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Industrial Cameras
Lumenera Corporation
Lumenera offers a wide range of industrial cameras based on CCD and CMOS sensors, providing a variety of unique camera features to satisfy your imaging applications.
Lumenera cameras leverage the most used interfaces, to ensure that your images get from the camera to your computer using the method that makes the most sense for your application, none of which require a costly and complex frame grabber.
- USB 3.0 for high transfer speeds allowing for faster frame rates at a high resolution
- USB 2.0 to rely on the stability, ubiquity and ease of a plug-and-play interface
- GigE for an extremely long reach using low cost standard cables.
Lumenera cameras feature a standard GPIO connector for external synchronization of lighting and peripheral device control.
Lumenera Industrial Cameras
Mightex Industial Cameras
USB Cameras
CCD - Line Scan Cameras ( USB 2.0 )
PixeLINK manufactures, optimizes and markets industrial cameras for a range of industrial vision and machine vision system applications.
Download - Industrial Machine Vision Cameras Catalogue
New USB 3.0 Cameras
PixeLINK's Prometheus and Hyperion USB 3.0 camera lines are ideal for OEMs and organizations seeking reliable, high quality industrial cameras with fast data transfer speeds.
More details can be found at Pixelink's web site:
XIMEA are in the forefront of machine vision and imaging technologies, spearheading the advancements of research which resulted in remarkable product lines like xiQ - USB3 Vision cameras, xiRAY – X-ray cooled CCD cameras. Breakthroughs followed with first PCI Express camera, USB 3.0 to CameraLink cable and recently smallest Hyperspectral cameras in the world.
- USB3 Vision compliant cameras - xiQ
- USB 3.0 with CCD scientific cameras - xiD
- Hyperspectral cameras based on USB3 - xiSpec
- Subminiature USB Cameras 5Mpix
- PCI Express high-speed cameras - xiB
Next >> Particle image velocimetry - PIV


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The Whole Frog Project
The DSD "Whole Frog" project is intended to introduce the concepts of modern, computer based 3D visualization, and at the same time to demonstrate the power of whole body, 3D imaging of anatomy as a curriculum tool. The goal of the Whole Frog Project is to provide high school biology classes the ability to explore the anatomy of a frog by using data from high resolution MRI imaging and from mechanical sectioning, together with 3D surface and volume rendering software to visualize the anatomical... More
Material Type: Tutorial
Technical Format: HTML/Text
Date Added to MERLOT: March 23, 2006
Date Modified in MERLOT: March 23, 2006
Submitter: Scott Cooper
Reviewed by members of Editorial board for inclusion in MERLOT.Editor ReviewVery good quality; in queue to be peer reviewedavg:
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subset: commoncrawl


text:
Straw dolls Killing Curse
by: Runnable • 37
All Android applications categories
All Android games categories
by: Runnable • 37
Let's spread the stress of everyday life.
Sometimes daily, and unpleasant, but I will stab the knife macro to write a name on this doll.
I feel fine. Murderer, too lost.
How To Play
How to play, it will be smooth.
To write the name of the asshole, just, just tap the screen.
That way, knife'll stick Gusagusa to face.
But, we I do not know the person even really dead.
I There is also a ranking. I watch who is in who did dispel a grudge.
Tags: curse straw dolls , straw and curses , curse straw dolls wiki
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from 37 reviews
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Free - V13.0 - 8M
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This Cleeng WordPress plugin is no longer supported, as we decided to discontinue it in February 2014. Please see for reasons and alternative solution
We don't longer support WordPress plugin but you can still sell your content (blog posts, web pages, images, videos and more) using our API: http://cleeng.com/open.
Questions? Contact us at email@example.com so we can help you with your migration.
Requires: 2.9.2 or higher
Compatible up to: 3.5.2
Last Updated: 3 years ago
Active Installs: 20+
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Adorned with the lavish scent of vanilla cupcake the FOREO candle is a cute tea light perfect for creating a relaxing atmosphere in any room. K.D.
Thank you for visiting FOREO Cupcake Candle (Free Gift) on happybeauty.co.uk
We bring the products from many websites to one website for you to search, save and compare.


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Companies that aspire to be better environmental stewards invest in strong environmental, health and safety management, otherwise known as EHS. From an environmental standpoint, it involves creating a systematic approach to managing waste, complying with environmental regulations, or reducing the company's carbon footprint. Successful EHS programs also include measures to address ergonomics, air quality, and other aspects of workplace safety that could affect the health and well-being of employees.
Management-level environmental, health and safety, and sustainability leaders are the environmental stewards of the corporate world, working behind the scenes at many of the country's largest companies to comply with regulations, advocate for progressive environmental policies, and protect workers' safety.
Engineers or scientists by training, EHS Managers bring a highly specialized skill set to their work, marrying technical expertise with management skills to translate corporate policy into practice.
With the advent of sustainability, our members' skills and experience are more important than ever. EHS leaders are increasingly responsible for designing and implementing strategies to take companies beyond compliance.
These initiatives involve tasks such as:
The corporate EHS function, which oversees environmental, health and safety compliance began to merge at the management level around 1990.
The first area is environmental management, which emerged as a profession in the 1970s, following the creation of the U.S. Environmental Protection Agency (EPA) and other state-level regulatory systems. As companies began limiting waste to prevent pollution, they needed engineers to adapt scrubbers, filters, and other process changes to existing manufacturing systems. Workplace safety and occupational health also grew in importance during this time, with the passage of legislation such as the Occupational Safety and Health Act of 1970.
Over time, companies developed systematic way of complying with environmental, health and safety regulations. Corporations began tracking key measures and looking for ways to improve their performance. Then, in the 1990s, improvements in data technology management made it easier for an organization to analyze its operations. Around that time, corporations began to merge oversight for environmental, health and safety programs through a new management role called EHS. The newly appointed leaders, who began their careers in one of the three sub-disciplines, started to create systems to drive EHS progress across all operations.
Today, with the advent of sustainability, EHS professionals are leading corporate efforts toward sustainability. Building on their decades of experience, EHS leaders are striving to meet this challenge, creating systems to reduce energy use, conserve water, and better communicate with stakeholders. Indeed, a 2009 NAEM survey found that two-thirds of the sustainability initiatives at member companies are being led or managed by the EHS function.
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"As a professional association, our mission is to serve our members," said Executive Director Carol Singer Neuvelt. "We hope everyone will take this opportunity to share their input and help us improve the quality of your NAEM experience." The association uses responses from the annual Member Feedback survey to innovate its programming and finetune its benefits.
Today the National Association for Environmental Management (NAEM) published its first report from the EHS & Sustainability Software Ratings Project, a new research initiative to evaluate user satisfaction with commercial software systems.
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Laos to Vietnam
Take an unforgettable journey through the beautiful landscapes and captivating cities of Laos and Vietnam. Discover the delights of Luang Prabang and Hoi An, visit revered Buddhist temples and ornate palaces, explore mystical caves and colourful markets, cruise Halong and the Mekong and top off your adventure in Saigon!
Countries Visited: Laos, Vietnam
Please Note: from 01 Feb 2017 this tour will become 16 days in length. Please see our Laos to Vietnam - 16 day tour for details.
Saturday. Welcome to Laos! Airport arrival transfer and hotel check in. Spend the afternoon and evening at leisure.
Overnight: Vientiane
Vientiane city tour
After breakfast we explore the charming capital on a city tour. Highlights include Wat Si Saket - the oldest Buddhist monastery temple in the country, the former royal temple of Haw Pha Kaeo, Pha That Luang monument and the Buddha Park with its incredible array of Hindu and Buddhist sculptures. We also visit to the COPE Centre, a charity working with victims of unexploded bombs and mines. End the day with a spectacular sunset dinner besides the Mekong River.
Overnight: Vientiane | Breakfast, Dinner
Vang Vieng
Vientiane – Vang Vieng. This morning we journey north through breathtaking scenery to Vang Vieng. Along the way we visit Ban Keun, famous for its salt extraction plant and a village of local Lao rice wine whiskey distillation. A next stop is the busy and colourful market of Thalat market, where local hill tribes come to trade and shop and the
11th century archaeological site of Vang Xang. Upon arrival in picturesque Vang Vieng, spend the remains of the day at leisure or opt to explore the local caves, take a scenic bike ride or go tubing along the river.
Overnight: Vang Vieng | Breakfast, Dinner
Tham Jang Cave, Ban Huai Ngai village
Vang Vieng – Luang Prabang. We explore the famous caves of Tham Jang this morning and visit Ban Huai Ngai village before travelling north to the enchanting Luang Prabang.
Overnight: Luang Prabang | Breakfast
Temples of Luang Prabang
Consider rising early this morning to view the daily ritual of saffron-clad monks and their procession down the streets of Luang Prabang collecting alms from the residents. Then a morning tour, taking in the highlights of Luang Prapang - the fabulous UNESCO Listed former royal capital. Sightseeing includes the ancient temples of Wat Visoun
and Wat Aham, the Ock Pop Tok weaving centre and the beautifully ornate former Royal Palace. In the afternoon we stop at ethnic minority villages before arriving at the beautiful Khouangsi waterfall.
Overnight: Luang Prabang | Breakfast
Wat Sene & Wat Xieng Thong
Discover more of Luang Prabang's holy sites with a morning visit to Wat Sene and the magnificent Wat Xieng Thong. Then we set sail on a scenic cruise up the Mekong River to visit the incredible Pak Ou caves, which are crammed with Buddha images of all shapes and sizes, stopping at villages en route to sample local rice wine and shop for local handicrafts.
Overnight: Luang Prabang | Breakfast, Lunch
Fly Luang Prabang - Hanoi
Luang Prabang - Hanoi. Today offers free time for you to relax by the swimming pool or further explore Luang Prabang. Late this afternoon we fly from Luang Prabang to Hanoi in Vietnam. Day 8 offers free time for you to explore Vietnam's gracious capital. Lively markets, beautiful lakes, ancient pagoda's and the thriving, historic old city, are all easily navigated on foot.
Overnight: Hanoi | Breakfast x 2
Junk boat sailing
Hanoi – Halong Bay. A scenic drive early this morning leads us to the stunningly beautiful UNESCO World Heritage Site of Halong Bay. Boarding our traditional wooden junk boat we cruise the emerald waters soaking up the panoramic vista of the thousand or so karst limestone islands that stud the bay.
Later opt for a refreshing swim in one of the many sheltered coves before taking row boats to the pristine waterway known as 'Dark & Bright Lagoon'. Tonight, there's a Vietnamese cooking demonstration held on the sundeck before an impressive seafood dinner is served.
Overnight: Deluxe Junk Boat | Breakfast, Lunch, Dinner
Hidden grottoes, Halong Bay
Halong Bay - Hanoi - Hue. Start the day with a Tai Chi class on the sundeck or a traditional massage. After exploring a lofty grotto hidden beneath towering cliffs, we return to port.
Arriving to Hanoi mid afternoon an hour or so is spent exploring the quixotic web of streets, known as the '36 streets of the old quarter' by cyclo (rickshaw). The motorbike swarming narrow lanes are each named after various guilds of the city's artisan who established themselves here centuries ago. There is Silver Street, Silk Street, Comb Street, Paper Street and more. We explore the maze of rambling streets framed by narrow front tube houses and may have a chance to sample the exotic fruits, sizzling noodle dishes and delightfully sticky snacks being offers by the pavement vendors. After time to freshen up we board our overnight train (4 berth sleeper cabin, basic standard) on the 'Reunification Express' railway line to Hue.
Overnight: Sleeper train | Breakfast
Imperial Hue
Arriving into Hue we embark on a guided sightseeing tour of the 19th-century Nguyen empire capital. We visit the Thien Mu Pagoda, home to the oldest monastery in the city, whose 21m high tower has become something of a symbol for Hue and the citadel. Within the citadel is the Imperial Purple Palace, an exact copy of the Forbidden City in Beijing, with its impressive ramparts, formal moats and imperial palaces, some of which lay in ruin.
In the countryside lies the Royal Tombs of the Nguyen kings, here we'll view the elaborate mausoleums of Emperors Tu Duc and Khai Dinh. As the sun sets opt for a cruise in a long boat along the gentle Perfume River, beautifully illuminated at night.
Overnight: Hue | Breakfast, Lunch
Buddhist sanctuaries
Hue - Road of the Ocean Clouds - Hoi An. Today we take the scenic Hai Van Pass (Road of the Ocean Clouds), which offers magnificent views of beaches to one side and lush hills to the other. En route we stop for a walk along China beach, featured in Francis Ford Coppola's movie 'Apocalypse Now'. Perhaps enjoy a refreshing swim in
the sea before continuing our journey along the coast road to Hoi An.
The charming, old-world trading port of Hoi An with it cobbled streets, traditional homes and tiny shop houses is a perfect place to lose yourself in a by gone era. Boutique restaurants, hip cafes along the waterfront, delightful craft shops and artisans including some of Asia's best bespoke tailors (whose services come at a nominal price), all can be found here.
On a short walking tour of the enchanting historical town, we'll visit the Chua Ong Pagoda, Chinese Assembly Hall, 200-year-old Tam Ky house, former merchants' homes and the 400 year-old Japanese Covered Bridge.
Overnight: Hoi An | Breakfast
Tra Que village
A bicycle ride into the countryside, leads us to Tra Que village. Here,we discover age old farming practices and learn about traditional medicine. It's a hands on experience today where we'll assist with tending the fields and gardens and cooking lunch.
Overnight: Hoi An | Breakfast, Lunch
Hoi An - at leisure
A free day for you relax or further sightsee. You may wish to take a relaxing rowboat journey along the river or spend the day lazing by the beach or hotel pool. It's also possible to take an optional excursion to the most holiest and evocative of Vietnam's Cham sites, My Son or to Quang Ngai, the site of the My Lai massacre memorial. The massacre was a significant turning point in the Vietnam War and the story is told through photo presentation on a walk through the village.
Overnight: Hoi An | Breakfast
Crusing the Mekong
Hoi An - Saigon. Early morning flight to Saigon. Drive to the Mekong Delta. Often referred to as the 'rice bowl' of Vietnam, the fertile Mekong Delta is famous for its abundant harvests of tropical fruits, flowers and rice, as well as it fantastic views while boating along the canals. Taking our sampan from Vinh Long we'll cruise Cai Be's maze of waterways visiting local cottage industries that produce popcorn, coco candies and paper along the way. Lunch is served today in a traditional wooden home on Dong Hoa Hiep Island.
Overnight: Can Tho | Breakfast, Lunch
Mekong & Saigon
Can Tho - Saigon. Early today we visit colourful Cai Rang floating market and drive to Saigon. Once called the Pearl of the Orient, modern Saigon is a thriving metropolis on the move. Sleek sky scrapers, gourmet restaurants, designer malls and swanky bars and spas are scattered between ancient pagodas, colonial era landmarks and lively street markets. Our walking tour of Saigon includes visits to the Notre Dame Cathedral, Old Post office and the sombering War Remnants Museum. Evening at leisure.
Overnight: Saigon | Breakfast
Monday. Today offers free time in Saigon till your departure transfer to the airport. Opt for a relaxing foot massage, shop for souvenirs at Ben Thanh Market or visit the grand Independence Palace, with its secret bunker and military command centre beneath!
If extending your stay consider joining us on a day trip to the Cu Chi Tunnels. Here you can go underground to explore the vast network of tunnels and hideouts used by Viet Cong guerrilla fighters, see booby traps, trap doors or test your skill with an AK 47 at the firing range.
Cu Chi Tunnels - Viet Cong HQ
Discover the Cu Chi Tunnels - a vast underground network of tunnels and hideouts used by Viet Cong guerrilla fighters during the 1960's. Often lead by a relative of a Viet Cong fighter in green fatigues you'll walk the bush trails discovering grass covered trapdoors, ingenious, yet gruesome booby traps and hidden underwater entrances in rivers. There is also an opportunity to go underground and pop off a few rounds at the firing range. Our Cu Chi Tunnels bolt-on includes return transportation to and from Cu Chi, guided tour and 1 night accommodation in Saigon.
Prices & Dates
Prices shown are per person travelling. 'Twin/Double' prices per person apply when there are 2 people travelling, sharing a room. The 'Single supplement' applies for single travellers who require their own room and needs to be added to the 'Twin/Double' price. If you are happy to be paired up with another single traveller of the same sex on your tour, this can be arranged provided there is another single traveller booked on the tour date of your choosing.
Departure dates noted with a 'G' are guaranteed to operate. All other departure dates are guaranteed with a minimum of 2 persons.
Supplementary Prices
This tour is also available on a private basis - for details please see the Supplementary Prices above.
The hotels listed below are ones which we frequently use on this tour. We reserve the right to substitute these hotels to ones of a similar standard when necessary.
For all our tours and tailor-made holidays we provide you with a clear categorisation of all hotels we use. The REGIONAL CATEGORY indicates the local rating of each hotel in each respective country. We have also rated each hotel using OUR CATEGORY, which will be in line with generally accepted western hotel grading standards.
Basic hotels and simple accommodation is a no frills option with an adventurous authentic feel.
Standard accommodation equates to a Western 3-star standard, always featuring en-suite rooms and usually a restaurant.
Superior accommodation equates to a Western 4-star standard, featuring en-suite rooms and usually a restaurant and often a swimming pool and/or a fitness centre.
Deluxe accommodation equates to a Western 5-star standard, usually featuring spacious, en-suite rooms, a restaurant, swimming pool and fitness centre and an array of amenities, excellent service and customer care.
Lavish accommodation equates to a Western 5-star plus standard - the creme de la creme. Featuring spacious, en-suite rooms, a restaurant, swimming pool and fitness centre and an array of amenities, this accommodation is a cut above the rest. Sheer opulence!
Mercure Hotel, Vientiane
Renowned for offering travellers superb business and leisure conveniences in a pleasant surrounding, the fashionable rooms of this modern hotel are spacious and contemporary in design. Impeccable service is combined with superb amenities including a range of sporting facilities, entertainment services and a fitness centre.
Elephant Crossing Hotel, Vang Vieng
Boasting breath-taking views of majestic limestone mountains, this boutique hotel creates a special Laotian ambience with a traditional open-air sala (pavilion) for relaxing, lounging and dining. The riverside restaurant and bar offers stunning views of the river and surrounding scenery whilst the beautifully furnished rooms each have a private balcony. The accommodation is situated on the banks of the Nam Song River, this hotel is perfectly located for stunning views of the unspoilt landscape of Vang Vieng.
Santi Resort and Spa, Luang Prabang
Set just outside the main town of Luang Prabang, the Santi Resort and Spa is a modern property set in manicured gardens. Guest rooms are set on two levels and are spacious with excellent amenities. Meals are served in the main restaurant and the outdoor pool is perfect for a cooling afternoon dip. If you need to get into town then take advantage of the free shuttle service that runs nearly every hour. Located on the outskirts of Luang Prabang.
Sunway Hotel, Hanoi
This ambient, boutique hotel combines traditional appeal with modern pleasures. Rooms are furnished in a contemporary fashion with an array of amenities for added comfort. Its restaurant provides a great variety of Vietnamese cuisine and you are welcome to enjoy cocktails and live music in the Jazz Bar or relax in the hotel's health spa.
Bhaya Classic Junk Boat, Halong Bay
This premier cruise boat offers 18 well appointed cabins with en suite amenities. Cabins are contemporary in design, whilst the finer touches have a distinct oriental influence. All cabins feature large windows creating a bright and airy atmosphere as well as scenic views. Facilities and services onboard include a dining room and bar, a sunbathing area on-deck, masseur and small library. This boat departs from the port of Halong City and plies its route through the karst peaks of Halong Bay during their journey and overnight stay on the water.
Mondial Hotel, Hue
Just a 5 minute walk from the Ho Chi Minh museum, the Mondial Hotel is a contemporary hotel with excellent amenities. Guest rooms benefit from spacious interiors, comfortable beds and lots of mod-cons. There is complimentary Wi-Fi for guests, an outdoor pool and onsite spa - perfect for a re laxing massage. As well as the delicious Huong Xuan Restaurant there is also the Lobby Lounge - great for cocktails before dinner!
Vinh Hung Riverside Resort, Hoi An
Vinh Hung Riverside Resort offers luxury and gracious hospitality in a traditional Vietnamese environment right on the banks of the Thu Bon river with top notch facilities.
Victoria Hotel Can Tho, Can Tho
This attractive, colonial-style resort is tastefully decorated with well-appointed rooms and a wide range of facilities including a spa, tennis courts, open-air bar, restaurant and a gym. The hotel also offers sunrise and sunset cruises to the floating markets aboard the Lady Hau junk.
Northern Hotel, Saigon
Located in Saigon's central business district, the Northern Hotel offers comfortable and stylish accommodation. Guest rooms are contemporary in style and are decorated with warming tones and excellent en suite facilities. The onsite restaurant offers a variety of European and Asian dishes set on the mezzanine floor. The hotel also offers complimentary use of computers in the lobby and a fully equipped gym for those who wish keep fit whilst staying in the city.
Trip Highlights
Not Included
Tipping is not a natural part of many Western cultures and many of us feel uncomfortable, or unsure, about when, or how much, to tip. However, in Laos, tipping makes up a significant part of many people's wages so it's important that we get it right. For this reason we've developed a very simple system to take all the hassle out of tipping. With our 'tipping made easy' policy, a nominal pre-determined amount is collected from all group tour participants to cover tips en route. This then saves you the hassle of when and how much to tip bellhops, luggage handlers, local guides and other support staff through the tour. Our 'tipping made easy' doesn't include a tip to your group tour leader. Naturally, though, the amount is up to you as tipping is an entirely personal gesture.
Tour Bolt-ons
The driver was outstanding - his courteousness and driving ability. The guide was thorough, knowledge of Buddhism and the Wats, courteous and considerate. "


text:
Here's podcast number 2 – Northern Voice. We loved it so much we wanted to tell you all about it! northern-voice.m4a
One Comment
OMG it's a good thing I didn't have a mouthful of coffee when you made your final comment (no spoilers here) or the laptop would be toast now.


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- 02-10-2014, 01:28 PM Thread Author #1
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Galaxy Tab 3 as a frisbee?
Next week i get a free Samsung Galaxy Tab 3 from my internet provider.
Now i want to make a funny youtube video and wonder what i should do with it.
I already had an idea to use it as a frisbee, film from the tablet and throwing the tablet.
But i tried that with my windows phone and the video turned up kinda useless, you just get dizzy and its laying on the ground.
Nothing fun about it, so i was wondering if anyone have a good idea for a youtube video.
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Re: Galaxy Tab 3 as a frisbee?
I feel that you are a detestable person with a weak will and exceeding desire for attention. You know what you can do with your tablet, but it won't be something that can go on youtube. If you have no use for the thing mail it NIB to a childrens hospital or something. Get out.
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text: The only evidence left of a mystery tribe is bodies in jarsEsther Inglis-Arkell5/19/12 1:00pm9EditPromoteGo to permalinkA long lost Cambodian tribe has left only one trace behind, but it's a significant one. Human remains have been found in jars. The latest have been found about one hundred and sixty feet up a cliff.


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California storm brings round of odd weather
SAN FRANCISCO – The latest winter storm to move into California brought some odd weather to the region, including thunderstorms in Northern California and snow in the mountains of Southern California, forecasters said.
Thunderstorms were in the forecast Sunday for the San Mateo and Monterey County coasts, with lightning strikes reported early Sunday, the National Weather Service reported Sunday.
Snow was also expected in some of the higher elevations of the Santa Lucia Mountains, a mountain range that runs from Monterey County south to San Luis Obispo.
In Southern California, the storm dropped snow as low as 3,500 feet early Sunday, and winds with gusts topping out at 50 mph were expected in some mountain areas and in the foothills of the San Gabriel Valley. The storm could dump up to four inches of snow before moving out Southern California Monday morning, forecasters said.
Along the beaches, officials were warning about dangerous rip currents and waves as high as 15 feet from Big Sur south to Point Conception in Santa Barbara County.
A high surf advisory was in effect through Monday night for the area.
In the Sierra Nevada, forecasters said snow showers were expected throughout Sunday, with the heaviest snow falling in Mono County, where up to five inches was expected to accumulate.
Near Lake Tahoe, ski resorts in the area were expected see about two inches of new snow, on top of the one or two inches of snow that fell Saturday and early Sunday.
Officials said Sunday that tire chains were required on all vehicles except four-wheel drives on Highway 50 over Echo Summit and on Highway 88 over Carson Pass.
Tire chains or snow tires were also required on a 75-mile section of Highway 395 along the eastern Sierra between Bridgeport and Carson City, Nev.
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It opens on the sunstruck bustle of Copacabana beach, where Tristao Raposo, a young black street hood, meets Isabel Leme, a younger upper-class white girl. He gives her a signet ring, stolen from a gringa tourist, and she invites him back to her uncle's baronial apartment. It's safe to say they're hot for each other, and before you can say 'that's amore' a sizzling Updikean bedroom scene is underway. Tristao 'felt his cashew become a banana, and then a rippled yam', on which exotic tuber Isabel eagerly loses her virginity. Love is professed on both sides, but their wrong-side-of-the- tracks romance comes a cropper on the reef of social propriety. Isabel's uncle alerts her absent diplomat father once the lovers go on the lam, and hired goons track them down to their bolt-hole in Sao Paulo. Isabel is led back to the cossetted prison of home, but after two years at university in Brasilia she is reunited one day with Tristao, and again they escape, this time to the jungly embrace of Brazil's wild west.
It will not take the reader very long to discern in this accelerated sequence of union, separation and flight the lineaments of a fairytale. And a myth: Updike's model is the legend of Tristan and Iseult, prototype victims of doomed love. After a bright beginning the author tilts an ominous shade on his story, forcing the star-crossed lovers to struggle for their lives against the savage privations of the country, 'with its atrocious history, its sordid stupid masses, its eternal underdevelopment, its samba on the edge of chaos'. Following three years' hard labour in a gold mine for Tristao, and the same in a brothel for Isabel, they retreat into the treacherous Mato Grosso, losing various children and taking their chances with poisonous roots, teeming insects and vampire bats. As if that isn't enough, they also appear to have fetched up in an ancient time-zone, where brutish tribes and dwarfish Indians lurk at every turn; the pair eventually fall into the untender hands of throwback Portuguese bandeirantes, who throw shackles on Tristao and marry off Isabel to one of their chiefs.
That the story forages in the landscape of magic realism is appropriate to a novel set in Brazil: the genre is closely associated with the volatility and romanticism of Latin America. That it is John Updike doing the foraging is something of a mystery: a master realist aiming for the hazy fugues of magic realism seems highly perverse, like a concert pianist playing an accordion. Martin Amis once hailed Updike as 'a writer who can do more or less as he likes', a facility which can, of course, be blithely abused, as many who have read S or The Coup or even last year's Memories of the Ford Administration will testify. It is perfectly inevitable that a writer of such range will cast his net wide, yet it is arguable that the further Updike strays from his personal domain - adultery and disillusion in the somnolent suburbs of New England - the less successful he is. Whether in the Buddhist ashram in S or the African state in The Coup, one felt the slightly bored playfulness of a writer trying to entertain himself, the head brimful of research but the heart not fully engaged.
So it is with Brazil. Even Updike's stock in trade is showing marks of fatigue. What has always been a source of alarmed delight in his work is the unabashed gaze he fixes on sex and its comedy of sly second-guessing and desperate connivance. Here the eye constantly snags on bizarre descriptions of sexual organs; he is particularly fond of that 'yam' of Tristao's, and Isabel fares little better with 'her semi-seen, furry, rousing cranny' (more furry tail than fairytale); put them together and you get 'two exotic flowers so contrarily evolved'. Nor do you have to be a keen combatant in gender politics, or whatever you want to call it, to feel affronted by a phrase like 'the criminal bliss of rape'. Updike is too canny not to realise how close to the wind he's sailing, but his penchant for the idea of woman-as-sperm-receptacle is not one even his admirers are much inclined to defend.
As for the famously lush prose style, it's barely allowed an outing. At one point Isabel's remote father is described as speaking Portuguese with a 'flavourless neutrality' after his peregrinations as an ambassador: 'He knew so many other languages that his mind was always translating; his tongue had no home.' A nice observation, and pertinent to this book, which itself has the slightly stilted manner of a translation. Updike keeps trotting out gnomic locutions like 'Too much courage becomes the love of death' and 'It takes a sad childhood to make us eager to be adult', which have a flavourless, not to mention pointless, neutrality all of their own. There's also a moment of authorial intrusion, with Updike acting as a sort of benign chorus: 'Though this chapter covers the greatest stretch of time, let it be no longer than it is]' A hearty amen to that.
And what of Brazil itself? We must assume that Updike harbours some affection for this huge, harsh country, if only in the loving, meticulous detail with which he conjures the acreage of forest and swamp and scrub. Animal and vegetable life is faithfully logged too, yielding further proof of Updike's casual genius for assimilating vast tracts of knowledge. Where previously he might have unfurled a litany of different beers and made it sound like a religious incantation, here he describes jungle delicacies with a touch of Elizabeth David: 'the purplish, cherry-sized fruit of the araca, which smells of turpentine and makes the saliva in one's mouth fizz, and the pods of the inga which are stuffed with sweet-tasting down, and wild pineapples whose flesh abounds in big black seeds and tastes of raspberry, and the pears called bacuri and that even greater delicacy named the acai, which overnight curdles into a fruity cheese'.
What doesn't get much of a look-in is the human side; Updike sets his amorous pair against a squalid backdrop of bandits and crooks, whores, pimps and rapacious peasants. His take on the place reminded me of P J O'Rourke's quip about Florida: a careful reading of the novel will do more to damage the Brazilian tourist trade than anything except an actual visit to Brazil. It's a case of don't go out after dark, don't drink the water and don't talk to anyone carrying a cut-throat razor.
In the end its hope of racial harmony, even of miscegenation, seems a vain fancy. Despite much energetic coupling - and several children - Isabel never conceives by Tristao's seed. All of the old prejudices and stereotypes are left in place at the story's bitter, and beautifully orchestrated, conclusion. Brazil overall is a disappointment, but it should be put in perspective. Within the Updike oeuvre, it's just a postcard in a gallery of modern masters. Won't somebody tell him to stay at home?
- More about:
- Brazil
- Pear (fruit)
- Sao Paulo
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Xernona Clayton
Xernona Clayton was born on August 30, 1930 in Muskogee, Oklahoma, USA. She is a producer and actress, known for 19th Annual Trumpet Awards (2011), 18th Annual Trumpet Awards (2010) and 17th Annual Trumpet Awards (2009). She has been married to Paul L. Brady since 1974. She was previously married to Ed Clayton. See full bio »
Born:in Muskogee, Oklahoma, USA


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Best live Zeppelin yet!
This 3 cd set is just unbelievable! Zeppelin at its best! Blows away The Song Remains The Same Live! They could have just been 'on' for those 2 shows or the recording exceptionally re-engineered or both. Go buy the cd set and the dvd as well. You will not be disappointed! Excellent! It was a long time coming but well worth the wait! Great music that only Zeppelin could do!
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Current Residence: Way down there on the map. Look further down, there ya go.
deviantWEAR sizing preference: Don't think i have one
Favourite genre of music: again, all over the place. But it would be easier for me to just exclude country and similar styles
Favourite style of art: I love cartooney/comic-ish style, anything that's slightly more than mundane
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Favourite cartoon character: Shredder


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Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial
DOI: 10.1186/cc11159
© Pickkers et al.; licensee BioMed Central Ltd. 2012
Received: 27 September 2011
Accepted: 23 January 2012
Published: 23 January 2012
To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed.
Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety.
There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial.
The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.
Trial Registration
www.clinicaltrials.gov: NCTNCT00511186
Keywordssepsis systemic inflammatory response syndrome septic shock acute renal failure therapy
Septic shock is the most common cause of acute kidney injury (AKI) [1], and is associated with considerable morbidity and mortality [2–4]. Currently, there is no single drug approved for the treatment of sepsis-induced AKI [5].
Alkaline phosphatase (AP) is an endogenous enzyme that exerts detoxifying effects through dephosphorylation of endotoxins [6, 7] and pro-inflammatory extracellular ATP [8]. Local AP concentrations reflect the host defense against endotoxin in the kidney [9], and during ischemia enzyme levels are markedly depleted, associated with the development of AKI [10]. Apart from local effects in the kidney, AP may attenuate the innate immune response, as dephosphorylation of endotoxin abolishes its biological activity and induces tolerance to subsequent endotoxin exposure [11]. In animal models of sepsis, AP administration attenuates the inflammatory response and reduces mortality [12, 13].
In a previous trial investigating the safety and pharmacokinetics in patients with sepsis (with and without evidence of AKI), Heemskerk et al. showed that administration of AP was associated with a decreased expression of inducible nitric oxide synthase in proximal tubule cells isolated from urine related to an attenuated urinary excretion of the proximal tubule injury marker glutathione S-transferase A1-1 (GSTA1-1) [14]. However, this previous trial had not been powered to test clinical renal endpoints, as it had also enrolled patients without AKI. Therefore, the current prospective trial focusing on severe sepsis patients or septic shock with evidence of AKI was required to examine the effects of AP on clinical renal endpoints, urinary excretion of various markers of tubular injury, and circulating inflammatory markers.
Materials and methods
Patient selection and design
Patient entry selection
Inclusion criteria
• Age: 18 to 80 years, inclusive
• Diagnosis: proven or suspected infection
• Two out of four SIRS criteria of systemic inflammation [36]
- Core temperature > 38° or < 36° Celsius
- Heart rate > 90 beats/minute (unless the patient has a medical condition known to increase heart rate or is receiving treatment that would prevent tachycardia)
- Respiratory rate > 20 breaths/minute, PaCO2 < 32 mmHg or the use of mechanical ventilation for an acute respiratory process
- White-cell count > 12,000/mm3 or < 4,000/mm3 or a differential count showing > 10% immature neutrophils.
• Acute Kidney Injury, defined as:
• Rise in serum creatinine level to > 150 μmol/L (1.70 mg/dL) within the previous 48 hours, in the absence of primary underlying renal disease, OR
• Minimally at Stage 1 Kidney Injury according to AKIN creatinine criteria: Increase in serum creatinine > 26.2 μmol/L (0.30 mg/dL) or increase to > 150% (> 1.5-fold) from baseline in the previous 48 hours in the absence of primary underlying renal disease and where baseline creatinine is less than 150 μmol/L (1.70 mg/dL)), OR
• Minimally at Stage 1 Kidney Injury (AKIN) Urine Output criteria: Urine Output < 0.5 mL/kg/h for > 6 h and following adequate fluid resuscitation when applicable, in the absence of underlying primary renal disease and where baseline creatinine is less than 150 μmol/L (1.70 mg/dL).
• Written informed consent obtained prior to any study intervention.
In addition to the above, acute onset of end-organ dysfunction (other than renal failure) in the preceding 12 hours unrelated to the primary septic focus and not explained by any underlying chronic disease [15]may be present (not compulsory) for patient qualification for enrollment)
Exclusion criteria
• Pregnant women or nursing mothers and fecund females not on effective contraception
• Known HIV (sero-positive) patients
• Patients already on RRT at entry
• Patients receiving immunosuppressant therapy or on chronic high doses of steroids equivalent to prednisone 1 mg/kg/day
• Patients expected to have rapidly fatal disease within 24 hours
• Known confirmed gram-positive sepsis
• Known confirmed fungal sepsis
• Acute pancreatitis with no established source of infection
• Any previous administration of exogenous AP
• Participation in another investigational study within 90 days
• Patients not expected to survive for 28 days due to other medical conditions such as end-stage neoplasm
• Known allergy to dairy products including cow milk
• Sepsis without renal failure as defined in Entry Criteria
• History of chronic renal failure or history of persistent creatinine level equal or greater than 150 μmol/L (1.70 mg/dL) prior to entry for reasons other than the current sepsis condition
Patients were randomly assigned in a 1:1 ratio to AP or placebo. Study medication was packaged according to a randomization list in blocks of four, labeled with subject number and additional administration information. Each patient to be entered in the study was assigned the next consecutive number. Both placebo and AP were supplied as a clear, colorless, sterile, pyrogen-free solution in 10 mL type I glass vials with a Teflon-coated bromobutyl rubber stopper and indistinguishable from each other. The responsible pharmacist calculated the exact volume of AP or placebo to be administered to each patient based on body weight and treatment code. The master randomization list was held by Choice Pharma Ltd. 65 Knowl Piece Wilbury Way, Hitchin Hertfordshire, SG4 0TY UK. Individual sealed envelopes with the treatment code for each patient were filed in a secure location at each hospital and at Choice Pharma Ltd. 65. Data were entered into a clinical database by CRM Biometrics (Boehringer Mannheim, Germany). AKI was defined according to the Acute Kidney Injury Network (AKIN) criteria [16] and the criteria for initiation of RRT (in all cases continuous veno-venous hemofiltration, CVVH) were standardized per the Acute Dialysis Quality Initiative (ADQI) consensus [17].
Apart from the safety endpoints required by regulatory authorities for phase-II trials, the primary efficacy outcome measure was a prospectively defined composite end-point, including recovery of endogenous creatinine clearance (eCrCl), the need for RRT throughout the 28-day study period, and the total duration (hours on RRT per total number of patients; cumulatively for multiple interventions over the period). eCrCl was measured every 24 h with the following formula: eCrCl (mL/minute) = (Urine Creatinine (μM or mg/dL) × Volume (mL))/(Serum Creatinine (μM or mg/dL) × Time (minutes)
In addition, combinations of alternative parameters were tested exploratorily (see Additional file 1).
The secondary endpoints were changes in the urinary excretion of biomarkers of renal injury [18, 19]: kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), glutathione S-transferase (GST)A1-1 and GSTP1-1 (see additional file 2); serum concentrations of lipopolysaccharide-binding protein (LBP), IL-6, C-reactive protein (CRP), and procalcitonin (PCT); changes in Sequential Organ Failure Assessment (SOFA) score; duration of ventilator support; length of ICU and hospital stay; and all-cause mortality.
Safety was evaluated by adverse event (AE) monitoring and any abnormalities during clinical management throughout the trial, reported according to MedDRA (Medical Dictionary for Regulatory Activities [20]), and overseen by an independent Data Safety Monitoring Board (DSMB).
This trial was designed by P Pickkers and JG van der Hoeven and approved by AM-Pharma. All investigators were responsible for their own data collection. Statistical analysis was conducted by an independent agency: CRMB Biometrics GmbH, Boehringer Mannheim, Germany (J Schmitz and J Hartung). AM-Pharma was not involved in the interpretation of the data, in the preparation of the manuscript or in the decision to submit the manuscript for publication. The trial was funded by a grant from AM-Pharma BV who provided active and placebo AP enzyme.
Assays methodology
Arterial blood (arterial line, every 12 h) and urine (indwelling catheter, every 6 h) were freshly collected (and subsequently frozen at -80°C) during 48 h of treatment and daily thereafter until Day 7. Urinary KIM-1, NGAL, IL-18, GSTA1-1 and GSTP1-1 [18, 19] were assayed in duplicate by enzyme-linked immunosorbent assay (ELISA), maximum intra- and interassay coefficient of variation (CV) of 10 and 15%, respectively (see Additional file 2). Routine hematology, biochemistry and CRP were evaluated by each hospital's laboratory; PCT was analyzed centrally at UMC Laboratories (Nijmegen, The Netherlands); LBP and IL-6 were determined centrally by TNO Quality of Life Laboratories (Zeist, The Netherlands).
The intention-to-treat (ITT) population was used for efficacy evaluations, per prospective Statistical Plan. Since the variation of the combined clinical renal end-points in septic patients is unknown, the hypothesis assumed a standardized difference of 1.0 (mean treatment difference/SD), with 80% power and alpha at 5% (two-sided), which required at least 17 patients per treatment group. Appropriate methodology was applied to the data regarding testing for distribution, including application of central limit theorem [21] where parametric tests were applied to non-normally distributed data. The primary efficacy measure of combined renal parameters was calculated according to the method of Hartung [22]; eCrCl was analyzed by repeated measures ANOVA, RRT requirement by Fisher's exact test, and RRT duration by t-test. For eCrCl, missing values (typically after Day 7, due to ICU discharge) were imputed from last-observation-carried forward (LOCF). Systemic and urinary biomarkers were analyzed by repeated measures ANOVA with baseline concentrations as covariate. Safety variables were compared using Fisher's exact test. Analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC, USA).
Analysis sets and patients' characteristics at entry
Baseline Parameter*
(n= 16)
Placebo (n= 19)
Male: n (%)
13 (81)
14 (74)
Age: mean (SD) years
65 (12)
67 (15)
Height: mean (SD) cm
176 (10)
174 (8)
Weight: mean (SD) kg
86 (12)
80 (14)
Heart rate: mean (SD) bpm
103 (23)
105 (22)
Systolic BP: mean (SD) mmHg
103 (26)
110 (26)
Diastolic BP: mean (SD) mmHg
52 (13)
55 (13)
Temperature: mean (SD) °C
37 (1)
37 (1)
APACHE-II score: mean (SD)
24 (7)
23 (8)
SOFA score: mean (SD)
10 (4)
11 (5)
AKIN stage 1: %
AKIN stage > 1: %
Urine production: mean (SD) mL/kg/hour
0.6 (0.4)
0.6 (0.7)
Serum creatinine: mean (SD) μmol/L
164 (48)
214 (120)
Creatinine clearance: mean (SD) mL/minute
50 (27)
40 (37)
(Nor)epinephrine: mean (SD; n) μg/kg/min
0.32 (0.25;13)
0.40 (0.28;15)
Dopamine/dobutamine: mean (SD; n) μg/kg/min
1.50 (2.12;2)
0.25 (0.35;2)
Renal variables
Secondary efficacy parameters
Urinary biomarkers of renal injury
Serum concentrations of inflammatory markers
Clinical management parameters
Decrease in SOFA score evaluated during ICU stay was not significantly different between groups (see Additional file 3 for tabulated results of secondary clinical parameters). The reduction in total SOFA score was mainly caused by an improvement of kidney function. No relevant effects of AP on the other SOFA parameters were found. Length of stay in ICU was 25 ± 18 days for placebo and 11 ± 8 days for AP (P < 0.02). Total length of hospital stay was 31 ± 26 days on AP and 47 ± 36 days on placebo (P = 0.14).
The 28-day overall mortality after inclusion in the AP group was 7/16, compared with 6/20 in the placebo group (Log rank test, P = 0.25). All deaths were attributed to the underlying condition by the attending physicians and were subsequently reviewed by DSMB.
Safety results
Safety results
All adverse events (AEs)
n (%)
130 (100)
154 (100)
Treatment-emergent AEs*
n (%)
124 (95)
147 (96)
Patients with treatment-emergent AEs
n (%)
15/16 (94)
20/20 (100)
Non-serious treatment-emergent AEs a :
Atrial fibrillation
Decubitus ulcer
Abdominal pain
Impaired gastric emptying
Atrial flutter
All serious treatment-emergent AEs
Septic shock
Respiratory failure
Gastrointestinal necrosis
Hepatic necrosis
Gall bladder necrosis
Electrolyte imbalance
Cardiac arrest
Electrocardiogram QT prolonged
Blood calcium decreased
Depressed level of consciousness
Brain neoplasm
Renal failure
Therapy cessation
Echocardiogram abnormal
In this prospective, randomized, double-blind, placebo-controlled phase-II trial in patients with severe sepsis or septic shock and evidence of AKI, administration of exogenous AP enzyme was shown to improve overall renal function, based on endogenous creatinine clearance, requirement and duration of renal replacement therapy. The latter were in line with urinary excretion of some markers of renal injury and with serum markers of systemic inflammation. By focusing our evaluations on patients with AKI secondary to sepsis, our results complement and expand our knowledge of the effects of AP previously reported in a general population of sepsis patients with and without AKI [14]. To the best of our knowledge, this is the first clinical trial in critically ill adults with sepsis that investigates measures of renal function combined with a panel of urinary biomarkers of renal injury. We found significant differences between treatment groups for KIM-1 and IL-18 excretion, both described to have prognostic importance for RRT requirement and mortality in patients with AKI [18, 23]. Urinary excretion of other markers showed similar trends that did not reach significance likely due to a large variance between patients and inadequate power. For example, NGAL also showed a significant decrease in the AP-treated patients, while no change was observed in the placebo-treated patients. Because of the fact that the baseline values of NGAL were higher in the AP-group, this difference between groups did not reach significance. Apart from variance and the small patient groups, power was further attenuated by the fact that not all markers could be determined in all samples because of limited urine volume.
Animal experiments indicate that the dephosphorylating enzyme AP is depleted in the kidney following an ischemic insult [10]. Pharmacological restoration of endogenous AP levels in the kidney may prevent further renal damage or improve renal recovery, for which possible mechanisms include dephosphorylation of extra-cellular ATP. Extracellular ATP released from necrotic cells may directly activate the Nrlp3 inflammasome through the P2X7 receptor and co-stimulation by reactive oxygen species (ROS) or lipopolysaccharide (LPS) [24]. Alkaline phosphatase dephosphorylation of ATP and LPS results in reduced activation of the Nrlp3 inflammasome. As a consequence, the secretion of the pro-inflammatory cytokines is reduced, leading to less neutrophil infiltration in renal tissue, with lower local and systemic inflammatory response [25]. Dephosphorylation of extra-cellular ATP locally also results in higher levels of adenosine which, upon binding to its receptor, exerts potent anti-inflammatory and renal tissue protective effects [26, 27]. The combined effect of modulation of local ATP and adenosine by AP results in reduced tissue damage, and the significantly faster reduction of the injury markers KIM-1 and IL-18 found in our trial corroborate this mechanism. Extracellular ATP levels are controlled by AP and other ectonucleotidases that are expressed along the renal arterioles and tubules [28]. The importance of ATP metabolizing enzymes is demonstrated by the finding that 5' ectonucleotidase (5'NT, or CD73) and NTDPase1 (CD39) provide protection against AKI in animal models [29, 30]. The close structural and functional relationships between alkaline phosphatase and other ectonucleotidases and their therapeutic effect suggest that their modes of action may be similar.
Apart from local effects in AP-depleted kidneys, it is also thought that AP binds and detoxifies endotoxin that may be present in the blood stream [11], thereby modulating the inflammatory cascade in patients with sepsis, which may eventually result in less organ damage. We found a more pronounced decline in the systemic inflammatory parameters CRP, LBP and IL-6 which are known to be induced by endotoxin in patients treated with AP relative to controls [31]. This finding is in agreement with animal experiments [13], but was not found during experimental human endotoxemia using AP [32] or during the previous trial in patients with sepsis [14]. The large inter-individual variation in inflammatory markers during experimental human endotoxemia or in septic patients may account for this. In the present study we studied a more homogeneous group of severe sepsis or septic shock patients with AKI, while in the previous trial patients with sepsis with and without AKI were enrolled [14]. Since endotoxin is only present in Gram-negative bacteria and because of the putative relevance of AP-related detoxification of endotoxin, both completed phase-II trials in septic patients aimed to exclude Gram-positive sepsis. Nevertheless, almost half of enrolled patients did not show evidence of Gram-negative infections. Of interest, we found the beneficial renal effects of AP to be similar in patients with or without proven Gram-negative infections, but this does not exclude endotoxin detoxification being an important mechanism by which AP protects the kidneys. Indeed, in humans with severe sepsis or septic shock, increased circulating concentrations of endotoxin have been found in primary infections with both Gram-positive and Gram-negative bacteria [33]. Apparently, the primary infection is not a major determinant of increased circulating endotoxin levels in these patients, as intestinal translocation of endotoxin may also play a role [34]. In the present study we did not measure blood endotoxin levels, but we found that the kinetics of LBP was similar in patients with and without Gram-negative infections, and that the decline of LBP levels was significantly more pronounced in AP-treated patients. Thus, detoxification of endotoxin by AP may also contribute to the observed beneficial effects regardless of the primary bacterial pathogen. The observed effects of AP on the course of inflammatory biomarkers in the plasma suggest that AP exerts anti-inflammatory effects (possibly by detoxifying LPS); however, a direct effect of AP on the kidneys may also result in a swifter normalization of the circulating inflammatory biomarkers
There are several limitations of our study. First, the overall sample size was small. Availability of safe bovine AP enzyme and financial considerations were the main reasons for the small sample. The small number of adverse effects implicate that our study was not powered to detect differences in safety measures. Importantly, despite the latter and the heterogeneity of patients presenting with severe sepsis or septic shock, the remarkable consistency of findings in this trial (attenuation of urinary excretion of markers of renal damage and improved clinical outcomes), and in the previous trial in sepsis patients [14], suggest a strong signal that demands further study. The effects on eCrCl are likely to result in a beneficial effect on the need for RRT when tested in a larger trial. Nevertheless, we acknowledge that small differences in, for example, baseline creatinine may be responsible for some of the differences in outcome measures and this represents a limitation of the small study size. The enrollment criteria applied in this study may have resulted in inclusion of patients with AKI who were within their therapeutic window of opportunity. It is plausible that in previous studies [5, 35] in which other, possibly effective, pharmacological interventions were tested in AKI, patients were enrolled in whom renal damage was beyond repair. The results of the two trials with bovine-origin AP enzyme and the restrictions of using bovine protein, indicate the need to develop a human recombinant AP and to evaluate its effects in clinical trials. Further trials should be conducted with caution and include sufficient interim analyses to determine if the AP treatment worsens mortality, irrespective of its impact on renal function.
A second issue that may need further explanation is the fact that we calculated the eCrCl for all patients, including those on RRT. We found that eCrCl was restored to normal range in the AP group within the first seven days, while it remained impaired in the placebo group. Although eCrCl calculations may overestimate the recovery of renal function in the non-steady-state period, the improvements in eCrCl were sustained during the whole study and remained significantly superior on AP treatment relative to placebo throughout the 28-day period. We are confident that the renal replacement therapy used in our study did not unduly or significantly influence eCrCl evaluations, and it was associated with stable, albeit lower serum creatinine values throughout the intervention period, although any such interference would have benefitted the control group which required proportionally more RRT interventions. Importantly, a sensitivity analysis excluding patients on RRT confirmed that CVVH did not significantly influence the interpretation of creatinine clearance data. Finally, one could argue that subjectivity of the chosen parameters for the primary efficacy variable of combined renal parameters (eCrCl, RRT requirement and duration) could influence the conclusions. For this reason, combinations of alternative parameters were tested exploratorily (see Additional file 1) and the beneficial effects of AP were shown to be maintained or further enhanced. The effects on eCrCl are likely to result in a beneficial effect on the need for RRT when tested in a larger trial.
In septic patients with evidence of acute kidney injury, treatment with alkaline phosphatase improved overall renal function as represented by three main clinical parameters: endogenous creatinine clearance, requirement and duration of dialysis. The course of biomarkers of renal injury and systemic inflammation, as well as the clinical progression, corroborate the observed beneficial effects on renal function. These results suggest alkaline phosphatase treatment may be efficacious for these patients and a larger trial, preferably with recombinant human AP, is needed to further investigate these findings.
Key messages
Alkaline phosphatase is an endogenous enzyme that exerts detoxifying effects through dephosphorylation of endotoxins and pro-inflammatory extracellular ATP.
Administration of bovine alkaline phosphatase to sepsis patients attenuates the urinary excretion of markers of tubular injury.
In the present randomized, double-blind placebo-controlled phase 2 trial in patients with severe sepsis or septic shock with evidence of acute kidney injury treatment with alkaline phosphatase improved overall renal function as represented by three main clinical parameters: endogenous creatinine clearance, requirement and duration of dialysis.
The results in renal parameters were supported by more pronounced reductions in circulating inflammatory markers and in the urinary excretion of markers of tubular injury in AP-treated patients relative to placebo.
5' ectonucleotidase
Acute Dialysis Quality Initiative
adverse event
acute kidney injury
Acute Kidney Injury Network
alkaline phosphatase
adenosine triphosphate
C-reactive protein
coefficient of variation
continuous veno-venous hemofiltration
Data Safety Monitoring Board
- eCrCl:
endogenous creatinine clearance
enzyme-linked immunosorbent assay
glutathione S-transferase A1-1
- glutathione:
glutathione S-transferase P1-1
intensive care unit
kidney injury molecule-1
lipopolysaccharide-binding protein
last-observation-carried forward
mean arterial pressure
- MedDRA:
Medical Dictionary for Regulatory Activities
neutrophil gelatinase-associated lipocalin
reactive oxygen species
renal replacement therapy
statistical analysis software
sequential organ failure assessment.
This trial was designed by P Pickkers and JG van der Hoeven and approved by AM-Pharma. All investigators were responsible for their own data collection. Statistical analysis was conducted by an independent agency: CRMB Biometrics GmbH, Germany (J Schmitz and J Hartung). AM-Pharma was not involved in interpretation of the data, in the preparation of the manuscript, or in the decision to submit the manuscript for publication. The trial was funded by AM-Pharma BV who provided active and placebo AP enzyme. The authors are grateful to Jennifer Schmitz (CRM Biometrics GmbH) and to Professor J Hartung (Dortmund University, Germany) for performing the statistical analyses.
Authors' Affiliations
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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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The Reading Blue Devils football team won Friday's home conference game against Mariemont by a score of 12-7.
The Reading Blue Devils football squad scored 12 points and restricted the visiting Mariemont Warriors to 7 in the Blue Devils league victory on Friday.
The Blue Devils now possess a 3-4 record. They put it on the line next when they travel to Wyoming for a Cincinnati Hills battle on Friday, October 10. Reading will face a Cowboys squad coming off a 29-13 league win over Madeira (Cincinnati, OH). The Cowboys record now stands at 5-2.
Coming up next, the Warriors face the Taylor Yellowjackets (North Bend, OH) in a Cincinnati Hills battle, on Friday, October 10. Mariemont will attempt to advance on its 0-7 season record. The Yellowjackets enter the battle with a 2-5 record after their 62-0 league loss to Indian Hill (Cincinnati, OH).
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Widows and Suitors in Early Modern English Comedy
By (author) Jennifer Panek
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Widows and Suitors in Early Modern English Comedy by Jennifer Panek
Book DescriptionThe courtship and remarriage of a rich widow was a popular motif in early modern comic theatre. Jennifer Panek brings together a wide variety of texts, from ballads and jest-books to sermons and court records, to examine the staple widow of comedy in her cultural context and to examine early modern attitudes to remarriage. She persuasively challenges the critical tendency to see the stereotype of the lusty widow as a tactic to dissuade women from second marriages, arguing instead that it was deployed to enable her suitors to regain their masculinity, under threat from the dominant, wealthier widow. The theatre, as demonstrated by Middleton, Dekker, Beaumont and Fletcher and others, was the prime purveyor of a fantasy in which a young man's sexual mastery of a widow allowed him to seize the economic opportunity she offered.
Buy Widows and Suitors in Early Modern English Comedy book by Jennifer Panek from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9780521832717
(228mm x 152mm x 17mm)
Pages: 254
Imprint: Cambridge University Press
Publisher: Cambridge University Press
Publish Date: 14-Oct-2004
Country of Publication: United Kingdom
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Books By Author Jennifer Panek
Widows and Suitors in Early Modern English Comedy, Paperback (May 2007)» View all books by Jennifer Panek
Jennifer Panek examines the early modern character of the lusty widow in her cultural context.
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Author Biography - Jennifer Panek
Jennifer Panek is Assistant Professor of English at the University of Ottawa.
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To better understand the meaning of HONOR, certain examples of its usage are presented.Examples from famous English prose on the use of the word HONOR
"Such an honor it is"
"It would be such an honor if you would attend"
"She's always going on about how i should be upholding the family honor"
"Made a banquet to his honor" - This term honor was used by Henry Wadsworth Longfellow in the Poem The song of hiawatha.
"My hand i extend and my honor i offer;" - This term honor was used by Carol Stecher and Jim Foreman in the Poem Love poem.
"Happy in marriage, honor and love" - This term honor was used by Earl J. Dawson Jr. in the Poem Love poem.
"We honor checks and drafts"
"Bestow an honor on someone"
"We were inducted into the honor society"
हिंदी मे अर्थ[+]
अंग्रेजी मे अर्थ[+]
उदाहरण और उपयोग[+]