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Associate Tax Analyst - San Francisco Do you want to work for a Pre-IPO powerhouse?  Do you want to work with great people? MuleSoft is going through a period of explosive growth and we want a Tax Analyst who will provide broad general support to all aspects and8/27/2015 San Francisco, CA Save This Job
The Senior Accounts Payable Specialist will be responsible for the timely and accurate posting of invoices into the accounting system and the weekly payment to vendors and employees. This role will liaise closely with senior managers for invoice authorization, and will8/16/2015 Cambridge, MA Save This Job
Finance/Accounting San Luis Obispo, CA Summary: The Associate Financial Analyst is responsible for the ongoing analysis of the Company?s operating and financial results. This position will be deeply involved in the Company?s annual budgeting process and will help drive the9/28/2015 San Luis Obispo, CA Save This Job
JOB DESCRIPTION The Senior AR Associate serves as a Subject Matter Expert (SME) for AR Follow-up within client-focused revenue cycle operations and assists coworkers and the Service Manager with questions and escalations as well as communicating issues, trends, concerns and8/19/2015 Louisville, KY Save This Job
Job Locations US-IL-Chicago Category Accounting/Finance Type W-2 Employee More information about this job: Overview: Shiftgig, one of Chicago?s hottest and fastest growing technology companies, is actively seeking a Bookkeeper. You will perform a variety of bookkeeping and8/31/2015 Chicago, IL Save This Job
ID 2015-3081 Job Locations US-MD-Landover Category Compliance More information about this job: What We're Looking For: 2U is seeking an experienced senior staff-level audit associate (CIA and/or CPA strongly preferred) to assist with the formation of an internal audit function8/5/2015 Landover, MD Save This Job
Location: Portland, OR, United StatesAPPLY ABOUT JIVE SOFTWARE Jive Software is the leading provider of modern communication and collaboration solutions for business. Our products empower people and organizations to work better together, using technology that adapts to their9/9/2015 Portland, OR Save This Job
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This etext was produced from The Counterfeit Man - More Science Fiction Stories by Alan E. Nourse published in 1963. Extensive research did not uncover any evidence that the U.S. copyright on this publication was renewed.
hated me because I scared them! It didn't hurt me too much, because I thought I knew why they hated me, I could understand it, and I went off to Bairdsley without even crying. They were going to come see me every week, but do you know how often they managed to make it? Not once after I was off their hands. And then at Bairdsley Aarons examined me and decided that I was a cripple. He didn't know anything about me then, but he thought psi was a defect. And that was as far as it went. I did what Aarons wanted me to do at Bairdsley. Never what I wanted, just what they wanted, years and years of what they wanted. And then you came along, and I came to the Study Center and did what you wanted."
It hurt him, and I knew it. I guess that was what I wanted, to hurt him and to hurt everybody. He was shaking his head, staring at me. "Amy, be fair. I've tried, you know how hard I've tried."
"Tried what? To train me? Yes, but why? To give
An intriguing story of a highly-gifted telepathic woman who can literally see things through other people's eyes and cast her mind out to anyone in her vicinity. The story is told from her point of view, but her point of view includes other people's thoughts, so the story includes good characterizations of several people.
It gives new meaning to "use it or lose it."
When the economic downturn ends Matty Cruzs co... Read more
Cara Devon has always suffered curiosity and im... Read more
A telekinetic teenager. A telepathic child. A p... Read more
A century after an apocalyptic war reduces all... Read more
Fall in love with the Kensington siblings in th... Read more
See it as donating a moment of your social media time, every little thing helps us improve and stay online.
The list of books below is based on the weekly downloads by our users regardless of eReader device or file format.
See more popular titles from this genre.

subset: commoncrawl


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18yr Evan Kenny GOP Elected Delegate Barred from GOP Convention
Maddow covers Tampa rally and 18-year-old RP delegate barred from GOP convention. Source: http://www.youtube.com/user/LibertarianPaulicy
By: Rebel_Radius | Comments: 15 | Views: 1359 | Votes: 0 | Shared: 0
Location: United States | Leaked: Jul-10-2012 in Politics
Three women on flight from Doha barred from entering France after refusing to remove their face veils
By Leon Watson PUBLISHED: 15:38, 12 June 2012 UPDATED: 16:11, 12 June 2012 A police union says three Saudi women who refused to remove their face veils at Paris' Charles de Gaulle a
By: usounddodgy | Comments: 97 | Views: 3129 | Votes: 2 | Shared: 1
Location: France | Leaked: Jun-12-2012 in World News
The human history of Dinosaurs Nobody barred
This time ANYONE can comment on this load of garbage. No-one is barred or banned. By me. Unlike those hatemongering anally retentive religious brain dead fuckwits. Not that I am judging them.
By: Agincort | Comments: 42 | Views: 1114 | Votes: 0 | Shared: 0
Leaked: Mar-3-2012 in Propaganda
White Congressional candidate barred from debate with black candidates
Liz Carter, a white woman from Georgia, has been barred from a debate for Congressional candidates. The reason? She's white. ***************** ***************** Because Liz Carter is white, sheâ€
By: Songun | Comments: 35 | Views: 7826 | Votes: 1 | Shared: 0
Leaked: Jun-4-2010 in News
Two women barred from flight to Pakistan for refusing full-body scan
Two women, one a Muslim, have become the first people to be barred from boarding a flight because they refused to go through a full-body airport scanner. Manchester airport confirmed today that the
By: easyrob33 | Comments: 38 | Views: 10394 | Votes: 1 | Shared: 0
Leaked: Mar-3-2010 in News
Palestinian expert on settlements barred from foreign travel
Palestinian expert on settlements barred from foreign travel By Amira Hass Interior Minister Eli Yishai has banned Palestinian geographer Khalil Tufakji, a resident of Jerusalem, from traveling
By: angloirishcad | Comments: 35 | Views: 7767 | Votes: 0 | Shared: 0
Leaked: Feb-8-2010 in Middle East
UK Fatties Barred From Giving Birth At Hospitals
Pregnant women are to be barred from giving birth at their local hospital if midwives consider them to be too fat, it emerged today. Mothers-to-be with a body mass index of over 34 – the equivale
By: MarkusMarone | Comments: 25 | Views: 11430 | Votes: 0 | Shared: 2
Leaked: Nov-13-2009 in News
Students: Chicago nightclub barred blacks
Where in the US constitution does it say you have the right to admittance to a nightclub ? It happens to all of us. ================================== (CNN) -- Students from Washington Universi
By: Steve677 | Comments: 48 | Views: 7040 | Votes: 0 | Shared: 2
Leaked: Oct-26-2009 in News
Immigrants who jeer at British troops in the street to be barred from gaining citizenship
Immigrants who jeer at British troops in the street or 'show disregard for UK values' will be barred from gaining citizenship. Migrants wanting a UK passport will also have to pass a history test
By: Hypnojive2 | Comments: 64 | Views: 10056 | Votes: 2 | Shared: 0
Location: Luton, Luton, United Kingdom (UK/GB) | Leaked: Aug-3-2009 in News
Murder victim's son barred from killer's hearing (Canada)
OTTAWA -- The son of a woman who was raped, strangled and left to rot in the woods has been blacklisted from the killer's parole hearing. Jeremy Mead, who was six years old when he watched his mom
By: pootin | Comments: 18 | Views: 10068 | Votes: 0 | Shared: 1
Leaked: May-18-2009 in News
Turkey: Israel must be barred from UN
Turkey's Prime Minister has called for Israel to be barred from the UN as long as it ignores international calls to stop war on Gaza. "How is such a country, which does not implement resolutio
By: red_pill | Comments: 27 | Views: 4667 | Votes: 3 | Shared: 0
Leaked: Jan-16-2009 in Middle East
Blind man's guide dog barred from restaurant for offending Muslims
Alun Elder-Brown, a recruitment executive, said he was left feeling "like a piece of dirt" after being barred from bringing the animal into Kirthon Restaurant in Tunbridge Wells, Kent, on religious gr
By: ezpose | Comments: 101 | Views: 7995 | Votes: 2 | Shared: 2
Location: Tunbridge Wells, Kent, United Kingdom (UK/GB) | Leaked: Dec-16-2008 in News
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By Memes!
By awkwardly trying to step out of a marriage proposal photo, one man stepped right into several other iconic pictures and, perhaps, the Meme Hall of Fame.
Published July 23, 2013 49k views More Info »
- Uploader
1,157 Funny Votes
665 Die Votes
48,876 Views
Published July 23, 2013
Categories: Funny Pictures Internet Memes Photoshopped Funny
The Extremely Awkward Original
Sorry, The Beatles. Big fan.
Excuse me, I forgot my thermos.
Let me get out your way, so you can finish.
Oh man, looks like you're doing something important here.
Hey, sorry. Just trying to cross the street. Don't let me slow you down.
Gosh this keeps happening. Congrats on the grandson.
Yikes. Not again. Why can't I remember? Always cross on green.
That's my bad. Hope this doesn't go on my permanent record.
Sorry everyone. I keep doing this.
Again, this one is definitely my bad.


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Regal Beach Club
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TripAdvisor Reviews Regal Beach Club Seven Mile Beach
Travel Blogs from Seven Mile Beach
No snorkeling, unfortunately
... him there. But the water today was choppy. Only Ira and Fran were good swimmers. So Ira canceled the tour. We were not happy about this tour guide - he should at least send someone to where he said we were supposed to meet them and tell us. A guy to write off for sure!
So what would we do? We decided to take a taxi to the 7-mile beach and that's what we did. We first walked with Chris and Lucy on the sandy beach for a while, admiring the aqua ...
Day 11, Grand Cayman
... ship we booked ourselves an island tour. It was cracking, a local man called Reed who had been doing island tours for 40 years. We took the coastal road to Dolphin cove via seven mile beach. Reed pointed out the oldest house in the island, the governors house and various other significant landmarks. Grand Cayman is actually a British Colony. Upon arrival at Dolphin Cove, we had a stop and a treat to a dolphin show. It was a ...
Arrival day
... Anyway, finally took off and had an uneventful trip. One interesting thing was that we flew over Cuba. We weren't sure if we were allowed to fly over.
Haven't seen much yet. The airport is less than 15 minutes from the condo. The condo is very nice. Ironically, Alex's room and bathroom are larger than ours. Very nice screened/covered balcony and a huge unscreened deck with a propane grill. We unpacked and then went down to the beach. The sand isn't as soft ...
Visiting Family in Cayman Islands
... too short visit. We didn't have a lot of time at Grand Cayman and our visit with Jason, Monette, and the girls, was far too short. But, here, we discovered family lore. We're so proud and so very happy for Jason and Monette for the way they are bringing up three very charming and lovely daughter's in Cayman. We can understand why Tony, is always waiting for more pictures of the girls, and why the families in Vancouver are always waiting for their annual visits. ...
Day 104/106 - El paradís / Paradise
... we went to the Coral Gardens where we say beautiful fish and nice coral. The highlight was a Big Green Moray Eel. Amazing sight. We also say a Stonefish which is very poisonous.
It was a very nice day. Tomorrow we are off for more adventures.
Hem canviat completament d'ambient, de Xile al Carib, passant per Lima i Miami. �s el ...


text: Articles de revista http://hdl.handle.net/2117/3112 2015-10-10T09:14:17Z Control-flow speculation through value prediction http://hdl.handle.net/2117/23987 Control-flow speculation through value prediction González, José; González Colás, Antonio María In this paper, we introduce a new branch predictor that predicts the outcome of branches by predicting the value of their inputs and performing an early computation of their results according to the predicted values. The design of a hybrid predictor comprising the above branch predictor and a correlating branch predictor is presented. We also propose a new selector that chooses the most reliable prediction for each branch. This selector is based on the path followed to reach the branch. Results for immediate updates show significant misprediction rate reductions with respect to a conventional hybrid predictor for different size configurations. In addition, the proposed hybrid predictor with a size of 8 KB achieves the same accuracy as a conventional one of 64 KB. Performance evaluation for a dynamically scheduled superscalar processor, with realistic updates, shows a speed up of 8 percent despite its higher latency (up to four cycles). 2001-12-01T00:00:00Z Network aware performance evaluation of prefetching techniques in CMPs http://hdl.handle.net/2117/23050 Network aware performance evaluation of prefetching techniques in CMPs Torrents Lapuerta, Martí; Martinez Morais, Raul; Molina Clemente, Carlos This study focuses on the importance of quantifying the effect of prefetching on the interconnection network of a multiprocessor chip. This kind of microarchitectural effects are often quantified using simulators. However, if prefetching traffic in a CMP (Chip MultiProcessor) system is to be accurately evaluated, simulators should simulate not only the memory hierarchy module and the multicore system, but also the network-on-chip. Unfortunately, no open-source simulator is able to evaluate all these elements at the same time. This paper describes how to develop a prefetching module for the gem5 CMP simulator and how to integrate this into the Ruby memory system. Moreover, by using the infrastructure developed in this study, this paper shows the importance of taking the network effect in prefetching-related studies into account, in order for accurate results to be obtained: not doing so may lead to mistaken conclusions. For this purpose, we have carried out a detailed analysis of the behavior of three different prefetching engines, providing not only the typical statistics for instructions per cycle and the miss rate, but also specific network and prefetching statistics. 2014-06-01T00:00:00Z Impact of finfet and III-V/Ge technology on logic and memory cell behavior http://hdl.handle.net/2117/21907 Impact of finfet and III-V/Ge technology on logic and memory cell behavior Amat Bertran, Esteve; Calomarde Palomino, Antonio; García Almudéver, Carmen; Aymerich Capdevila, Nivard; Canal Corretger, Ramon; Rubio Sola, Jose Antonio In this work, we assess the performance of a ring oscillator and a DRAM cell when they are implemented with different technologies (planar CMOS, FinFET and III-V MOSFETs), and subjected to different reliability scenarios (variability and soft errors). FinFET-based circuits show the highest robustness against variability and soft error environments. 2013-11-20T00:00:00Z Comparison of SRAM cells for 10-nm SOI FinFETs under process and environmental variations http://hdl.handle.net/2117/19931 Comparison of SRAM cells for 10-nm SOI FinFETs under process and environmental variations Jaksic, Zoran; Canal Corretger, Ramon We explore the 6T and 8T SRAM design spaces through read static noise margin (RSNM), word-line write margin, and leakage for future 10-nm FinFETs. Process variations are based on the ITRS and modeled at device (TCAD) level. We propose a method to incorporate them into a BSIM-CMG model card for time-efficient simulation. We analyze cells with different fin numbers, supply voltages, and temperatures. Results show a 1.8× improvement of RSNM for 8T SRAM cells, the need for stronger pull-downs to secure read stability in 6Ts, and high leakage sensitivity to temperature (10× between 40°C and 100°C). As a specific example, we show how the RSNM of a 6T SRAM cell can be improved by using back-gate biasing techniques for independent-gate FinFETs. We show how WLMN is increased by reducing the strength of pull-up transistors when reverse back-gate biasing is applied on it and how the RSNM can be increased by reducing the strength of access transistor by reverse back-gate biasing of pass-gate transistors. When combining these two techniques, RSNM can be improved up to 25% without compromising cell write ability for any sample. In general, when compared to previous technologies, read stability is untouched, writeability is reduced, and leakage keeps stable. 2012-12-01T00:00:00Z Exámenes no presenciales http://hdl.handle.net/2117/19454 Exámenes no presenciales López Álvarez, David; Sánchez Carracedo, Fermín; Cruz Díaz, Josep Llorenç; Fernández Jiménez, Agustín Los exámenes tradicionales están orientados a la evaluación sumativa, no a la formativa. Su objetivo es evaluar, no facilitar el aprendizaje, y debido a ello provocan un aprendizaje superficial más que un aprendizaje profundo: los estudiantes perciben que su futuro a corto plazo depende de su nota en un examen, por lo que orientan su estudio a aprobar dicho examen. En este artículo se propone una alternativa: un examen no presencial que realiza tanto evaluación sumativa como formativa. Es un tipo de examen que los estudiantes realizan fuera de clase a lo largo de un periodo de tiempo mucho más largo que el de un examen tradicional, lo que les ayuda a conseguir un aprendizaje profundo. En el artículo se presentan los resultados de una experiencia de 11 semestres utilizando este tipo de exámenes en una asignatura de la Facultat d'Informàtica de Barcelona. 2012-12-01T00:00:00Z The contribution of Type IA supernovae to the galactic iron abundances http://hdl.handle.net/2117/18906 The contribution of Type IA supernovae to the galactic iron abundances Bravo Guil, Eduardo; Isern Vilaboy, Jordi; Canal Corretger, Ramon The thermonuclear explosion of a mass-accreting white dwarf in a close binary system is thought to be at the origin of Type Ia supernovae. Standard models, which ignite carbon at densities higher than 2-4 x 10 exp 9 g/cu cm, give, however, a large production of species like Fe-54, Ni-58, and Cr-54, which has been regarded as incompatible with the solar system abundances. In this paper we analyze the weight of the constraints imposed by nucleosynthesis of the Fe-peak nuclides to the aforementioned scenario for Type Ia supernovae when the contribution of Type II and Type Ib supernovae to the galactic iron abundances is also taken into account. We find that the production of the aforementioned nuclides predicted by standard SNIa models is in fact compatible with the solar system abundances when the yields from gravitational-collapse supernovae are adjusted to reproduce the Ni abundances in low-metallicity stars. 1993-03-01T00:00:00Z On the photometric homogeneity of type IA supernovae http://hdl.handle.net/2117/18905 On the photometric homogeneity of type IA supernovae Bravo Guil, Eduardo; Domínguez, Inmaculada; Isern Vilaboy, Jordi; Canal Corretger, Ramon; Höflich, P.; Labay, Javier The dependence of the characteristics of the light curves of Type Ia supernovae on the ignition density of the progenitor white dwarf is studied with the aid of two models of propagation of the thermonuclear burning front: as a deflagration and as a delayed detonation. The light curve is computed from opacities which take into account the velocity gradients. The results show that in all cases the resulting light curves roughly agree with observations and that they are not sensitive to the ignition density of the white dwarf. Only the model corresponding to a deflagration starting at a density of 8 x 10 exp 9 g/cu cm shows a deviation from the general behavior, having a significantly lower luminosity at maximum. A dispersion of about 1000 km/s is found in the computed expansion velocities at maximum, which compares well with that found in the observations. 1993-03-01T00:00:00Z The migration prefetcher: anticipating data promotion in dynamic NUCA caches http://hdl.handle.net/2117/16508 The migration prefetcher: anticipating data promotion in dynamic NUCA caches Lira Rueda, Javier; Jones, Timothy M.; Molina, Carlos; González Colás, Antonio María 2012-01-01T00:00:00Z Implementing end-to-end register data-flow continuous self-test http://hdl.handle.net/2117/16287 Implementing end-to-end register data-flow continuous self-test Carretero Casado, Javier Sebastián; Chaparro, Pedro; Vera Rivera, Francisco Javier; Abella Ferrer, Jaume; González Colás, Antonio María While Moore's Law predicts the ability of semiconductor industry to engineer smaller and more efficient transistors and circuits, there are serious issues not contemplated in that law. One concern is the verification effort of modern computing systems, which has grown to dominate the cost of system design. On the other hand, technology scaling leads to burn-in phase out. As a result, in-the-field error rate may increase due to both actual errors and latent defects. Whereas data can be protected with arithmetic codes, there is a lack of cost-effective mechanisms for control logic. This paper presents a light-weight microarchitectural mechanism that ensures that data consumed through registers are correct. The structures protected include the issue queue logic and the data associated (i.e., tags and control signals), input multiplexors, rename data, replay logic, register free-list and release logic, and register file logic. Our results show a coverage around 90 percent for the targeted structures with a cost in power and area of about four percent, and without impact in performance. 2011-08-01T00:00:00Z TRAMS Project: variability and reliability of SRAM memories in sub-22nm bulk-CMOS technologies http://hdl.handle.net/2117/16283 TRAMS Project: variability and reliability of SRAM memories in sub-22nm bulk-CMOS technologies Canal Corretger, Ramon; Rubio Sola, Jose Antonio; ASenov, Asen; Brown, Andrew; Miranda, Miguel; Zuber, Paul; González Colás, Antonio María; Vera, Xavier The TRAMS (Terascale Reliable Adaptive MEMORY Systems) project addresses in an evolutionary way the ultimate CMOS scaling technologies and paves the way for revolutionary, most promising beyond-CMOS technologies. In this abstract we show the significant variability levels of future 18 and 13 nm device bulk-CMOS technologies as well as its dramatic effect on the yield of memory cells and circuits. 2011-12-22T00:00:00Z


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Recent Meetups
July 9 · 5:30 PMMarketing Meetup + Free Johnnie Walker Scotch Tasting!Welcome to Surrey Business MVPs 1st Summer Meetup of 2015! If you're a Scotch Whiskey lover AND you're having a tough time driving traffic to your business and don't... Learn more
May 1 · 12:30 PMBeta Collective 1-Yr Anniversary OPEN HOUSE!Time sure flies...and Surrey's first and only coworking space has miraculously reached its 1-year milestone! To thank all of those who believed in our project from Day 1... Learn more
April 10 · 11:00 AMTired Of Working Alone From Home? Why Not Try Coworking Instead?Beta Collective is once again inviting entrepreneurs to get out of their home or coffeeshop office, and come work for free out of our shared workspace alongside other... Learn more
March 25 · 11:30 AMFree Biz Workshop: Let's Talk Social Media (Facebook Strategies)Build revenue-generating content and gain long-term followers on Facebook. Bring your lunch and hear from Sherri-Lee Woycik, a Social Media Marketing Maven, here at Beta... Learn more
March 24 · 5:30 PMLearn all about 3D Printing! Cool demos and more...Hey gang, Surrey City Hall is playing host to the city's first meetup devoted to 3D Printing. Organizer Eugene Suyu, CEO of Tinkerine Studios, is inviting the business... Learn more
- See all past Meetups


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Topics > Alumni Association
You Deserve a Break Today!
Take a look into the past, with commentary on select ads provided by U.Va. history professor and BackStory co-host Brian Balogh.
Black Alumni Weekend
Over the second weekend in april, more than 1,800 people—including nearly 1,200 alumni—attended Black Alumni Weekend on Grounds.
Ordinary Genius
Twelve-year-old engineering student Henry Muhlbauer discusses his life on Grounds
On the Go
The new U.Va. Magazine app can now be downloaded through the iTunes Store, Amazon and Google Play.
For the Record
Keep in touch with your classmates! Help with the Alumni Association's new alumni directory.
Admission Advice
The Alumni Association's Admission Liaison Program provides a point of contact and a source of information for alumni families who have children applying to U.Va. Here
Milestones for Ridley
Past and present Ridley Scholars gathered together to celebrate Ridley's 25th anniversary.
Reunions 2012
On Reunions Weekend, 4,700 alumni and guests came home to Grounds to celebrate. They enjoyed seminars, class dinners and receptions for student and Greek organizations. Popular
9 Tips for New Grads
Whether you're anxious or eager—most likely a combination of both—the switch from full-time student to full-time resident of the "real world" will have some
Admission FAQs
What services does the Alumni Association offer to alumni and their children applying to the University?
The University of Virginia Office of Admission defines a legacy student as the
Sharing Connections
Kenneth Liu and Rodney Davis had similar interests—both wanted to strengthen their connection to the University after graduating. They found similar solutions among the Alumni Interest Groups
Painting Away the Blues
Gloomy weather spurred Rebecca Lewis to undertake a project that is now a bright spot among her artistic endeavors.
An acrylic painting of a path winding through
Interaction is the Bee's Knees
Photo by Christian Gromoll
When math professor Christian Gromoll takes students to visit his beehives this spring, learning about colony behavior will be only part of the equation. Discovering
Admission FAQs
The University has several groups of alumni volunteers that work to educate and engage prospective students through various events and programs. Two of these are UVaClubs and the Virginia
Imagination Without Limits
Alumna Fri Forjindam imagines the fantastic, then brings it to life at amusement parks.
Up on the Roof
The Rotunda renovation moved one step closer to completion as workers spent part of the summer tackling the next challenge: painting the roof.
Presidential Treatment
After studying at perhaps the most architecturally famous school in America, a number of U.Va. graduates have gone on to work at presidential places and end up preserving more than just buildings.
Architecture alumnus Michael Perry draws inspiration from birds to design new homes—that attach to the sides of other buildings.
Going the Distance
The 2014 Gallup-Purdue Index measures the long-term success of college graduates along three axes—and shows that U.Va. alumni come out ahead of their peers on each.
World Class
Former U.Va. women's soccer players Morgan Brian and Becky Sauerbrunn reunite with former coach Steve Swanson and bring home the World Cup.
Virginia Wins College World Series
The Cinderella-story Cavaliers defeated Vanderbilt in three games to take home the program's first national title.
Bringing the Team Together
Kristin J. Behfar offers three helpful tips for how teams can communicate more effectively and function more smoothly.


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A Focus on Energy: Royalty Trusts
Instapundit: America's IP Laws Need to be "Pruned Back"
Today, the Supreme Court declined to overrule its prior decision in Brulotte v. Thys Co., 379 U.S. 29 (1964), and maintained its ruling that a patent holder cannot charge royalties for the use of his invention where the use...more
Fifty years ago, in Brulotte v. Thys Co., the U.S. Supreme Court held that the collection of royalties after a patent's expiration constitutes per se patent misuse. Although criticized by scholars, antitrust agencies, and the...more
On average, the U.S. Supreme Court historically hears fewer than one patent case each term. For example, in the 14 years between 1982 and 1995, the Court decided only five patent cases. In the seven years between 1995 and...more
The U.S. Supreme Court Friday agreed to revisit a longstanding precedent that bars patent owners from collecting royalties after their patents have expired, even if those post-expiration payments represent compensation for...more
This week marks the first Monday in October, which for Supreme Court watchers is a holiday: the start of a new term. While not everyone gets that excited about the new term, there are several cases that the Court intends to...more
In 2007, the United States Supreme Court ruled that patent licensees could challenge their obligation to pay patent license royalties under a license agreement without first breaching the license agreement by halting royalty...more
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July 21, 2014
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Golf on TV: June 13, 2012
U.S. Open: ESPN, Thursday-Friday, 10 a.m.-noon, 2-7 p.m., Monday playoff, if necessary, 9-11 a.m.; NBC, Thursday-Friday, noon-3 p.m.; Saturday-Sunday, 1-7 p.m.
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Samsung begins production of 256GB V-NAND flash memory
Samsung has begun mass production of 256GB 3D V-NAND that will be used in its SSDs.
Samsung has begun mass production of 256GB 3D V-NAND that will be used in its SSDs.
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To learn more about Ty Alaxandar's story, read his recent AMTC interview. He is excited to continue following God's call on his life and is thankful for his supporting fans. "I love every single one of my fans. Whether you've been here since day one, or this is day one of you supporting my dream. If you support me I support you 100 percent. This journey won't be easy, but as long as I've got you all I'm grateful," Ty said.
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Page 1
The disconnect between animal models of sepsis and human
Daniel Rittirsch, L. Marco Hoesel, and Peter A. Ward1
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
of sepsis include cecal ligation and puncture, as-
cending colon stent peritonitis, and the i.p. or i.v.
injection of bacteria or bacterial products (such as
LPS). Many of these models mimic the pathophys-
iology of human sepsis. However, identification of
mediators in animals, the blockade of which has
been protective, has not translated into clinical
efficacy in septic humans. We describe the short-
comings of the animal models and reasons why
effective therapy for human sepsis cannot be de-
rived readily from promising findings in animal
sepsis. J. Leukoc. Biol. 81: 137–143; 2007.
Frequently used experimental models
Key Words: cecal ligation and puncture ? lipopolysaccharide ? ro-
Sepsis with its complications is still a major challenge in
contemporary medicine. Approximately 700,000 patients are
affected annually at huge costs for the healthcare system.
Depending on the standards of medical care, the worldwide
mortality rates in septic humans range from 30% to 70% (with
an aggregate mortality rate of ?50%) [1, 2]. Despite more than
20 years of extensive research and development of numerous
therapeutic approaches used in clinical settings, the incidence
of sepsis and the number of sepsis-related deaths are rising [2].
For a long a time, it was believed that sepsis was caused by an
overwhelming immune response of the patient to invading
microorganisms, but in only ?50% of the patients showing
symptoms of sepsis, bacteremia can be detected by standard
culture methods [3]. This was taken into account when the
term, systemic inflammatory response syndrome (SIRS), was
established in 1992 (see below). Thus, SIRS describes a hy-
perinflammatory state of the immune/inflammatory systems
represented by elevated levels of proinflammatory mediators
with development of multi-organ dysfunction syndrome and
multi-organ failure (MOF) [4]. A tight regulation of the im-
mune/inflammatory system is crucial for maintaining the bal-
ance between protective and tissue-damaging responses. SIRS
and sepsis are characterized by a loss of control over inflam-
matory responses, which can be provoked by a variety of
causative insults.
Several different animal models of sepsis have been devel-
oped, in most of which a local intra-abdominal infection is
generated to initiate systemic inflammation. Common experi-
mental models used in sepsis research currently pursue two
different strategies: a septic focus originating from injection or
release of feces into the peritoneal cavity or injection of bac-
teria or microbial components (e.g., LPS) into the abdominal
cavity or bloodstream. These approaches attempt to mimic
pathophysiological changes typically seen in septic patients,
ranging from bacteremia to SIRS to septic shock to multi-organ
dysfunction and subsequently, death. Numerous therapeutic
attempts have targeted proinflammatory mediators and have
had promising effects when used in animal models of sepsis,
but virtually all have failed to demonstrate clinical efficacy in
human clinical trials [5, 6]. Although typical symptoms such as
hyperthermia (progressing to hypothermia), tachycardia, and
tachypnea can be observed in septic animals, other parameters
such as levels of pro- and anti-inflammatory cytokines differ
between animals and humans with sepsis, providing a possible
explanation as to why human clinical trials based on effective
treatment strategies in animals have failed. As a result, the
initial euphoria and optimism to find a potent therapeutic
strategy for septic patients were dampened, and pharmaceuti-
cal companies often consider sepsis research to be a "grave-
yard" rather than a promising investment with payoff.
In this review, the more frequently used models of experi-
mental sepsis are discussed with their advantages and disad-
vantages and limitations. We try to bridge the gap between
animal and human sepsis to address the question as to why
insights from animal studies cannot be transferred categori-
cally from the laboratory to the clinical setting.
SIRS is defined by the combination of typical clinical symp-
toms in the presence (sepsis) or absence (SIRS) of microbial
(bacterial, fungal, or parasitic) infection: hypo/hyperthermia
(?36°C or ?38°C), tachycardia (?90 beats per minute),
tachypnea (?20 breaths per minute or PaCO2?32 mmHg), and
leukocytosis/leukopenia {white blood cell count ?12,000/mm3
or ?4000/mm3or presence of ?10% immature (band) forms;
Table 1; ref. [4]}. The most frequent sources of infection are
lung, abdomen, and urinary tract, but in only 40–60% of
1Correspondence: Department of Pathology, University of Michigan Medi-
cal School, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA. E-mail:
Received August 31, 2006; accepted September 1, 2006.
doi: 10.1189/jlb.0806542
0741-5400/07/0081-137 © Society for Leukocyte Biology
Journal of Leukocyte Biology
Volume 81, January 2007
Page 2
patients with sepsis does bacteremia occur. Originally, the
leading cause of septic shock was considered to be an infection
with gram-negative bacteria, but gram-positive infections in
sepsis are currently as frequent or more so than gram-negative
infections, followed by fungi and parasites as causative agents
of sepsis [7]. It should be noted that the frequency of fungal
sepsis has been on the rise [8].
At particular risk to develop SIRS or sepsis are elderly and
immunocompromised patients. The average age of patients
with sepsis or septic shock ranges from 60 to 65 years [2]. As
would be expected, the risk of mortality rises with increasing
age [1, 9]. In addition, a variety of underlying diseases as well
as presence of organ dysfunction and the individual's genetic
predisposition may increase the risk of SIRS and sepsis [10].
The initial insult or infection can lead to an overwhelming
reaction of the innate immune system with activation of proin-
flammatory cascades (e.g., the complement system) and ap-
pearance of various mediators (TNF-?, IL-1, IL-6, C5a, and
many more), resulting in SIRS and progressive MOF [11, 12].
At some point in sepsis, anti-inflammatory factors [such as
IL-4, IL-10, IL-1 receptor antagonist (IL-1RA), and others] are
released, perhaps representing a compensatory, anti-inflamma-
tory response, although this is debatable. Too much proinflam-
matory mediator release may trigger an uncontrolled, inflam-
matory response, resulting in consumptive depletion of the
clotting system, and excessive release of anti-inflammatory
mediators may contribute to immunosuppression or anergy,
which occurs in humans with sepsis. In this regard, there may
be iatrogenic reasons for compromised immune system func-
tion in septic patients. Inotropic agents, morphine, and allo-
genic blood transfusions are known to induce immunosuppres-
sion [13–16]. The coincidence of the imbalance of the immune
and inflammatory responses during SIRS and sepsis is still
poorly understood and requires further intensive, basic re-
LPS model
The systemic administration of endotoxin as a model of sepsis
underlies the notion that it is the host response that causes the
clinical features of sepsis and not the intact pathogen per se.
Endotoxin is part of the outer membrane of the cell envelope of
gram-negative bacteria. The term endotoxin is often used ex-
changeably with LPS, as LPS represents the main biologically
active component of endotoxin. The i.v. infusion of LPS as well
as its instillation into the abdominal cavity causes sepsis-like
symptoms, accompanied by similarities to pathophysiological
responses in patients with sepsis, such as hematological alter-
ations [17]. Furthermore, LPS infusion induces an increase of
proinflammatory cytokines in serum [18, 19], another parallel
to septic patients, whose elevated cytokine levels correlate with
severity of the disease [20]. TNF-? and IL-1 have emerged to
play a crucial role in the development of in vivo responses to
LPS and have become targets of therapeutic interventions in
septic humans [21]. The injection of recombinant TNF-? or
IL-1 can induce many of the features caused by LPS and by
sepsis itself [22, 23]. Based on promising results of TNF-?
blockade in LPS animal studies, several clinical trials were
performed using TNF-? antibodies or soluble receptors
(TNF-SR p55, p75). In trials using the SR p55, there was no
improvement of survival [24]. A study with p75 even showed a
dose-dependent increase of mortality in septic patients [24].
Overall, these trials failed to improve survival, although a trial
meta-analysis of a cohort of the more seriously ill septic
humans suggested a beneficial effect of TNF-? blockade [25].
The need to identify a subset of septic humans who would
benefit from TNF-? blockade substantially limits this type of
intervention in septic humans. Similarly, the blockade of IL-1
by the so-called IL-1RA did not significantly reduce sepsis-
related mortality in large clinical trials [26]. Only patients with
the highest risk of death seemed to benefit from use of IL-1RA
[27]. Finally, it turns out that the LPS experimental model and
sepsis in humans differ in several key points, especially in the
profile of cytokine release. Cytokine levels (TNF-?, IL-6, CXC
chemokines) peaked much later and occurred at much lower
levels in human patients with sepsis as well as in the model of
cecal ligation and puncture (CLP; described in detail below)
when compared with effects of LPS infusion [12, 17]. Such
findings suggested that the LPS model may not accurately
reflect sepsis in the CLP model or in septic humans. Another
confounding factor related to the linkage of TNF-? with sepsis
is the finding that in CLP mice, the interception of TNF-? with
antibody actually made survival worse [28–30]. The hypothesis
TABLE 1.Human Sepsis Criteria
hyperthermia or hypothermia
leukocytosis or leukopenia
SIRS ? infection
severe sepsis:
sepsis ? organ failure (lactacidosis, kidney failure, ARDS,aliver failure, thrombocytopenia)
septic shock:
severe sepsis ? hypotension
core body temperature ? 38°C or ?36°C
?90 beats/min
?20 breaths/min or PaCO2? 32 mmHg or respiratory support
?12,000 cells/mm3or ?4000 cells/mm3
aARDS, Acute respiratory distress syndrome.
138 Journal of Leukocyte Biology
Volume 81, January 2007
Page 3
that circulating endotoxin (LPS) causes shock in sepsis is
contestable [31], as when endotoxin is detected in the blood of
patients with sepsis, the levels are low [32]. It is not surprising
that blocking of endotoxin (with antibody) in septic humans as
well as other therapeutic interventions failed to show beneficial
effects [33]. Endotoxemia has been used in baboons [34] and in
human volunteers [19, 35] to define the temporal patterns and
diversity of mediators appearing in the blood compartment.
Infusion of live, gram-negative bacteria (Escherichia coli) has
been used in nonhuman primates [34]. In these models, block-
ade of TNF-? has generally been protective, but the real
question here is whether such findings can be applied to septic
humans. As a result of these many observations, the LPS model
may not represent a valid model to simulate sepsis, although it
can be used to determine the pathophysiology of endotoxemia
(Table 2).
Fecal pellet model and bacterial inoculum model
The model of fecal pellet peritonitis mimics sepsis induced by
i.p. administration of feces [36]. A pellet most commonly
within a fibrin clot is used [37, 38]. Without additives, feces
instillation leads to rapid death or recovery of the animals [39].
In many respects, the fecal pellet model, with the mixed
aerobic and anaerobic flora, resembles the CLP and the colon
ascendens stent peritonitis (CASP) models (below). The fecal
pellet model has been widely replaced by other models, such
as the bacterial inoculum model.
The bacterial inoculum model features a known number of
E. coli CFU, which are infused i.p. [40]. Usually, "adjuvants"
may be added [40], but the procedure can also be performed
without such additives [41, 42]. Injection of pure cultures of
bacteria without a carrier is considered to represent another
model of endotoxin shock rather than of peritonitis [43]. Nu-
merous variants of i.p. bacterial delivery exist, such as using
different species of bacteria (e.g., Bacteroides fragilis) or a
combination (E. coli plus B. fragilis) [44]. The mortality rate
depends on the species of animals used and the number of
bacteria administered, so that this model becomes more con-
trollable and reproducible than the fecal pellet deposition. The
fecal pellet and bacterial inoculum models mimic abscess
formation following peritonitis rather than abdominal sepsis,
especially when B. fragilis is involved [45]. This could be the
reason why treatment with antibiotics and fluid resuscitation
reduces the mortality rate to 20%; in this model, the abscess is
often walled off [46].
CASP model
A CASP model has been used to induce sepsis in mice. The
idea behind this model is that intestinal leakage (e.g., after
major abdominal surgery) leads to bacterial invasion of the
peritoneal cavity followed by organ failure, septic shock, and
death. A stent is inserted into the ascending colon, generating
a septic focus [47]. With a maximum mortality of 100% within
the first 48 h, the use of stents of different sizes can modify
mortality rates. The CASP model has been shown to result in
organ dysfunction similar to that seen in septic patients. Acute
lung injury, renal failure, and bone marrow cell dysfunction
have been reported following CASP [48–50]. Proinflammatory
mediators such as IL-1 and IFN-? are thought to play an
important role in this model of sepsis as well [47, 51]. Survival
in the CASP model seems to be TNF-?-independent as op-
posed to the CLP model (see below) [47]. Although pathophys-
iological changes after CASP appear to be similar to those in
human sepsis, the nature of the model limits its use. Stenting
the colon ascendens creates a constant leakage of bowel con-
tent, mimicking the situation of an insufficient anastomosis
following bowel surgery, which is often followed by sepsis.
CLP model
Similar to CASP, an abdominal septic focus leads to a polymi-
crobial infection of the peritoneum in the model of CLP,
eventually resulting in bacteremia, SIRS, sepsis, septic shock,
and usually death. This model features ligation immediately
below the ileocecal valve followed by through-and-through
needle puncture of the cecum. Subsequently, animals develop
typical symptoms of sepsis or septic shock and a high mortality
rate [28, 49]. Since the first description of the CLP procedure,
it has been used extensively as a model for experimental sepsis
[52]. Besides analysis of survival, the complex pattern of
cytokine expression has been investigated extensively. The
main proinflammatory cytokines, IL-6 and TNF-?, have been
shown to increase following CLP. Further, it has been reported
that high levels of IL-6 strongly correlate with survival after
CLP, a phenomenon that also occurs in human sepsis [53–55].
We have investigated the role of the anaphylatoxin C5a and its
receptor C5aR during sepsis. Using the CLP model, we have
found that blocking C5a or C5aR by administration of antibody
significantly improves survival and prevents the development
of organ dysfunction [56, 57]. Similarly, blockade of IL-6
results in increased survival of septic mice following CLP [58].
In contrast, if TNF-? were inhibited by administration of
TNF-? antibodies or using p55 (TNF-?R I)-deficient mice, the
mortality increased [57–60]. As described above, levels of
TNF-? peak earlier and are much higher in the LPS model
than in the CLP model.
Despite its clinical relevance and widespread use in sepsis
research, a concern of the CLP model is consistency. The
outcome after CLP is strongly associated with several factors
TABLE 2. Comparison of LPS Infusion and CLP Model in Rodents
LPS infusion Cecal ligation and puncture
clinical symptoms (rapid hypothermia) develop within a few hours
leukopenia followed by leukocytosis
early, high transient levels of proinflammatory cytokines
protective effects of anti-TNF-?
clinical symptoms develop within 12–24 h
leukocytosis or leukopenia
late, moderately high levels of proinflammatory cytokines
(IL-1?, TNF-?, IL-6, C5a)
anti-LPS or anti-TNF-? without protection
serum LPS levels very low to nondetectable
Rittirsch et al.
Disconnect between rodent and human sepsis 139
Page 4
during the procedure. The length of the cecum ligated is a
major determinant of mortality [59]. Moreover, not only does
the distance of cecum ligated influence survival, serum levels
of proinflammatory cytokines such as IL-6 and TNF-? are
increased markedly with increasing length of cecum ligated
[59]. Other factors affecting mortality following CLP are size of
needle used for the puncture, the number of punctures, fluid
resuscitation, and antibiotic treatment. As a consequence, it is
of great importance that the procedure of CLP is performed
with high consistency and reproducibility to evaluate findings
obtained from septic animals. In summary, the model of CLP
has become the most widely used model for experimental
sepsis and is currently considered the "gold standard" in
sepsis research, with the caveat that mixed aerobic and anaer-
obic gram-negative bacteria predominate (Table 2).
Nonhuman, primate models of sepsis
Sepsis models involving the i.v. infusion of live E. coli have
been used in baboons. Endpoints have included survival
curves, biochemical evidence of disseminated intravascular
coagulation (DIC), and appearance in serum/plasma of proin-
flammatory cytokines (IL-6, IL-8, TNF-?). Treatment with anti-
TNF-? or with antithrombin III markedly improved survival,
reduced evidence of DIC, and reduced blood levels of proin-
flammatory cytokines [60–62]. Treatment of E. coli-infused
monkeys with anti-C5a also improved survival and biochemical
parameters of sepsis [63, 64]. Infusion of LPS into baboons or
humans results in appearance of proinflammatory mediators in
blood and evidence of DIC [65, 66]. The infusion of live E. coli
has been described as a type of "acute intoxication" in which
similar blood levels of E. coli are not seen in septic humans
[67]. The levels of TNF-? occurring after infusion of LPS or
live E. coli into animals (including mice) are high and sus-
tained, in contrast to the transient levels of TNF-? in septic
humans [68]. All of these observations raise the question as to
whether the nonhuman, primate models of sepsis are surrogates
for human sepsis. Because of ethical reasons as well as the lack
of access to intensive care facilities, models of bacterial peri-
tonitis have not generally been used in nonhuman, primates,
creating a gap between rodent models of bacterial peritonitis
and septic humans.
In spite of substantial research in experimental sepsis models,
few if any of these promising findings have been shown to be
therapeutically efficacious in septic patients based on clinical
trials [69]. Only three therapeutic strategies that improve pa-
tient outcomes in sepsis are currently being used on intensive
care units. These include administration of low-dose glucocor-
ticoids, intensive insulin therapy, and infusion of activated
protein C (APC) [70–72]. However, APC represents one of the
first approved drug (with restrictions) for the treatment of sepsis
which may affect the inflammatory response. APC specifically
targets the clotting pathway and may affect parameters of the
inflammatory response. Patients with sepsis only benefit from
an early intervention, even if the therapy consists solely of
supportive, nonspecific treatment [73]. Therefore, the question
remains as to whether the animal models currently used to
study sepsis differ too much from septic humans or if research-
ers and physicians get lost in translation when attempting to
adapt their findings into daily practice.
The Shock Society and the International Sepsis Forum ded-
icated a symposium about that issue held on Oak Island, Nova
Scotia, in 2005. There is an abundance of preclinical models of
shock and sepsis, but we have yet to determine if and how
promising findings obtained from these models can be trans-
lated to the setting of human sepsis. Obviously, there are clear
differences between laboratory animals and patients. Mice and
rats are housed in specific pathogen-free areas, may often be
inbred strains, have the same age and weight, and most im-
portantly, do not have comorbidities (such as diabetes, hyper-
tension, and pre-existing immunosuppression among others)
seen in septic humans. In light of the fact that most humans
with sepsis are ?50 years old, and as most mice used in sepsis
are ?3 months old (with an average lifespan of 24 months), it
is possible that there is a "disconnect" between the study of
mice and humans with sepsis. Furthermore, the experimental
models have a precisely known time period. In contrast, we
encounter patients of different ethnicities, ages, and weight,
and most of the time, we are uncertain when the symptoms first
emerged. In addition, there are differences between rodents
and humans on the molecular level. For instance, human
C-reactive protein (CRP), an acute-phase protein and popular
marker for inflammation, is known to be an activator of the
complement system in humans, but in contrast, rat CRP does
not influence the complement system [74, 75]. The fact that
there are differences between TLRs in mice and in humans
could also affect interpretation of sepsis studies in the two
species [76]. Therefore, the simple transfer of knowledge from
animals to humans is highly illusive. To investigate underlying
pathomechanisms that will allow us to develop effective ther-
apies for sepsis patients, we must aim at models of sepsis that
resemble human sepsis as closely as possible.
Almost all of the sepsis models currently in use involve the
primary administration of bacteria, bacterial cell wall compo-
nents, or other organisms that subsequently trigger the immune
system. However, there are many other initial events such as
burns, major trauma, or surgical procedures that can lead to a
systemic inflammatory response. Therefore, findings obtained
from the CLP model, for example, can be applied to patients
with abdominal perforations as the initial event leading to
peritonitis and sepsis. However, other patients may have ex-
perienced different insults, which may eventually result in
sepsis as well, but other pathways may have been activated,
perhaps explaining why so many clinical trials have failed.
Many immunomodulating strategies have been used on the
basis of experimental data from animal studies. However, the
conditions seen in experimental animal models of sepsis do not
necessarily reflect the pathophysiological situation of patients
with severe sepsis or septic shock. As outlined above, sepsis in
animals and in humans depends on many variables and often
differs in its severity, which in turn may be closely linked to
beneficial effects of immunomodulating strategies. As already
mentioned, except for APC, none of the anti-inflammatory
strategies, which showed promising effects in experimental
140 Journal of Leukocyte Biology
Volume 81, January 2007
Page 5
sepsis, has improved the outcome in studies of patients with
sepsis [6]. This may be partly a result of the inhomogeneity of
patient populations in most of the sepsis clinical trials. Here,
inclusion and exclusion criteria seem to be crucial. Although
the above-mentioned definitions for SIRS and sepsis are crit-
icized for being too sensitive and not adequately specific, they
are still commonly used as the standard criteria for the enroll-
ment of patients into clinical trials [77]. This may explain why
some clinical trials involving small numbers of patients showed
significant results, but such beneficial effects failed to materi-
alize in controlled, randomized Phase III trials, as the benefit
of anti-inflammatory therapies in septic animals as well as in
humans with sepsis is tightly linked with the severity of disease
[78]. In other words, the most desperately ill patients had the
greatest benefit. Therefore and as a result of the fact that an
early intervention may be beneficial [73], the establishment of
a reliable system for diagnosing and staging sepsis is required,
just as it is represented by the tumor node metastasis (TNM)
system for classification of malignant tumor diseases. An at-
tempt in this direction was undertaken 2001 with the creation
of the PIRO system as a tool for clinicians as well as for
researchers to diagnose sepsis [10]. Besides the initial injuri-
ous or infective insult and the presence of organ dysfunction,
the patient's predisposition and current status of the immune
response are taken into account. In the future, a system for
diagnosing and prognosing sepsis should be endorsed by bi-
omarkers such as mediator profiles or receptor status [79].
Based on a "molecular fingerprint" providing information about
the individual situation and stage of disease, patient-targeted,
therapeutic strategies could then be pursued.
With regard to the human sepsis syndrome, sepsis models
such as CLP closely resemble the course of sepsis observed in
patients, characterized by an early hyperdynamic, hypermeta-
bolic state, followed by a pronounced hypodynamic, hypometa-
bolic state. However, we need to realize that there is no single,
ideal model of sepsis. The sepsis syndrome is a complex and a
therapeutically challenging disorder involving several organ
systems. It is in the nature of basic research that usually, single
pathways or mechanisms are being investigated in a rather
isolated manner in experimental models, whereas a septic
patient presents as a complex and interconnected system that
is out of balance. Although one of the attributes of using mice
for basic research lies within the availability of gene knock-
outs, one has to be aware that results obtained from animals
cannot suffice to draw conclusions on an individual patient.
Nevertheless, animal models represent an important and in-
dispensable tool to derive a better understanding of the under-
lying molecular and genetic mechanisms of SIRS and sepsis.
Thereby, the limitations of the particular animal model used to
investigate sepsis must be kept in mind.
How to bridge and extrapolate data from animal sepsis to the
setting of human sepsis is a daunting challenge. As indicated
above, the interventions that have been protective in septic
animals have not shown clinical efficacy in humans. This does
not mean that animal models of sepsis are irrelevant or that
they provide irrelevant information for application to humans.
It is likely that animal models will be useful, provided we
understand their limitations. First, we need to determine what
the most relevant animal models of sepsis are. As suggested
above, the most relevant model is probably not endotoxemia or
massive infusion of live organisms. CLP may be one reasonable
surrogate of human sepsis, but it may not yield information
relevant to the increasing incidence of sepsis caused by gram-
positive bacteria and fungi. Accordingly, it would seem that
several models of sepsis featuring live organisms should be
used. Furthermore, there is nothing wrong with the use of
products from live organisms, such as staphylococcal toxins,
provided limitations in the interpretation of such data are
acknowledged. Second, we need to consider if the use of
nonhuman primates will provide data that are different from
information generated from septic rodents. The major difficulty
here is the expense of such studies, the substantial animal
welfare concerns, and the need to have intensive care-type
facilities if nonhuman primates are to be used. It would cer-
tainly be important to know if the use of the larger animals
resulted in divergent data about the pathophysiology of sepsis
and the mediators involved as compared with findings in ro-
dents. Third, the age of the animals may lead to different data,
as described above. Should animal sepsis studies be rede-
signed to reflect more accurately the corresponding age of
septic humans where advanced age is clearly known to be a
risk factor? Mediator profiles in aging mice might be quite
different from those in young mice and might therefore require
a reassessment of the most important mediators. Fourth, should
animals undergoing sepsis studies be treated in manners sim-
ilar to septic humans? In addition to fluid resuscitation and
broad-spectrum antibiotic treatment, should they receive
agents such as morphine, inotropic drugs, or allogenic blood
transfusions, all of which can lead to immunosuppression as
well as other outcomes?
Clearly, there are no definitive answers, but these observa-
tions underscore the exciting challenges that lie ahead if we are
able to make new progress into more effective, therapeutic
interventions in human sepsis.
This work was supported by National Institutes of Health
Grants GM-29507, HL-31963, and GM-61656.
1. Angus, D. C., Linde-Zwirble, W. T., Lidicker, J., Clermont, G., Carcillo,
J., Pinsky, M. R. (2001) Epidemiology of severe sepsis in the United
States: analysis of incidence, outcome, and associated costs of care. Crit.
Care Med. 29, 1303–1310.
2. Martin, G. S., Mannino, D. M., Eaton, S., Moss, M. (2003) The epidemi-
ology of sepsis in the United States from 1979 through 2000. N. Engl.
J. Med. 348, 1546–1554.
3. Riedemann, N. C., Ward, P. A. (2003) Anti-inflammatory strategies for the
treatment of sepsis. Expert Opin. Biol. Ther. 3, 339–350.
4. Bone, R. C., Balk, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus,
W. A., Schein, R. M., Sibbald, W. J. (1992) Definitions for sepsis and
organ failure and guidelines for the use of innovative therapies in sepsis.
The ACCP/SCCM Consensus Conference Committee. American College of
Rittirsch et al.
Disconnect between rodent and human sepsis141


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Home Depot Hiring 450 Workers In Maine
The Home Depot will be hiring about 450 part-time and temporary workers at their 11 locations in Maine.
The Home Depot will be hiring about 450 part-time and temporary workers at their 11 locations in Maine.
Something that has been building for a couple of years and now has reached an all-time high is 'self-gifting'. There has been a 27% jumping in the last 5 years of people buying gifts for their own personal use. They usually spend $237 on self-gifting.
Girl Scout cookies are going digital. It's the Digital Cookie program that will go into effect this month. According to a spokeswomen for Girl Scouts of Eastern Massachusetts, Katie O'Reilly, it makes sense to have online sales in the digital age.
The United States national debt has now hit the $18 trillion mark. That is the highest the national debt has been and many are questioning how much money the government is spending under President Obama.
The heating season in Maine is underway and heating oil prices dropped this past week. The Governor's Energy Office reports that the average price of heating oil in Maine dropped three cents per gallon this week for a statewide average of $3.09.
Trying to celebrate the success of the Kansas City Royals at their amazing season and appearance in the World Series, Birdies Panties Shop in Kansas City designed 'Lucky Royals' boyshorts. They were all printed and ready to go on sale when Homeland Security showed up and confiscated the underwear.
About a week ago, The Just Cookin' Diner in Dallas, North Carolina took off all of the prices from their menu. Dana Parris, the owner of the diner, told the Gaston Gazette, that she had decided to leave her foods' pricing up to God and her customers.
Netflix wants to get into the movie business in a big way and to the end they have signed Adam Sandler to four movie deal. The movies will be exclusively on Netflix and Sandler will star in and produce each film.
Gas prices in Maine dropped slightly this week for a statewide average of $3.44 a gallon. That's according to the gas price-monitoring website gasbuddy.com.


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Lionel Richie
Sponsored By
Lionel Richie Lands Las Vegas ResidencyRichie will call Sin City home starting this spring.
Lionel Richie Named MusicCares Person Of The YearPharrell, Lady Antebellum and Luke Bryan will perform Lionel's songs at the annual MusicCares Person of the Year event in February.
JACK's Inside Track: Lionel RichieLionel's a Legend--who else do ya know that can stay up All Night Long while Dancin' On the Ceiling?
Elton John, Lionel Richie To Co-Headline BonnarooAlso on the bill: Jack White, Kanye West, Skrillex.
Lionel Richie Announces 'All The Hits All Night Long' TourGet ready to dance on the ceiling as five-time GRAMMY winner Lionel Richie hits the road this fall on his 'All The Hits All Night Long' tour.
On The Charts: John Mayer's 1970s-Inspired No. 1, Slash & Lionel Richie Make Top 10
Kelly Clarkson Talks Lionel and Premieres New Video
Santana, Willie Nelson Debut In Top 20 On Album Chart
On The Charts: Beastie Boys Re-Enter Top 20, Lionel Richie Falls Further
Lionel Richie Sings Duets, But Won't Host "Duets"
Madonna Breaks Another Record
Madonna & Lionel Richie Share Twitter Love As They Top Billboard Album Chart


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This property allows you to book online with a credit card. After submitting a reservation request, the owner or manager has 24 hours to accept, at which time your card will be charged and you will receive an email confirmation
Recent Ventana Canyon reviews
"This condo is beautiful and very comfortable. It is well equipped with highe-end kitchen appliances, washer and dryer, and luxurious bed and bathroom linens. There are lots of nice little touches throughout. Wifi access was a bit of an issue, but we were able to use the internet line access. Proximity to Sabino Canyon, the Ventana trail, and a supermarket made this a very convenient place to stay. I'd definitely stay here again!"Guest: Annette F. Date of Stay: January 2015 Review Submitted: February 3, 2015View listing
"This is a great area for Hiking, cycling or just hanging out at the pool. The complex has a couple of pools that are quite and peaceful. There is a gate on the property to the Ventana trail. The condo is wonderful with lots of windows and nice view of the mountains. The two bedrooms and bathrooms are at opposite ends so if you have guests there is privacy. Kitchen is well appointed with every thing you need. Owners are very accommodating with exceptional communication."Guest: tcycle Date of Stay: March 2015 Review Submitted: April 17, 2015View listing
"If the pictures of this wonderful retreat don't say it all then a stay here will. We were blown away by the sophisticated but practical interior design of this beautiful home. Everything was provided and no detail was missed. The huge walk in closet, modern kitchen and secluded outdoor patio make Chez Rochelle the most comfortable experience you can imagine the moment you walk in the door. Shopping is close by and Sabino Canyon Park is 5 minutes away. We will recommend Chez Rochelle to everyone we know and we will be back to enjoy its warmth and comfort for many years to come."Guest: Jim a. Date of Stay: November 2014 Review Submitted: December 9, 2014View listing
"So great I have reserved for Feb and Mar 2016. Condo has: convenient location to outdoor activities and services, is comfortable and well maintained and decorated, safe and quiet, and owner is very helpful. P.S. My little Dachshund loves it!"Guest: cheryl d. Date of Stay: February 2015 Review Submitted: May 9, 2015View listing
Featured Destinations: Palm Springs Vacation Rentals, Cabins in Colorado, Big Bear Cabin Rentals, San Diego Vacation Rentals


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Tips and strategies for the SAT test can be very helpful on test day and learning how to approach the test should be part of your SAT prep in addition to working on content
General tips for high SAT scores
Relax the night before the test
Don't cram. You are being tested on knowledge that you have accumulated over the course of the year. And over the past few months especially, you've been taking SAT prep. Studying at the last minute will only stress you out. Go to a movie or hang out with a friend -- anything to get your mind off of the test!
Rely on the strategies you've learned through SAT test prep
The SAT help you've gotten over the past few months has included a number of specific strategies that are guaranteed to increase your score during SAT testing. The tips below highlight a number of these strategies. If you need a brief refresher, be sure to check out the free SAT practice test available here at Peterson's.
Test specific tips for high SAT scores
Critical Reading: Sentence Completions
Sentence completions test both your vocabulary and your understanding of the logic of a sentence. Each question is a sentence containing either one or two blanks. Your job is to figure out which answer correctly completes the sentence. As you read, try to predict what word should go in each blank. Sometimes you can guess the meaning of one blank, but not the other. In that case, scan the answer choices, look for a word similar to the one you've predicted, and then eliminate the answer choices that don't match up.
Critical Reading: Reading Comprehension
The Critical Reading test now includes both long and short reading passages. Skim each passage to see what it's about. Don't worry about the details -- you can always look them up later if you need to. Just look for the main ideas. Then tackle the questions that direct you straight to the answer by referring you to a specific line in the passage. If you have time afterward, you can try solving the harder questions.
Writing: Multiple-Choice Questions
There are three types of multiple-choice writing questions on the SAT. The first group, Improving Sentences, tasks you with selecting the correct version - the one that is clearly written and grammatically correct -- of an underlined portion of a sentence. Sentence Error questions ask you to figure out which part of a sentence contains an error. Those on Improving Paragraphs test your ability to organize and clarify information. For all of these question types, think about the simplest, clearest way to express an idea. If an answer choice sounds awkward or overly complicated, chances are good that it's wrong.
Writing: Essay
You will be given an open-ended essay prompt (topic) that asks you to state a viewpoint and support it. Essays are scored holistically, which means that the final score is based on an overall impression. It is important to develop your ideas and express them clearly, using examples to back them up. Your essay does not have to be grammatically perfect, but it does have to be focused and organized. The standard five-paragraph essay can be an effective way to make your point.
Math: Multiple-Choice Questions
As you work through the multiple-choice math questions, you'll be given reference information (formulas and facts), but you'll need to know how to use them. You're allowed to use a calculator, but it won't help you unless you know how to approach the problems. If you're stuck, try substituting numbers for variables. You can also try plugging in numbers from the answer choices. Start with the middle number. That way, if it doesn't work, you can strategically choose one that's higher or lower.
Math: Grid-Ins
These questions are not multiple-choice -- you come up with an answer and fill it into a grid. The grid does not contain a minus sign, so there is no way to indicate that a value is less than zero. That means that an answer can't be a negative number. Unlike the multiple-choice questions, you won't be penalized for wrong answers, so make your best guess even if you're not sure. You can't grid mixed numbers, so if you get a mixed number as an answer, you'll have to convert it to an improper fraction or a decimal.


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God damn! Phantasy star online 2?!
I didn't see that coming and I couldn't be more stoked. After litterally thousands of hours spent in PSO over the last decade surprisingly I still havn't quite had enough of it.
PSO has been the game I keep finding myself called back to. The dreamcast failed, i kept playing. The servers went down, i moved to the PC. The PC community made their own servers and i've been there ever since.
Playing PSO with an xbox 360 controller and a keyboard on a PC using translated, modified japanese code isn't quite where i expected to be after a decade but here we are!
Sequel time!
I'm crazy, i know. But someone here must appreciate this announcement as much as I.
God damn! Phantasy star online 2?!


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LittlePete... Photographer
Tanya SmithModel Female Grand Junction, Colorado, US My MM URL: http://www.modelmayhem.com/Taynamarie
Mayhem # 2614964
About MeMy name is Tanya I'm looking for some networking here, I would love to pursue a career in modeling.. I've done photo shoots and promotional events for Hooters, Budweiser, Harley Davidson and other independent companies. I been told I'm a natural when it comes to entertaining people and being in front of the camera, there's nothing else I'd rather do.
LittlePete... Photographer
Michael McCarthy Photographer
Gary Rickard Model
Matt Janson Photography Photographer
bngprod Photographer
Hindley Model
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The Florida judge for George Zimmerman's second-degree murder trial said Thursday that the jury will be allowed to consider a lesser charge of manslaughter.
The judge made that ruling in response to a filing from prosecutors, NBC reported. Attorneys for the plaintiffs had asked for the inclusion of two lesser charges — manslaughter and felony murder in the third degree with child abuse as the aggravating factor. The judge allowed one — manslaughter.
Defense attorneys had protested the idea of the jury being allowed to consider lesser charges at all.
SEE ALSO: Miami police riot training 'purely coincidence' leading up to George Zimmerman verdict
Mr. Zimmerman could face life in prison if convicted of second-degree murder in the February shooting death of 17-year-old Trayvon Martin. He's claimed he shot the teen in self-defense, in accordance with Florida "Stand Your Ground" gun laws.


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Wednesday, October 24, 2012
6 comments
Being an Indian I grew up in scented environments--the most frequent scents wafting in on the Breeze from our huge Garden.For me the Floral Scents have always fascinated me--and my childhood was spent experimenting with Flowers---trying to make ... Read more
Tuesday, October 23, 2012
8 comments
Monday, October 22, 2012
7 comments
Sudhir---Planning some Mischief
Sudhir was a great one for throwing Parties---but celebrating his Birthday was a big no-no for him.The same courtesy however did not extend ... Read more
Monday, October 22, 2012
5 comments
Compliments of HICOCKHALEY
Borrowed from CHERIRIDELL
Where is your Cell?
Your Mother?
Your Father?
Your Favourite Thing?
Your Dream last night?
Favour... Read more
Friday, October 19, 2012
9 comments
Laughing at Me
New York 2007
Read more
Thursday, October 18, 2012
8 comments
Meha, Sudhir and me
Lotta and Sudhir
Read more
Tuesday, October 16, 2012
10 comments
Sudhir at the Computer
Laughing at something Sayali said!!!
A Human heart is like a "Maha Sagar" or a... Read more
Monday, October 15, 2012
10 comments
Well I'm getting orders--like the Spider I invite these poor Folks into my "Kitchen" instead of "Parlour"!!!The Ingredients are fresh and the Food is good,light and tasty----making those that eat my Tiffins love it.The biggest problem however i... Read more
Friday, October 12, 2012
8 comments
That I like to cook is an understatement--that I find Cooking a great way to release pent -up Emotions is another---but I had never thought of turning it around as a method to keep myself busy!!The local Branch of the Bank where I do my Transact... Read more
Sunday, October 07, 2012
6 comments
Writing about my life with Sudhir has been therapeutic----it has acted like a release for some of my feelings and innermost thoughts--which surprisingly I can never vocally express!!!It's not that I don't talk--I've been amply endowed with the "... Read more
Saturday, October 06, 2012
6 comments
Accepting Cancer came easy to me because I honestly had lived a good life---and I believed in going while everything was good.Unfortunately I did not go---but seeing Sudhir's face gave me the strength to face the rigours of a highly toxic Chemo-... Read more
Friday, October 05, 2012
5 comments
After Dengue, the first 6 months I was on a strict Diet--surviving mainly on Boiled/steamed food---for too many Salads too could cause a problem of Stomach Infections.My Liver Enzymes and the rest settled back into their original rhythm and once... Read more
Friday, October 05, 2012
3 comments
By early 1989 I had begun suffering from tremendous Water Retention and severe Cramps before my periods---making it impossible for me to reach for anything on the floor without suffering a spasm instantly.A visit to my Gynaec. Usha Tai revealed ... Read more
Thursday, October 04, 2012
5 comments
Our Life before I fell sick was really going great.Our daughters had grown up---Sudhir was a Grandpa at 50 and I a Grandma at 41---the birth of our grand daughter Meha adding a new dimension to our lives.We were still young young enough to enjoy... Read more
Thursday, October 04, 2012
10 comments


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