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Are you looking for Vinyl in Western Cape? Hotfrog showcases more than 80 popular businesses related to Vinyl in Western Cape! Find a specific region or suburb using the left navigation.
Cape Town, Western Cape
Reminisce is the
place to get your old vinyls, VHS, cassettes etc. converted to the latest media
formats and then put onto CD or DVD. This way you…
More info
lers of the biggest range of Wood Flooring, Carpets, Vinyl & Novilon, Luxury Vinyl Tiles and Blinds
We supply and install quality products at comp…
- 05-23-2011
- 09-24-2010
- 08-21-2010
- 08-10-2010
- 07-05-2010
Florida, Western Cape
Vinyl car stickers, sign and signage concept and design. We specialise in car, bus and truck decals on vinyl printing in full colour. Vinyl signs and signage on cromadek, abs, perspex, correx or komatex and other substra…
CorrexCar StickersOutdoor Signsdecals
Magnum Carpets for decor and interiors including blinds, curtain fabrics, rugs, vinyl flooring and laminated flooring
Wall to Wall carpetsBambooCarpetsCarpet
Table View, Western Cape
For your convenience we have a mobile sample library , providing personal service and advice in the comfort of your home. Our comprehensive showroom is also available to assist you in your choice of flooring, full blind…
Our central location makes The Bargain Foam & Mattress Centre easy to find from both the Northern and Southern suburbs of Cape Town We stock a large range of foam, mattresses, vinyl and much, much more
Milnerton, Western Cape
Our flooring installers offer high quality workmanship and professionalism, decades of experience in fitting a wide range of flooring including; Carpeting, Carpet Tiles, Vinyl Sheeting, Vinyl Tiles, Solid & Engi…
Vinyl TilesCarpet
We specialize in signage installations and graphic designs in the Cape Town area. Our services include neon signs, light boxes, various vinyl applications and media, new designs, 3d designs, sandblasting, window branding…
CorrexIndoor SignageOutdoor SignsNeon
Somersetwest, Western Cape
We are Printers of Top Quality Canvas, Vinyl, Banners, textiles. We also have a business hub for all your business cards etc.
Our prices are the best in Capetown. 24 hour service
Become a re seller, contact us
Woodstock, Western Cape
From concept to completion XXL Digital Print is truly a one stop shop that can handle your most challenging projects and deliver them on time and on budget We can also print outdoor sign such as advertising hoa…
Brackenfell, Western Cape
We supply quality laminate flooring, luxury vinyl tiles, wall to wall carpets, bamboo flooring and blinds to residential an commercial clients throughout the Western Cape/ Peninsula.
Carpet City, founded by three brothers has been servicing the flooring trade in the Western Cape since 1985 Vinyl and laminates makes Carpet City one of the most experienced and professional flooring company's …
Stuck 2 U sells and distributes Iron On Name Labels, Vinyl Name Stickers and Easy to Apply Durable Stickers to mark children's clothing, personal items, school stationery as well as your personal belongings
Kraaifontein, Western Cape
DECO SIGNS For all your signage needs. WE DO SIGNS FOR: BIKES BOATS ADVERT BOARDS WINDOWS BUSSNESES VINYL { STICKERS } CUT OUT LETTERS BANNERS VEHICLE SIGNAGE AND LOTS MORE PLEASE CONTACT ME: TOMMY THOMPSON 0768955275 07…
Vinyl StickersCar SignageStickersvehicle signage
Smart Art - Get your favourite images printed on wallpaper, canvasses, floor tiles and textiles
StickersWall CoveringsPrinting Companystretched canvas
For all your signage needs in the Western Cape.
3D, LED, Vehicle Branding, Pylons, Sandblasting, Chromadek, billboards and much more.
PylonsdecalsStickersVehicle branding
Designer Blinds & Floors in South Africa specialises in designer blinds, shutters, awnings, carpets, laminates and vinyl flooring, among other home décor items
LaminatesPrior Written ConsentCarpetsFlooring
We believe in creating value for our customers by striving to reduce costs and maintaining good customer relationships We are happy to meet you at your premises to discuss and measure up for your digital or cut…
CorrexIndoor SignageSignage CompanyStickers
Hermanus, Western Cape
You name it, we'll label it!
Happy Me Labels has a wonderful range of personalised vinyl name labels.
Ensure that your kids come home with the right gear!
Choose from 5 different SIZED stickers, 5 different FONTS and …
The main concept is to design for you with you, in building yourbusiness. Being in the industry for so long, I want to help you save moneywithout being taken for ride, where some companies will use a cheap product andsel…
Our team has been working with vinyl applications for the past 5 years and will use our expertise to assist your to create signage that will attract your customers We offer the small business a cost effective wa…
L&A Numberplates & Signs , For all you branding & printing needs! Using the most advanced computer-aided equipments, coupled by a highly dynamic team, we are able to develop ideas and concepts into reality.…
Letteringvinyl letteringAdvertising FlagsContravision
Dear Business Owner, If you have any signage requirements, Do not hesitate to contact us for an obligation free quote Click on the following link to view our portfolio. We specialise in: Application of digitally printed …
Letteringmagnetic signsSignPERSPEX
Durbanville, Western Cape
Need a sign in a hurry? 24hr Signs is dedicated to producing high quality signs within 24hrs. We offer a wide range of chromodek signs, vinyl cutting and much more. Try 24hr Signs, you won't be disappointed!
vinyl cuttingSignssignageAdvertising Signs
Strandfontein, Western Cape
A dynamic duo, working as a team to give you specialized services, at the lowest possible rates, with a vision for professional support and high quality services. We are dedicated in our aim for personalized customer sat…
large format printing
SP Supplies provide the best services when it comes to various forms of printing, office supplies, book binding and finishing, till rolls, labeling from water bottles to normal stickers, not to mention our cutting edge g…
Stickersbook bindingPostersLabels
George, Western Cape
CAW Signs in George are manufacturers of large and small signs, perspex, illuminated as well as chromadeck signage We specialise in vehicle signage and magnetics, stickers, screenprinting, full colour images, b…
Illuminated SignsNeonNeon SignsStickers
Vivacé Signs & Design is a ONE STOP SHOP for all your signage needs. With 34 years experience in the signage industry, our experience is to your advantage. We look forward to building a vivacious image for your com…
Custom SignsNeonSignPERSPEX
Millroy Artysands Sandblasting and Laser has been operational in the Western Cape for over 15 years. Millroy Artysands Sandblasting and Laser specialises in on-site sandblasting and sandblast vinyl applications anywhere …
sandblast vinyl
cape town, Western Cape
S&G Signs is rated as one of the top corporate signage suppliers in South Africa We design, manufacture, install and maintain signage on a national basis A professional staff compliment and more than 60 ye…
NeonCorporate SignageSignssignage
Our thorough knowledge of all wallcovering mediums will provide you with the expert installation you require We endevour to give you the best value for money installation, and service for a hassle free hanging …
Water Wise Liners manufacture a wide range of P.V.C and Vinyl products for the market, from D.I.Y kits to more complex structures. Build your own ground dam. Water Wise D.I.Y. Pond and Dam liners are ideal for dams and p…
Somerset West, Western Cape
We are a family business, established in 1972, situated on Somerset West that has specialized in the manufacturing of components for the kitchen, office and shop fitting industry since 1985 Services we offer in…
We have Showrooms, offices and warehouse facilities in both Johannesburg and Cape Town, as well as a national distribution and installation network We enjoy being the first port of call for customers looking fo…
belgotexnouwensCommercial FlooringAccess flooring
We supply detailed information on different flooring types for residential or commercial use, find flooring retailer listings, suppliers and manufactures and much more
xiamen, Western Cape
the supplier of solvent-based acrylic adhesive, high temperature coating and sealant, UV glue and FRP adhesive from China
ABSDecorative Glass
Can't find Vinyl company near near Western Cape? Let us know by adding the missing business here.
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Results 1 to 2 of 2
- 03-23-2014, 09:42 AM Thread Author #1
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[FREE] Clean Droid: Best app in Android Tools category.
Clean Droid, A must have Android optimization and cleaner app.
All the optimization features you need to take good care of your Android phone is now in just one app.
★ Features ★
☆ Trash Cleaner: standard and advanced trash cleaners.
☆ Clean full system cache.
☆ Clean temporary data of Facebook, Whatsapp, WeChat, Instagram, PicsArt, PicSay, Mozilla Firefox and 100+ other apps.
☆ Clean advanced cache files and temporary data.
☆ Clean app leftovers when an app is uninstalled.
☆ Automatically clean your device when cache size > 100MB, > 250MB, > 500MB, or periodically.
☆ Privacy Cleaner: Clean your privacy apps.
☆ Clean standard browser history, browser search.
☆ Clean Google Play history.
☆ Clean chat records.
☆ Clean saved records of downloaded apps.
☆ Clean passwords, history, cache and other user data via easy settings of top Android apps.
☆ Booster: RAM and Game boosters.
☆ Boost your RAM using our super RAM booster.
☆ Play games with higher speed using our Game booster. average boost of 15% for most games.
☆ Automatically boost RAM at screen off, or when RAM used is > 70%, >80%, >90%, >95%, or periodically.
☆ App Manager: Manage installed apps and stored apks.
☆ Batch uninstall apps.
☆ Batch backup apps.
☆ Batch share apps (apk of any installed apps)*
☆ Batch install apps.
☆ Move apps to SD.
☆ Move apps to Phone.
☆ Automatically backup newly installed apps.
☆ Automatically move newly installed apps to SD.
☆ Notify of idle/less-used apps in your device.
☆ Network Rescan Tool: Refresh your network connection easily without rebooting the phone.
☆ WiFi Rescan Tool: Lost WiFi connection? try our fast WiFi rescanner.
☆ Supported Language:
☆ Chinese (Simplified).
☆ French.
☆ Italian.
☆ Japanese.
☆ Korean (South Korea).
☆ Russian.
☆ Spanish (Spain).
Ruhax code runs.
- 10-29-2014, 08:00 AM Thread Author #2
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Re: [FREE] Clean Droid: Best app in Android Tools category.
Clean Droid got acquired by SimilarWeb, Website Traffic & Mobile App Analytics | SimilarWeb
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subset: commoncrawl


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With just a quick scan or photo of the front and back of a check, Deposit2GO lets you deposit checks from virtually anywhere with your cell phone or scanner*.
And personal GTE Deposit2GO deposits are now "real-time". That means no more waiting or wondering when your money is available!
It's convenient, easy and safe: GTE members have deposited over $10M!
So, the next time you need to make a check deposit, give Deposit2GO a try! Download the iPhone 2.0 app**, Android phone app or the Windows phone app. Want to see a quick Deposit2GO how-to video? Click here.
GTE's Member Advantage can earn you 2.49% APY** on Checking and Savings. Learn More Here.
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PO Box 172599 | Tampa, FL 33672-0599 | 813.871.2690: Local | 888.871.2690: Toll Free


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'Bandai' Quilted Hoodie
Product not available
Have questions?
Chat with us or call 1.888.282.6060.
HideDetails & Care
A quilted, color-blocked hoodie keeps it cool and casual without sacrificing style.
- Approx. length from shoulder: 26".
- Measurements taken from size Medium and may vary slightly by size.
- Front zip closure.
- Front slant pockets.
- Ribbed trim.
- Polyester; machine wash.
- By Topman; imported.
- The Rail.


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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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Showing Results: Most Recent
This review is from: Huawei E3272 150Mbps Cat4 4G LTE FDD/TDD USB Modem
Pros: Outstanding 2G Modem. Think of it as your own portable 9600 baud modem.
Cons: Unlocked, check. Right frequency bands, check. Can activate it? Absolutely not.
AT&T, Sprint and T-Mobile won't activate this on anything other than 2G.
This review is from: Intel BOXD54250WYK1 2 x 204Pin SO-DIMM Intel HD Graphics 5000 NUC Kit
Pros: Possibly the most awesome purpose built desktop environment I've seen. I'm very big into smaller is better and this guy is actually velcro'ed to the back of my monitor. For desktop users, this is entirely what they would need for day to day productivity or personal use. The lack of unneeded ports and therefore the overall efficiency of design strikes the perfect balance for most uses.
Cons: I would naturally want to deploy these as desktops within a larger environment, but the barebones nature of it being a kit would make my assembly time more difficult than I would like.
Other Thoughts: This would be a great opportunity for an integrator to build and configure these machines so users could self-install.READ FULL REVIEW
This review is from: HP NW280AA#ABA
Pros: A nice stepwise improvement over prior models.
Cons: Misses the mark in capturing the level of sophistication available given current technology.
Other Thoughts: The idea of a calculator is somewhat outdated but will certainly resonate with students who need intentionally limited functionality during exams. It is somewhat hard to imagine this being part of what I would travel with outside of the classroom environment.READ FULL REVIEW


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Dear friends of Meet Kate
A new year, new plans and projects and of course a new project report! In this first project report of 2012 you can read all about the plans of Meet Kate, our new board and saying goodbye to Mark van Doorn. Let's make it a year filled with challenges and great results:
She inspires... We invest. Get involved!
Friendly greetings from both The Netherlands and Ghana,
Myrthe Oostenbach and Kelly de Vries
Chairman and Director of Meet Kate
- Plans for 2012
After a fantastic 2011 it is time to focus on the new year to come. We are facing and exciting and challenging year. Because, we are starting with the construction of our primary school. This primary school will give high-quality and personal education to 200 children from the surrounding area. Small classes, individual coaching, computer lessons and sports and games will be the main focus of the Meet Kate International Primary School. The construction was supposed to start February 1st, but our contractor was in a car accident and is in the hospital with two broken leg. We expect to start the construction in early April. Feel better soon Robert!
Coming months we will keep you posted through our website, social media, project reports and our newsletter. We have raised 100.000 dollars so far and with this money we can finish the first 2 phases of the project. Through GlobalGiving we hope to raise the final 40.000 dollars needed to finished the first floor of the school. Curious about the plans and blue prints? We have added the link here for you.
- Changing of the guards
To execute all these plans, we need active and enthusiastic board members. We therefore decided to shift and expand a bit in our board. After some good interviews, we have finally completed our new board. This is the group of people that will make it happen in 2012! Click on the link below for everyone's motivation and meet our board!
Kelly de Vries: President
Myrthe Oostenbach: Chairman
Nienke Mauritz: Secretary
Jurriaan Verweij: Treasurer
Muriel Koch: Board member Communication
Joline Deen: Board member Fundraising
Dianne Swinkels: Board member Fundraising
Tom Bijkerk: Board member Webhosting
- Thanks, Mark!
Mark van Doorn, project manager of 'Meet Kate is going to school', has lived in Ghana for a year. He ensured that six children are able to finish their high school. He talk about his experience at Meet Kate:
"What a year I've had. Living and working in Ekwamkrom, Ghana, where the Meet Kate Children's Home has been up and running since August 2010. Coming up with new projects, evaluating them, accepting and rejecting children to the Children's Home and also dealing with all the adjustments in your personal live. I only worked for Meet Kate for 12 months, but it has given me experiences and knowledge I couldn't have gotten in The Netherlands in 20 years. On Monday, January 16th 2012 I flew back to The Netherlands where I'll adjust to the fast, hasty and luxurious life. This way I'm learning about two totally different worlds. I have yet to figure out which suits me best. I do know that the experience that I got from working for Meet Kate convinced me of the use of their work and makes me want to experience a year like this again."
Every month we will give you an update on our projects on GlobalGiving. If you would like to get daily update, become friends with us on Facebook for the latest pictures, movies and stories. You can also visit our website: www.meetkate.org for more information or to subscribe to our monthly newsletter.
Project Reports on GlobalGiving are posted directly to globalgiving.org by Project Leaders as they are completed, generally every 3-4 months. To protect the integrity of these documents, GlobalGiving does not alter them; therefore you may find some language or formatting issues.
If you donate to this project or have donated to this project, you will get an e-mail when this project posts a report. You can also subscribe for reports via e-mail without donating.
We'll only email you new reports and updates about this project.


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The overall goal of this proposal is to understand how pancreatic progenitors are produced from undifferentiated endoderm during embryonic development. Our rationale is that this information will be invaluable to efforts to differentiate human stem cells into -cells and other pancreatic cell types in vitro, for use in transplantation therapies for diabetic patients. Our strategy is to exploit the zebrafish as a powerful vertebrate model to study the earliest steps in the process of normal pancreas development. We propose three Specific Aims, which build upon our previous work, and exploit a novel cell transplantation technique that allows us to test germ-layer specific gene function. In work published during the previous funding period, we used this approach to establish that the signaling molecule Retinoic Acid (RA) is an instructive mesoderm-derived positive regulator of pancreas development, which acts directly on endoderm to specify the foregut region. By contrast, we showed that transcription factor Cdx4 is a negative regulator of pancreas development, which functions within posterior endoderm to set the posterior limit of the pancreas. In preliminary experiments we have used microarray analysis to identify endodermal targets of RA signaling. Intriguingly, these targets include molecules able to negatively-regulate RA signaling, as well as transcription factors, including Hox gene products, likely to function downstream of RA to specify pancreatic progenitors.
In Aim 1 we will test the hypothesis that Cyp26 and Nr2f negative-regulators of RA-signaling function to regulate regionalization of endoderm to foregut by controlling the precise size of the RA signaling domain. These experiments will make use of pharmacological inhibitors, zebrafish mutant analyses, morpholino-knockdown of gene function, and germ-layer specific cell transplantation.
In Aim 2 we will test the hypothesis that RA and Cdx4 positively regulate expression of endodermal Hox transcription factors that function to promote or block pancreas development, respectively. We will identify RA and Cdx4 regulated Hox genes, then use gain and loss-of-function approaches coupled with germ-layer specific cell transplantation to test their roles in endoderm regionalization.
In Aim 3 we will investigate the roles of two additional candidate RA-targets previously implicated in early pancreas development: the Hb9 and Tcf2 transcription factors. We will use mutant analysis and morpholino-knockdown to test the hypothesis that these transcription factors specify distinct subsets of endocrine pancreas cell types. Finally, we will investigate how Hox genes, Hb9 and Tcf2 interact within the transcription factor network that functions downstream of RA to specify pancreatic cell types. The proposed experiments will provide novel information relevant to the manipulation of pancreas cell types in vitro. In addition, this work will provide new insights into the regulation of the RA signaling pathway, which is critical for many different developmental and physiological processes.
The long-term goal of this proposal is to inform efforts to cure diabetes by cell-transplantation. Our general strategy is to make use of the zebrafish, a small fresh-water aquarium species, as a convenient model system to study how the vertebrate pancreas forms during normal embryonic development. Our rationale is that an increased understanding of the intricacies of this process will prove invaluable to the development of methodology to differentiate human stem cells into pancreatic ?-cells and other endocrine cell types in vitro.
|Eames, Stefani C; Philipson, Louis H; Prince, Victoria E et al. (2010) Blood sugar measurement in zebrafish reveals dynamics of glucose homeostasis. Zebrafish 7:205-13
|Kinkel, Mary D; Eames, Stefani C; Philipson, Louis H et al. (2010) Intraperitoneal injection into adult zebrafish. J Vis Exp :
|Prince, Victoria E; Kinkel, Mary D (2010) Recent advances in pancreas development: from embryonic pathways to programming renewable sources of beta cells. F1000 Biol Rep 2:17
|Kinkel, Mary D; Prince, Victoria E (2009) On the diabetic menu: zebrafish as a model for pancreas development and function. Bioessays 31:139-52
|Ward, Andrea B; Warga, Rachel M; Prince, Victoria E (2007) Origin of the zebrafish endocrine and exocrine pancreas. Dev Dyn 236:1558-69
|Stafford, David; White, Richard J; Kinkel, Mary D et al. (2006) Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells. Development 133:949-56
|Stafford, D; Hornbruch, A; Mueller, P R et al. (2004) A conserved role for retinoid signaling in vertebrate pancreas development. Dev Genes Evol 214:432-41


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|icon see you.
Welcome to the graphics community of meezardra and her sister kayumite. We offer icons, banners, icon tutorials and the occasional fanmix. Since September 2008 we have been members only; all entries will be public for specific number of days. When taking our graphics you must credit either one of us or enamelicons. Enjoy your stay. ♥
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Lev: What's their deal? Try NFL's best new rivalry
Two of the NFL's five best teams reside in the same division. They're co-favorites to represent the NFC in Super Bowl XLVIII. And they have all the makings of an enduring, bitter, beautiful blood feud.
Move over, Bears-Packers. Step aside, Ravens-Steelers. Saddle up, Cowboys-Redskins. There's a new rivalry in the NFL, and it's about to shift the league's axis of power due west.
No team has had a better offseason than the Seattle Seahawks. No team has a brighter future than the San Francisco 49ers – except, perhaps, for the Seahawks. They're both members of the NFC West, meaning they'll face each other at least two times a year. Meaning at least two matchups between electric young quarterbacks, coaches with a history of bad blood and teams whose disdain for each other is swelling.
Led by new-age QB Colin Kaepernick and brash coach Jim Harbaugh, the 49ers came within 5 yards of winning Super Bowl XLVII. Led by new-age QB Russell Wilson and brash coach Pete Carroll – who famously clashed with Harbaugh during their college days – the Seahawks finished a half-game back in the division and advanced to the second round of the playoffs.
Neither club rested on its success. The 49ers traded for veteran receiver Anquan Boldin, who helped beat them in the Super Bowl, and have a stockpile of picks in the upcoming NFL draft. The Seahawks dealt for dynamic multipurpose threat Percy Harvin and quietly signed in-their-prime defensive ends Cliff Avril and Michael Bennett.
Super Bowls aren't won in spring, but the 49ers and Seahawks have positioned themselves as powerbrokers for 2013 and beyond. Handicapper RJ Bell of Pregame.com lists San Francisco and Seattle among four favorites to win next year's Super Bowl; Denver and New England of the AFC are the others. Additionally, the 49ers and Seahawks made the top five in three sets of late-March NFL power rankings (CBSSports.com, ESPN.com and NFL.com). ESPN.com's experts ranked Seattle No. 1, San Francisco No. 2.
Their offseason maneuvers have felt like an arms race played out on the bottom-of-the-screen transaction ticker, two Super Bowl aspirants trying to one-up each other. Except, according to Carroll, that isn't what the Seahawks are doing at all.
"The last thing we're going to do is evaluate how we are based on everybody else," Carroll said at last month's league meeting in Phoenix. "To me, that's one of the worst mistakes you can make.
"We're just trying to get better and work really hard at what we can control. That other aspect of it, the other team, the other factors outside, who won the league last year, I could care less about that. It doesn't have anything to do with us."
As you might expect from coaches who've quarreled in the past, Carroll and Harbaugh have differing views on rivalry dynamics. Back in 2009, Carroll, then at USC, objected to a late 2-point conversion attempt by Stanford's Harbaugh in a Cardinal blowout by asking him, during the postgame handshake, "What's your deal?" Today's deal, regarding rivalries, is benign by comparison but no less interesting: While Carroll promotes his all-about-us philosophy built on intra-roster competition, Harbaugh subscribes to the popularly held belief that you build your team to beat the other teams in your division.
"I look at the Cardinals and the Seahawks and the Rams as ... public enemies Nos. 1, 2 and 3," Harbaugh said. "You play them twice. You play them more than you play the other teams. And there's a championship at stake.
"Do I look at them more? Yeah."
Not only does Harbaugh pay close attention to what the rest of the NFC West is doing, he views the offseason upgrades by the Seahawks and others as "a good thing."
"It makes you play your best," Harbaugh said. "It makes you rise to that occasion."
Carroll is aware of the moves the 49ers have made, include signing steady veteran kicker Phil Dawson and reclamation-project cornerback Nnamdi Asomugha. Carroll just isn't obsessed with them. He wasn't that way at USC, and he isn't that way now.
"Jim's done a marvelous job in San Francisco," Carroll said. "They've done everything you can do to put themselves in a great position. They happen to be in our division, so we're going to duke it out again this year. (But) we're not trying to match them. We're trying to take care of our own.
"The challenge is to be disciplined about staying focused on what you can control. The pitfall, the big stumble out there, is to do what you're asking me to do, to worry about what everybody else is doing, to keep up with the Joneses."
Or the Harbaughs.
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This review is from: Pandigital Novel 7" Tablet 1GB Android eReader Kindle On-Board (R70G100)
Pros: Nice price and it works alot better using one of my old palm styli that I still had in the drawer. But a word of CAUTION: the latest upgrade version from pandigital is older than this one and you will lose Kindle if you "upgrade" I am now searching on how to get back the original operating version.
Cons: Resistive screen
Other Thoughts: It is only my second tablet but I think my wife with her fingernails will like this one.READ FULL REVIEW
This review is from: Foxconn R10-S4 Intel Dual-core Atom 330 Intel 945GC Intel GMA 950 Barebone
Pros: quiet, small, cheap, easy to work on.
Cons: none so far.
Other Thoughts: After reading the many reviews, I ordered this with 2 GB. It arrived on schedule and came with the excellent fold out instruction sheet. I installed Ubuntu 10.10 on a 1TB drive I had using my wife's Dell and then easily installed that drive in the Foxconn case. It started right up and I was shortly surfing the net. I then upgraded to Ubuntu 11.04 and that went well also. Ubuntu recognized the 4 cores.READ FULL REVIEW


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|Message view
|« Date » · « Thread »
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|John Kaputin <KAPU...@uk.ibm.com>
|Cannot attend the weekly call
|Mon, 04 Jun 2007 12:30:50 GMT
Lawrence, I'm unable to attend this week's Woden call. As I was away last week and am on a course this week, I don't have much progress to report. I'll post a status update to the list anyway, later today. I'd suggest we cancel this week's call, but will check email tonight in case there's any questions or further input required from me. John Kaputin Web Services Development, Hursley Laboratory IBM United Kingdom Ltd Hursley Park MP211, Winchester, SO21 2JN, UK. email: firstname.lastname@example.com Tel/Fax: +44 (0)1962 817363 (internal 7-247363) Unless stated otherwise above: IBM United Kingdom Limited - Registered in England and Wales with number 741598. Registered office: PO Box 41, North Harbour, Portsmouth, Hampshire PO6 3AU --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: firstname.lastname@example.com
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More Videos...
65 Chevy Impala SS open headers irritates my neighbor
Here's my original high school car, numbers matching (327 c.u.i.) bought in 1972. Decided to open the headers and cruise around my subdivision a little, but end up ticking off my neighbor. I didn't even drive by his house - he lives up the block the opposite direction. When he heads to the back of my car to take a pic of my license plate, I realize this could turn against me. Funny thing is, he doesn't actually recognize me until I get out of the car - then we "share the love".
1966 Impala 427 SS ScottieDTV Kavalcade Of Kool 2015
A 1966 Impala that I shot at the ScottieDTV Kavalcade Of Kool....Another cool build by Big Oak Garage....Great stance....427 Big Block under the hood...A very cool Car..Check it out!!!!...Follow me for more awesome videos weekly Mon-Fri!! See more cool stuff at http://www.scottiedtv.com Check it out!!!
1966 Chevrolet Impala, as seen on classic restos.
66 Chevy impala, that has been restored, winner of show and shine Summernats,
66 SS Impala Burnout
Nice old school ss sand still


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Tracey Moffatt
May 4–
13, 2012
Tracey Moffatt (Australian, b. 1960) is a filmmaker, video artist, and photographer whose stylistic experiments draw upon both popular culture and her own background, examining subjects such as Aboriginal subjugation, maternal domination, gender stereotypes, and class division. Her most recent video series, Montages, is a decade-long labor of love in which Moffatt and her editor, Gary Hillberg, create "hymns to cinema" by mining Hollywood films to craft new narratives relevant to Moffatt's themes. This retrospective of Moffatt's films and videos offers a comprehensive look at her moving-image oeuvre. All films are from Australia and written and directed by Tracey Moffat.
Organized by Jenny He, Curatorial Assistant, Department of Film.
The exhibition is made possible by The International Council of The Museum of Modern Art.
Licensing of MoMA images and videos is handled by Art Resource (North America) and Scala Archives (all other geographic locations). All requests should be addressed directly to those agencies, which supply high-resolution digital image files provided to them directly by the Museum.
Requests for permission to reprint text from MoMA publications should be addressed to email@example.com.


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I just ordered a Stratus. I am looking for a recommendation for a DAC that will do the Stratus justice. It looks to me like the Master 7 is a contender, but I am very curious as to what people in this thread like with the Stratus. I will initially be using the DAC with a USB connection. Suggestions highly appreciated!
Edited by gmm1 - 3/15/14 at 6:24am


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Badjao Village Isla Verde Fire Davao City 4/4/2014 Part 4
- published: 06 Apr 2014
- views: 3265
Over 2,200 homes were razed which included the entire Badjao village at Isla Verde and our learning center. The Badjao need your help. Donations can be sent via paypal to email@example.com Any questions you may have can be sent to the same address. The Babina Monare Badjao learning Center is located in Davao City on the island of Mindanao in the Southern Philippines. Why did we name our school the Babina Monare Badjao Learning Center? Babina Monare was one of ten siblings and the sister of Carmina and Almira Monare who have been a part of my feeding program from the very beginning. Babina was chosen by her family as the most likely to succeed in school and eventually be able to find employment and earn enough money to help her family out of their current state of poverty. All of the money for sending Babina to school was raised through begging and selling trinkets on the streets of Davao. The money collected had to be split between food to eat on a daily basis and the costs of sending her to school. You can imagine how difficult this would be for a family of eleven which included the children\'s mother. Babina was able to make it to third grade and was the only person in the family who could read and write. They had a long term plan that unfortunately did not end the way they had hoped. Just last year Babina was bitten by a mosquito which carried the Dengue virus. The illness which followed unfortunately took her life. I felt that naming the learning center after her would be an appropriate way to honor the achievements she made during her short time here on Ear...


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|Publication number
|Publication type
|Application number
|Publication date
|Mar 26, 2002
|Filing date
|Dec 7, 1998
|Priority date
|Aug 5, 1987
|Fee status
|Also published as
|Publication number
|David M. Long, Jr.
|Original Assignee
|Alliance Pharmaceutical Corp.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (14), Non-Patent Citations (33), Referenced by (5), Classifications (40), Legal Events (16)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of U.S. application Ser. No. 08/138,485, filed Oct. 15, 1993, which now U.S. Pat. No. 5,847,009 on Dec. 8, 1998, which is a continuation-in-part of U.S. application Ser. No. 07/417,796, filed Oct. 4, 1989, now U.S. Pat. No. 5,284,645, issued on Feb. 8, 1994, which is a continuation-in-part of U.S. application Ser. No. 07/082,846, filed Aug. 5, 1987, now U.S. Pat. No. 4,987,154, issued Jan. 22, 1991.
This invention relates to the use of therapeutic agents in conjunction with the parenteral administration of lipid dispersions comprising colloidal suspensions of particulate lipids or particulate matter in association with lipid. It relates particularly to the use of therapeutic agents to reduce or eliminate the transient physiological stress reaction observed when fluorocarbon emulsions, emulsified lipids, and liposomal formulations are administered in vivo.
Fluorocarbon emulsions have many useful applications in medicine as intravascular and extravascular imaging or contrast agents. Also, the capacity of fluorocarbons to dissolve high concentrations of oxygen make them suitable as temporary red blood cell substitutes and as oxygen transport agents in the treatment of local ischemia. Frequently, however, the intravascular administration of fluorocarbon emulsions, and other agents comprising lipid dispersions, is accompanied by a mild transient systemic inflammatory and febrile response. The response is usually innocuous, and can be in many respects, beneficial; however, it can cause a period of discomfort for the recipient.
Several sources of physiological stress that occur during the administration of the lipid dispersions described, including the macrophage phagocytosis of particles, as well as the stress provoked by reduced oxygen tension, interrupted blood flow, or infection, can elicit a transient inflammatory response. The response is physiologically and biochemically mediated by the metabolic products of arachidonic acid, i.e., prostaglandins, thromboxane, and leukotrienes.
The biosynthesis of prostaglandins and thromboxane begins with the conversion of free arachidonic acid to an endoperoxide prostaglandin intermediate, PGH2, by means of a cyclooxygenase enzyme. PGH2 is then made available as the precursor for several end product prostanoids. Among these prostanoids are prostacyclin, PGI2, formation of which is catalyzed by prostacyclin synthetase; the active prostaglandins PGF2a. PGE2, and PGD; and the thromboxane, TxA2, the formation of which is catalyzed by thromboxane synthetase.
The prostaglandin and thromboxane end products have various effects on cells, but primarily act on macrophages and platelets to release other substances that in turn mediate an inflammatory response characterized by infiltration of the tissues with neutrophils, deposition of immune complexes, edema, and pain.
The prostanoids can have effects that oppose each other; for example, PGI2 and TxA2, the biologically most active of the prostanoids, exert opposite vasoactive and hemodynamic effects: PGI2 is a potent vasodilator and inhibitor of platelet aggregation, whereas TxA2 is a vasoconstrictor and promoter of platelet aggregation.
Various agents are known to inhibit or attenuate the biological activity of prostaglandins and thromboxane. Imidazole, a compound related to the naturally occurring amnino acid histidine, inhibits thromboxane synthetase and prevents the synthesis of TxA2; other agents, such as aspirin, ibuprofen, and indomethacin inhibit cyclooxygenase, thus preventing the synthesis of all the prostanoids.
Macrophage phagocytosis not only triggers the release of arachidonate metabolites, but also the release of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF). These substances are known to elicit a febrile response via a mechanism of induced local release of prostaglandins in the hypothalamus of the brain. Corticosteroids, e.g., dexamethasone, can inhibit and down-regulate the release of cytokines from macrophages, and cyclooxygenase inhibitors, e.g., ibuprofen, can inhibit the formation of prostaglandins in the hypothalamus.
It would be advantageous to prevent the undesirable transient effects observed during the intravenous administration of lipid dispersions. Accordingly, it is an object of the invention to provide methods to prevent or ameliorate these effects by use of an agent which prevents a systemic inflammatory or febrile response by inhibiting the synthesis of prostaglandins, thromboxane and cytokines, or preventing their release from macrophages.
It is also an object of the invention to provide methods to prevent these adverse effects by the use of other agents which act to suppress an inflammatory or febrile response.
According to the invention there is provided a method for reducing the Transient Adverse Physiological Response (TAPR) in an animal to parenterally administered particulate dispersions, comprising the steps of administering an anti-inflammatory drug prophylactically to an animal in need thereof in an amount sufficient to oppose the TAPR response; and then administering said particulate dispersion parenterally to a patient. The method is an improvement over previous procedures of administering particulate dispersions, wherein the improvement comprises a prophylactic administration of an anti-inflammatory drug so as to prevent or ameliorate the symptoms of a transient adverse physiological reaction (TAPR) to the particulate dispersion which occasionally occurs, significantly in humans.
The particulate dispersion can comprise, for example, a dispersed lipid, fluorocarbon, or an emulsified triglyceride. The particulate dispersion can also be a liposomal formulation.
According to the method described, the prophylactic drug may be a corticosteroid; preferably the corticosteroid is dexamethasone or methylprednisone. Alternatively, the prophylactic anti-inflammatory drug is a cyclooxygenase inhibitor, a phospholipase A2 inhibitor, or an agent that otherwise inhibits the synthesis of prostaglandins and thromboxane. In one preferred embodiment, the cyclo-oxygenase inhibitor is chosen from the group consisting of indomethacin, ibuprofen, aspirin, and naproxen.
In the application of the method, the dose of the prophylactic anti-inflammatory drug is administered from 30 minutes to 24 hours prior to the procedure of injecting a particulate dispersion into an animal. The prophylactic drug can be administered in two or more doses. The method also comprises the further step of administering the prophylactic anti-inflammatory drug, either continuously or at intervals of time during and after the injection of a particulate dispersion into an animal.
The invention also includes fluorocarbon emulsions comprising an effective concentration of an agent that opposes the TAPR response, selected from the group consisting of steroidal and non-steroidal anti-inflammatory agents, antipyretic agents, and non-narcotic analgesics. The emulsion can, for example, comprise an effective TAPR-opposing amount of indomethacin, ibuprofen, naproxen, or combinations thereof. The anti-inflammatory agent can be aspirin, other salicylates, drugs having an imidazoyl group, or any of the non-steroidal anti-inflammatory agents of the various chemical classes disclosed herein. Alternatively, the emulsion can comprise an effective TAPR-opposing amount of a corticosteroid. In preferred embodiments, the corticosteroid can be dexamethasone or methylprednisone.
FIG. 1 demonstrates the Transient Adverse Physiological Response (TAPR) to particulate lipid on administration of 90% perfluorooctylbromide emulsion (Imagent�BP) to anesthetized swine: (a) increase in mean pulmonary arterial pressure; (b) relative skin color; (c) cardiac output.
FIG. 2 demonstrates the TAPR response to 20% fluorocarbon emulsion (Fluosol�, Alpha Therapeutics, Los Angeles, Calif.) in anesthetized swine as increased mean pulmonary arterial pressure when administered alone, and compared to a decreased response with aspirin pretreatment.
FIG. 3 demonstrates the febrile response of swine to the parenteral injection of lipid dispersions: (a) Imagent�BP; and (b) Intralipid�20%, a 20% I.V. nutritive fat emulsion, comprising neutral triglycerides and phospholipids.
FIG. 4 demonstrates the effect of cyclooxygenase inhibitors in opposing the fluorocarbon (Imagent�BP) induced rise in mean pulmonary arterial pressure in anesthetized swine: (a) intravenous indomethacin (INDO); (b) oral ibuprofen, 1 h before injection; (c) oral aspirin, 1 h before injection.
FIG. 5 demonstrates the effect of cyclooxygenase inhibitors in opposing the febrile symptoms of the TAPR response to fluorocarbon emulsion (Imagent�BP) in conscious swine: (a) oral ibuprofen, 20 mg/kg, administered 1 h before injection; (b) oral naproxen, 5 mg/kg, administered 1 h before injection.
FIG. 6 demonstrates the effect of corticosteroids in opposing the febrile symptoms of the TAPR response to fluorocarbon emulsion (Imagent�BP) in conscious swine: (a) oral methylprednisone, 5 mg/kg, administered 12 h and 2 h before injection; (b) oral dexamethasone, 1 mg/kg, administered 12 h and 2 h before injection.
In all of the figures, data are represented as the mean�standard error of the mean (N =number of animals tested).
The present invention provides methods of preventing or ameliorating the symptoms of an undesirable physiological response which frequently accompanies the parenteral administration of lipid dispersions by the prophylactic administration of therapeutic drugs which act to oppose the response in patients receiving such treatment.
A lipid as described herein is any hydrophobic substance of a fatty, oily, or waxy consistency, extractable in nonpolar organic solvents, for example, ethers or chloroform, such substances including fatty acids, their esters and alcohols, phospholipids, mono-, di-, and triglycerides of the fatty acids (fats), sterols, and waxes, whether of natural origin, from mineral, vegetable, or animal sources, or synthetic compounds, alone or in combination with nonlipid substances or other lipid species.
A particulate dispersion as described herein is any system comprising a suspension of particles, and from about 1 nanometer to about 7 microns in size, such dispersions being, for example, liquid/air (aerosols); solid/solid; liquid/liquid (emulsions); or gas/liquid (foams). Lipid dispersions that are emulsions include those having a continuous aqueous phase wherein a lipid emulsifying agent is used to coat particles. Lipid dispersions also include liposomal preparations, comprising unilammelar or multilammelar lipid vesicles, made up at least in part of an amphipathic lipid such as a phospholipid, in suspension in an aqueous medium.
Fluid therapeutic agents comprising dispersed lipid particles or dispersed lipidcoated particles are parenterally administered to patients in a variety of medical regimens. Common lipid dispersions in therapeutic use in humans include, for example, emulsions of radiopaque compounds used as contrast media in diagnostic radiography, emulsions of fats used as nutritive infusions, liposomal formulations comprising lipid-encapsulated bioactive agents; lipids such as lipid A used as immunostimulating adjuvants, or the waxy or oily layers of biodegradable or bioerodible material into which therapeutic agents have been incorporated for delayed or metered release.
Fluorocarbons have the capacity to dissolve oxygen and are therefore useful as transport agents to supply oxygen to ischemic tissues in the body. Other physical properties of brominated or iodinated fluorocarbons make them useful as contrast agents for radiography, computer assisted tomography (CAT scan), ultrasonography, and magnetic resonance imaging (MRI). Fluorocarbon compounds are hydrophobic and are therefore immiscible with body fluids. Emulsification makes it possible to introduce these substances into the circulatory system of the body in a readily dispersible form in which the fluorocarbon droplets are coated with an amphipathic substance which is commonly lipid in nature.
The present invention comprises methods for prophylaxis of the inflammatory response that can accompany the parenteral administration of fluorocarbon emulsions. These emulsions can be made up of an appropriate fluorocarbon, an aqueous phase, and an emulsifying agent. The emulsion can be maintained within a defined pH range by a buffer, for example, an amino acid, phosphate buffer, or other physiologically suitable buffer.
Fluorocarbon molecules used in these emulsions may have various structures, either straight or branched chain or cyclic, as described in Riess, J., Artificial Organs 8(1):44-56 (1984). These molecules may also have some degree of unsaturation, and may also contain bromine or hydrogen atoms, or they may be amine derivatives. The fluorocarbons may be present in the emulsion in useful concentrations ranging from about 20% to 125% weight per volume (w/v). As used throughout, concentrations defined as weight/volume are understood to represent grams/ml and % weight per volume to represent grams/100 ml.
Emulsifying agents may be anionic, cationic or nonionic surfactants or combinations thereof as are well known to those in the chemical arts, or they may be mixtures of synthetic compounds such as Pluronic F-68™, a condensate of ethylene oxide with propylene glycol, as used in U.S. Pat. No. 4,073,879 to Long. Fluorosurfactants, such as those described by J. Riess et al., Int'l Symposium on Blood Substitutes, Montreal, May, 1987, are particularly suitable and can also be used. Emulsifying agents may also be mixtures of the above agents. Alternatively, emulsifiers may be natural amphipathic compounds such as phospholipids, particularly the phosphatidylcholines, wherein combined hydrophilic and hydrophobic properties enable the molecule to interface with both aqueous and fluorocarbon systems, thereby forming the emulsion droplets. There are various species of each class of phospholipids, such as the phosphatidyl-cholines, comprising various pairings of saturated and unsaturated fatty acids in the glycerol structures. Phosphatidylcholines are an abundant natural material (lecithin) which may be purified from egg yolk, or may be produced synthetically (Avanti Polar Lipids, Pelham, Ala.).
The phospholipid emulsifying agent is included in the emulsion, usually in the range of 2 to 14% w/v, increasing in proportion to the fluorocarbon concentration. The preferred amount of phospholipid is 2.5 to 5% w/v for an emulsion comprising 75% w/v bromofluorocarbon and 3.5 to 10% w/v of phospholipid for an emulsion with 100% w/v bromo-fluorocarbon. In a preferred embodiment, the phospholipid comprises at least 2% w/v of the emulsion.
Fluorocarbon emulsification may be carried out generally by processes which provide energy to the system to break up the fluorocarbon volume into small droplets of lipid coated fluorocarbon dispersed in an aqueous medium. In a sonication emulsification process, bursts of energy are released from the tip of a probe inserted into mixed emulsion components. In a mechanical emulsification process, such as performed by a Microfluidizer™ apparatus (Microfluidics, Newton, Mass. 02164), energy is supplied by mechanical stress applied to the fluid emulsion components.
The aqueous phase of the emulsion may have components dissolved therein which give the emulsions desirable physiological properties. For example, it may comprise an osmotic agent to bring the emulsion to physiological isotonicity. The osmotic agent may be sodium chloride, or it may be a polyhydroxyl compound, such as a sugar or mannitol. The aqueous phase will also contain soluble buffering agents.
Emulsions having various concentrations of fluorocarbon are useful in different applications, for example, when used as contrast media, for treating ischemia, or when applied intravascularly or within cavities of the body. Accordingly, useful formulations will include those having fluorocarbon concentrations in ranges equal to or greater than 20 to 125%, preferably 40 to 100%, most preferably 60 to 80%. Preferred fluorocarbon emulsion formulations are those disclosed in U.S. Pat. Nos. 4,865,836; 4,987,154; 4,927,623; and 4,951,673 (D. M. Long, Jr.), which are hereby incorporated by reference. The higher concentration emulsions are desirable for their efficiency in transporting oxygen or when used intravascularly to provide contrast for radiographic studies. Low concentration emulsions may be useful in imaging large body volumes. Fluorocarbon concentrations in emulsions are limited by the capacity of the emulsifying agent used, the efficiency of the emulsification process, and by a limiting viscosity.
Transient Adverse Physiological Response (TAPR) to the Intravenous Administration of Lipid Dispersions
Occasionally, human patients receiving fluorocarbon emulsions intravenously experience transient "flu" like symptoms, comprising mild chills or fever, anorexia or nausea, myalgia, particularly as lower back pain, and general malaise. To extrapolate that response to and from animals, we have observed that the intravenous administration of fluorocarbon emulsions to swine provokes an exaggerated, but predictable, physiological response comprising hemodynamic changes, an inflammatory response, and fever. The hemodynamic changes comprise an increase in mean pulmonary artery pressure, an increase in pulmonary vascular resistance, and a slight decrease in cardiac output. These exaggerated and consistent hemodynamic changes are peculiar to species belonging to the order Artiodactyla, and do not occur predictably in other animal species. These effects, together with the inflammatory response evidenced by flushing of the skin, are attributed primarily to activation of the cyclooxygenase pathway of the arachidonic acid cascade. A swine receiving a fluorocarbon emulsion injection also experiences a febrile response attributed to local hypothalamic release of prostaglandins.
The reaction of mammalian species belonging to the order Artiodactyla (sheep, goat, ox and swine) to injections of polystyrene microspheres, fat emulsions (Intralipid�), liposomes, and gram negative organisms has been clearly demonstrated. There is clinical evidence that human subjects respond to the parenteral introduction of lipid dispersions with symptoms analogous to those observed in swine. The intravenous infusion of nutritive 10% and 20% soybean oil fat emulsions, comprising neutral triglycerides and phospholipids in emulsified fat particles approximately 0.5 microns in size, into humans is found to produce symptoms of dyspnea, cyanosis, nausea, vomiting, headache, flushing, fever, sweating, drowsiness, and vertigo in about 1% of patients. (Intralipid(t product inserts 716013-1, 716023-1, (August, 1988), Kabivitrum, Inc. Alameda, Calif. 94501). Almost 20% of patients experienced one or many of symptoms comprising chills, rigor, fever, sinusitis, jaw pain, malaise, nausea, dizziness, urticaria, periorbital edema, and itching eyes after receiving intravenous injections of iodinated poppy seed oil (EOE13), in emulsified particles 1-4 microns in size, with a mean diameter of 1.7 microns, as a contrast agent for computerized tomography [CT], (Miller, D. et al., American Journal of Radiology 143:235-243 (1984). The placebo group in a study of the administration of a colloidal dispersion of amphotericin B/cholesterol sulfate formulations experienced headache and nausea (Guo, L. et al., as reported in Liposomes in Drug Delivery: 21 Years On, The School of Pharmacy, University of London, 12th-15th December, 1990).
We have designated the responses of swine to parenteral injection of fluorocarbon emulsions a Transient Adverse Physiological Response (TAPR). It is believed that the observed human response to fluorocarbon emulsions, even though different, is mediated through the same mechanism: that of the TAPR observed in swine. Further, based on the evidence that (a) the TAPR response to parenteral fluorocarbon emulsions parallels the response to parenteral lipid emulsions in both swine and humans, such reactions varying only in severity and duration; (b) the TAPR of swine to parenteral fluorocarbon emulsions is independent of fluorocarbon concentration or total dose; and (c) control groups in studies of liposomal therapy in humans, who presumably receive only empty liposomes (Guo et al., supra), also experience a TAPR-like response, the previously unrecognized provoking agent is the particulate lipid component itself. All are inflammatory responses arising from identical physiological and biochemical mechanisms, and for that reason the analogous response seen in response to the administration of other types of lipid dispersions in both species, is amenable to the same therapy and prophylaxis as that for the administration of fluorocarbon emulsions according to the methods of the invention.
Prophylaxis for the Acute and Delayed TAPR Response to Fluorocarbon Emulsions and Other Lipid Dispersions
The TAPR response of humans and other animals to the administration of fluorocarbon emulsions and other lipid dispersions as described above comprises both an acute transient reaction and a delayed reaction. The acute transient reaction of the swine to the intravenous administration of fluorocarbon emulsions comprises a rise in pulmonary artery pressure which may be accompanied by a slight increase in respiratory rate and a flushing of the skin; in human and other species the acute response includes flushing and lower backache. The delayed response in most species is febrile in nature and is not accompanied by any hemodynamic change.
Both the acute and delayed reactions can be prevented or ameliorated by prophylactic treatment with drugs that block the action of cyclooxygenase and prevent the activation of the arachidonic acid cascade. Both reactions can also be prevented or ameliorated by prophylactic treatment with steroids. Prophylaxis provides a preferred therapeutic management of both the immediate and delayed response because it allows the dosage of the patient according to his needs and independent of the fluorocarbon emulsion composition or rate of administration. However, a prophylactic approach to TAPR can be combined with co-administration of anti-inflammatory agents together with the fluorocarbon emulsion, as demonstrated in the following examples.
Domestic swine (10-20 kg) were used as models to study the response to fluorocarbon emulsions, based on the substantial body of published research regarding the sensitivity of the species to particulate injections. The primary response is a rapid and substantial rise in pulmonary vascular resistance and in some animals a significant degree of skin flushing. We have discovered that the mechanism of these responses is related to the particle-induced activation of pulmonary intravascular macrophages which reside in vast numbers on the endothelial lining of the pulmonary circulation in these species and is therefore not specific to fluorocarbon emulsions. Upon activation and as a part of the normal phagocytic response to foreign particles, these cells generate substantial quantities of prostaglandins and thromboxane secondary to the stimulation of the arachidonic acid cascade. Thromboxane in particular is a potent agonist in pulmonary vascular smooth muscle and will cause substantial increases in pulmonary vascular resistance. Prostaglandins (i.e. prostaglandin D2) are thought to cause the skin flushing reaction that is associated with the vitamin, niacin.
When swine were administered fluorocarbon emulsions, as described in Example 1, physiological responses similar to those known for the particulate injections described above were observed, comprising an increase in pulmonary arterial pressure, a decrease in cardiac output, and skin flushing. The effect was independent of the concentration of fluorocarbon in the emulsions, in view of the finding that both 20% Fluosol� and 90 to 100% Imagent� (Alliance Pharmaceutical Corp., San Diego, Calif. 92121) caused similar hemodynamic changes in the swine model. These responses were transient and were resolved by 2 hours post injection. Both responses are attributed primarily to products of the arachidonic acid cascade. Plasma samples taken at the beginning and during the course of the intravenous injection indicated no increases in levels of histamine, serotonin, or bradykinin.
The prophylactic administration of cyclooxygenase inhibitors, including intravenous indomethacin, oral ibuprofen, and oral aspirin, was found to prevent the acute hemodynamic response to fluorocarbon emulsions in anesthetized swine as indicated by increases in mean pulmonary artery pressure (Example 2; FIGS. 4(a), 4(b), 4(c)).
Swine also respond to fluorocarbon emulsion injections with a delayed febrile response. At approximately 2 hours post injection, there is a rise in core body temperature (Example 3) which continues for up to 6 hours post injection. There are no accompanying hemodynamic or hematological changes. The results indicate that cyclooxygenase inhibitors also block this observed delayed febrile response. The febrile reaction is not prevented by prophylactic treatment with aspirin or acetaminophen, but was significantly suppressed by prophylactic doses of ibuprofen, and attenuated by prophylactic doses of naproxen (a propionic acid derivative), FIGS. 5(a) and 5(b). Differences in efficacy among various specific drugs are correlated with plasma half-life. The active cyclooxygenase-inhibiting moiety of aspirin, acetylsalicylic acid, has a plasma half-life of 0.25�0.03 hrs; ibuprofen, the more efficacious agent, has a longer half-life of 2�0.5 hrs. While naproxen has a greater potency and longer plasma half-life than ibuprofen, its rate of oral absorption is influenced by the presence of food in the stomach, and is therefore difficult to achieve effective plasma levels of this drug by means of orally administered therapy.
The delayed febrile response is also effectively blocked by means of prophylactic treatment with steroids (Example 3B). Methylprednisone, FIG. 6(a), attenuates the response, whereas dexamethasone, FIG. 6(b), effectively suppresses or eliminates the response.
Other therapeutic agents are effective in treating the TAPR response described. One amino acid derivative, imidazole, a nitrogen containing cyclic radical present in the side chain of the amino acid histidine, has therapeutic properties which ameliorate the hemodynamic and inflammatory responses of subjects. The therapeutic effects of imidazole appear to flow from a number of physiological mechanisms. One theory of mechanism, underlying its anti-inflammatory effect, is related to its ability to inhibit the production of thromboxane.
For all the reasons stated above, adverse responses of the TAPR type to the administration of any lipid dispersion, including fat emulsions provided parenterally for nutritive purposes or parenteral liposomal therapies, can accordingly be treated or prevented according to the methods of the invention in a manner identical to that disclosed for treating the response to fluorocarbon emulsions.
The method generally comprises administering a prophylactic dose of a therapeutic drug of the types or classes described within a period of time before the injection of fluorocarbon emulsion or other lipid dispersion begins. In preferred applications, the administration of the anti-inflammatory agent is continued throughout the injection of the agent.
Anti-inflammatory therapeutic drugs can be administered orally, transdermally, or parenterally; i.e., intravenously, intraperitoneally, and the like, and in any dosage form as appropriate: (a) for oral administration, as tablets, capsules, or dissolved or dispersed in a liquid carrier; or (b) for parenteral administration; e.g., dissolved or dispersed in a suitable liquid carrier or emulsified. These drugs are available commercially in clinically useful form, as indicated above.
Whatever dosage form of the drug is used, the amount of the anti-inflammatory compound administered in humans should be sufficient to effect a substantial mitigation of the adverse hemodynamic and febrile responses associated with fluorocarbon emulsions in vivo. Generally, the effective dose can be estimated from the manufacturer's indicated dose on the product insert or on effective doses reported in pharmacology references, such as, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics MacMillan, N.Y., 1976; especially Chap. 17, Analgesic-Antipyretics, p. 314, and Chap. 72, Adrenocortical Steroids, p. 1604; or The Physicians Desk Reference, 1991 Edition, Medical Economics Corporation, Oradell, N.J. Preferred ranges for total dose of anti-inflammatory agents to provide prophylaxes for a TAPR-like response are from 0.300 to 3.000 grams of aspirin, 0.200 to 1.600 grams ibuprofen, and 25 mg to 200 mg indomethacin.
Effective prophylactic activity requires that a sufficient level of anti-inflammatory agent be present in the body of the patient before administration of the fluorocarbon emulsion or other lipid dispersion. To achieve the appropriate levels, doses of the drugs are given in the 24 hour period preceding the scheduled procedure. The times and intervals of the premedication schedule are determined by the half-life of the specific drug, according to procedures known to those skilled in the art. Preferred administration schedules for the anti-inflammatory agents are one dose about 1 hour prior to administration of the lipid dispersion and at appropriate intervals thereafter to maintain effective blood levels of the drug. Preferred ranges for total dose of corticosteroids is 5 mg to 100 mg for both prednisone and methylprednisone and 0.5 to 25 mg for dexamethasone. The corticosteroids can be administered preferably in two doses prior to injection of the lipid dispersion, most preferably at 12 hours and 2 hours before the fluorocarbon emulsion is injected, and at appropriate intervals thereafter as appropriate to maintain their effective blood levels. Dosage and schedule may be adjusted or modified according to experience and clinical judgment.
Administration of Anti-inflammatory agents in Conjunction with Lipid Dispersions:
In addition to the prophylactic therapy disclosed above, the TAPR response can be ameliorated by the administration of anti-inflammatory agents incorporated into fluorocarbon emulsions or other lipid dispersions to ameliorate the inflammatory response associated with the administration of these formulations in vivo. This therapy can be carried out either in conjunction with the prophylactic therapy disclosed or it can be used independently.
Copending application Ser. No. 07/417,796 provides fluorocarbon emulsions containing, as a component of formulation, imidazolyl-based anti-inflammatory agents which are inhibitors of thromboxane synthetase, cyclooxygenase, or phosphodiesterase activators. The emulsions may also include other similarly acting agents, for example, aspirin, ibuprofen, and indomethacin. These therapeutic agents are found to reduce the fever, anorexia, and malaise which occur during intravenous administration of fluorocarbon emulsions. Experimental work indicates that drugs which are imidazole derivatives, such as N(7-carboxyheptyl)imidazole, 1-methyl-imidazole, 4-(2-(1 H-imidazol-1 yl)ethoxy)benzoic acid (dazoxiben), and imidazo(1,5-pyridine-5-hexanoic acid) (CGS 13080), (Ciba-Geigy, West Sussex, United Kingdom) act effectively to inhibit thromboxane synthetase in the rat (Maguire, E. and Wallis, R., Thrombosis Research 32:15-27 (1983), and these drugs may be similarly incorporated into fluorocarbon emulsions or other lipid dispersions in comparable concentrations.
It has been found according to the above-referenced application Ser. No. 07/417,796 that symptoms observed in reaction to intravenous administration of fluorocarbon emulsions to tumor-bearing animals can also be alleviated by cyclooxygenase inhibitors such as ibuprofen. Other anti-inflammatory agents, comprising aspirin (acetylsalicylic acid) or other salicylates, indomethacin (1-(pchlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) and ibuprofen ((�)-2-(p-isobutylphenyl)propionic acid) may be added to fluorocarbon emulsions or to imidazole or histidine-containing fluorocarbon emulsions in established therapeutic concentrations to enhance the anti-inflammatory effects thereof. Accordingly, these drugs may be added to fluorocarbon emulsions of the invention in amounts sufficient to establish a total dose of 300 to 5000 mg of aspirin; 200 to 1600 mg of ibuprofen; and 25 to 200 mg of indomethacin.
Other agents are available which inhibit an inflammatory response by potent and selective biological actions. One of these is SQ 29,548, [1S-[1α, 2β(5Z) 3β4α]] -7-[3[[ 2-heptenoic acid (Squibb Institute for Medical Research, Princeton, N.J.) which acts to inhibit vasoconstriction and platelet aggregation by blockade or antagonism of thromboxane A2 receptors. The pharmacology of SQ 29,548 is described by Ogletree, M. L. et al. Jour. of Pharmacol. and Exper. Therapeutics 234(2):435-441 (1985). Another is LY53857 (Eli Lilly, Indianapolis, Ind.) which acts by blockade or antagonism of serotonin receptors. The action of LY53857 is described in Golino, P. et al. Circulation 79:911-919 (1989). These drugs can therefore be usefully incorporated into the fluorocarbon emulsions of the invention separately or together in doses of about 0.2 mg/kg body weight for each drug.
Further, the fluorocarbon emulsions can comprise several classes of non-steroidal anti-inflammatory agents; for example, those listed in the Merck Index (Eleventh edition, 1989), Merck therapeutic category 15, as derivatives of aminoarylcarboxylic acid; arylacetic acid;arylbutyric acid; arylcarboxylic acid; arylpropionic acid; pyrazoles; pyraxolones; salicylic acid; and thiazinecarboxamides. The emulsions can also comprise non-narcotic analgesics (Merck Therapeutic category 6) known to have anti-inflammatory activity. The dose ranges for parenteral administration of these agents are in some cases well known to those skilled in the art; in other cases, the effective emulsion concentration of the agents can be determined from known effective peak plasma levels and biological half-life data that appears in references such as the Physician's Desk Reference, 13th Edition (1992) published by the Medical Economics Company, at Montvale, New Jersey 07645; or in pharmacological textbooks and formularies.
All of the agents found to be efficacious in reducing the inflammatory response to fluorocarbon emulsions can be similarly applied in treating the inflammatory TAPR response that occurs following the administration of other lipid dispersions.
The present invention is described in detail using the following examples; however, the methods described therein are broadly applicable, and are not to be understood as limited thereby in any way whatsoever. In the following examples, all temperatures are set forth uncorrected in degrees Celsius.
Cardiovascular Response
These experiments were initiated in order to examine the cardiovascular effects of Imagent�BP (perfluorooctyl bromide emulsion, Alliance Pharmaceutical, San Diego, Calif. 92121) on domestic swine. The hemodynamic and skin color responses to a standardized intravenous infusion of the test emulsion (with or without prophylaxis) were compared to recent, but historical, responses to saline placebo infusion in young (10 kg) white-skinned domestic farm pigs.
All animals were fully anesthetized (ketamine-sodium pentobarbital), placed on positive pressure ventilation, and instrumented for determination of pulmonary artery pressure, cardiac output, ECG (electrocardiogram), right atrial pressure, and whole blood samples collections. Changes in skin color were also quantified using a relative color scale ranging from normal (light pink) to darker shades of pink and purple. Continuous electrocardiographs and oscillographic recordings of blood pressures were made. At least 30 minutes of baseline data were collected before intravascular administration of the substances. After control recordings, infusion of the pigs was carried out with 3 ml/kg body weight of either fluorocarbon emulsion as Imagent�BP (90% or 100% perfluorooctylbromide) or saline at a rate of 2 ml/min i.v. over 15 minutes. An additional sow was injected with Fluosol�, (Alpha-therapeutics, Irvine, Calif.), 20% fluorocarbon; 3 or 15 ml/kg, 2 ml/min. (FIG. 2, dose of Fluosol� equal in perfluorocarbon dosage to the Imagent�BP dosage).
Data were recorded at 5 minute intervals for the first 15 min, again at 30 minutes, and at 30 minute intervals between 30 and 90 or 120 min. The responses were recorded for a total of 90 minutes after the onset of infusion. Blood samples were drawn before, and 15 to 30 minutes after doses of control, test or reference material. Values for mean pulmonary arterial pressure (mPAP), cardiac output, cardiac index, CBC and skin color were determined.
The responses produced by Imagentg�BP and not seen in the placebo group included an elevation in mPAP, FIG. 1(a) (systemic arterial blood pressure was unchanged) and a skin flush, FIG. 1(b). Platelet counts rose immediately, and white cell levels increased 90-120 minutes post-infusion. No effect on cardiac output, FIG. 1(c), mean arterial pressure, or heart rate was noted.
The magnitude of the MPAP increments was much greater and more sustained in swine infused with Fluosol�(See FIG. 2) than in the Imagent�BP animals.
A series of experiments was conducted to evaluate the effects of prophylactic treatment with cyclooxygenase inhibitors on the acute hemodynamic response to intravenous injection of 90% Imagent�BP in anesthetized swine. Both control and test swine were treated by injection of fluorocarbon emulsion as described in Example 1. Animals receiving prophylaxis were administered indomethacin (0.5 mg/kg p.o.) prior to administration of the test article. Test swine were treated prophylactically with indomethacin, ibuprofen and aspirin. Indomethacin was administered intravenously in an initial bolus of 10 mg/kg followed by a continuous injection of 6 mg/kg/hr over the course of the fluorocarbon injection; Imagent�BP was administered intravenously to the treated animal and to a control for 15 min at a rate of 2 ml/min to a level of 3 ml/kg, FIG. 4(a). Ibuprofen was administered orally to a test animal in a dose of 20 mg/kg and 1 hour later Imagent�BP was administered intravenously to the ibuprofen treated animal and a matching control for 15 min at a rate of 2 ml/min to a level of 3 ml/kg, FIG. 4(b). Aspirin was administered orally at a dose of 5 mg/kg 1 hour prior to Imagent�BP (90%) injection; Imagent�BP was administered intravenously to the aspirin-treated animal and to a matching control at a rate of 2 mL/kg to a level of 3 ml/kg in a period of 15 min, FIG. 4(c).
Premedication with indomethacin virtually prevented all of the hemodynamic reactions in the Imagent�BP treatment groups. Ibuprofen significantly attenuated the mPAP responses, which returned quickly to baseline values. Prophylaxis with aspirin appeared to completely block any increases in mPAP. Aspirin was similarly effective in maintaining the blood cell counts (erythrocytes, leukocytes, platelets) at a level nearly identical to that seen with the saline control.
Swine were instrumented 48 hours prior to study for determination of core body temperature using a catheter-tipped thermistor, and for intravenous injection using an axillary vein catheter. On the day of study, core body temperature was determined at baseline and at regular intervals for 6 h after intravenous injection of Imagent�BP. The delayed febrile response to intravenous Imagent�BP (90% perfluorooctylbromide emulsion) was evaluated and compared to an equal volume injection of normal saline. Imagent(RBP induced a febrile response which peaked at approximately 3.5 h after initiation of the injection. The peak response constituted nearly a 1� C. rise in core body temperature.
A: Treatment with Cyclooxygenase Inhibitors
In test animals treated prophylactically with ibuprofen at an oral dose of 20 mg/kg, the febrile response was significantly suppressed throughout the 6 h time course FIG. 5(a). In test animals treated prophylactically with naproxen at an oral dose of 5 mg/kg, an attenuated febrile response was observed in comparison to the control group FIG. 5(b).
B: Treatment with Corticosteroids
The delayed febrile response to Imagent(VBP was evaluated in conscious swine after prophylactic treatment with two different corticosteroids. Methyl prednisone (5 mg/kg) was administered orally to a set of eight test animals 12 hours and again 2 hours prior to initiation of Imagent�BP injection. Dexamethasone (1 mg/kg) was administered orally to another set of eight animals using the same dose-timing regimen. In the animals receiving methylprednisone, an attenuated febrile response was observed after injection of Imagent�, FIG. 6(a); in those animal receiving dexamethasone, the Imagent�BP-induced febrile response was completely blocked FIG. 6(b).
These results suggest that prophylactic treatment with corticosteroids in general and with dexamethasone in particular will effectively suppress or eliminate the emulsioninduced febrile response in conscious swine.
It should be apparent from the foregoing that various other agents may be substituted in the examples to give similar results. Accordingly, the invention may be embodied in other specific forms without departing from it in spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not to be restrictive, and the scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All modifications which come within the meaning and range of the lawful equivalency of the claims are to be embraced within their scope.
|Cited Patent
|Filing date
|Publication date
|Aug 26, 1974
|Aug 17, 1976
|University Of Illinois Foundation
|Non-toxic brominated perfluorocarbons radiopaque agents
|Aug 16, 1976
|Feb 14, 1978
|University Of Illinois Foundation
|Brominated perfluorocarbon radiopaque agents
|Jul 3, 1979
|Jul 14, 1981
|Nyegaard & Co. A/S
|Process for the preparation of a sterile injectable physiologically acceptable solution of an X-ray contrast agent and solutions of the X-ray contrast agent and a buffer
|Jan 15, 1980
|Aug 25, 1981
|Juro Wada
|Contrast composition for angiography
|Dec 9, 1981
|Nov 15, 1983
|Dr. Franz Kohler Chemie Gmbh
|Protective solution for heart and kidney and process for its preparation
|Jan 14, 1986
|Sep 12, 1989
|Fluoromed Pharmaceutical, Inc.
|Brominated perfluorocarbon emulsions for internal animal use for contrast enhancement and oxygen transport
|Jan 4, 1988
|May 22, 1990
|Alliance Pharmaceutical Corp.
|Dissolution of gas in a fluorocarbon liquid
|Aug 19, 1988
|Aug 28, 1990
|Alliance Pharmaceutical Corp.
|Magnetic resonance imaging with perfluorocarbon hydrides
|Aug 5, 1987
|Jan 22, 1991
|Alliance Pharmaceutical Corp.
|Biocompatible, stable and concentrated fluorocarbon emulsions for contrast enhancement and oxygen transport in internal animal use
|Apr 25, 1996
|Sep 23, 1997
|Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion
|Title not available
|Oct 23, 1986
|Apr 29, 1987
|Kabi Pharmacia AB
|A nutritive emulsion having oxygen-transporting properties, and process for its preparation
|Aug 5, 1988
|Mar 15, 1989
|Alliance Pharmaceutical Corp.
|Fluorocarbon emulsions for in vivo use
|Aug 18, 1987
|Feb 9, 1989
|Chemex Pharmaceuticals, Inc.
|Method for the treatment of body tissues and the administration of drugs thereto
|Abe, H., et al. (1985) Role of histidine-related compounds to intracellular buffering in fish skeletal muscle. Am. J. Physiol. 249:R449-454.
|Aiken, J. et al. (1981) Endogenous prostacyclin contributes to the efficacy of a thromboxane synthetase inhibitor for preventing coronary artery thrombosis. Jour. Of Pharmacology and Experimental Therapeutics 219(2):299-308.
|Cadnapaphornchai, P. et al. (1982) Effect of imidazole on the recovery from bilateral ureteral obstruction in dogs. Amer. J. Physio. 243:F532-F536.
|Cao, Y-Z., et al. (1987) Regulation by vitamin E of phosphatidylcholine metabolism in rat heart.. Biochem. J. 247:135-140.
|Ferrari, F. et al. (1985) Behavioural pharacology of imidazole, a potential antidepressant agent. Arch. Int. Pharmacodyn 277:303-312.
|Ferrari, F. et al. (1986) Imidazole has similar behavioural effects to yohimbime. Psychopharmacology 88:58-62.
|Ferrari, F. et al. (1987) Effects of imidazole and some imidazole-derivatives on lisuride-induced mounting and aggressiveness. .Psychopharmacolgy 93:19-24.
|Fitzgerald, G.A. et al. (1983) Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J. Clin. Invest. 71:1336-1343.
|Golino, P. et al. (1989) Simulataneous adminstration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis. Circulation 79:911-919.
|Guo, et al. Liposomes in Drug Delivery: 21 years on the school of pharamcy, University of London, Dec. 12-15, 1990.
|Kazic, T. (1977) Action of methylxanthines and imidazole on the contractility of the terminal ileum of the guinea pig. European J. of Pharmacology 41:103-111.
|Kresh, J. et al. (1987) The relative buffering power of cardioplegic solutions. J. of Thoracic and Cardiovascular Surgeory 93(2):309-311.
|Lianos, E.A., et al. (1983) Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. J. Clin. Invest. 72:1439-1448.
|Maruire, E. and Wallis, R. (1983) In vivo redirection of prostaglandin endoperoxides into 6-keto PGFI alpha formation by thromboxane synthetase inhibitors in the rat. Thrombosis Research 32:15-27.
|Maruire, E. and Wallis, R. (1983) In vivo redirection of prostaglandin endoperoxides into 6-keto PGFI α formation by thromboxane synthetase inhibitors in the rat. Thrombosis Research 32:15-27.
|Matheson, I., et al. (1975) The quenching of singlet oxygen by amino acids and proteins. Photochemistry and Photobiology 21:165-171.
|Miller, D. et al. (1984) CT of the liver and spleen with EOE-13: review of225 examinations. Am. Jour. Of Rad. 143:235-243.
|Needleman, P. et al. (1979) Platelet and blood vessel arachidonate metabolism and interactions. J. Clin. Invest. 63:345-349.
|Needleman, P., et al. (1977) Application of imidazole as a selective inhibitor of thromoboxane synthetase in human platelets. Proc. Natl. Acad. Sci. 74(4):1716-1720.
|Needleman, P., et al. (1977) Thromboxane synthetase inhibitors as pharmacological tools: differential biochemical and biological effects on platelet suspensions. Prostaglandis 14(5):897-907.
|Nilsson, K. et al. (1976) Contraction of glycerol extracted fibres of smooth muscle by acetylocholine and imidazole in the presence of a Ca-binding microsomal fraction from rabbit colon. Acta Physiol. Scand. 98:407-411.
|Ogletree, M. et al. (1985) Pharmacological actions of SQ 29, 548, a novel selsctive thromboxane antagonist. J. of Pharmacol. and Exper. Therapeutics 234(2):435-441.
|Okegawa, T., et al. (1983) Endotoxin induces chronic prostagladin and thromboxane synthesis from ureter-obstructed kidneys: role of inflammatory cells. J. of Pharmacology and Experimental Therapeutics 225(1):213-218.
|Parkhouse, W., et al. (1985) Buffering capacity of deproteinized human vatus laterails muscle. J. Appl. Physiol. 58(1):14-17.
|Patterson, G. et al. (1985) Effects of imidazole and indomethacin on fluid balance in isolated sheep lungs. J. Applied Physiol. 58(3):892-898.
|Pukerson, M. et al. (1985) Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal renal abalation. Proc. Natl. Acad. Sci. USA 82:193-197.
|Redondo, J. et al. (1986/1987) Potentiation of interleukin-2 activity by levamisole and imidazole. Immunology Letters 14:111-116.
|Reiss, J. (1984) Reassessment of criteria for the selection of perflurochemicals for second-generation blood substutes: analysis of structure/property relationships. Artifical Organs 8(1):44-56.
|Riess, J. et al. (1987) Design, synthesis and evaluation of fluorocarbons and surfactants for in vivo applications new perfluoroalkylated polyhydroxylated surfactants. Int'l Symposium on Blood Substitutes. Montreal, May 1987.
|Saito, H., et al. (1984) Effects of a selective thromboxane A2 synthetase inhibitor on immune complex glomerulonephritis. Nephron 36:38-45.
|Schirmer, W., et al. (1987) Effects of ibuprofen, indomethacin, and imidazole on survival in sepsis. Current Surgeorgy Mar.-Apr. 102-105.
|Tai, H.-H. and B. Yuan (1978) On the inhibitory potency of imidazole and its derivatives on thromboxane synthetase. Biochem. Biophys. Res. Commun. 80(1):236-242.
|Zipser, R., et al. (1980) Exaggerated prostablandin and thromboxane synthesis in the rabbit with the renal vein constriction. Circulation Research 47(2): 231-237.
|Citing Patent
|Filing date
|Publication date
|Oct 20, 2011
|Nov 19, 2013
|Jaipal Singh
|Cerivastatin to treat pulmonary disorders
|Nov 18, 2004
|Jun 2, 2005
|Reinhart Gale M.
|Compositions for treating keratinous surfaces
|Apr 20, 2006
|Nov 16, 2006
|Mark Mugerditchian
|Production of emulsions of pharmaceutical compositions
|Oct 3, 2007
|Jun 26, 2008
|Revlon Consumer Products Corporation
|Compositions for Treating Keratinous Surfaces
|Mar 10, 2009
|Feb 17, 2011
|Sony Corporation
|Fuel cell and method for manufacturing the same, enzyme-immobilized electrode and method for manufacturing the same, and electronic apparatus
|U.S. Classification
|424/450, 514/263.31, 514/570, 514/165, 514/386, 514/277, 514/400
|International Classification
|Cooperative Classification
|European Classification
|Jun 5, 2000
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About KoritheMan
Basement-dwelling pseudo-otaku with a thrill for forecasting on the side.
By: KoritheMan , 7:46 AM GMT on December 24, 2012
The potential exists for a significant severe weather outbreak over the central Gulf Coast states on Christmas Day.
As an amplifying mid- to upper-level trough over the four corners region pivots eastward during the day today (Christmas Eve), it is likely to undergo significant intensification, resulting in surface cyclogenesis across the deep south. Model prognoses suggest that the trough will experience a negative tilt (northwest to southeast orientation), which is a situation that is usually helpful for severe weather. In addition, model soundings show some rather sizable hodographs evolving throughout the day today and especially into Christmas Day, along with substantial CAPE values. Surface-based storms may evolve across portions of central and eastern Texas this evening as the aforementioned trough begins to deepen. As the day progresses, this threat is expected to be maximized by a strong low-level jet which is expected to promote a threat for damaging winds within stronger convective downdrafts, which is supported by 0z soundings across Texas and Louisiana. In addition, very large hail appears to be possible with any elevated thunderstorms that develop within this region (central to east Texas, extending to perhaps far western Louisiana). There is obviously some tornado potential in these areas, but the overall threat appears to be somewhat conditional, namely in regards to the mode of storm development (surface based vs elevated). Directional and speed shear should be more than adequate in this region to promote a marginal tornado risk.
On Tuesday/Christmas Day, the real fun is anticipated to begin as the low-level jet reaches its maximum potential. Indeed, there appears to be enough speed shear within the lower troposphere to promote the potential for hurricane force wind gusts -- perhaps up to 70 kt in some of the most favorable areas. This would occur if the primary convective mode is a squall line or Mescoscale Convective Complex (MCS). Assuming we establish more discrete storms, these are the ones that will pose the risk for tornadoes, possibly strong and long-lived. The greatest threat for tornadoes will probably occur from west-central Louisiana to southwestern Alabama during the afternoon/evening hours of Christmas Day. Areas south of these areas appear to be more at risk for damaging winds, and there exists the potential for this event to be widespread, resulting in downed trees and power lines.
In addition, with very high precipitable water values of 1.5 to 2.0 inches, torrential rainfall and associated flash flooding will pose a considerable risk even if the other threats are somehow mitigated. The Storm Prediction Center (SPC) in Norman, Oklahoma has placed areas from central Louisiana to west-central Alabama under a Moderate Risk for severe weather, which is their second highest alert.
Figure 1. Latest 2-day Convective Outlook by the Storm Prediction Center (SPC) in Norman, Oklahoma. Note the Moderate Risk area highlighted from central Louisiana to west-central Alabama.
This has the potential to be a substantial severe weather episode. Please monitor the weather, and if a warning -- particularly a tornado warning -- is issued -- take cover immediately. Heed the warnings and do not venture outside if possible.
The views of the author are his/her own and do not necessarily represent the position of The Weather Company or its parent, IBM.
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Solution Brief: Select a RAID level for video surveillance solutions to meet customers' capacity, resolution quality, data protection, footage retention, and budget needs. (v.1, Oct. 2011)
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Lot 50: ENGLISH VICTORIAN BUCKLE FORM DIAMOND RING
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Campanile Montpellier Sud
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