Coast 2012 and was on the event shirts......check it out!!!
1940 Ford Street Rod
A 1940 Ford Street Rod that Griffey's Hot Rods and Restorations built for the Brother of a famous NASCAR engine builder..Check out the video to find out which one...
1932 Ford 5 Window Coupe Street Rod
This 1932 Ford 5 Window is over at Alloway's Hot Rod Shop having a few things changed and freshened up...While it was there I thought you all would like to check it out...Alloway built it so you know it a very cool quality Car...but what really caught my eye was the 302 Boss up under the hood...this thing is way BAD!!!...check it out!!


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arrow on target
After a game of mini golf, Luis and I went to The Nemacolin Field Club for some archery lessons. Our teacher used to compete. He was a really good teacher -- he didn't pressure us too much. We concentrated on consistency and getting a feel for it. He gave Luis a compound bow, while I got just a plain one. I had a really great time! I'd like to take it up some time.
Unfortunately, Luis didn't manage to hit the target. But I took this picture that made it look like he did. He really was just a quarter of an inch off.
3,365 views
1 fave
4 comments
Taken on October 10, 2010


text: In 2016, the Southern University Games will return to Melbourne for the first time since 2009. Footscray, located in the western suburbs of Melbourne, will host the event for the first time, coinciding with the 100 year celebration of Victoria University. Major event partners, Victoria University and Maribyrnong City Council are ready to welcome over 2,000 university students from 13 universities this July. For an overview of the venues in use at Games time, check out the virtual venue tour.


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Curses And Hexes in Chandler, Arizona
In light and in love, enter! My name is Phelan, I am a white witch and root worker located in Atlanta, GA. I have clients from all over the world and have worked with them in Chandler, Arizona or Greensboro, NC, magic knows no boundaries for it to bring magical change to your life; magic is energy capable of reaching anybody, anywhere; therefore, where you live in conjunction with me is unimportant, but if you live in Atlanta we can arrange a meeting for a consultation or a psychic reading. Simply create an account to contact me online or call me at 678-918-3333, I can also assist you with psychic phone readings in person or by phone to increase your awareness about the condition of your life.
Besides being a white witch, I am also a gifted psychic. I am clairvoyant, clairsentient and clairaudient, I often combine my psychic gifts with my magical workings in order to tune into my client and to lend greater insight to the issues that they are dealing with, it is my belief that we are all magical beings. I offer psychic readings in person if you are in the Atlanta area or by phone if you are located elsewhere.
Hidden secrets and truths untold are often revealed to me about a client through the art of candle gazing, a candle reading is a valid esoteric art used by the few practitioners who understand its value, get a candle reading today and experience the art of true divination.
If you are in need of magical help, sign up for a user account, you can also call me at my Atlanta number (678-918-3333) Mon-Fri from 1-9 pm EST.
Blessed Be, Phelan
Curses And Hexes | Black-magic | Chandler, Arizona


text:
More Videos...
Ultimate Velocity 800 BHP EVO Launching!!!!
800 BHP Evo ripping down the road, listen to that Exhaust!!!
Mercedes Benz E63 AMG vs Mitsubishi Lancer Evo 6 TME
The AMG has tuned ECU and the Evo VI Tommi Makinen Edition has 2.0 forged engine, gt35r @1.7 bar, about 550 BHP El AMG tiene chip y el Evo VI Tommi Makinen Edition tiene motor 2.0 forjado, email@example.com bar y cerca de 550 BHP. Hope you like it Rate and comment THANKS FOR WATCHING! On Facebook: http://www.facebook.com/pages/Cars-Tuning/190413530994478
Honda Integra Type-R vs Mitsubishi Lancer Evo vs Subaru Impreza STi GC8
- Honda Integra Type-R DC2 with b20vtec engine 240hp - Mitsubishi Lancer Evolution ~300hp - Subaru Impreza STi GC8 300+ hp - Cameraman - Mitsubishi Colt with 4G63 Evo 9 Engine
1000HP Audi RS6 DTM - REDLINE Revs + Accelerations!
This video features the famous 1000HP Audi RS6 Avant DTM equipped with a very loud catless Milltek Exhaust system. As we all know, Jon Olsson has driven this RS6 in the 2015 Gumball 3000 rally (Stockholm to Vegas). After the rally he has sold this car to dealer in The Netherlands. The video features some brutal redline revs, accelerations and more! Update: The famous Audi RS6 DTM was found burned down this morning after it was stolen during an armed robbery last night! R.I.P. Liked the video? Click the 'like' button, comment, and subscribe! Follow me: Subscribe: http://www.YouTube.com/GUMBAL FACEBOOK: http://www.fb.com/GUMBALTV INSTAGRAM: http://www.instagram.com/GUMBALTV TWITTER: http://Twitter.com/GUMBALTV http://www.gumbal.tv


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Changes related to "Iberia Parish, Louisiana"
This is a list of changes made recently to pages linked from a specified page (or to members of a specified category). Pages on your watchlist are bold.
16 February 2017
|m 16:49
|Iberia Parish, Louisiana Genealogy (diff | hist) . . (+41) . . Denisepoulsen (talk | contribs) (Formatted breadcrumb)


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text:
SailNet Community (http://www.sailnet.com/forums/)
- Tartan (http://www.sailnet.com/forums/tartan/)
- - Need pics of windlass installations (http://www.sailnet.com/forums/tartan/103044-need-pics-windlass-installations.html)
Need pics of windlass installations
I'm pulling the trigger on a maxwell rc10-8 next month.
I'd like to see pics of peoples installations. Wiring, switches, placement, etc. to get an idea of what I'll do.
Thnaks in advance,
s/v 'no name yet' :-)
77 T37 c/b
Re: Need pics of windlass installations
1 Attachment(s)
Here's my install. On the left side bottom is an up foot switch. I also have sn up/down switch at the pedestal.
On the right, under the cushions is the breaker.
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Dr. Barber earned her medical degree from the Medical University of South Carolina (MUSC) College of Medicine in Charleston where she was inducted into the MUSC Gold Humanism Honor Society. Following medical school, she completed her Residency training at the Florida State University Pediatric Residency Program in Pensacola where she was named Outstanding First-Year Resident. She has been involved in several community volunteer activities, including a medical missions trip to Venezuela, a project to prevent obesity in Charleston, South Carolina, and organizations such as the Leukemia & Lymphoma Society. She is also a member of the Escambia County Medical Society.Read more
For the best healthcare for your needs, choose a doctor who specializes in your medical condition.
Check to see that this provider treats your medical condition.
Check to see that this provider performs the procedure that you need.
Check to see if your provider has any malpractices, board actions, or sanctions.
Learn more about where this provider went to medical school, residency, and more.
Check to see what languages this provider and/or staff speak.
View memberships and affiliations associated with this provider.
Likelihood of recommending Dr. Barber to family and friends is 5 out of 5
Pediatrics Specialist
Pediatrics Specialist


text: We're sorry, Personalised 2015 Diary Butterfly On Vintage Linen is no longer available Why not try one of these instead? Personalised Social Calendar by Rosie Robins £27$46.33€32.35$34.59 free UK delivery Leather Five Year Diary by Oh So Cherished £29.99$51.46€35.94$38.42 free UK delivery Leather Five Year Diary With Lock by Oh So Cherished £32.99$56.61€39.53$42.27 free UK delivery Modern Black Leather Five Year Diary by Oh So Cherished £34.99$60.04€41.93$44.83 free UK delivery Pinch to zoom Personalised 2015 Diary Butterfly On Vintage Linen by polkadots & blooms £27$46.33€32.35$34.59 14 customer reviews(14) This item is no longer available free gift wrap Favourite Favourite View your favourites personalisation (required) formatformat (required)2015 week to view diary2015 day a page diary (+ £2.50)format (required)2015 week to view diary2015 day a page diary (+ $4.29)format (required)2015 week to view diary2015 day a page diary (+ €2.99)format (required)2015 week to view diary2015 day a page diary (+ $3.20) we're sorry we're sorry, This item is no longer available buy a gift voucher related categories weddings > living & decorating > stationery > diaries & journals trends > diaries & calendars home > 2015 calendars & diaries by polkadots & blooms Location: London, GB read seller's profile see seller's complete range more items from this seller Personalised Travel Notebook Floral And St... by polkadots & blooms £22$37.75€26.36$28.19 Personalised Embroidered Notebook Butterfly by polkadots & blooms £21$36.04€25.16$26.90 Personalised Glasses Case Butterfly by polkadots & blooms £19.50$33.46€23.37$24.98 Personalised Embroidered Notebook Flower by polkadots & blooms £21.50$36.89€25.76$27.55 Personalised Glasses Case Pheasant by polkadots & blooms £20.50$35.18€24.56$26.26 Personalised Coffee Cosy - Lavender Vintag... by polkadots & blooms £38$65.21€45.54$48.69 view all you may also like PRODUCT DETAILS CUSTOMER REVIEWS DELIVERY RETURNS Made in Britain can be personalised free gift wrap eco-friendly save for later With a lovely new colour scheme for this holiday period the personalised diary helps to keep track of events and activities in 2015. This personalised diary is a wonderful present for that special women in your life - mum, grandmother or partner. The diary is made from genuine vintage linen, appliqued with a butterfly and embroidered free hand machine embroidered with your choice of name or message.The cover can be removed from the casebound diary and reused in years to come. Handmade in the UK. The diary is made from genuine vintage linen, appliqued with a choice of designs and embroidered (free hand machine embroidered or hand embroidered with your choice of name or message. The cover can be removed from the casebound diary and reused in years to come. Each notebook is unique and no two books are exactly the same. Fabrics may vary from those shown in the illustration, they will be similar but not always identical. All our notebooks are handmade in the UK. The 2015 (January - December) diary is made of FSC paper and comes either in a 'day to a page' or 'week to view' format. I am very happy to gift wrap your diary for free. Please specify gift wrapping option and message, if required, upon checkout. made from: 100% vintage linen, 100% organic cotton lining, liberty fabric and fairly traded raw silk, fsc hardbound diary dimensions: The diary comes in a A5 format. Gift notification card: If you would like to purchase a gift from polkadots & blooms, but it is too late to make the personalised gift in time for the special occasion, you can give a personalised gift card instead.The gift card will let your family or friends know that your gift from polkadots & blooms is being made and will be with them shortly (estimated delivery date will be advised on the card). Posted within 2 working days after receipt of payment We can send the gift card either to yourself, or directly to the gift recipient. Please specify the delivery address upon checkout if different from the billing address. We will gift wrap the card for you and add a message on the gift tag if required (please specify on checkout) product code: 201298 14 customer reviews see more customer reviews read about our product rating system ratings guide trusted independent customer feedbackforum excellent bad good poor This product is dispatched to you by polkadots & blooms. You have 28 days, from receipt of cancellable goods, to notify the seller if you wish to cancel your order or exchange an item. Please note: goods that are personalised, bespoke or made-to-order to your specific requirements, perishable products and personal items sold with a hygiene seal (cosmetics, underwear) in instances where the seal is broken are non-refundable, unless faulty. Read more about our returns policy.Should you choose to return or exchange your order you will need to deliver the item(s) to the UK, where this seller is based. polkadots & blooms's return policy Please see notonthehighstreet.com's returns policy.


text:
Chevrolet Bel Air for Sale
Selected Filters:Type of Ad: Vehicles for Sale Make: Chevrolet Model: Bel Air Remove All
1955 Chevrolet Bel Air
Houston, TX
1955 Chevrolet Bel Air Restomod. Chevrolet 350 with Borla 8 Stack Induction System. Automatic, Air conditioning. All the modern conveniences and reliability with... More
1957 Chevrolet Bel Air 2dr Sedan
Staunton, IL
2dr Sedan, St Rod, lots of upgrades, SBC V8, 4spd, power disc brakes, drilled and slotted rotors, brand new tubular control arms, urethane bushings,... More
1965 Chevrolet Bel Air 4dr
Staunton, IL
4dr, good body, newer paint, orig int, 6cyl, auto, rally wheels, runs/drives good... More
American Made Restoration Sheetmetal for Classic Chevys. Find Out Why it Matters.
1966 Chevrolet Bel Air
Staunton, IL
1966 chevy belair 4dr sedan, good candidate for restoration, rally wheels, v8, auto, runs and drives good... More
1963 Chevrolet Bel Air 4dr Sedan
Staunton, IL
Nice orig car, good body and paint, good orig int, 69,xxx act mi, 230 6cyl, auto, runs good... More
1962 Chevrolet Bel Air
Staunton, IL
4dr Sedan Hot Rod, custom paint, nice redone int, mag wheels, V8, auto, runs/drives good... More
1956 Chevrolet Bel Air Sedan
Staunton, IL
4dr Sedan, nice body and paint, nice redone interior, V8, 3spd, good deluxe bumpers, runs/drives good. ... More
1955 Chevrolet Bel Air 2 Door
Mundelein, IL
Check out this 1955 Chevrolet Bel AirRebuilt 327 with 2 fours and double hump heads bored 30 over with flat top pistons Mild cam... More
Advertiser since 2013
$130,000 (est.)
1957 Chevrolet Bel Air Convertible
Fernandina Beach, FL
1957 Chevrolet Belair 2-dr Convertible Designer: Clare Mackichan Estimate: $100,000 - $130,000 Chassis Number: VC57B132527 Decoded: V=V8 engine; C=Belair Series; 57=1957; B=Baltimore MD< assembly, 132527=Serial Engine: 283... More
1957 Chevrolet Bel Air Sport Coupe
Bridgeport, CT
Redline Restorations Sales is proud to offer this stunning example of a 1957 Chevrolet Bel Air Sport Coupe. A perfect restoration was applied to... More
$30,000 (est.)
1955 Chevrolet Bel Air
Fernandina Beach, FL
1955 Chevrolet Belair 4-dr Sedan Designer: Clare Mackichan Estimate: $20,000 - $30,000 Without Reserve Chassis Number: C55A048996 Decoded: C=Belair Series; 55=1955;... More
1957 Chevrolet Bel Air
Lakeland, FL
283 V-8, automatic. Power top, seat belts front and rear, floor mats, dual exhaust. Fender skirts, dual mirrors, padded dash. stainless trunk trim, factory... More
1957 Chevrolet Bel Air
Chatsworth, CA
This 2 door hardtop 1957 Chevrolet Belair was a frame off restoration on a very clean and straight and solid car. The... More
1958 Chevrolet Bel Air
Concord, NC
A beautiful two-tone exterior and nicely coordinated custom interior give the impression of a great cruising classic. But when you lift the hood... More
Advertiser since 2008
1962 Chevrolet Bel Air 2 Door Sedan
St. Louis, MO
1962 Chevrolet Bel Air Hardtop Coupe Extremely clean and original that has under gone a nut & bolt restoration Beautiful Autumn Gold Metallic exterior and Fawn... More


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Member Since: 07.17.2016
My name is Rick Shuttleton. I am primarily a Single-family investor based out of the Phoenix, AZ area. I am looking to connect with Investment properties. Make sure to Friend me and Like my Connected Investors profile.
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Your results within of Medicine Hat, AB
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stump removal medicine hat ab
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Lot 559: BLACK DIAMOND MINK BRAND DARK BROWN FUR COAT.
Fashion Auction
by Sloans & Kenyon
October 20, 2016
Chevy Chase, MD, USALive Auction
Past Lot
Looking for the realized and estimated price?
Description: BLACK DIAMOND MINK BRAND DARK BROWN FUR COAT.
Condition Report:
Fur has some damage
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