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The Gruffalo
Please log in or register to add this to your basket.
Click on a performance date and time below to check price and availability.
Family Theatre
All ages
A&G Theatre on the Square, Sandton
Age Restriction:
Directed by: Tara Notcutt
This West End smash hit combines songs, laughter and storytelling theatre with a wonderfully catchy score and original music and lyrics. The South African production will feature all the characters, songs and storyline from the original, with a uniquely local charm, energy and charisma. The picture book The Gruffalo, written by Julia Donaldson and illustrated by Axel Scheffler in 1999, is a worldwide phenomenon, having sold over 13 million copies in 75 editions worldwide. The stage production brings the Gruffalo characters to life while remaining true to the story.
Booking and ticketing info:
PAPPAS special: A 'Pappas' ticket includes a children's meal at Pappa's Restaurant (meal, sides & a milkshake) valued at R80, and a discounted ticket to the show. Book your ticket and call the restaurant to reserve your table before or after the show. Note that this special can only redeemed by people under 12 – accompanying adults pay full price and order off the regular menu. See the full children's menu here
– Note that the concession price listed is for children under 16 and pensioners over 65.
– There is no reserved seating for this performance.
– A group booking of 10 or more full price tickets to a performance qualifies for a discount, which is applied automatically on check-out.
– 2-for-1 Tuesdays – purchase two tickets to any Tuesday performance and only pay for one! This discount will be applied at the check-out stage and is valid for any number of tickets as long as it is a multiple of two.
Giving someone the gift of Gruffalo? Excellent idea – buy your tickets and then download this card to give them on their special day…..


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Enjoy 1-year online access to Family Foundations magazine. Note: This is an online subscription only.
The Couple to Couple League International, Inc.
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subset: commoncrawl


text:
8 Hotels in Tayang gefunden
Resultat 1-8
Qionghai, Aihua East Road, Qionghai.
Qionghai, Yinhai Road
Qionghai, Middle Section of Yinhai Road
Qionghai, 9 Binhai Avenue Boao Town
Qionghai, No. 188 Shanji Road, Jiaji Town,
Qionghai, 39 Renmin Road, Qionghai. 0
Qionghai, Entrance of Yinhai Highway 0
Huafeichang, No. 148 Haohua West Road, Qionghai


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Peppys Coy Boy- 7 year old, 15.2 hand sorrel gelding. AQHA registered and Peppy San Badger bred. Coy is put together perfectly and turns heads everywhere…SOLD
Stella- 14 year old, 14.3 hand bay Quarter Horse mare. No white markings. Beautiful head with a long thick tail. Super stocky solidly built mare that can…SOLD
Jim- 10 year old, 15.0 hand bay Quarter horse gelding. This handsome bay gelding can do almost any job asked of him. He's been a ranch horse his whole…SOLD
Prescrip Fur Wimpy aka Missouri- AQHA bay gelding foaled 4-14-98. Here is a horse that is super handy broke and broke to death. Super well bred gelding…SOLD
Dream Eyed Pete is ready for work! This stunning Quarter Horse is absolutely ready for the next level - he reins, has been trained through lower level…SOLD
Stella-13 year old Quarter Horse mare. Absolutely no white on her. Here one mare that is safe for anyone to ride and enjoy. Pretty as a picture too! This…SOLD
Spirit- 14 year old, 15.0 hand grade Quarter Horse gelding. Sorrel with a big white blaze. Spirit is from North Dakota and was brought east 4 years ago…SOLD
Stretchy- Aged 20's Quarter Horse gelding. Black with a brown muzzle. I aquired Stretchy from a 75 year old women that owned him for 20 years. Financially…SOLD


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Chapter 20: Digestive System. Chapter 21: Urinary System. Functions of Digestion. Ingest food Break down food in to small molecules: Mechanical digestion- Chemical digestion – Absorption Elimination. Carbohydrates. Include sugars and their polymers Monomer is the monosaccharide
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Chapter 21: Urinary System
Accessory organs – food does not pass through
Excretory system


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Housinglist.com is a premier resource for rent to own and lease to own homes in Kodiak, AK. It allows buyers and sellers to quickly find deals and contact information on rent to own or lease to own houses in Kodiak, AK. HousingList.com covers the full range of conventional rent to own homes, lease to own homes, for sale by owner (FSBO) homes, REO foreclosure homes, and pre foreclosure homes. Finding affordable Kodiak, AK rent to own homes has never been easier!
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We recommend upgrading to the latest Internet Explorer, Google Chrome, or Firefox.
If you are using IE 9 or later, make sure you turn off "Compatibility View".
Handpicked brands for you
Win a HOONIGAN series Autometer boost gauge! @Autometerproducts has some real simple rules to get in the runnings to win, make sure to head over to their page for the details. #boss14 @coreyhosford


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Category: Stock Graphic, Illustrations
Stock Graphic >> Illustration - American Bald Eagle Head Stars Circl 330610 by patrimonio @ CreativeMarket
File Size: 1.87 MB; Vector: Yes.
Illustration of an american bald eagle head viewed from the side set inside circle with stars in the background done in retro style.The zipped file includes editable vector EPS, hi-res JPG and PNG image.
Buy Now ~ $10
American Bald Eagle Head Stars Circl
by patrimonio
Keywords: american eagle, bald eagle, eagle, bird, head, raptor, flying, stars, side view, animal, wildlife, illustration, artwork, graphics, retro, circle.


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Does you child wake up in the middle of the night or constantly fights going to bed? Try these 5 Tips For Helping Children Fall Asleep Faster And Sleep Better. It really works for us.
I have two children ages 6 and 1. My 6 year old son started sleeping through the night at around 2 years of age. My 1 year old sleeps through the night since she was 3 months old (and was exclusively breastfed at the time).
Yes, kids are different just like adults. My husband wakes up happily at 6:00am but I really have a hard time early in the mornings. I need at least 8 good hours of sleep a day to feel good and energized the following day.
We are all different and some children definitely need a little help. This is why I am sharing these 5 Tips For Helping Children Fall Asleep Faster And Sleep Better.
My son was never a good sleeper as a baby or toddler. Now he finally goes to bed at around 8:30pm to 9:00pm and wakes up at 7:00am. I had to fight for MONTHS to get him to go to bed that early.
The trick? Creating an environment that allows sleep really helps. After a lot of research I found many natural ways and tips to help him sleep better. Changing his routine and making some adjustments really made a difference.
Kids need to sleep well for their optimal health and development. This is why I am sharing my top 5 Tips For Helping Children Fall Asleep Faster And Sleep Better with you. I hope that I can help you if you are having trouble putting your kids to bed or keeping them asleep at night.
5 Tips For Helping Children Fall Asleep Faster And Sleep Better
1. Magnesium
Magnesium is such a wonderful mineral that not only strengthens the immune system, but also has calming effects. You can give your kids a magnesium supplement like Natural Vitality Kids Natural Calm (good for kids 4 years and older), or a bath (good for all ages). Magnesium is a miracle mineral. My kids definitely sleep better when they take an Epsom Salts bath. Want more information? Check out my Detox Bath For Kids post.
2. Cherries
Cherries are one of the few natural sources of melatonin, which is responsible for the regulation of the body's internal clock and sleep-wake cycle. Researchers believe it's the combination of melatonin and the anthocyanins in tart cherries that might help you sleep better at night.
Making delicious smoothies is a great way to incorporate cherries in your kid's diet, increase their level of melatonin, and help them sleep better at night.
3. No Food After Dinner
You know how your kids ask you for a snack right before bedtime? My son used to ask me for snacks before bedtime all the time. The problem is most snacks contain sugar and it wasn't helping him fall asleep. Now we have dinner at around 6:00pm and I make sure he eats a full meal so he won't be hungry and ask for a snack or milk before bedtime. I can see the different and how easily he falls asleep now.
4. No Electronics Before Bed
This was a tough one to implement because my son loves watching tv and playing with the computer or iPad. We had to limit the use of electronics at home and we saw a huge improvement in his quality of sleep and overall behavior. I now let him watch tv before dinner for about 30 mins to 1 hour or use the iPad or computer. 1 hour a day and that is it. No tv, and no electronics before bedtime. This is very important because if he is playing with the iPad he simply cannot fall asleep easily and has such a hard time.
If you want to learn more, please see The iPad Is A Far Bigger Threat To Our Children Than Anyone Realizes.
5. Essential Oils
Essential oils are soothing, relaxing, and can put you in the mood for going to bed very easily. I love my essential oils and use them everyday. They are also a great natural way to make your home smell wonderful without toxic chemicals. A few drops of Lavender essential oil in my diffuser before bedtime is just wonderful. I really think it relaxes my kids and makes them fall asleep easily. Lavender is part of our bedtime routine while reading a book before bed.
Want to learn more about essential oils, what are they good for, and which ones are safe for kids? Check it out HERE.
This information should not replace professional advice by a qualified medical or herbal practitioner.
This post contains affiliate links. The products linked are the products I use and recommend. If you purchase a product through an affiliate link, your cost will be the same but Creative And Healthy Fun Food will automatically receive a small commission. Your support is greatly appreciated.


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924 E DARREL Road, Phoenix, Arizona
$159,9005 Beds3 BathsContract Pending
$159,9005 Beds3 BathsContract Pending
924 E DARREL Road, Phoenix, Arizona 85042 - This house is move in ready! This home features 4 bedrooms and 2 full bathrooms. Tile throughout the house, freshly painted and lots of storage. Nicely updated kitchen with beautiful back splash and breakfast bar. It also features a studio/apartment next to the house that has it's own entrance and features a full kitchen, full bathroom and bedroom it can be used for family or for lease/income. Must see for yourself!
Listing Courtesy of Planet Realty
"I cannot speak more highly of Robert Joffe. He represented my wife and I on the sale of our house in Arcadia and the purchase of a new one. Not only does Robert know the Arcadia market better than any other agent I have met, but he also has integrity, which in today's world is a rare commodity. If I could give him six stars, I would do so."


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RNA-binding proteins regulate a number of cellular processes, including synthesis, folding, translocation, assembly and clearance of RNAs. Recent studies have reported that an unexpectedly large number of proteins are able to interact with RNA, but partners of many RNA-binding proteins are still uncharacterized.
Increasing evidence indicates that RNA plays an active role in a number of neurodegenerative diseases. We recently introduced a theoretical framework, catRAPID, to predict the binding ability of protein and RNA molecules. We used catRAPID to investigate ribonucleoprotein interactions linked to inherited intellectual disability, amyotrophic lateral sclerosis, Creutzfeuld-Jakob, Alzheimer's, and Parkinson's diseases.
I found these nice lines about Enrico Fermi. I do really like the way he was teaching his people.
No regular seminars, but a continuous flow with his collaborators.
(I am sorry that the original file is in Italian, but I can translate for you in case).
It seems that the use of equations does not help to get published in biological journals (1). Yet, for some of us the equations have a clear, powerful and almost irreplaceable meaning. Benedetta and I collected a number of equations related to protein oligomerisation (2). Some formulas deal with very basic principles that can be applied to other polymers. Some equations were derived by us to predict the aggregation rates, with or without fitting of internal parameters.
A good colleague of mine, Marc Marti, sent me this article by Sidney Altman, which I find very inspiring. I enclose here the abstract


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The Atlanta Hawks win over the Miami Heat on Saturday means the New York Knicks are out of the playoffs for the first time in four seasons.
Carmelo Anthony will miss the postseason for the first time in his 11 seasons as a pro.
The Knicks failure to make the playoffs means that their 2014 first-round pick will be in the lottery. But that pick will go to Denver as part of the 2011 trade for Anthony.
The Knicks will now try to re-sign Anthony if and when he opts out of his contract on July 1. The Knicks can offer Anthony the most money, but on Friday, Anthony seemed intrigued by the Chicago Bulls and coach Tom Thibodeau.
"Thibs is a great coach, his system kind of reminds me of Gregg Popovich's system," Anthony said, via the New York Daily News.
"You put anybody in that system and it's going to work. That's what they've been doing. They've had guys sitting out all season long, guys that's been in and out of the lineups and they seem to get it done."
Anthony considered joining the Bulls before forcing a trade to New York. But after a four-year career with the Knicks, playing with Derrick Rose, Joakim Noah and Thibodeau might be too hard to pass up again.
"What is it like to play for Thibs?" Anthony asked.
The Knicks host the Bulls (47-32) at the Garden on Sunday.


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|Vathakuzhambu Recipe | Kalyana Vathakuzhambu Recipe
|Preparation Time
|5 mins
|Cooking Time
|20 mins
|Recipe Category
|Recipe Cuisine
|South Indian
|1 lemon size
|Sundakai vathal/Manathalai vathal
|1 teaspoon
|To taste
|Grated Jaggery
|1 teaspoon
|1 teaspoon
|Red Chillies
|Urid dal
|2 teaspoon
|Pepper Corns
|1 teaspoon
|Curry Leaves
|1 teaspoon
|Mustard seeds
|1 teaspoon
|Bengal Gram Dal
|1 teaspoon
|A Pinch
- Soak the tamarind in water and extract the juice
- Pour the ghee in the pan and fry the pepper, red chillies, urdhal, curryleaves and hing and grind it into a paste in a mixer and set aside
- Pour the ghee in the pan and add the sundakaivathal and the fry for a minute and then keep it aside. Pour the ghee in the pan and add the mustard seeds. When the mustard seeds begins to sputter, add the channa dhal and hing and fry till it becomes light brown color.
- Add the tamarind extract and salt and allow it to boil till the raw smell of tamarind goes off. Now add ground paste and allow it to boil for 5 minutes. When the pepper smell goes off, switch off the flame and add a pinch of jaggery.
- Now the delicious vathakuzambu is ready to serve with hot rice and Fried/sutta Appalam.
|Vathakuzhambu Recipe | Kalyana Vathakuzhambu Recipe


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ZELIONI Handlebar-End weights made of aluminium billet. CNC machined. Matt-black anodised. Endcaps with ZELIONI Logo.
SIP-TIPP: Combine it with suitable mirrors and grips.
Please note: The handlebar end mirror such as ACTION, AGILA, FERRARA or MONTANA can be mounted on the handlebar end weights without an adapter kit is required.


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WakeEd's Leadership Council provides guidance and strategic input to the Board of Directors.
While it is primarily an advisory body, the Leadership Council is made up of members who are often deeply involved in public education. Many of the members began their work with WakeEd as directors.
The Leadership Council meets quarterly. Its formal role is defined in the organization's bylaws.
2017-2018 Leadership Council
Chair, Scot McAlexander, Xenith Bank
Members (Listed alphabetically)
Matt Calabria, Wake County Board of Commissioners Vice-Chair
Tim Clancy, Clancy & Theys Construction Company
Marty Clayton, Duke Energy
Adrienne Cole, President and CEO of Greater Raleigh Chamber of Commerce
Frank Daniels, Jr., The Josephus Group, LLC
Dick Daugherty, IBM, Retired
Sandy Fain, News & Observer, Retired
Dudley Flood, Education Consultant
Lynne Garrison, Garrison Consulting Group LLC
Patti Gillenwater, Elinvar
Ben Goldstein. CAPTRUST Financial Advisors
Dub Graham, Hunton & Williams, Retired
Bob Hatley, Paragon Bank
Jessica Holmes, Wake County Board of Commissioners
Sig Hutchinson, Wake County Board of Commissioners Chair
Monika Johnson-Hostler, Wake County Public School System, Board Chair
Roddy Jones, Davidson and Jones Corporation
Henry Knight, Electronics Unlimited, Retired
Christine Kushner, Wake County Public School System Vice-Chair
John Mabe, Nexsen Pruet, PLLC
James Maynard, Investors Management Corporation
Caroline McCullen, SAS
Tom Oxholm, Wake Stone Corporation
Virginia Parker, Bank of America
Richard Urquhart, Investors Management Corporation
J. Blount Williams, Alfred Williams & Company
G. Smedes York, York Properties/McDonald York
Steve Parrott, Wake Education Partnership President


text: I just ordered my incredible from verizon.. I got it for the incredible price of 162.00! (w/ the new every two discount and an online discount.. also free over-night shipping with a promo' code) I have to wait another month to get it because its backordered but I look at it as another month to educate myself on the incredibleness of the incredible! Im incredibly excited! I want you all to tell me how incredibly excited you are for me to be getting my incredible. k thanks!


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Installing or replacing your roof can be a complicated task without the help of professional roofers. This is due to the risk posed if the job is not done right. Therefore, it calls for expertise to have your roofing done in a proper and safe manner. The challenge that faces most people roofing Ottawa or Edmonton homes is how to find the best roofing company, bearing in mind the many companies available are legitimate, while some others are not. So, how do you determine the best contractors for your roofing in Edmonton or Ottawa? Below are some tips to assist you.
• Get in touch with several contractors
In both Edmonton and Ottawa you are likely to come across several roofers who may provide the same services, but at different prices. Hence, the importance to talk to several roofing companies. Take some time to find as many roofers as possible and compare their services and prices. From that, come up with the three best contractors and take the time to visit each one personally. Make your move based on the one that appeals to you the most. You can base this on the contractor's communication, reasonable but not necessarily the lowest price bid, as well as the reasons the contractor gives you to trust your project to them.
•Get it in writing
A legitimate roofing company in Edmonton Alberta or Ottawa Ontario should be ready to give you a written contract detailing all essential terms of engagement. The details covered in the contract should include the whole project's price, the time it should take to complete the roofing, safety procedures and roofers liability, roofing materials, clean-up methods, and many others. X4icorp.com recommends you ensure that all these details are clearly elaborated on in writing. This enables you to have a base of questioning if the final roof results do not match those written down.
•Check the company's credentials
Roofing Edmonton roofs is a precarious and dangerous procedure if not handled by qualified personnel. It is crucial that you get everything right about the contractors or subcontractors qualifications before hiring one of the many companies available. Ask about the roofer's experience, licenses, and insurance. Professional companies like X4icorp Edmonton and Ottawa will always screen their roofers to ensure that they have the necessary knowledge of roofing. They also ensure that their contractors have the appropriate workers compensation and liability insurance. Therefore, it is important that you ask to see the roofer's insurance, as this can help you avoid liability in case the contractors are involved in an accident while working in your home. You can also check if the company is registered to the BBB, and check their rating if they are.
•Find out if the company offers warranty
Remember, it may take some time for a damage to show up after a roof is improperly installed. Besides, your contractor's insurance cannot protect you due to costs from poor installation. Hence, you need to ensure that the roofer or company you hire offers an extensive warranty. If located in Edmonton or Ottawa, ensure that the company you hire offers both product and installation warranty. This guarantee enables you to avoid paying additional charges for the repair of the damages caused by your contractor's error.
•Seek for references
Word of mouth is the best way to get confirmation about the roofer's reputation. Ask the roofing companies you are just about to hire to provide you a list of some of their references. Take some of your time to contact each one of them, asking about the experience they had with the roofers. Also, head over to the companies website and websites like GAF.ca to find out the previous clients reviews. With such information, there is a chance that you can predict the work your roofer or contractors will perform. If located in Edmonton or Ottawa, do not just go for the first contractor you come across. Ask to get at least three references from your roofer. If you have a friend, relative, or neighbor who had his/her roof recently installed or repaired by Ottawa roofers, ask them to recommend to you some of the local companies that greatly assisted in their roofing.
Using the tips covered above will serve to benefit you a lot if you are not sure of the roofing company to select for your roof in Edmonton and Ottawa. Do not just go for the companies that offer you the lowest price bid, but ensure that your roofers pass your questions based on the above-covered points.


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The most important things at a glance
|New / used:
|Year built:
|White / Grey
|2x Yanmar (240 PS Diesel)
|1.500 h
|21 kn
|Max. speed:
|28 kn
|8,84 m (29,0 ft.)
|3,35 m (11,0 ft.)
|300 l
|Anchored at:
|Plymouth County, MA
Full list of details about this ad
|No detail information available, please contact the dealer to find out more about this listing.
Description & specificationsEnglish description
This 1986 Aquasport is not you typical fishing boat. It is completely decked out for fishing but also has the creature comforts you would expect in an express cruiser. The cabin comes equipped with a full service galley, dinette table and sleeping capacity of up to six. Head includes a full vanity and shower with auto flush and surge sensor to ensure proper disposal. Up top, you will be greeted with the same comforts as well as full electronics including Furuno Navigation, autopilot, fish finder and depth gauge. The tuna tower is also well equipped and will bring out the tournament fisher in anyone who ventures to come aboard. To find another boat with similar creature comforts and fishing equipment you would spend well over $300k brand new. With all the extra money you save on this boat, you can spend those long weekends on the water fishing and enjoying the good life. Please submit any and ALL offers - your offer may be accepted! Submit your offer today! We encourage all buyers to schedule a survey for an independent analysis. Any offer to purchase is ALWAYS subject to satisfactory survey results. Take a look at ALL ***ORIGINAL PICTURES*** of this vessel on our main website at POPYACHTS DOT COM.Contact us for a free BoatHistoryReport.com report on this vessel. We pay upfront for a report on every vessel possible, and we provide this peace of mind to our buyers at no charge and with no commitment. All you have to do is ask! At POP Yachts, we will always provide you with a TRUE REPRESENTATION of every vessel we market. We are a full-service brokerage company, ready to assist you in purchasing any boat anywhere! Please allow us to be your eyes and ears on the ground and assist you with your next vessel purchase. Thank you for visiting and we look forward to speaking with you! - Stock #18371
Here you can download an exposé of the current ad. To display the document you will need the Adobe Acrobat Reader which you can obtain here for free.Exposé Download
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@Edukator. So what does that transale to in cm's please?
Chat Forum
OP – re specific recommendations, I'm not a gear freak and don't change my stuff year on year so am happy skiing anything really. All I meant what you suggest would be more than enough down and up for a good skier. Most will be fine with lighter/cheaper options, unless you are a heavy skier and fancy yourself as the next Seth Morrison, incessantly charging huge drops etc, in which case you might benefit from going stiffer/bigger/heavier. From trying others' gear and my own there's doesn't seem much bad new stuff around so it's really down to preferences – which you won't know for a while but can make a good guess based on what you currently do downhill at least.
Re length of skis, like others I'd go a little shorter than you suggest but its totally down to preferences. For reasons given by others above, reasonably straight and not massively wide too. Other than reasons given above, for me the logic is that I'm skiing mostly in the UK where big skis aren't always best. I also prefer shorter skis on my back when inevitably ending up in silly situations, and I feel like for steep gullies (or anything narrow, trees – not often in the UK) that they are a bit easier to handle for someone of my abilities. Having said that if I was living on Hokkaido or in some shack in BC where it dumps feet of fresh for 6 months of the year then I'd go for a massive swallowtailed thing...
One practical or housekeeping note: if the huts you use are anything like the ones I've used, there will be nowhere for washing. This means you'll be using the bog then eating with unwashed hands; on the Haute Route I suffered with steadily worsening diarrhoea, which made me feel increasingly weak and was unwelcome on the final day when we had three cols and three glaciers to cross. Some antiseptic wet wipes would have solved that problem and it would have been nice to have a refreshing face wash every evening as we got quite sweaty during the days. Thin gloves are a must and if you buy a base layer, choose a white one because the traditional Helly top in dark blue soaks up a lot of heat from the sun when you're skinning up in a snow bowl in hot sunshine.
Sun block (100%) for your nose, lipsalve with sunblock, sun hat and very dark glasses are also vital.
What I remember from the Haute route is not the skiing, which was fairly easy, but the psychological difficulty of the diarrhoea, lack of sleep and living in stinking clothes! If the weather had been bad or I'd suffered with blisters or an injury, that would have finished me.
Thanks Gents. Yes, being in the Alps is a bit of an acquired taste. The huts are usually very basic. As you say, no facilities and either a chemical loo, a fetid pile to add to or a draughty long drop down the side of whatever crag the hut is on. I must have climbed in the Alps probably two dozen times and the scrap to get out onto your route is still a pleasure to behold....
I'm not you so I can't suggest a ski length for you. I'm 1m74/68kg, my Tour Guides are 176cm and my MX11s 165cm. My 55kg wife uses 155cm Elan Alaskas.
Well just to update this with the 'after' stuff.
Just returned from a 4 day hut to hut tour around Val d'Isere with a Guide and two chums. I've been climbing in the Alps many, many times and this was the first Guided trip for me.
Each day we skinned about a 1000m of vertical ascent and skied another 1000m of descent. Weather and snow conditions were absolutely shite. Very warm with strong southerly winds, very poor viz with flat light, wet cement to ski and very high avalanche risk....
I bought boots (Scarpa Maestrale RS's) before I went and picked up skis (Scott Cruise Airs), bindings (Dynafit Verticals), skins, poles, ski crampons and touring specific crampons/ice axe over there. I also picked up a decent transceiver/probe/shovel package a well. Prices are much cheaper than the UK especially in Albertville but choice was a bit restricted right at the end of the season.
Despite crap conditions, I'm really up for it again next year as I see it as a natural development to my piste skiing which is getting a bit routine. I'm going to concentrate on improving off piste as this is not something I've spent a great deal of time working on in the past.
Great stuff. Love ski touring but in reality of it done very little:several 4000m peak trips and quite a few day hits from here in Grenoble. Off to do the dome des écrins on the 14th and might pop up the barre on foot if time allows. Got some brand new waybacks and plum guides sitting in the garage.
Topic Closed
This topic has been closed to new replies.


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Shaved blonde Zoey Monroe tied up and fucked doggy style
Duration: 3min 15sec Views: 10 215 Submitted: 1 year ago Submitted by:
Description: Zoey Monroe is a girl that is really turned on by doggy style sex. The blonde is fucked on the bed by her lover and he is pressing her against the soft surface of the bed fully as that makes her really happy.
Channel: Brazzers Network
Pornstars: Zoey Monroe


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LOVE IT! I knew I could count of you guys to have some great stories of your own!
Absolutely loved the "bathroom novel" vs. "regular novel" concept. And I agree, really heavy reading is inappropriate as it interferes with the intense concentration required to fulfill the mission!
Love the faces in the drapes! I try not to focus on the decor of my bathroom too much because I will find too many things wrong in there!
My friends and family always want to know how I can possibly read as much as I do! I just don't have the heart to tell them, although if they were even mildly observant, they would certainly figure it out!
For me, a VERY successfull "mission" is one where I don't even have the opportunity to crack the spine of a book, or get to the first paragraph of a magazine article. Clearly, those instances are very rare indeed.


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Schuylkill driver facing DUI charge
A Schuylkill County driver is facing a charge of driving under the influence (DUI) following a one- vehicle crash that occurred about 3:05 a.m. Thursday, Aug. 12, along Second Mountain Rd., at Manheim Rd., in North Manheim Township.
State police at Schuylkill Haven said John L. Zimmerman, 21, of Cressona, was driving a 2005 Mazda 6S eastbound at a high rate of speed when he lost control. The car struck an embankment along the berm, then overturned twice before coming to rest on its roof.
Zimmerman admitted to consuming alcohol prior to the crash, troopers said, and is facing the DUI charge.


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text:
There is another electric company out there helping restore power.
Guernsey-Muskingum Electric Cooperative has been gradually restoring power to their customers, with the goal to be finished by this weekend.
"We have about eight hundred yet still out and our goal is to get ninety-nine percent this evening and I think we'll be there. But that last few hundred are going to be the slow and toilsome. Some of the individuals and that will be through Saturday and Sunday at least," said Brian Bennett of the Guernsey-Muskingum Electric Co-Op.
They have sixty-five lineman and support staff out. Crews from Ohio, Kentucky, Pennsylvania and Tennessee are all assisting, putting in sixteen hour days.
"If I can emphasize one thing, it's that please call in if you're without power, we want to be able to wrap our arms around everybody and know exactly so that we can get everybody on and not let anyone slip through the cracks," said Bennett.
There is also a full staff at the co-op waiting to take phone calls. Any Guernsey-Muskingum member without power is urged to call in and let them know. 1-800-521-9879


text:
With blue skies, bright sunshine and the Arabian Gulf as your backdrop, you couldn't ask for a more spectacular setting than the Palm Lawn at Kempinski Hotel Ajman. Offering room for up to 350 people, this tree-lined outdoor venue is well suited to a variety of occasions: whether it is providing stunning photo opportunities for an unforgettable wedding reception, or a pleasant space for an outdoor banquet.
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text:
GraphicRiver Jungle of Trees Against the Sky 9702877
Stock Vector \ Conceptual \ Nature \ Landscapes
Travel \ Tropical \ Summer \ Vector \ Rainforest \ Season \ Plants \ Against
Stock Vector - Jungle of Trees Against the Sky 9702877 by Nearbirds @ GraphicRiver
Stock Vector \ Conceptual \ Nature \ Landscapes
Illustration jungle trees against the sky
Layered: Yes; Graphics Files Included: JPG Image, Vector EPS, AI Illustrator; Minimum Adobe CS Version: CS.
Set of Spring Colored Doodles; Postcard Dedicated to Spring; Jungle Background ; GUI Treasure Hunt; Map of Treasure Hunting; Cave With Waterfall and Magic Tree ; Fantasy Cave with a Waterfall.
Keywords: art, backgrounds, beauty, cartoon, climate, cloud, drawing, environment, fantasy, flower, forest, grass, green, illustrations, landscapes, leaf, locations, nature, paintings, plants, rainforest, season, sky, summer, travel, tree, tropical, vector, wild, woods.


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Galaxy Blue Sapphire Plaza is designed with highest level of international standards of development. This commercial mall will have 22 floors which are being built on a corner plot and is situated on 130 meter wide road which connects Noida and Greater Noida as two major and metropolitan cities of Delhi NCR Region. This development is also well connected to Ghaziabad through NH 24 and to Faridabad through FNG highway.
For more details:
Galaxy Blue Sapphire Plaza
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Call us: 9555807777
Visit: http://www.galaxygroup.org.in/galaxy-blue-sapphire/
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text:
VILLAGE OF SPRINGVILLE, N.Y. -- Alyssa Hearn's father, Christopher, described his daughter as a "beautiful little girl."
The young girl was killed when she was pinned under a school bus after exiting it on West Main Street near North Buffalo Street in the Village of Springville, according to the Erie County Sheriff's Office.
Sunday, the Springville community came together for a vigil to honor her short life and to help grieving students and families.
They gathered at the Springville-Griffith High School football field at 1 p.m. with pink and purple balloons, which they released during the ceremony into the blue sky.
The Erie County Sheriff's Office says the incident remains under investigation.


text:
11:01 PM [bassman] Poppy3 do you think there will be a few days between the two if IQD rv first ....
11:03 PM [poppy3] bassman, no i think they will go together if at all possible. They have held out for over a year now and been held up three times because of Maliki . I am sure they will try and go together. poppy3
poppy3] bassman it is possible but not very probable if Iraq keeps moving forward and the senior leadership continues to agree with one another instead of throwing shoes. VND is being pushed by China but their MOF doesn't want any further obligations to china than they already have especially in their banking sector. I would say if Iraq doesn't rv by the 15th look for VND to go on their own but it will be a smaller RV then if they can hold out till Iraq rv's. popp
[abbababy] daniandquin I just wish we would hear something already. I just think "O", has a big hand in this and it is all about his upcoming election. I figure if he can hold off the wolves until July or August that will give him a good looking economy with all of us buying come Sept, Oct.
[daniandquin] abbababy to be honest, i think that august would be too late for the influx of new money to positively effect the US economy. The trickle down effect to make any sort of tangible change would have to be at least 6 month IMO
Read More Link on Right
[tb30] abbababy I was thinking the same thing, I just don't know if that will be enough time to get the economy flowing again.
[abbababy] daniandquin We are talking about millions of people buying homes for cash, cars, furniture etc. that will happen in a month to see. Even if it is falsified it can truly show by October. This is not the first time #'s have been used to win an election. Need to go back and look at the history .
[daniandquin] here's my thoughts: it's not enough to just have a bunch of new millionaires spending money to boost the economy. To really REALLY be seen, that economic boost needs to entail new businesses, hireing new staff,.... and that cant' be accomplished in less than 6 months
[heartfelt] daniandquin I agree with you. The 3rd quarter financial reports don't come out till Sept so O actually needs this in June to see it reported in the reports. It won't do him any good if results are seen before election.
Osthaffn] abbababy i recognize that many want to say that EVERYTHING is our president's fault... but an R V alone will not keep in him in office; the economy needs to get moving, and that will take about 6 months post R V ... so "if" he were manipulating things, he would manipulate it to happen NOW
[Osthaffn] not in another month or two
[marjieann] Takes several months to get in the system,need at least 5 to 6 months,someone stated they were putting up a billboard and tell that Bush,Chaney did this ,not O
wirelessguy] Osthaffn O is not imo controlling this. The delay is with PTB well above him in the financial chain.
[Osthaffn] wirelessguy I agree, I think this is so much bigger than our own country, and its the complexity of it all that has led to this being such a difficult process
[marjieann] gUESS we will have to leak the Truth out somehow,maybe other Truths will come out before and we won't need to
[Osthaffn] abbababy all of those consumer based purchases that you mentioned, don't have an impact on manufacturing or any other industry for for that matter for MONTHS... all that does is reduce inventories that are already in the system, it does NOT translate into immediate jobs, it just doesn't!
[abbababy] daniandquin Well I am not a genius, but I open & started a business with $1,000. in 1982 worst economy in less than a month. It doesn't take a rocket scientist to open a business. You just need to dedicate your time & efforts & get it done. If you want something bad enough it can happen.
[Nameless56] abbababy Opening a business and having a good idea what your doing isnt the problem. The problem is jumping through all the local state and federal hoops
[abbababy] daniandquin Kept the business going for 10 years. finding good people was a situation, but nowadays there are too many people out of work for that to be a situation. I just feel things can move faster than ya ll think. ut it does take really wanting to do something to help the economy.
[Osthaffn] abbababy I know from my personal work in IT in the manufacting sector, that strong sales in one quarter, does not translate into new jobs the next quarter
Osthaffn] abbababy that's wonderful! but do you think everyone who has invested in the IQD has your same drive and ambition? (how many will want to just park their money somewhere while they park their butts in the sand with a umbrella rum fruit drink?)
[Digs] Osthaffn count me in for the sand an umbrella rum drink.... planning on spending some quality family time on the beaches of Puerto Rico for a few weeks/months... lol
[dopeygrl] sono That is the purpose of this exchange package. The one everyone is signing up for. Is it not? To get a higher rate.
[sono] dopeygrl There are....as I understand it two components to the bank packages... one deals specifically with the rate of exchange that everyone (small and large) will be able to take advantage of... the second component is the bank perk package which, if you chose to avail yourself of...
dopeygrl] sono We are talking about the exchange rate part.
[sono] dopeygrl will give you access to high end services...it is this component...the bank perk package...that I would totally agree with you will most likely (I have not seen details) would and should carry with it a need to leave a % of your funds on account. If you do not choose to avail yourself...
sono] dopeygrl of the perks... and this is conjecture on my part... no bank will be able to force you to leave one dime in your account even one minute after the exchange occurs... as long as you have met the 24 hour requirement for establishing your new account..
Comments are closed.


text:
Indiana Pacers vs. Milwaukee Bucks - 12/31/15 NBA Pick, Odds, and Prediction
Milwaukee Bucks (12-21) at Indiana Pacers (18-12)
NBA Basketball: Thursday, December 31, 2015 at 6:00 pm (Bankers Life Fieldhouse)
The Line: Indiana Pacers -6.5 -- Over/Under: 200 See the Latest Odds
The Indiana Pacers play host to the Milwaukee Bucks at Bankers Life Fieldhouse on New Year's Eve.
After three straight losses, the Pacers bounced back with two straight wins and had their eyes on a third before losing at Chicago in overtime last night. George Hill led the scoring with 20 points, Paul George added 19 but Monta Ellis struggled and finished with just 13 points on four of 19 shooting as the Pacers lost to the Bulls by 102-100 in overtime on an alley-oop play to Jimmy Butler with just 1.2 seconds left in the game. With the loss, Indiana drops to 18-13 on the season and 7-9 on the road where they've lost six of their last seven.
USA TODAY Sports
Meanwhile, the Bucks have lost eight of their last 11 overall and are in danger of losing a fourth straight after losing to the Thunder by 131-123 on Tuesday. Khris Middleton led the scoring with 36 points, Giannis Antetokounmpo added 27 points while Michael Carter-Williams had 19 but it still wasn't enough as the Bucks just couldn't defend without fouling, sending the Thunder to the free throw line with regularity where they connected on 37 of 40 attempts. With the loss, Milwaukee drops to 12-21 on the season and 3-15 on the road.
In ATS trends, the Bucks are 4-11 ATS in their last 15 road games against a team with a home record above .600 and 4-8 ATS in their last 12 road games overall, while the Pacers are 9-4 ATS in their last 13 home games and 2-9 ATS in their last 11 games playing on zero days rest.
The Pacers will be facing a tough task of guarding this young Bucks team on zero days rest, but the Bucks have been a terrible road team all season so I'm sticking with Indiana to bounce back and win at home.


text:
Acrosser Technology introduced the fanless AR-V5403FL in-vehicle computer. The AR-V5403FL features the Intel 945GME chipset, Intel Core 2 Duo/Core Duo/Core Solo/Celeron M processer support, and intelligent power management. The AR-V5403FL can operation at -15°C to 50°C and withstand vibration up to 2G (complies with IEC60068-2-64) and shock up to 50G 11ms (complies with IEC60068-2-27). The rugged in-vehicle PC is ideal for fleet management, vision procession, telemetric, traffic safety control and other vehicle applications. The Acrosser AR-V5403FL is available now.
AR-V5403FL Features
- Intel 945GME+ICH7 chipset
- Supports up to Intel Core 2 Duo T7400
- Intelligent Power module
- Fanless design with heat pipe
- Display: VGA
- RS-232 interface: 2 external, 2 internal
- USB x 4, Mic-in/Speaker/Remote control
- Storage: CF card / 2.5″ HDD bracket swappable without open case
- GPIO Board, 2 in / 2 out
- 2 x Gbps RJ45 LAN port with LED
- Optional GPS / WiFi/ Bluetooth / 3.5G module
- Changeable Fuse design
- I/O on one side
- DC power input of 9V to 32V
- Optional uninterruptible power supply for emergency back-up
More information: Acrosser


text:
The first Sydney store for the great British designer has opened in Sydney CBD's Westfield complex.
Measuring 135 square metres, the new Paul Smith Sydney store follows the opening of his first Australian store in Collins St, Melbourne in 2012.
Local fashion media attended the official opening in the store during the week, taking in a curated selection of clothing, shoes and accessories for men, with a focus on lightweight tailoring featuring cotton and linen wool blends, unstructured and soft in a wide range of Italian cloths: silk flannels, blurred checks, knitted wools and indigo seersucker. Iconic Paul Smith designs feature alongside a cactus embroidered shirt, knitwear that nods to Paul's love of cycling and paisley and prints from the Autumn/Winter 16 catwalk.
As with the Melbourne store, a highlight for customers will be the chance to peruse the eclectic picture wall made up of artworks, objects and things Paul has been sent alongside a range of found objects and art for sale including a table by Edward Wormely and artworks by artists including British artist Aaron Kasmin and Danish artist, Allen Schmidt.


text:
Photo by PHOTO PROVIDED
Parma Community General Hospital could became part of the University Hospitals health system by the end of 2013. Officials of both organizations announced that they have signed a letter of intent to explore adding the Parma hospital to the University Hospitals system. This is the second such announcement from University Hospitals in less than two weeks. In late June, UH announced plans to explore an agreement to combine with EMH Healthcare in Lorain County. Agreements with both EMH and Parma Community are expected to be finalized by the end of the year. Patients shouldn't expect the Parma hospital, or any of the other health centers University Hospitals works with, to become mere branches for the main UH campus at University Circle, according to Tom Zenty, CEO of University Hospitals. Mr. Zenty said in an interview with Crain's that UH always has invested heavily in its member organizations, citing past investments in the Geauga, Bedford and St. John hospitals. The goal is not to send patients to the main campus for specialists, he said, but rather to equip those member hospitals with the tools necessary to best serve patients. "Our goal is to provide superior clinical care as close to the communities our patients live as we can," Mr. Zenty said. That goal was an important one for Parma Community. Terrence G. Deis, the hospital's president and CEO, told Crain's that both organizations believe providing services in the community is more convenient for patients and less costly. Mr. Zenty said there could be opportunities to replicate at the Parma hospital University Hospitals' programs such as those found at the Harrington Heart & Vascular Institute, the Seidman Cancer Center and Rainbow Babies & Children's Hospital. Rainbow already provides some on-call neonatal services at Parma Community, Mr. Deis said, and he found that program and others affiliated with University Hospitals have been "very successful."
Pressures grow on independent hospitals
The commitment to bring expanded services to the community, along with University Hospitals' strong reputation and compatible culture, made the potential partnership a straightforward one, Mr. Deis said. Because many of the more than 500 physicians working with the Parma hospital are independent, University Hospitals' experience working with independent medical staff also was a consideration. Mr. Zenty said he thinks independent hospitals are looking more often to align with strong medical systems. As health care reforms start to take hold, those freestanding hospitals may have a "limited life" going forward, Mr. Zenty said. Every year for about the past decade, Parma Community has looked at whether remaining an independent hospital was the best choice, Mr. Deis said, and this agreement with UH would be a future-looking one. He said it's becoming increasingly difficult for an independent hospital to remain that way, citing downward pressure on reimbursements by insurers and the increased need for investments in equipment and physician recruitment and retention. In working together, the hospitals could find ways to save in areas such as purchasing and supply chain management, Mr. Zenty said. And the two may be able to collaborate in areas such as information technology and philanthropy. University Hospitals and Parma Community already have worked together on a purchasing collaborative in the past with EMH Healthcare and Southwest General in Middleburg Heights. University Hospitals now has formal partnerships or some sort of collaboration in the works with all of those groups. Mr. Deis said a lot of details of any combination still must be determined, and he could not give any specifics about what the potential agreement would mean for employees. He did say, however, that the intention is to grow the Parma hospital, not cut it. That can only be good for employees, he said. As both Parma Community and University Hospitals are nonprofits, the potential collaboration is not categorized as an acquisition. Mr. Zenty said under the agreement, Parma Community would become a full member in the UH system. In 2012, University Hospitals had annual revenues of $2.3 billion. It employs about 18,000 people. Parma Community employs about 2,000 people and had revenues in 2012 of about $183 million. Mr. Zenty said he could not comment on whether University Hospitals had plans for similar partnerships in the region.


text:
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- - Italian sizing
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Rick Owens Lilies' dark-shadow wool-jersey long-sleeved T-shirt is a classic urban staple. Layer it over a tank with a long black maxi skirt and add polish with statement silver jewelry. Shown here with an Alexander Wang bag and boots, Burberry cuff, Bassike skirt, Rick Owens Lilies top and a Pamela Love ring.
- Dark-shadow wool-jersey long-sleeved top with a V-neck. Rick Owens Lilies top has an intentionally worn finish, raw hem and simply slips on. 30% rayon, 30% nylon, 20% wool, 20% angora. Dry clean.
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text:
Even the shortest life is precious, Larkin tells abortion hearing
The grief of a woman who travelled to England for an abortion shows human life was present, Northern Ireland's top law officer argued yesterday.
Attorney General John Larkin QC made the courtroom claim as he challenged a judge's finding that it was wrong to prohibit the termination of a foetus unable to exist outside the womb.
Mr Larkin and the Department of Justice are appealing a landmark verdict that abortion law here is incompatible with human rights legislation.
The NI Human Rights Commission, who issued the original proceedings, is also mounting a cross-appeal in a bid to have the regime declared discriminatory.
Last year, the High Court ruled that the failure to provide exceptions to the near-blanket ban for cases of fatal foetal abnormalities (FFA) and victims of rape or incest breached rights.
The Commission took legal action after the Department of Justice launched a public consultation on amending the law that ended with a recommendation for new legislation on FFA.
The Commission said that did not go far enough because there were no provisions for pregnancies resulting from sex crimes.
During the original case, arguments were also made on behalf of Sarah Ewart, a woman from Northern Ireland who went to England for an abortion after learning her unborn baby had no chance of survival.
Challenging the verdict in the original case at the Court of Appeal, Mr Larkin referred to submissions from both Ms Ewart and another unidentified woman who gave a name to the baby she was carrying with an FFA.
"Each were expressing grief for the loss of a baby," he told a panel of three senior judges.
The Attorney General contended that the High Court ruling had erroneously failed to weigh the two women's experiences in the balance.
"One is dealing with life that may be of short duration but is nonetheless precious," he said.
"When the trial judge says there's no human life to protect, that's plainly wrong."
Mr Larkin went on to claim the Commission lacked the necessary victim status to bring judicial review proceedings.
Further arguing that no unlawful act had been identified, he said: "This goes to the core of the Commission's jurisdiction to bring these proceedings."
The appeal continues.
Belfast Telegraph


text:
Correctly And Strategically Working With The Camera Flash During Indoor Digital Photography
Posted on Oct 08, 2009 | Comments 1
If you are working with indoor lighting and cannot seem to get it right you may need to fall back on using your camera flash. [lighting techniques]
By not being able to get indoor lighting right we mean you may not be able to grasp the kind of control you want on your indoor lighting sources or maybe the indoor lighting sources are too close to your subject or too far away from your subject.
Oftentimes we are photographing a subject in an area that is just too small and enclosed to get the proper form of indoor lighting under control.
In these cases we will need to utilize the flash on our digital camera. While this isn't an ideal choice it can be successful and deliver beautiful photographs if used properly and with the correct techniques.
Did you know that the reach of a flash on the standard and even advanced digital camera is only 10-15 feet? This means that if your subject is further away than 10-15 feet of your camera the flash will not properly do its job. In these cases you may need to use the properties of an external flash.
Posted in: Performance Metrics
Comments (1)
Pretty good information on indoor photography.what are the best locations for indoor photography?


text:
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Tel: 01422 365840
Then why not pay our Grill Room a visit - this is our steakhouse, serving the finest locally sourced produce available, from quality meats to delicious seafood, plates full of flavour are created in our state of the art Kopa Charcoal-grill oven. An extensive wine list and knowledgeable staff compliment the meaty menu, creating an unforgettable dining experience.
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text: I'm trying to get a handle on typical values. What water supply temperature is typical? Has anyone seen any wild variations from published supply charts or are they pretty accurate? I'm calculating that I will need about 32 BTU/hr/sqft at design temperature. I was originally thinking about using staple up under the first floor, but the Uponor Appendix E and Zurn design manual shows that would require a water supply temperature somewhere around 180F! Joist Trak shows low 140s. A sandwich type system appears to require temperatures in the upper 140s or low 150s. That's for about half the total square footage that will be wood with an R value of .7 or so. I'll need a lower temperature for the other 50%, which is tile. Has anyone used Joist Trak? It looks like a quality product.


text:
|Publication number
|Publication type
|Application number
|Publication date
|Jan 20, 1987
|Filing date
|Jan 4, 1985
|Priority date
|Jan 4, 1985
|Fee status
|Publication number
|Steven C. Quay
|Original Assignee
|Salutar, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (2), Non-Patent Citations (2), Referenced by (35), Classifications (10), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This invention relates to MR Ferrioxamine contrast agents, and more particularly to FOM family and amide homologs thereof.
Heretofore Fe(III) chelates have been employed in paramagnetic contrast agents in the form of DTPA-Fe 3.
It is therefore an object of this invention to provide improved Ferrioxamine contrast agents for MR imaging.
It is another object of this invention to provide MR Ferrioxamine contrast agents having a high stability, a low toxicity and which are physiologically tolerable.
It is a further object of this invention to provide Ferrioxamine contrast agents in pharmacological form with a low osmolarity.
It is a further object of this invention to provide Ferrioxamine contrast agents which are in vivo responsive.
It is a further object of this invention to provide Ferrioxamine contrast agents which are organ selective.
It is a further object of this invention to provide Ferrioxamine contrast agents which reveal disruption of the normally intact blood-brain-barrier, as occurs in events such as tumors, trauma, and infection.
It is a further object of this invention to provide a method of using such Ferrioxamine contrast agents.
It is a further object of this invention to provide an MR system employing such Ferrioxamine contrast agents.
Briefly, these and other objects of the present invention are accomplished by providing a chemically stable physiologically tolerable FOM contrast agent in a pharmacological state, for in vivo use during diagnostic magnetic resonance (MR) imaging. The contrast agent enhances the MR image of a subject within the MR scanning magnetic field. The paramagnetic metal ion Fe(+3) locally affects the MR scanning magnetic field to reduce the T1 relaxation time of local protons within the subject. The contrast agent contains a Ferrioxamine chelator (FOM) securely bonded around the Fe(+3) ion at six coordination points. FOM-B has the form: ##STR1## for chemically isolating the heavy metal Fe(+3) ion from the in vivo environment. Homologs of the FOM family of contrast agent contain a functional amide group "A" of the form: ##STR2## wherein "n" is an integer from 0 to 18 indicating the number of Carbon atoms in the Carbon-Hydrogen chain portion of each amide group. The FOM family of contrast agents (and amide homologs) are dispensed in a pharmaceutically acceptable vehicle means such as water. The Carbon-Hydrogen portions of the agent become associated with water of hydration which increases the associated with water of hydration which increases the paramagnetic strength of the contrast agent. The Fe ion has a valence of +3 and produce a contrast agent molecule of zero net charge.
Further objects and advantages of the Ferrioxamine (FOM) family of paramagnetic contrast agents, and the method of use thereof, will become apparent from the following detailed description and drawing in which:
FIG. 1A is a diagram showing the chelate structure of a Ferrioxamine-B (FOM-B) contrast agent;
FIG. 1B is a diagram showing the chemical structure of the FOM-B contrast agent of FIG. 1A;
FIG. 1C is a diagram showing the chemical structure of a general Ferrioxamine-amide homolog contrast agent;
FIG. 2A is a diagram showing the chemical structure of a branched isomer of Pentyl Amide FOM;
FIG. 2B is a diagram showing the chemical structure of a cyclo isomer of Butyl Amide FOM;
FIG. 3A is a diagram of a normal cerebral arteriole;
FIG. 3B is a diagram of a cerebral arteriole showing extravascular hemorrhaging;
FIG. 4 is a time-FOM concentration chart showing the retention of FOM in the extravascular space after arterial injection of the FOM contrast agent;
FIG. 5 is a cut-away perspective view of an MR system showing the motion platform and subject using Ferrioxamine paramagnetic contrast agents; and
FIG. 6 is a flow chart showing a method of using the Ferrioxamine paramagnetic contrast agents.
The present paramagnetic contrast agents are amide homologs of the Ferrioxamine (FOM) chelates A, B, C, D1, D2, E, and F. These FOM chelates are brownish red, and readily soluble in polar solvents such as water and ethanol. Chemically FOMs are related to the sideramycins antibiotic group. Ferrioxamine-B (FOM-B) is the most common and stable member of the FOM family, and has the general chemical name:
N-[5-[3-(5-Aminopentyl hydroxycarbamoyl) propionamido]pentyl]-3[[5-(N-hydroxyamido)pentyl]carbamoyl] propionohydroxamic acid.
The probable physical chelation structure of the members of the FOM family is a classic octahedron (8 faces, 6 apexes).
FOM-B is shown in Figure lA. The FOMs are strong chelators having six polar bond coordination points (Oxygens 104), which enclose the paramagnetic Fe(III) ion on all sides.
The amide homologs of FOM-B have the general three unit chemical structure (I, II, III) shown in FIG. 1B. The specific number of carbon atoms in the Carbon-Hydrogen chain portion of the amide group is indicated by "n". The number of Carbons in the methylene CH2 chain between the --CONH-- active group and the terminal methylene --CH3, is "n-1".
The amide homologs of Ferrioxamine have the general form:
Amide Homolog of FOM=A-FOM
where A is a general amide group of the form: ##STR3## and FOM is Ferrioxamine. The particle (osmolarity) to paramagnetic (molar relaxivity) ratio for (FOM-3)(Fe+3) contrast agents is 1:1, and can be prepared in highly concentrated solutions while retaining isotonicity with body fluids.
FIG. 1C shows the tri-unit chemical structure of a general FOM chelate. The water of hydration 108 which collects around the amide CH2 chains offers a reliable source of protons (H+) 110 for resonanting with the applied MR fields. Protons 110 have a high probability of being within the local magnetic field variation produced by the paramagnetic Fe ions. These protons form a class of protons for MR imaging which is distinct from random in vivo protons. The prolonged association time of bound water 108, and the close proximity of protons 110 to the Fe ion, establishes a definite and distinct I1 relaxation time which is longer than the I1 for random protons. As a result, protons 110 provided by the water of hydration appear at a higher intensity in the MR image.
The amide family of FOM contrast agents include the normal higher alkyl groups:
______________________________________Higher Alkyl Amide n Properties of Interest______________________________________Ferrioxamine 0 ExcellentMethyl-FOM 1 renal andEthyl-FOM 2 blood-brain barrierPropyl-FOM 3 contrast agent.Butyl-FOM 4 DemonstratesPentyl-FOM 5 renal andHexyl-FOM 6 hepatobiliaryHeptyl-FOM 7 imaging.Octyl-FOM 8.______________________________________
The single long hydrophobic amide chain, together with the FOM(-3)-Fe(+3), renders the chelate an isosteric substitute for fatty acids. The tissue level of the chelate is high in those organs which have efficient fatty acid uptake systems such as the lepatobiliary system.
The amide family of FOMs contrast agents include the higher alkyl groups and the branched and cyclo chain isomers of each group. For example FIG. 2A shows a multi branched isomer of Pentyl-FOM. FIG. 2B shows N-cyclobutyl amide FOM, an isomer of Butyl-FOM.
The fundamental reaction in forming the members of the FOM chelate family is the combining of three molecules of trihydroxamic acid: ##STR4## around an Fe+3 atom. Crude FOM results from the fermentation of Actinomycetes. The letter designations A, B, C, D1, D2, E, and F refer to the diffusion rates in paper chromatography and ion exchange columns.
One method of forming the various amide homologs is to react the appropriate acylchloride or acid anhydride homolog (HOM) of alkyl carbocyclic acid, to the FOM base forming: ##STR5## where NH2-R is the initial FOM.
Venously introduced contrast agents are immediately distributed throughout the circulatory system for imaging. Organs such as the kidney, brain, liver, and heart receive substantial blood flow; and provide selective images which are agent enhanced.
The higher homologs of Amide-FOM tend to be less polar and to bind more to serum proteins, increasing their circulation time. They tend to be extracted from circulation by the liver and excreted in the hepatobiliary system. The amide contrast agent passes through the bile duct (controlled by the ampulla of Vater) and is absorbed into the colon. The Amide contrast agents are suitable for imaging the hepatobiliary (liver-gall bladder) system.
The lower homologs tend to be more polar and remain in solution longer. These homologs are kidney selective and suitable for imaging the kidney, ureter, and bladder.
Oral introduction of the FOM contrast agents requires a higher volume. The agent fills the luminal channel of the digestive system for providing a volume or bulk MR image.
FIG. 3A shows the cross section of normal arteriole endothelial cell 330 in a human brain. The members of the FOM family (and amides thereof) do not readily pass through basement membrane 334 (the endothelial cell wall), from arteriole lumen 336 into the normally limited extravascular space, 340:N surrounding the arteriole region. The endothelium of the cerebral arterioles and capillaries form a continuous basement membrane of tight inter-endothelial junctions and intra-endothelial marginal fold 342. In addition, pinocytosis of substances through vesicle 344 transport is minimal. The tight permeability properties of the cerebrum endothelial walls define the "blood-brain-barrier" (BBB); and limits the flow of material in order to maintain the homeostasis of the neuronal environment. FOM and other large molecules normally pass through the cerebral vascular system within minutes after venous injection as shown in FIG. 4 (Time verses FOM concentration). The dashed curve "NORMAL (intravascular)" rises and falls sharply.
FIG. 3B shows accumulated arterial blood within enlarged extravascular space 340:E; which has penetrated the BBB through rupture 348 in endothelial wall 334. A portion of the FOM circulating within the vascular system becomes trapped within the enlarged extravascular space. The stagnant nature of enlarged space 340:E causes the FOM in the accumulated blood to be retained for a longer period of time as shown by the solid curve "HEMORRHAGE (extravascular)" of FIG. 4. Traces of the injected FOM may remain in cerebral hemorrhage area for hours before diffusing back into the vascular system.
The paramagnetic properties of the FOM enriched extravascular blood establishes a shorter T1 relaxation time for the local protons within enlarged space 340:E. In the resulting MR image, space 340:E is displayed at a higher intensity, highlighting the accumulated blood.
The luminal blood flow is moving within the vascular system and therefore appears dark (no image). The temporary high serum FOM level in the vascular blood flow is not displayed. The background tissue is unenhanced by FOM and is also dark. An extravascular imaging window developes almost immediately after injection of the FOM contrast agent, and can extend for several hours thereafter. The highest contrast image is obtained when the extravascular FOM reaches its highest concentration. This preferred time for imaging occurs shortly after the peak in intravascular FOM concentration (dashed curve), when the two curves intersect.
FOM highlighted images of cerebral regions are useful in studying hemorrhage, infection and disease processes involving disruption of the BBB. These disease include trauma, both acute and subacute (subdural hemotoma), and tumors, both primary and secondary.
The stable powder state of the Ferrioxamine (FOM) contrast agents have an indefinite shelf life, and is the preferred state for shipping and storage. The contrast agent in water solution (or other solvent) is packaged in small storage vials, and frozen under a vacuum. The low pressure sublimates the solvent, leaving crystals of the contrast agent. The vial is sealed to prevent entry of contaminants, and to preserve the internal vacuum. The resulting freeze-dried, vacuum sealed powder, is highly stable and free from environmental degradation effects.
The stable-powdered contrast agent may be raised to a pharmacological state by the addition of a solvent such as water, serum, albumin solutions, or saline. A typical injectable composition contains about 10 mg human serum albumin (1 percent USP Parke-Davis) with an FOM concentration of and from about 20 to about 200 mg/ml (20-40 mg/ml preferred). A 0.01 M phosphate buffer (pH 7.5) may be employed containing 0.9 percent NaCl. The pH of the aqueous solutions may range between 5-9 (preferably between 6-8) over a volume range of between about 5 ml to about 150 ml (10-30 ml preferred). The storage vial may have twin compartments containing the desired amounts of powdered FOM and solvent for a single application. When the seal between the compartments is broken, the FOM goes into solution at the desired concentration for immediate use. The aqueous solution is also stable in a filtered sterilized state if kept in the dark.
Magnetic resonance (MR) imaging system 500 has two magnetic components which scan subject 504 for obtaining MR data enhanced by the presence of contrast agent 508. Bulk magnetic field Mz from Z field source 510 causes paramagnetic particles such as local hydrogen protons within the subject to aline with the Z axis. Periodic or rotating field Mxy from XY field generator 514 extends between XY electrodes 516. The subject to be scanned is positioned on support platform 520 and moved through the magnetic fields by drive 522. Rotating field Mxy is tuned to cause resonant precession of the local protons within the tissue of interest. Each local proton precesses about the Z axis in response to a particular frequency of rotating field Mxy. When rotating field Mxy is removed, the precessing protons decay back into alinement with Mz.
The decay period of the local protons (spin lattice relaxation time T1) varies between organs and between conditions within the same organ. Tumor tissue tends to have a longer T1 than healthy tissue. The presence of the paramagnetic metal ions Fe causes a shortening of the proton T1, without substantially affecting T2. The energy of precession is released forming a free induction signal. Grid detector 526 senses the decay signals which are stored and processed by data processer system 530. to form an image 532 on monitor 536.
The imaging system is further disclosed in Scientific American, May 1982, pages 78-88, and "NMR A Primer for Medical Imaging" by Wolf and Popp Slack Book Division (ISBN 0-943432-19-7), which disclosures are hereby incorporated by reference.
FIG. 6 shows a method of imaging subject 504 with MR system 500 employing an paramagnetic contrast agent 508.
(Step 1) PROVIDING a physiologically tolerable contrast agent 508 in the form: FOM or amide homolog thereof dispensed in a suitable carrier vehicle.
(Step 2) INTRODUCING the FOM contrast agent into subject 508 orally or by intravenous injection.
(Step 3) WAITING for the FOM to distribute into the organ of interest, and for the amide functional groups to cooperate with the in vivo environment.
(Step 4) IMAGING the subject with MR system 500 to obtain an enhanced MR image.
Extravascular applications have a wide imaging window, and time involved in the waiting step may be short or extensive. Comparison or subtraction imaging, requires an initial step of providing data from a prior MR imaging, and the final step of subtraction comparing the prior MR image with the current MR image. A historical base line image from the subjects file may be employed as the prior image. Alternatively, a current MR image made without the use of a contrast agent may be employed.
It will be apparent to those skilled in the art that the objects of this invention have been achieved as described hereinbefore by providing an improved physiologically tolerable contrast agents with a high stability, and a low toxicity. The contrast agent has a high paramagnetic effect due to the amide water of hydration, and a low osmolarity due to the amide bonding. The variability of the amide structure permits a range of vivo response and organ selection, including surface selectivity of the colon.
Clearly various changes may be made in the structure and embodiments shown herein without departing from the concept of the invention. Further, the features of the embodiments shown in the various Figures may be employed with the embodiments of the other Figures.
Therefore, the scope of the invention is to be determined by the terminology of the following claims and the legal equivalents thereof.
|Cited Patent
|Filing date
|Publication date
|May 18, 1964
|Oct 7, 1969
|Bickel Hans
|Trihydroxamic acids
|Title not available
|Pykett, I., Scientific American, May 1982, pp. 78 88.
|Pykett, I., Scientific American, May 1982, pp. 78-88.
|Citing Patent
|Filing date
|Publication date
|Jul 3, 1986
|Sep 13, 1988
|Advanced Magnetics Incorporated
|Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents
|Sep 11, 1987
|Oct 4, 1988
|Kabushiki Kaisha Toshiba
|Material for diagnosis by nuclear magnetic resonance imaging
|Jun 4, 1987
|Sep 5, 1989
|Salutar, Inc.
|Determination of fallopian tubal patency by magnetic resonance imaging
|Jul 27, 1988
|Apr 10, 1990
|Nippon Oil Co., Ltd.
|Process for making skin marker
|May 8, 1987
|Jun 12, 1990
|Salutar, Inc.
|Dipyridoxyl phosphate NMRI contrast agents
|Sep 14, 1988
|Aug 28, 1990
|Advanced Magnetics, Incorporated
|Biodegradable superparamagnetic metal oxides as contrast agents for MR imaging
|Sep 16, 1987
|Nov 27, 1990
|Regents Of The University Of California
|Contrast agents for nuclear magnetic resonance imaging
|Jun 23, 1989
|Feb 12, 1991
|Salutar, Inc.
|Dipyridoxyl phosphate chelating compounds
|Jun 23, 1989
|Feb 12, 1991
|Salutar, Inc.
|Certain dipyridylphosphate chelatable compounds capable of forming metal ion chelates
|Aug 31, 1988
|Sep 3, 1991
|Wayne State University
|Contras agent having an imaging agent coupled to viable granulocytes for use in magnetic resonance imaging of abscess and a method of preparing and using same
|Jan 13, 1989
|Sep 24, 1991
|Ciba-Geigy Corporation
|Process for the preparation of complex compounds
|Sep 19, 1989
|Dec 3, 1991
|Advanced Magnetics Inc.
|Silanized biodegradable super paramagnetic metal oxides as contrast agents for imaging the gastrointestinal tract
|Jun 11, 1987
|Feb 18, 1992
|Salutar Inc.
|Preparation of oxamine complexes
|Jun 23, 1989
|Feb 25, 1992
|Salutar, Inc.
|Dipyridoxyl phosphate NMRI contrast agent compositions
|Sep 14, 1990
|Jul 14, 1992
|University Of Georgia Research Foundation, Inc.
|Receptor-mediated delivery system
|Jul 6, 1990
|Jul 14, 1992
|Salutar, Inc.
|Dipyriodoxyl phosphate chelating compound intermediates
|Jul 15, 1991
|Sep 8, 1992
|Wayne State University
|Method and contrast agent for use in magnetic resonance imaging of abscess
|Mar 31, 1992
|Jun 15, 1993
|Advanced Magnetics, Inc.
|Hydrated biodegradable superparamagnetic metal oxides
|Aug 7, 1992
|Dec 7, 1993
|Biomedical Frontiers, Inc.
|Polymer-deferoxamine-ferric iron adducts for use in magnetic resonance imaging
|Oct 3, 1991
|Feb 8, 1994
|Advanced Magnetics Inc.
|Hepatocyte specific receptor mediated endocytosis type magnetic resonance imaging contrast agents
|Mar 22, 1993
|May 24, 1994
|Nycomed Innovation Ab
|Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging
|Oct 27, 1992
|Jul 12, 1994
|Ciba-Geigy Corp.
|Metal complexes of polyethylene glycol carbamate derivatives of desferrioxamine B
|Aug 3, 1992
|Aug 30, 1994
|Advanced Magnetics, Inc.
|Receptor mediated endocytosis type magnetic resonance imaging contrast agents
|Jul 20, 1992
|Oct 4, 1994
|Advanced Magnetics, Inc.
|Hepatocyte specific composition and their use as diagnostic imaging agents
|Apr 8, 1994
|Jun 13, 1995
|Ciba-Geigy Corp.
|Polyethylene glycol carbamates
|Jul 20, 1994
|Aug 20, 1996
|Bioquest, Incorporated
|Preparation and use of novel injectable RES avoiding inorganic particles for medical application
|Dec 17, 1993
|Oct 8, 1996
|Regents Of The University Of California
|Amino-acyl-type and catecholamine-type contrast agents for MRI
|May 18, 1995
|Oct 21, 1997
|Advanced Magnetics, Inc.
|Hepatocyte-specific receptor-mediated endocytosis-type compositions
|Sep 15, 2006
|Mar 16, 2010
|Siemens Aktiengesellschaft
|Method for the graphical representation of a medical instrument inserted at least partially into an object under examination
|Mar 20, 2006
|Mar 22, 2016
|Bayer Healthcare Llc
|Apparatus and method for detecting fluid extravasation
|Sep 15, 2006
|Apr 12, 2007
|Marcus Pfister
|Method for the graphical representation of a medical instrument inserted at least partially into an object under examination
|Mar 24, 1987
|Oct 6, 1988
|Silica Gel Gmbh Adsorptions Te
|Nmr-diagnostische fluessigkeitszusammensetzungen
|May 6, 1988
|Nov 9, 1988
|Nycomed Salutar, Inc.
|Dipyridoxyl phosphate nuclear magnetic resonance imagery contrast agents
|Aug 3, 1989
|Sep 6, 1995
|Advanced Magnetics, Inc.
|Receptor mediated endocytosis type diagnostic agents
|Jul 1, 1987
|Jan 14, 1988
|Advanced Magnetics, Inc.
|Biodegradable superparamagnetic materials used in clinical applications
|U.S. Classification
|424/9.365, 436/806, 600/420, 556/146, 436/173
|International Classification
|Cooperative Classification
|European Classification
|Oct 14, 1986
Owner name: SALUTAR, INC., SUNNYVALE, CA, A CA CORP
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:QUAY, STEVEN C.;REEL/FRAME:004613/0845
Effective date: 19861006
|Mar 22, 1988
|Certificate of correction
|Jul 3, 1990
|Fee payment
Year of fee payment: 4
|Aug 30, 1994
|Maintenance fee reminder mailed
|Jan 22, 1995
|Lapse for failure to pay maintenance fees
|Apr 4, 1995
|Expired due to failure to pay maintenance fee
Effective date: 19950125


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