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Diamond in the rough: Steele becomes star point guard for Jimmies
Getting Hannah Steele to Jamestown was the trick.
Once she got here, her talent took over.
Former Jimmie head coach Mark Wiest lured the Circle Pines, Minn., native to Jamestown, and while she may have even surpassed his high expectations, it was clear early on she'd make a major impact.
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Posted by Anonymous
Feb 17 2010 - 1:42pm
Topic Page
News and Features
George W. Bush's budget is a true lie.
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How far can George W. Bush and his White House team go? On the two biggest issues facing them--the war and the budget--there is no end to their disregard for the truth.
The White House is trying to radically restructure the federal government's revenue-raising activities.
A questionable plan to wire poor schools has turned into a business boondoggle.
A vast impoverished population languishes in the midst of our economy.
Democrats need to offer a compelling vision of a morally based social contract.
A call to global activists meeting in India.
Why Martha Stewart should be found innocent.
CAFTA promises to extend the harmful impacts of NAFTA to Mexico's weaker southern neighbors.
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You can't go home again.
March 27, 2015
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Posted by jleeman
Feb 20 2013 - 6:52pm

subset: commoncrawl


text:
How many times have you
heard or read that in order to lose your unwanted weight you have to change
what you eat? You have to avoid certain foods and beverages. Cut out the fat
and the salt. Increase your consumption of fruits and vegetables. Eat fruit instead
of reaching for a salty snack food between meals.
And…what happened? Did you
do it? If you did it, how long did it last?
That's the problem with
straight-up advice. Almost no one who has excess weight to lose takes this kind
of advice. Or if they take it—listen to it and know it, even do it for a time,
they can't really count on the advice helping them sustain their weight-loss
So what's the answer? It
looks like the best answer is to understand that the weight-loss process
requires more than just advice. People who want to lose weight need something a
lot more powerful than advice. One power tool that is readily available is the
weight-loss diet. But again, the weight-loss diet is only as effective as the
dieter who is using it. Adherence to the diet is what determines successful
weight loss. Thus, the second power tool is what helps you to adhere and gets you to
stay on your diet. This is where using psychology to lose weight comes in.
Using psychology to lose weight is the second power tool.
What's so psychological
about losing weight is "getting yourself to" do what it takes emotionally,
motivationally, and behaviorally to stick to the weight-loss regimen. That's
why advice about what to eat and when not to eat goes unheeded. Such advice
doesn't even come near what people who want to lose weight need to know.


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Sock Dreams
We offer FREE USPS shipping on all US orders!
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Recycled fibers are just one of the reasons these socks are an environmentally friendly* choice in footwear -- not to mention the stylish pinstripes! Made from US grown fibers in the USA.
Sock size 10 - 13, fits men's shoe sizes 8-13. We found these also fit women quite nicely and will be nearly knee high on smaller legs and feet.
Additional Info: *all the fibers and dyes used in the EG ECO socks are grown and/or made in the USA.
Part of the EG Smith Green label, who donate a portion of their profits to organizations dedicated to environmental preservation.
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Label: EG Smith
Are the Denim sock's contrasting stripes purple or blue?
Would these be too large for a women's size 9 (in shoes)? I like the look of these socks but I don't think I'd like it with the ankle climbing up my calf...:)
You guys are always so amazing about sharing how different items fit on different bodies (which helps ensure happy customers!). I love your selection, and my friends always know that a Sock Dreams gift certificate never goes amiss as a gift in this household!
~ Andi S.


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Upcoming Events
Greenville High School Entrance
Click Here for More Information
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Spirit Week - Freshmen on Super Hero Day
Click Here to find out more about NJROTC
Click Here to Support the GHS Band
New ACT State Tests
Three new tests - ACT Aspire, ACT WorkKeys and The ACT College Readiness Test – will help teachers understand where students are succeeding and where extra help and/or academic focus are needed. Accommodations are provided for students with special needs. Click Here for More Information
2014-2015 Class Dues are Due
Collected Monday, Wednesday & Friday
Monday, 3/9/2015 through Friday, 4/17/2015
At lunch time in the Atrium
Freshman - $5.00
Sophomores - $10.00
Juniors - $20.00
Seniors - $20.00
Freshman and Sophomore Dues will only be collected on Wednesdays only from 3/9/2015-4/17/2015
Class dues are collected yearly to cover the cost of each classes' senior class expenses (graduation, senior pride day, senior breakfast, etc.). Any student that doesn't pay for their class dues is subject to penalty (ex. held report card, denial of prom participation, a held diploma, etc.).
GHS Talent Show
GHS Got Talent has been rescheduled for April 10 at 7pm. Rehearsal time is available in the auditorium Monday - Thursday 3/9-3/12 after school in the Auditorium.
If you have any questions, please see Ms. Kennedy Tickets will be on sale the week of March 16th during both lunches. $5 or $7 at the door.
Curriculum Night Presentation
Didn't Make it to Curriculum Night? Click Here to View the Presentation
Prom Tickets
Prom Tickets will go on sale March 9, 2015 during both lunch shifts in the atrium on Mondays, Wednesdays and Fridays. The cost is $25.00 per ticket before Spring Break and $35.00 per ticket after Spring Break.
Parking Passes for 2015-2016 School Year
In order to obtain a parking pass for the 2015-2016 school year, students must complete an Alive@25 course. Register for your course online at scaliveat25.com. A course will be offered on the Greenville High School campus on April 14, 2015 at 4:00pm. Limited seating capacity. Click Here for More Information
SAT/ACT Workshops
SAT/ACT workshops for all high school students hosted by the Urban League in partnership with the Sylvan Learning Center located at the University Center. Please see the attached flyer for additional details.
School Tours
School tours will be given during the following times:
Mondays 1:00 - 1:30 pm
Wednesdays 9:00 am - 9:30 am
Sign up by calling or emailing Kathryn Rowan, Magnet Coordinator (355-5518 / firstname.lastname@example.com).
US News and World Report Ranks GHS #9 in South Carolina
US News and World Report ranks Greenville Senior High Academy 9th within South Carolina. GHS received a national rank of 1253. Click Here For More Information
Online Anonymous Bullying Reporting Program
Bullying is any act of intentional aggressive behavior. It can take the form of physical or verbal harassment and involves an imbalance of power. At GHS, it is our goal to promote a caring community through building strong moral and ethical character.
Click this link to report any incidents of bullying you witness. All reports are anonymous and will be investigated. CLICK HERE TO REPORT AN INCIDENT
- School Report Card
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Letting the air out? Homescan analysis tests energy efficiency
New technology will give 1800 readings in 22 seconds with extremely accurate digital and infrared photos that pinpoint sources of problems in about two hours.
Jeremy Bales/Special
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McBrine: Ireland face Pakistan with confidence
Spin bowler Andy McBrine insists Ireland will go into Sunday's game with Pakistan full of confidence despite shipping a heavy loss to India.
Spin bowler Andy McBrine insists Ireland will go into Sunday's game with Pakistan full of confidence despite shipping a heavy loss to India.
RTÉ Sport's John Kenny goes through the various outcomes arising from Ireland's final pool match at the Cricket World Cup against Pakistan
England dodged the rain before completing their failed World Cup campaign with a comfortable nine-wicket Duckworth-Lewis method win over Afghanistan in Sydney.
New Zealand completed an unbeaten run in the cricket World Cup group stages on Friday by defeating Bangladesh by three wickets at Seddon Park.
We're at the business end of the Cricket World Cup and Ireland are on the verge of something special, writes John Kenny from Adelaide.
South Africa skipper AB de Villiers' accomplished showing with bat and ball helped the Proteas to a 146-run World Cup victory over the United Arab Emirates in Wellington.
Ireland have beaten the West Indies by four wickets in their opening Cricket World Cup clash in Nelson.
Zimbabwe wicketkeeper Brendan Taylor has offered his apologies to John Mooney after the Ireland all-rounder was the subject of an "unacceptable article" following his match-changing catch to help send the African nation out of the World Cup.
Pakistan's senior batsman Younis Khan wants to put on a big performance to beat Ireland in the World Cup on Sunday as a tribute to the national team's late coach Bob Woolmer.
Scotland bowler Majid Haq has been sent home from the World Cup after breaching the team's internal code of conduct, Cricket Scotland have announced.
Kumar Sangakkara became the first batsman to hit four successive centuries in a World Cup and Tillakaratne Dilshan stroked a fluent hundred in Sri Lanka's 363-9 against Scotland in a Pool A match at Bellerive Oval today.
Cricket Ireland has pledged to take action against the Zimbabwe Herald after an article titled "Alcoholic dumps Zim out of WC", which labelled John Mooney as shameless and dishonest.
Ireland captain William Porterfield drew consolation from posting the highest total against defending champions India in the cricket World Cup so far despite a crushing defeat today.
India took apart a diligent but limited Ireland attack to sweep to an untroubled eight-wicket victory at Seddon Park, which confirmed they will top Pool B in the cricket World Cup.
Look back as Ireland suffered a defeat to world champions India at the Cricket World Cup.
Ireland batsman Niall O'Brien believes the World Cup clash with India will be an opportunity for the side to showcase their ability to a huge audience.
Ireland go into the game against India knowing a quarter-final spot is tantalisingly close, writes John Kenny.
England's calamitous World Cup campaign suffered its final indignity as a 15-run defeat to Bangladesh sent them crashing out of the tournament amid controversy in Adelaide.
Glenn Maxwell scored the second-fastest century in World Cup history as Australia secured their place in the quarter-finals with an exciting 64-run win over Sri Lanka, Maxwell falling short of Irishman Kevin O'Brien's record by one ball.
New Zealand maintained their perfect record at the 2015 Cricket World Cup after securing a six-wicket win against Afghanistan in Napier.


text:
Erica Goode
Recent and archived news articles by Erica Goode of The New York Times.
Role of Illness in Germanwings Crash Raises Worry About Stigma
The intense focus on the co-pilot's mental illness has raised concerns that it could stigmatize mentally ill people and make it harder to identify troubled workers.
March 31, 2015, Tuesday
A Struggle to Save the Scaly Pangolin
A peculiar creature that looks like a four-legged artichoke is thought to be the planet's most frequently trafficked mammal.
March 31, 2015, Tuesday
Germanwings Crash Raises Questions About Shifting Ideas of Pilot Fitness
Aviation experts say that most screening programs in Europe and the United States are based on an honor system that relies on pilots volunteering information about their mental health.
March 29, 2015, Sunday
Suicide by Plane Crash Is Rare but Not Without Precedent
If Andreas Lubitz, the flight's 27-year-old co-pilot, was determined to kill himself, he would not be the first to use an airplane as a tool for self-destruction or to kill passengers and other crew members in the process.
March 27, 2015, Friday
Happiness Gap May Favor Liberals
New research focusing on behavior upends what was previously thought about the so-called ideological happiness gap.
March 13, 2015, Friday
Farmers Put Down the Plow for More Productive Soil
Soil-conservation farming, a movement that promotes not tilling fields and using "green" manures, is gaining converts in tough environments and markets.
March 10, 2015, Tuesday
Elephants to Retire From Ringling Brothers Stage
The animals have been an iconic part of the show, but the circus will phase them out by 2018, amid growing public concern over how they are treated.
March 6, 2015, Friday
Chickens Agree: Left Means Less; Right Means More
Scientists found that newborn chicks, like people, seem to map numbers spatially, associating smaller amounts with the left and larger ones with the right.
January 30, 2015, Friday
Learning From Animal Friendships
Interspecies interactions are all over YouTube. Yes, they're cute, but are they useful to scientists?
January 27, 2015, Tuesday
Una mirada científica a los videos de interacciones amistosas entre diferentes especies de animales
Pocas cosas parecen captar la imaginación del público que las interacciones amistosas entre diferentes especies.
January 27, 2015, Tuesday
Rss Feeds On Erica Goode
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犬 アイコンセット / Puppy icon set© honoka - See portfolio
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["ai","anger","animal","blackboard","character","cry","discovery","dog","drop","emotion","expression","face","feeling","fun","happy","icon","illustration","like","locate","mourn","point","problem","question","response","see","set","surprised","sweet","teacher","tell","variation","vector","wink"]ai anger animal blackboard character cry discovery dog drop emotion expression face feeling fun happy icon illustration like locate mourn point problem question response see set surprised sweet teacher tell variation vector wink See all keywords
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Xiaomi unveils Mi Box Mini and Mi Headphones
Xiaomi has rolled out a couple slick new devices for fans of streaming content and audio. The first of the new devices is the Mi Box Mini and it is the smallest set-top box we have seen in a long time. The device is so small that it sticks out of the outlet with nothing that actually sits on the TV or entertainment center.


text:
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When the weather outside is frightful (and even when it's not), this box has all of the essentials to keep you feeling cozy, pampered, and, we'll admit, a wee bit nostalgic for your snowsuit days. So go ahead—slip on some comfy socks, break out the board games, and thank goodness for central heating. A $105 value!
What a great collection! Kept the first one for myself, and after using some of the great products this weekend, am ordering more as gifts. From the fun Scrabble editon, the yummy bath soak and candle to the cozy socks, this one has a little something for anyone looking to bring a little holiday into their home.5
I ordered a Snow Day box for my best friend's birthday. The box has impeccable packaging (of course) tons of goodies, and a really cohesive them across all of the products. I loved the box so much that I actually ordered one for myself too. I can't wait to try the hot cocoa, take a long bubble bath and spend a cozy night in with my hubby. I highly recommend this box as a birthday, holiday, or hostess gift. Or, just get one for yourself.5
This is going to make a great Xmas gift! Fun socks, scrabble, marshmallows, body soak. The only think I wish was different would have been the fire place matches since we do not have a working fire place, & I wish you were able to choose the scents.
Other than that, it's awesome!
This is my 3rd Birchbox Home box and I really like everything in it for the most part. I feel the previous 2 Birchbox Home boxes were a much better value, though. This box has a lot of tiny sample-sized items whereas the previous 2 had a LOT more full-sized but were the same price. I think I would have been happier had their been more than 2 marshmallows and 2 servings of cocoa, or if at least one of the cosmetic products were full sized. That being said I will continue buying these Home boxes because they always contain such great products!4
I treated myself to this box and I'm glad I did. All the products are so cute and fun. I got the "cannabis" scented candle, which is really beautiful and smoky, and the cinnamon lip balm, which reminds me of gingerbread. The socks were wild, a pink zebra I can't wait to wear around the house! The L'Occitane lotion was smaller than expected but I'm still really happy with this box.5


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1119 Foothill Boulevard
La Cañada Flintridge, California, 91011
Commute to Downtown La Cañada Flintridge
Some errands can be accomplished on foot.
Score Details
1119 Foothill Boulevard has a Walk Score of 65 out of 100. This location is Somewhat Walkable so some errands can be accomplished on foot.
This location is in La Cañada Flintridge. Nearby parks include Memorial Park, Descanso Gardens and Glenhaven Park.
Explore how far you can travel by car, bus, bike and foot from 1119 Foothill Boulevard.
View all La Cañada Flintridge apartments on a map.
Popular apartment searches include fireplace, hardwood floor and furnished.
This location is in the city of La Cañada Flintridge, CA. La Cañada Flintridge has an average Walk Score of 31 and has 20,246 residents.Learn More About La Cañada Flintridge


text:
Clintons' Keystone cash: Agency lobbying for pipeline is a major donor to family foundation
New report examines surge in foreign donations to Clinton FoundationWednesday, Feb 18, 2015 4:11 PM UTC 0
Sustainability Clinton Foundation
New report examines surge in foreign donations to Clinton FoundationWednesday, Feb 18, 2015 4:11 PM UTC 0
New York has banned fracking. Was that for the best?Friday, Dec 19, 2014 8:07 PM UTC 0
A mesmerizing documentary explores the effects of the huge BP oil spill -- and why we're so eager to forget itWednesday, Oct 29, 2014 11:00 PM UTC 0
The power of the future may already be here. What is it?Friday, Oct 17, 2014 5:09 PM UTC 0
The GOP is hard at work trying to push through a bunch of terrible bills it's already passedWednesday, Sep 17, 2014 2:58 PM UTC 0
Debates over green energy may seem abstract. But for the people of West Virginia, it's a question of life and deathTuesday, Jan 21, 2014 4:15 PM UTC 0
A letter signed by 18 environmental groups pressures the administration to abandon its "all of the above" strategyFriday, Jan 17, 2014 3:09 PM UTC 0
The President is reportedly considering implementing several new domestic policies through executive actionMonday, Feb 11, 2013 2:13 PM UTC 0
Matt Damon and Gus Van Sant's "Promised Land" explores how fracking is poisoning small towns — like mineThursday, Jan 3, 2013 1:00 AM UTC 0
The candidates fight over who loves coal more in a completely ludicrous energy debateWednesday, Oct 17, 2012 3:15 PM UTC 0
A new survey suggests undecided voters want action on global warming, but Obama's probably not listeningMonday, Sep 24, 2012 6:20 PM UTC 0


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Basil leaves with black spots surrounded by light film...
BarleysGardenJanuary 8, 2013
I searched the forums but did not see an image quite like this one, if there already was a post for this please send link (thanks!).
These basil plants are only a few weeks old, just within the last few days they have started to have these dark/black spots that are surrounded by a sort of light-colored film.
The spots / areas do not scrape off, they seem to be in/on the leaves, unlike bug eggs or droppings.
Am not sure if I should just spray them with NEEM and see what happens or if there is another solution.
Please advise, there are approx 20-24 plants, all started from seed, and there is another set of seeds started just last week.
Thanks!! Have a great day!
- Barley's Garden


text:
- A favorite of butter manufacturers and top professional chefs Keeps butter soft and ready to spread for 30 daysRequires no refrigerationDishwasher safe for convenient cleanupCrafted from bone china for durability
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Pastel Pink Antique Collection Butter Bell Crock by L. Tremain
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Love the Butter Bell
Love the Butter Bell but feel the price is a little high. Received one as a gift but it was dropped and broken - had to get another one to replace it. Really liked it and I would have bought more as gifts if the price was lower or if buying multiples qualified for better pricing.I recommend this product.Was this helpful?
I love this product and the ability to keep my butter fresh and soft enough to spread!I recommend this product.Was this helpful?
Butter Bell Crock
Love, love, love my butter bell. We have two so we are never without spreadable butter.I recommend this product.Was this helpful?
Customer Reviews for Pastel Pink Antique Collection Butter Bell Crock by L. Tremain
Overall Rating:
5 out of 5 stars, based on 407 ratings
97% of reviewers recommend this product
94% say this is a "good value"
I really enjoy our Butter Bell. We only wish we would have purchased it sooner!I recommend this product.
- March 23, 2015
- By: Teresa
- From: KS
- I Cook: Every Day
- Style: Traditional
I love that it is not messy. I also love how easy it is to spread the butter. Thanks!I recommend this product.
- March 23, 2015
- By: Donell
- From: NY
- I Cook: When I Must
- Style: Traditional
I love the butter bell.It's practical and looks great in my kitchen and on the dining room table. I bought the antique yellow one which is beautiful. I intend on ordering several more later in the summer to give as birthday gifts to my friends. I am very impressed with the principle---how it works---as its really amazing.I recommend this product.
- March 21, 2015
- By: Carol
- From: MD
- I Cook: Every Day
- Style: Healthy
Other Uses for my Butter Bell
I have a butter bell that I use for butter but I also have one that I keep in the bathroom to hold coconut oil for hand lotion.I recommend this product.
- March 20, 2015
- By: Donna
- From: OH
- I Cook: When I Must
- Style: Simple
I love my Butter Bell so I bought one for my Secret Sister!I recommend this product.
- March 20, 2015
- By: Donna
- From: OH
- I Cook: When I Must
- Style: Simple


text:
Yii email registration
Closed - This job posting has been filled and work has been completed.
Job Description
I need an email registration process added to an existing Yii application. Currently the only way to sign in is using Facebook. We need to add the option for users to be able to sign up and login with an email address and password.
Please reply with an hourly estimate for how long this task will take you.


text:
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The Hairiest Girl in the World
Overweight Pets: Addressing the Epidemic
Father Forces "Grown" Daughter to Dress Like a Princess
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The 2014 BMW 435i Gran Coupe Order Guide has just been released to U.S. dealers for the ordering of dealer demo launch cars. As before, this list should generally be reflective of what options will be available for customer cars, though it may not be all-inclusive.
Expect the 4 Series Gran Coupe to hit showrooms by late Spring – early Summer of 2014. If you haven't seen what the 4 Series Gran Coupe will look like, have a look at our past photos, renderings and … CONTINUED
Have a close-up look at the BMW 4 Series Convertible (F33) exterior and interior.
The 2014 U.S. models start at $49,675 (428i) and $55,825 (435i) and will arrive in US showrooms in the first quarter of 2014, after making its world debut at the 2013 LA Auto Show next month.
For all official info on the 4 Series Convertible, see our Official Thread.
The story started with a Facebook post from Debra to BMW. And it ended with a surprisingly delivery of her new BMW 4 Series. What happened?
When Debra saw the BMW 4 Series Launchfilm, she decided to buy a BMW 4 Series Coupe instead of a Mercedes Benz and posted that on Facebook. Guess what: BMW somehow liked that and decided to take her by surprise at her delivery at the BMW Welt in Munich…
BMW 4 SERIES CONVERTIBLE WILL MAKE ITS WORLD DEBUT AND THE BMW i8, BMW CONCEPT X4 AND BMW 5 SERIES GRAN TURISMO WILL MAKE NORTH AMERICAN AUTO SHOW DEBUTS AT THE 2013 LOS ANGELES INTERNATIONAL AUTO SHOW
Additional Featured BMW Vehicles to Include: BMW i3, BMW 4 Series Coupe, BMW X5, BMW 5 Series Sedan, and the North American Debut of the BMW K 1600 GTL Exclusive Motorcycle
The new BMW 4 Series Convertible will make its world debut and the BMW i8, BMW 5 Series … CONTINUED
Here is a great real life look at the E92 3 Series coupe vs the F32 4 Series coupe.
BMWNA has announced the availability of the accessories products for the 4 Series coupe. See below the announcement and MSRP price list below.
The full M Performance Parts [see details] offering for the 4 Series will be available in Q2 of 2014.
Download the complete international version of the 4 Series Accessories Brochure (in PDF).
You can now configure / visualize your 4 Series Convertible at BMWUSA.com.
Harold Wood renders the upcoming 4 Series Gran Coupe based on recent images.
We take a look at the just revealed F33 4 Series Convertible [Official Thread] against the E93 3 Series Convertible which it replaces.
Congrats to BIMMERPOST member Kyokio for taking delivery of his "Superman Combo" Estoril Blue II and Coral Red interior 435i Coupe!
Check out some pics inside.
Here's the first sound clip for the 4 Series M Performance Parts exhaust system.
We have updated our official 4 Series Convertible thread with more wallpapers and the first video.
With 77,921 and 9,855 units sold year-to-date, the 3 Series Sedan and 4 Series Coupe combined are the best selling luxury car in America and Canada, respectively. Here is how it compares to its rivals for 2013 sales thus far.
1. BMW 3 Series / 4 Series – 77,921 units
2. Lexus RX – 73,279 units
3. Mercedes-Benz C-Class – 66,596 units
4. Lexus ES – 52,076 units
5. Mercedes-Benz E-Class – 46,006 units
6. Cadillac SRX – 40,506 units
7. BMW 5 Series – … CONTINUED
The all-new BMW 4 Series Convertible represents the latest chapter in the modern history of BMW Convertibles which dates back to 1987 and the first BMW 3 Series Convertible. As with the new BMW 4 Series Coupe, the 4 Series Convertible embodies the very essence of dynamics and aesthetic appeal in the premium segment. The "4" in its title headlines this new product line for the Convertible and emphasizes not only its stand-out design, but also the fact that any way you look at it, … CONTINUED
The previous set of 4 Series Gran Coupe photos may have given us our first look at the M Sport package equipped model, but our new photos give us the best look yet, and in Estoril Blue II, which has proved to be the most popular 4 Series color among our members yet (see color poll).
The Gran Coupe variant (F36) of the 4 Series effectively shares the same exterior styling as the Coupe, but with an elongated roofline and an extra pair of doors. The … CONTINUED
Here is the F33 4 Series Convertible in some official images.
The first M Sport 4 Series Gran Coupe has been spotted and there's no surprises here as its M Sport aero parts are the same as those of the 4 Series Coupe.
New commercial for the BMW 4 Series Coupe.
"With sleek design and performance prowess, the first-ever BMW 4 Series is simply irresistible."
May our single 4 Series owners experience this.


text:
Police officersTalk2
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These are notable Police officers that appear in the Grand Theft Auto series. This category lists all of the named police officers.
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" Larry was scheduled to be a character in the Grand Theft Auto series who was dropped during the...
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Jon Atkinson
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Daryl Bint


text:
A method is disclosed for treatment of disseminated fungal infection in a mammal comprising the administration of a fungicidally effective amount of Amphotericin B encapsulated in a substantially sterol-free liposome to the infected mammal. Also provided is an agent for treatment of disseminated fungal infection in a mammal comprising Amphotericin B encapsulated in a liposome which consists essentially of lipids other than sterols.
1. A therapeutic agent for treating disseminated fungal infection in a mammal, comprising Amphotericin-B encapsulated within a liposome, the liposome being substantially sterol-free and consisting essentially of one or more compounds selected from the group consisting of phosphoglycerides, phosphatidic acids, and sphingolipids.
2. The therapeutic agent of claim 1, where the compounds are selected from the group consisting of phosphatidylcholines, phosphatidylserines, phosphatidylglycerols, sphingomyelins, and phosphatidic acids.
3. The therapeutic agent of claim 1, where the compounds are selected from the group consisting of dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, phosphatidylcholine, and phosphatidylglycerol.
4. The therapeutic agent of claim 1, where the liposome is a stable plural lamellar vesicle.
5. The therapeutic agent of claim 1, where the compounds are selected from the group consisting of
Egg phosphatidylcholine
1-Palmitoyl-2-myristoyl phosphatidylcholine
1-Palmitoyl-2-stearoyl phosphatidylcholine
1-Stearoyl-2-palmitoyl phosphatidylcholine
Dimyristoyl phosphatidic acid
Dipalmitoyl phosphatidic acid
Dimyristoyl phosphatidylethanolamine
Dipalmitoyl phosphatidylethanolamine
Dimyristoyl phosphatidylserine
Dipalmitoyl phosphatidylserine
Brain phosphatidylserine
Brain sphingomyelin
Dipalmitoyl sphingomyelin and
Distearoyl sphingomyelin.
6. A method for treating disseminated fungal infection in a mammal, comprising administering to a mammal a fungicidally effective amount of Amphotericin B encapsulated within a liposome, the liposome being substantially sterol-free and consisting essentially of one or more compounds selected from the group consisting of phosphoglycerides, phosphatidic acids, and sphingolipids.
7. The method of claim 6, where the mammal is a human.
8. The method of claim 6, where the fungicidally effective amount of Amphotericin B is between about 0.4 mg of Amphotericin B per kg of body weight and about 4.0 mg per kg of body weight.
9. The method of claim 6, where the compounds are selected from the group consisting of phosphatidylcholines, phosphatidylserines, phosphatidylglycerols, sphingomyelins, and phosphatidic acids.
10. The method of claim 6, where the compounds are selected from the group consisting of dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, phosphatidylcholine, and phosphatidylglycerol.
11. The method of claim 6, where the compounds are selected from the group consisting of
Egg phosphatidylcholine
1-Palmitoyl-2-myristoyl phosphatidylcholine
1-Palmitoyl-2-stearoyl phosphatidylcholine
1-Stearoyl-2-palmitoyl phosphatidylcholine
Dimyristoyl phosphatidic acid
Dipalmitoyl phosphatidic acid
Dimyristoyl phosphatidylethanolamine
Dipalmitoyl phosphatidylethanolamine
Dimyristoyl phosphatidylserine
Dipalmitoyl phosphatidylserine
Brain phosphatidylserine
Brain sphingomyelin
Dipalmitoyl sphingomyelin and
Distearoyl sphingomyelin.
This is a continuation-in-part of Application Ser. No. 600,532, filed on Apr. 16, 1984, now U.S. Pat. No. 4,663,167.
The present invention relates to the treatment of disseminated fungal infections in mammals. More particularly, it relates to the use of Amphotericin B, encapsulated within liposomes comprised of lipids other than sterols, as a therapeutic agent for the treatment of disseminated fungal infections in mammals.
Infection is the cause of death in 51% of patients with lymphoma and 75% of patients with leukemia. Although bacteria are the causative organisms of many such infections, fungi account for 13% of the fatal infections in patients with lymphoma and for more than 20% of patients with leukemia. The fungus Candida albicans causes more than 80% of these infections, and Aspergillus spp. is also a frequent cause of such infections. In addition, fungal infection is a major cause of morbidity and mortality in patients with congenital and acquired deficiencies of the immune system.
Despite the fact that several new antifungal agents have become available, Amphotericin B remains the drug of choice for treatment of most systemic mycoses in cancer and other immuno-compromised patients. Amphotericin B, a polyene antibiotic, is a lipophilic compound which interacts with ergosterol in fungal membranes, thus creating transmembrane channels which permit the escape of many ions and metabolites that are essential to the cell's continued vitality. Unfortunately, the drug also interacts appreciably with the cholesterol found in mammalian cell membranes. This interaction with the cell membrane of mammalian cells is probably the basis of the toxic effects which it exerts on the mammalian kidney, hematopoietic system and central nervous system.
Amphotericin B is insoluble in aqueous solution, consequently it is supplied commercially as a combination of Amphotericin B, desoxycholate and buffers, suspended in a glucose solution to form a colloidal suspension for administration to the patient. It is usually given intravenously over a period of from two to six hours. Faster infusions may result in cardiotoxicity. Other toxic effects of Amphotericin B may manifest themselves as renal disfunction, anemia, fever and hypotension. Amphotericin B is supplied commercially under the brandname FUNGIZONE� by E. R. Squibb & Sons, Inc. The side effects and contraindications of FUNGIZONE� are discussed at page 1929 et seq. of the Physicians' Desk Reference, 37th Ed. (Oradell, N.J., Medical Economics Co., 1983), hereby incorporated by reference.
The toxicity of Amphotericin B limits the total amount of the drug which may be used in the treatment of a fungal infection. Furthermore, it is often ineffective in neutropenic and immunodeficient patients, patients who are highly susceptible to fungal infections. Consequently, there is a need for a system which decreases the toxicity of Amphotericin B to the mammalian system while simultaneously enhancing its effectiveness against the fungal infection.
It has recently been shown that the encapsulation of certain drugs in liposomes before administration to the patient can markedly alter the pharmacokinetics, tissue distribution, metabolism and therapeutic efficacy of these compounds. ("Liposomes" can be defined as lipid vesicles which are formed spontaneously on addition of an aqueous solution to a dry lipid film.) Further, the distribution and pharmacokinetics of these drugs can be modified by altering the lipid composition, size, charge and membrane fluidity of the liposome in which they are encapsulated.
Recently, liposomes have been used as carriers of Amphotericin B for treatment of murine leishmaniasis (New, R. R. C., et al., "Antileishmanial Activity of Amphotericin and Other Antifungal Agents Entrapped in Liposomes." J. Antimicrob. Chemother., vol. 8 (1981), pp. 371-381), histoplasmosis (Taylor, R. L., et al., "Amphotericin B in Liposomes: A Novel Therapy for Histoplasmosis." Am. Rev. Respir. Dis., vol. 125 (1982), pp. 610-611), cryptococosis (Graybill, J. R., et al., "Treatment of Murine Cryptococosis with Liposome-Associated Amphotericin B." J. Infect. Dis., vol. 145 (1982), pp. 748-752), and candidiasis (Tremblay, C., et al., "Comparative Efficacy of Amphotericin B (AMB) and Liposomal AMB (lip-AMB) in Systemic Candidiasis in Mice." Abstr. 1983 ICAAC. No. 755 (1983), p. 222). Liposome-encapsulated Amphotericin B has also been used for treatment of coccidioidomycosis in the Japanese macague (Graybill, J. R., et al., "Treatment of Coccidioidomycosis (coccy) in Primates Using Liposome Associated Amphotericin B (Lipo-AMB)." Abstr. 1982 ICCAC, No. 492 (1982), p. 152).
Administration of Amphotericin B in liposomes provides a more effective method for the treatment of disseminated fungal infections since more of the drug can be given to the infected mammal because of its reduced toxicity.
However, in all above-listed studies, and in all other reported studies of which Applicants are aware (other than their own) in which the composition of the liposomes is given, the liposomes are composed of several lipids, always including at least one sterol. The inclusion of a sterol in the formulation of the liposome was considered essential to the stability of the liposome containing the Amphotericin B. Because it was considered necessary to include a sterol in the lipids making up the liposome, all previous studies of which Applicants are aware were conducted with different proportions or types of sterols in the liposome. These studies represented attempts to define a formulation for optimal stability of the liposome and, simultaneously, increased therapeutic efficacy of Amphotericin B (see, for instance, Barza, M., et al., "Toxicity and Distribution in Mice and Activity In Vitro of Liposomal Amphotericin B (Lip-AMB)." Abstr. 1983 ICCAC, No. 281 (1983), p. 133 and Tremblay, C., et al., supra).
The present invention was made possible by the discovery (1) that sterols are not required to incorporate Amphotericin B into liposomes; (2) that sterols are not essential to the continued stability of an Amphotericin B containing liposome; and (3) that Amphotericin B in sterol-containing liposomes has much less demonstrable in vitro antifungal activity than does Amphotericin B encapsulated in non-sterol containing liposomes. Further, studies have shown that some of the lipids which have been used in the formulation of these Amphotericin B-containing liposomes are themselves toxic. For instance, Graybill, J. R., et al., conducted an experiment (reported in J. Inf. Dis. 145; 748 (1983)) in which mice infected with Cryptococcus neoformans were treated with liposome-associated Amphotericin B. The liposomes used by Graybill were composed of three complex lipids, sphingomyelin, stearylamine and dicetyl phosphate, and a sterol, ergosterol. It has now been shown that dicetyl phosphate and particularly stearylamine are toxic in mammalian systems in that they cause damage to the liver. Poste, Biol. Cell 47; 19 (1983).
Consequently, there is a need for a liposome delivery system for Amphotericin B which is stable and yet easily prepared, requires a minimal amount of lipid per unit of Amphotericin B encapsulated, thereby decreasing the potential toxicity of the lipids in the liposome itself, and which enhances the therapeutic efficacy of Amphotericin B. The present invention is directed to liposome-associated Amphotericin B which offers these advantages in that the liposomes are formulated from lipids other than sterols which were selected for their lack of toxicity to mammals and their ability to encapsulate a greater proportionate amount of Amphotericin B than previous sterol-containing liposome formulations.
The present invention is directed to a method for the treatment of a disseminated fungal infection in a mammal which involves the administration of a fungicidally effective amount of Amphotericin B, encapsulated in a substantially sterol-free liposome, to the infected mammal. Liposomes with the minimum achievable sterol content (zero if possible) are preferred. The amount of Amp B administered will usually range from about 0.4 mg/kg of body weight to about 4.0 mg/kg.
The present invention also concerns a therapeutic agent for treatment of a disseminated fungal infection in a mammal. The agent comprises Amphotericin B encapsulated within a substantially sterol-free liposome. The liposome consists essentially of one or more compounds selected from the group consisting of phosphoglycerides, phosphatidic acids, and sphingolipids. In another embodiment of the present invention, the compounds can be selected from the group consisting of phosphatidylcholines, phosphatidylserines, phosphatidylglycerols, sphingomyelins, and phosphatidic acids.
FIG. 1 is a graphical representation of the inhibitory and fungicidal effect of free Amp B and L-Amp B (liposomal Amp B), L-Amp B-C (Amp B in liposomes containing cholesterol) and L-Amp B-E (Amp B in liposomes containing ergosterol) on C. albicans 336.
FIG. 2 shows the effect of increasing Amp B concentration in sterol-free liposomes on the survival of mice infected with C. albicans.
FIG. 3 shows the effect of lipid composition on the survival of mice infected with C. albicans and treated with liposomal Amp. B.
The liposome-encapsulated Amphotericin B (Amp B) of the present invention may be prepared by a variety of methods. These methods involve the solubilization of the lipids in an appropriate solvent and the solubilization of Amp B in an appropriate solvent. The Amp B solution is then added to the lipid solution, and the solutions are distributed onto the bottom of a container. The solvent is then removed by evaporation, the lipid-Amp B film is dispersed in a salt solution, and the liposomes allowed to form by shaking.
It will be recognized by those with skill in the art who have the benefit of this disclosure that both the type of lipid and the proportion of that lipid in the liposome may be varied. Applicants have experienced particular success with the phosphoglycerides dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol DMPG) in a 7:3 DMPC:DMPG molar ratio. This formulation is non-toxic to mammalian systems and is capable of encapsulating 100% of the Amphotericin B available in solution. Combining these same lipids in a 9:1 DMPC:DMPG molar ratio reduces the encapsulation efficiency to 94.9%. Stable Amphotericin B-containing liposomes have been prepared from the phosphoglycerides phosphatidylcholine (PC) and phosphatidylglycerol (PG) in a 9:1 PC:PG ratio. However, liposomes of this formulation were capable of incorporating only 91.8% of the Amphotericin B available in solution.
As used throughout this specification, the term "sterol-free liposome" refers to liposomes comprised of lipid material of a type other than those lipids which may be considered "sterols", for instance, the sterols ergosterol or cholesterol. Other non-sterols, in particular, lipids selected from the phosphoglycerides and the sphingolipids, may be used in the Amp B-containing liposomes of the present invention. Selection of the appropriate lipids for liposome composition is governed by the factors of: (1) liposome stability, (2) encapsulation efficiency, and (3) non-toxicity to mammalian systems. It is expected that one of skill in the art who has the benefit of this disclosure could formulate liposomes according to the present invention which would optimize these factors from, for instance, the phosphoglycerides phosphatidylinositol and cardiolipin, the sphingolipids sphingomyelin and sphingosine, or any combination of these lipids with PC, PG, DMPC or DMPG. Other phosphoglycerides and sphingolipids that might be useful include
Egg phosphatidylcholine
1-Palmitoyl-2-myristoyl phosphatidylcholine
1-Palmitoyl-2-stearoyl phosphatidylcholine
1-Stearoyl-2-palmitoyl phosphatidylcholine
Dimyristoyl phosphatidic acid
Dipalmitoyl phosphatidic acid
Dimyristoyl phosphatidylethanolamine
Dipalmitoyl phosphatidylethanolamine
Dimyristoyl phosphatidylserine
Dipalmitoyl phosphatidylserine
Brain phosphatidylserine
Brain sphingomyelin
Dipalmitoyl sphingomyelin
Distearoyl sphingomyelin
Several types of liposomes are believed useful for encapsulating Amphotericin B in accordance with the present invention, including stable plural lamellar vesicles and multilamellar liposomes. Whenever "encapsulation" is used in this patent it is meant to include incorporation as well.
The liposome-encapsulated Amp B may then be administered to a mammal infected with a fungal infection. Studies have indicated that the maximum dose of free Amp B tolerated by mice is approximately 0.8 mg/kg of body weight and the LD50 is about 1.2 mg/kg. When encapsulated in liposomes, doses of up to approximately 12 mg of Amp B per kg body weight have been shown to result in no gross clinical evidence of toxicity. Nor do such doses cause abnormalities in the serum creatine, blood urea nitrogen and serum glutamic pyruvic transaminase levels of the mice. Histopathology revealed no sign cf kidney edema or nephrocalcinosis in mice receiving such doses. Total doses as high as 28 mg/kg of Amp B in liposomes have been given with no apparent acute side effect; no LD50 has been identified in the case of liposome-encapsulated Amp B. Comparable doses may be given to humans, again with no apparent toxicological symptoms.
The present invention may be better understood by reference to the following examples.
The liposome encapsulated Amp B of the present invention may be prepared according to either of the following methods.
The first method is described by Lopez-Berestein, G., et al., "Treatment and Prophylaxis of Disseminated Infection Due to Candida albicans in Mice with Liposome-Encapsulated Amphotericin B." J. Inf. Dis., vol. 147 (1983), pp. 939-945, hereby incorporated by reference. Briefly, the method of Lopez-Berestein, et al. involves the preparation of multilamellar vesicles as follows.
The lipids dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) were obtained from Avanti Polar Lipids (Birmingham, Ala.), and desoxycholate-free Amp B was obtained from Dr. Dan Bonner (Squibb Pharmaceuticals, New Brunswick, N.J.). DMPC and DMPG were dissolved in chloroform in a molar ratio of 7:3 DMPC:DMPG. Amp B was dissolved in methanol at a concentration of 40 μg/ml and the Amp B solution added to the chloroform containing the DMPC and DMPG. This mixture was placed in a rotary evaporator (Rotavapor�; Brinkman Instruments, Westbury, N.Y.) until all organic solvents were removed. Normal saline was then added and the vesicles formed by gentle agitation. Using this method, to prepare enough liposome-encapsulated Amp B to make up a single dose for a 50 kg patient at a dose of 0.8 mg/kg body weight (as discussed in Example 4) requires the drying of at least 1 to 1.5 liters of the Amp B-methanol solution. Under controlled temperature and pressure conditions, approximately 3 to 4 hours are required to evaporate this volume of the Amp B-methanol solution.
The preferred method for formulation of liposome-encapsulated Amp B in accordance with the present invention is as follows. The lipids DMPC and DMPG and Amp B were obtained from the same sources as described above. The Amp B is dissolved in chloroform in the presence of DMPC and DMPG in a 7:3 molar ratio. All other steps in the preparation of the liposome-encapsulated Amp B were the same as described above.
Using this method, 640 μg of Amp B was dissolved in 1 ml of chloroform (containing 25 mg of the lipid mixture), a significant increase over the 40 μg/ml which can be dissolved in methanol as in the method described above. Consequently, a decreased volume of Amp B solution is required with a concomitant decrease in the amount of time required to evaporate the solution.
In vitro tests were conducted to determine the effect of free Amp B, Amp B encapsulated in nor-sterol-containing liposomes, (L-Amp B), Amp B encapsulated in cholesterol-containing liposomes (L-Amp B-C) and Amp B in ergosterol-containing liposomes (L-Amp B-E). Desoxycholate free Amphotericin B was obtained from E. R. Squibb & Sons, Inc. Amp B was encapsulated in non-sterol containing liposomes by the method described by Lopez-Berestein, et al., and summarized in Example 1, above. In order to obtain the different doses necessary, lipid concentration was held constant as the Amp B concentration was decreased. The concentration of Amp B within the liposome was determined by scanning in a UV absorption spectrophotometer (Gilford Instrument Laboratories, Oberlin, Ohio) at 405 nm after the Amp B was dissolved in methanol. Cholesterol or ergosterol, obtained from Avanti Polar Lipids (Birmingham, Ala.), was added to the chloroform DMPC:DMPG solution at a molar ratio of 7:3:4 (DMPC:DMPG:sterol).
In vitro activity of free Amp B, L-Amp B, L-Amp B-C and L-Amp B-E was tested on the following yeast species, all clinical isolates obtained from the Clinical Microbiology Laboratories at the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston: Candida albicans, C. tropicalis, C. parapsilosis, Torulopsis glabrata and Cryptococcus neoformans. The YNB tube dilution method described by Shadomy, S., et al., "Susceptibility Testing with Antifungal Drugs." In Lennette, E. H., et al. (eds.), Manual of Clinical Microbiology, 3rd Ed. (Washington, D.C., American Society for Microbiology, 1980), pp. 647-653, hereby incorporated by reference, was used to perform all tests. All tubes were subcultured (10 μl ) onto Sabouraud-dextrose agar (SDA) (Scott/Randolph, Houston, Tex.) plates. Minimal fungicidal concentrations (MFC) were determined after incubation for 18 hours. The MFC was defined as the lowest concentration of Amp B that allowed no growth or growth of fewer than four colonies on the subculture plates.
The results are presented in Table 1. These data indicate that the MFC of L-Amp B was increased over that of Amp B in only 8 of the 19 strains tested, and that only in 4 of those 8 strains was the increase significant. The MFC of L-Amp B-C was increased over that of free Amp B in 11 of the strains tested, and in 7 of those strains, this increase was significant. The MFC of L-Amp B-E was higher than that of Amp B in 18 of the 19 strains tested, and the increase was significant in all 18 of those strains. It can be seen that, in terms of the killing of these fungal strains, the efficacy of these compositions may be ranked in decreasing order, with Amp B being most effective, then L-Amp B, L-Amp B-C and, finally L-Amp B-E.
This result was borne out by the killing curve of Amp B, L-Amp B, L-Amp B-C and L-Amp B-E shown in FIG. 1. This curve was constructed by incubation of C. albicans strain 336 for 18 hours at 35� C. For these tests, 0.1 ml was removed from all drug concentrations tested. Ten-fold serial dilutions were made, and 0.1 ml of each dilution (in duplicate) was plated onto SDA plates. Colony counts were made after incubation for 48 hours using those dilution plates which grew between 30 and 300 colonies per plate.
TABLE 1__________________________________________________________________________MFC (μg/Amp B/ml) RESULTS USING AVARIETY OF YEAST ISOLATESAND LIPOSOME PREPARATIONOrganisms Strain Amp B L-Amp B L-Amp B-C L-Amp B-E__________________________________________________________________________Candida albicans 306 1.6 1.6 3 >25*" 704 0.4 0.8 1.6* >25*" 1091 0.8 0.8 1.6 >25*" 57 0.8 0.8 0.8 >25*Candida tropicalis 251 3 6 12* >25*" 2463 1.6 1.6 3* 6*" 1784 3 3 3 >25*" 1324 1.6 1.6 1.6 >25*Candida parapsilosis 139 3 >25* >25* >25*" 1341 >25 >25 >25 >25" 2300 3 3 3 >25Candida glabrata 684 3 25* 25* >25*" 1905 3 3 3 12*" 2539 3 3 1.6 12*" 1172 1.6 3 1.6 6*Candida neoformans 222 1.6 0.8 3 25*" 843 0.8 12* 12* >25*" 881 1.6 12* 12* >25*" 595 0.4 0.8 1.6 6*__________________________________________________________________________ *Indicates MFC ≧4 fold difference compared to free Amp B.
As shown in FIG. 1, the effect of sterols on growth inhibition was minimal at lower drug concentrations. The sterol-containing liposomes had a protective effect that prevented the killing of fungal cells at higher Amp B concentrations (greater than 1.0 μg/ml). A 12-fold higher concentration of L-Amp-C was required to kill C. albicans 336 than either L-Amp B or free Amp B. L-Amp B-E was even less effective in killing C. albicans 336 than L-Amp B-C. As shown in FIG. 1, concentrations of 50 μg of Amphotericin B per ml were unable to kill the test organism when administered in ergosterol-containing liposomes.
Hale-Stoner mice, 6-8 weeks old and weighing 20-25 g, were obtained from The University of Texas Science Park (Bastrop, Tex.). Mice (10 per group) were injected intravenously with Candida albicans strain 336. This strain was grown for 18 hours on SDA plates at 37� C., washed and resuspended in saline. The mice were injected in the tail vein with 0.2 ml of the suspension containing 7�105 colony-forming units. This concentration consistently caused a disseminated infection which, after 48 hours, primarily affected the kidney, liver, spleen and lungs. The mice were injected on the second day of infection with a single dose of Amphotericin B.
Amp B was encapsulated in sterol-free and sterol-containing liposomes prepared by the method described in Example 2, above. Amp B concentration was determined at 405 nm as described in Example 2.
The effect of increasing concentrations of Amp B in sterol-free liposomes on the survival of mice is shown in FIG. 2. In each liposome case shown in FIG. 2, the liposomes contained 400 mg lipid/kg body weight.
Empty liposomes had no significant effect on mouse survival. At doses equivalent to the maximum amount of free Amp B tolerated by mice (0.8 mg/kg body weight), Amp B in non-sterol containing liposomes was as effective as free Amp B in prolonging the survival of infected mice. Increasing the concentration of Amp B in sterol-free liposomes resulted in a highly significant increase in survival time. On day 50 of the infection, 40% of the animals that had received 2 mg Amp B/kg were alive and 100% of the animals that had received 4 mg/kg were alive.
The effect of the lipid composition of the liposome on the survival of mice infected with C. albicans 336 was also evaluated. The results are shown in FIG. 3. Each liposome case shown in FIG. 3 used 1.6 mg Amp B in 200 mg total lipid/kg.
Administration of free Amp B improved survival time over the controls (control 50% survival, 5 days, free Amp B 50% survival, 10 days). Amp B encapsulated within liposomes (all animals alive on day 60) significantly enhanced the survival time compared to that of free Amp B (p<0.001, generalized Wilcoxon test). However, in this study there was no significant difference between the survival time of mice treated with Amp B in sterol-free liposomes as compared to the survival time of mice treated with Amp B encapsulated in cholesterol-containing liposomes or ergosterol-containing liposomes.
Three cancer patients have been treated for systemic fungal infections with liposome-encapsulated Amphotericin B (Amp B). Amp B was incorporated into multilamellar vesicles as described by Lopez-Berestein, et al., supra (see Example 1). Amp B content was determined by high performance liquid chromatography analysis as described by Nilsson-Ehle, I., et al. "Quantitation of Amphotericin B with Use of High-Pressure Liquid Chromatograph." J. Infect. Dis., vol. 135 (1977), pp. 414-422, hereby incorporated by reference. Phospholipid content was quantified by determining the organic phosphorus in the preparation by the method of Marinetti, G. V. "Chromatographic Separation, Identification, and Analysis of Phosphatides." J. Lipid Res., vol. 3 (1962), pp. 1-20, hereby incorporated by reference. The preparations were sterile as assessed by Bacter and plate culture studies. In all three cases, liposome-encapsulated Amp B was administered to the patients intravenously over 10-15 minutes.
A 13-year old female developed diffuse, poorly differentiated lymphocytic lymphoma a number of years ago. She achieved a complete remission following the administration of chemotherapy. Five years later, she was hospitalized with fever, fatigue and general malaise and malignant lymphoid cells were identified in the bone marrow. She was treated with parenteral cyclophosphamide, vincristine and prednisolone. Intrathecal cytosar, hydrocortisone and methotrexate were given prophylactically. After achieving complete remission, maintenance therapy was instituted with 6-mercaptopurine and methotrexate for six months, after which all chemotherapy was stopped.
During that hospitalization, she developed multiple infectious episodes including: typhlitis, Escherichia coli and Staphylococcus aureus septicemia, bacterial urinary tract infection and herpectic lesions of the skin. In the third month, therapy with Amp B was initiated for persistent fever and C. albicans urinary tract infection. After 16 days, 5-fluorocytosine (5FC) was added because of persistent fever. No response was obtained and ketoconazole was administered. In the fifth month, the patient remained febrile. The liver was palpable 4 cm below the right costal margin. She also had cardiomegaly, tachycardia and an S3 gallop. Computerized tomography (CT) of the abdomen showed multiple areas of radiolucency in the liver consistent with fungal abscesses. An open liver biopsy showed infarcted parenchyma and necrotizing abscesses in the liver, due to fungi. No organisms could be cultured from the specimen, but it was morphologically consistent with Aspergillus spp. Due to persistence of fever, clinical deterioration and worsening of the liver lesions, hepatic artery infusion with Amp B was started. The patient received a cumulative dose of more than 6 gm Amp B over a seven-month period. Throughout Amp B therapy, fever and chills were observed.
She continued to have a daily temperature of 38.5� C., and remained severely ill, anorectic and malnourished. She had become jaundiced (bilirubin 7 mg/dl). On physical examination of the chest, bilateral basilary rales and a grade II-III apical ejection murmur were detected. The abdomen was distended and diffusely tender, the liver edge was 8 cm below the right costal margin. On chest x-ray examination, there were bilateral pleural effusions, patchy pulmonary infiltrates in both lung fields, and the cardiac silhouette was enlarged. Computerized abdominal tomography showed increased hepatosplenomegaly with increased size of the radiolucencies already observed in the liver, and new lesions were detected in the spleen. Laboratory findings at that time, and during treatment, are summarized in Table 2. Anergy to skin test with recall antigens lymphopenia, an inverted T helper/T suppressor ratio (OKT4/OKT8=16.7/59.7%), and absolute values of T helper of less than 2000 cells/mm3 were observed throughout the course of her disease.
TABLE 2__________________________________________________________________________HEMATOLOGIC, HEPATIC AND RENAL FUNCTION STUDIESDURING LIPOSOMAL-AMPHOTERICIN B THERAPY Cumulative Dose of White Blood Creatinine Total Alk. Amphotericin B Cells n/mm3 / BUN Clearance Bilirubin LDH SGOT Phosp.Date (mg) Segmented % mg/100 ml cc/min mg/100 ml mu/ml mu/ml mu/ml__________________________________________________________________________Case 1Before treatment Baseline 8.8/9 37 44 7.0 256 123 253During treatment 484 4.5/29 14 61 0.8 134 60 350Case 2Before treatment Baseline 0.1/0 35 106 2.4 222 82 320During treatment 189 0.1/0 21 96 0.8 183 18 159Case 3Before treatment Baseline 19.6/88 5 36 0.8 277 125 304During treatment 551 17.5/72 10 67 0.5 193 49 298__________________________________________________________________________
Liposomal Amp B (sterol-free) was started at a dose of 0.4 mg/kg intravenously after all other medications were discontinued. No acute side-effects occurred after the first dose. Subsequent therapy was 0.6 mg/kg for 2 doses, and 0.8 mg/kg thereafter. Doses were given every 3 to 4 days for a total of 19 doses (total Amp B 484 mg, total lipid 20 gm). No acute or chronic toxicity was observed during the 3 months of liposomal Amp B treatment. Four weeks after the initial treatment, marked improvement in her general status was reflected by disappearance of fever, increased appetite, improved strength, decreased abdominal pain and hepatomegaly as well as resolution of the lung infiltrates and cardiomegaly. A repeated open liver biopsy performed 4 months after the onset of liposomal Amp B treatment disclosed only areas of fibrosis, and hemosiderosis. No fungal organisms were demonstrated. Six months after discontinuation of treatment, the patient was in excellent general condition.
A 22-year old male with acute lymphocyte leukemia had achieved complete remission after induction chemotherapy. Eleven months later, he was found to have recurrent leukemia in the bone marrow. After failing reinduction chemotherapy for four months, he was started on high dose cytosar (3 g/m2 /daily�12). He developed a lesion in the nasal turbinate which on biopsy and culture was found to be Aspergillus terreus. He received a total of 2.4 gm Amp B intravenously which was always associated with severe nausea, fever and chills.
The nasal lesions worsened in spite of Amp B therapy and new lung lesions appeared on chest x-ray examination which were compatible with typical "fungus balls." At that time, A. terreus was cultured from a lung specimen, bronchial washings and the sputum, urine and stool. The patient developed progressive dypsnea, severe neutropenia, and markedly abnormal liver function tests (Table 2). Anergy to skin tests was observed. He was given a total of 1.4 gm of Amp B by aerosolization without improvement.
Subsequently, sterol-free liposomal Amp B therapy was started at a dose of 0.4 mg/kg with no acute side-effects observed. Doses were repeated at 3-4 day intervals. After the sixth dose, he was afebrile, the nasal lesions had improved and there was clearing of the lung infiltrates on chest x-ray examination Improvement in liver function tests were observed (Table 2). A total of 5 doses of Amp B in liposomes were administered (total Amp B 189 mg, total lipid 5 gm). At that point, liposomal-Amp B therapy was discontinued due to the presence of hallucinations which were later found to be related to the use of several neuroleptic drugs.
Two weeks later, the patient developed new lung infiltrates and clinical evidence of diffuse intravascular coagulation (DIC), which was related to P. maltophilia septicemia. Post mortem examination showed evidence of DIC. This was evident by the presence of multiple thrombi in the lungs and kidneys. No fungal organisms were seen in the nose, liver or spleen. Fibrosis was evident in both lungs. Single microscropic foci containing a few fungal organisms were seen in one kidney and in one lung. P. maltophilia was cultured from the lung.
A 22-year old female was diagnosed of acute progranulocytic leukemia. She was treated with cytosar, daunorubicin, 6-thioguanine, vincristine and prednisone. A bone marrow test conducted one month after initiation of therapy showed a complete remission. Two months after initiation of therapy, she developed cavitary lung infiltrates and necrotizing retinitis. An open lung biopsy was done and the silver stain was positive for budding fungal hyphae. Therapy with Amp B and 5 FC was started. In the following month, she developed right upper quadrant abdominal pain and increased alkaline phosphatase. An abdominal CT scan in the following month showed multiple lesions in the liver and spleen. A liver biopsy showed yeast organisms which were consistent morphologically with Candida. From then on, the patient followed a gradually deteriorating clinical course, requiring continued hospitalization. She was treated with a total of 4 grams of Amp B during her 6-month hospital stay. She was also treated with 5 FC, miconazole and rifampin. A repeated open liver biopsy conducted five months after the abdominal CT scan showed lesions consistent with Candida microabscesses. Throughout this period, the patient continued to spike fevers of 102� F. with rigors.
At this point, the patient looked cachectic and had fever and rigors. An abdominal CT scan showed diffuse parenchymal lesions in the liver and spleen compatible with microabscesses. Sterol-free liposomal-Amp B therapy was started at a dose of 0.4 mg/kg for two doses and continued at 0.8 mg/kg every 72 hours, for a total of 500 mg of Amp B. After two weeks of treatment, the patient showed marked improvement in her clinical condition as evidenced by an increased caloric intake which resulted in discontinuation of IVH. The results of hematologic, hepatic and renal function studies are given in Table 2. She also had decreased abdominal pain and decreased liver span on physical examination. After 3 weeks, she was discharged and therapy was continued as an outpatient. A repeated open liver biopsy done two months after the onset of liposomal Amp B treatment showed no evidence of fungi. The patient continues in good general condition without evidence of chronic toxicity.
Several different liposome compositions were tested, using generally the same procedure described in Example 2, to determine the effect of the phospholipids chosen on the minimal fungicidal concentration of Amphotericin B when administered to mice infected with C. albicans. The compositions included one or more of the following: DMPC, DMPG, cholesterol (Chol), ergosterol (Erg), and stearylamine (SA). The results are shown in Table 3.
TABLE 3______________________________________EFFECT OF LIPID COMPOSITION ON THEMINIMAL FUNGICIDAL CONCENTRATION (MFC)OF LIPOSOMAL-AMPHOTERICIN BLipid MFC (μg ofComposition Molar Ratio Amp B per ML)______________________________________Amp B alone 1.6DMPC:DMPG 7:3 1.6DMPC alone 3.2DMPC:Chol 9:1 3.2DMPC:Erg 9:1 6.4DMPG alone 50DMPG:Chol 9:1 50DMPG:Erg 9:1 50DMPC:SA 7:3 12.5DMPC:SA:Chol 9:1 25DMPC:SA:Erg 9:1 25______________________________________
The above examples are presented for purposes of illustration only, and are not intended to be an exhaustive description of all embodiments of the present invention.
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This article is so biased that it is very obvious the author has been feeling threatened and insecure about the remarkably fast development of China, while the Western Europe, especially UK, is not confident in competing both emerging countries like BRICs, and the existing superpower, US.
Ironically, the fact that many efforts that're made by western politicians and media is confirming such insecure feeling.
I always fail to figure out the point to negatively interpret China's attitude and words instead of endeavoring to develop ourselves. First of all, the unemployement!
There is no way Western world will still be prosperous without China, neither will China without western world.
Forget about how China is reacting, and imagine how US people will react should California succeed from commonwealth.
Economic development and economic development! Employment and employment!
I read the American comments here with surprise. Americans are accusing China of doing everything they have done the past 200 years! I fear for world peace. America has always been a country full of insecure cowards who only ever feel safe if they can deceive themselves they are the most powerful and only fair nation on earth! While they deceive themselves of this, they continue to start wars all over the world.
This is how Americans used fear of everybody to fuel the cold war. Will these cowards now start a new cold war with China? I worry because China is a completely different cup of tea from Russia. America has always treated other countries who attempt to choose their own political system (e.e., communism, Cuba, Afghanistan, Vietnam) as enemies.
America needs to mind it's own business and stop poking its nose in other peoples affairs. They pretend they won world war 2 amongst others, (At least that's what their spin of an education propagandizes them with) when will these people understand they are no better than anyone else and not the worlds police. All their notions of superiority are pipe dreams built on hype.
When they have a star they have the audacity to call that person the most beautiful man or woman in the world. As if the world stops within the borders of the USA.
American attitudes needs to change, before they start more wars, they have changed Iraq into a breeding ground for Islamic terrorists. It wasn't enough that they went into Iraq and murdered a million + Iraqi civilians. They are now talking about starting trouble with other nations. When and where will they stop?
I don't even necessarily believe this story. I'll have to look for an alternative view on the same development. This article was of course written by an American.
The Americans here are already talking about trade embargoes against China even though it's clearly the USA who are the aggressors and stirring things between China and Taiwan. Selling Taiwan weapons is an act of aggression on a par with the Cuban Missile crisis. America was condemned for it's gung-ho action even by their WWII allies (Britain). Winston Churchill condemned the USA.
There will possibly be a WW3. America is spoiling for a fight and anxious to start more wars. The USA produce so many weapons they don't now what to do with.
I fear for this planet with cowboys like America around.
I would have to quote 江主席 who would probably say the Economist's view is:
Too Simple, Sometimes Naive
Aly-Khan Satchu, perkmashin:
Let's review a little history, shall we? The government of Taiwan was once the government of all China. Then the Communist revolution came, and the government lost control of mainland, keeping only Taiwan.
So Taiwan owes its existence only to US military aggression? Forgive me, but you're full of it. Your view fails to correspond to the reality of what happened.
And the proper Texas analogy would be if there was a revolt against the US government, and the rebels conquered the entire US with the exception of Texas. Texas would then have a legitimate claim to be the rightful government of the US, and if not that, then to be a separate country. Painting Texas as the rebels or "seccesionist" would be blatantly misleading.
And if the new US government were a dictatorship and Texas was still a democracy (even if an imperfect one), what should the rest of the world do? Let Texas be overrun by a dictatorship? Would that really be the right/just/moral thing to do?
If you're going to be an apologist for China, please try to do so without completely distorting the history of Taiwan.
GDP per capita [Wolfram Alpha]:
Taiwan --> $31,100
The issues is this simple. No rational person would chose poverty instead of afluence. The peaceful solution is for the PRC to increase the standard of living on the mainland. Do this, and everyone would be happy: the PRC population, PRC government, Taiwanese, US government.... Yes, the US military would be angry. But they need to leave Taiwan, S-Korea, Japan. WW2 has been over for 1/2 a century now.
If one reads through the history of China, this big country was many times divided through its past. Only through military efforts a central authority was imposed in the first place (212) and then maintained afterwards. People were never asked what they want. PRC is crushing slowly Hong Kong semblance of democracy and is trying to do so with Taiwan. If Taiwan has the money and will to buy weapons to deter PRC to impose its control over it, I say that US and Europe have the duty to help them. Otherwise it will appear that they are actually suporting of China and that their political elites would like to impose some authoritarian regimes in their own countries after all.
Maggie P:
The USSR was trying to install offensive (nuclear) missiles in Cuba. The US sold defensive stuff to Taiwan. That little difference rather spoils your comparison.
"while the cheapness of its currency keeps its trade surplus large"
If one take a basic economic class, s/he will know that is not true. For those who haven't take basic economic class, you should take it before writing in The Economist.
US Govt already proved that China didn't manipulate its currency in beginning of 2009.
1) US Govt said China manipulate its currency (2005 - 2008)
2) US Govt said China didn't manipulate its currency (2009)
3) US Govt said China continue to manipulate its currency (2010) and it should stop doing it.
US Govt deny itself and re-deny itself again. Interesting...
1) China said we didn't manipulate our currency (2500 B.C. - 2008 A.D.)
2) China said we told you we didn't manipulate our currency (2009)
3) China said we will continue tell you what we have been telling you (2010)
Taiwan, Tibet, and Currency issues are China's internal affair. US will face the consequences when it tries to use them for their own benefits.
China and Chinese are who they said they are. And they will reserve their right of doing things to protect their country unification and growth. And when they start doing it . . . people will know.
The article is rather baised really.
One nation comes up, the other must do whatever to remain in power. Im still not sure what is the "white men's burden" though? Profiting from the poorer part of the world in the name of justice? Please do share some of that responbility with me. You can take a break while I "take care" of you now.
The cold war is over. The question here is what is America doing meddling in china's backyard? China has a long humilating history of western interference in issues that undermine it's sovereignty. As china grows stronger obviously it will react more decisively to such offences. I think America should be weary of angering its vital tradeing partner - especially with the current state of their economy - and remember the Cuban missile crisis. Who would tollerate foreign arms so close to home? China definitely has good reason to behave resolutely - as it, like other states, acts to further it's own interests in the international arena.
In my opinion, some of the the articles in Economist are not free of bias, more so when dealing with China. I do admire the honest criticism that it reserves for the world. However, i expect it to be a bit balanced and logical in approach on certain political issues.
America is a great nation, for all its democratic values. However, the administrators in US have to learn that their political and economic weight has only to vane down in future. The more it is prepared to accept this, the less confrontationist it will be towards the world. Consider how America responded when Cuba, which is a different (if wrong) ideological regime, was being given support by erstwhie Soviet Union. We had a cold war and arms race for 50 years, just due to the ego-centric attitudes of US and Soviet.
As a reader, I would love to see the Economist advocating the disarmament issue irrespective of any political affiliations.
"When both China and Europe were at the same stage of development in the 17th and 18th century, China alone accounted for 80% of the world's economic output, today China accounts for barely 20%, it is historically inevitable that the industrialized China surpass the equally industrialized Europe once again at some point in the near future"
Bu the 18th Century China economic development was on par with Europe as a whole, but not the Western European countries. Not as developed as say Holland, GB or France, but like Spain, Hungary or Italy. Holland and England were still twice as rich as China on a per capita basis. China's share of the world's GDP was 35% in the 1700s. India was about 17-20%. In total they had a combined GDP of over 50%. China's itself was never 80%. Right now China's share of the world's GDP is about 7-8%. Its about 30-40% the size of the US economy. US share is about 20-25% now.
China is a rising power. The US, while still growing, is not growing at the pace of China. This should worry nations who value Freedom before Wealth. China is not, as the USSR did, beggaring its population. They are attempting to rise above America in economic terms, and thus become the most powerful nation on the globe, or at the very least, on par with the US in the Asia-Pacific Rim area.
The Chinese, however, are not fools. They may make political use of the tire tariff or this arms sale, but they won't jeopardize their economic relationship with the US. For that reason, they might sell arms to a Hugo Chavez or a Mahmoud Ahmadinjiad (sp), but they would draw the line at creating a terrorist hotbed close to home.
America must realize that the Chinese are not Hitler's Germany, nor the USSR. There is almost no limit to the economic power 1 Billion Chinese can generate. While I think there is some limits in that Dictatorship tends to concentrate power inefficiently and their banking system remains somewhat immature, there is a lot of potential growth still to go before they hit that wall imposed by their lack of economic freedom. They're still in what Rostow might term "Economic take-off", or at the very least, they're far from his definition of a mature economy. So, how far to go before they reach the limit of their power? Unknown. And the US State Department and its economic policy needs to be one of wise engagement. In time, I believe that a House Divided against itself cannot stand - the government cannot forever control its people and create two haves between those connected to government and those not. But how that crux point may involve will depend on the US-China relationship and how it grows and changes into the future, in my opinion.
Obama, a one term president, is an "empty-suit" who can speak very eloquently. This weakness of character and moral resolve has been read by the Chinese as less than a paper tiger, a weak willed pussy cat. Due to the present administration gaffes and weakness, it will not be long before China will be the SUPER POWER that will dictate policy to the USA.
"If the Chinese people want freer access to internet porn, let them take it up with their own government! Why should we force internet freedom down their throats?"
The point with internet freedom can also be seen as a trade issue. At least the Americans are honest enough to call Chinese actions for what it is. Google could have done it quietly and sent a letter to US Trade Representative to file a letter to the WTO accusing China of violating its WTO obligations.
Thank you for this excellent article. This is exactly the crux of my blog posting a few days ago. The Chinese respect power, and will only demand more from the West if they perceive weakness. So sell arms to Taiwan. Meet the Dalai Lama. Back India in this riiculous border dispute the Chinese are provoking. And tell Beijing that cyber attacks (whether on Google or the White House) are unacceptable.
The question that interests me about the possibility of a trade war is, economically speaking, does China need the U.S. more than the the U.S. needs China?
Both countries would, obviously, lose out to some degree if a trade war broke out from a wave of protectionism. But I have yet to see much quantitative evidence that the U.S. would suffer nearly as much as China would.
Does anyone have good supporting information (not just anecdotal conjecture) for or against this supposition?
post the long ideological war
rising nations struggle for pride of place
merchants and generals march together
Bismarck's ghost laughs
Taiwan is a democracy. Helping Taiwan hurts the US, but the US learned in the 20th century that it must stand by fellow democracies or see them fall. Now I'd be the first to admit invading places like Iraq to set up democracies is and was a fool's errand, but helping places that choose to be democratic is the best use of my tax dollars that I can think of. Mainland China can govern itself as it chooses, but if Taiwan wants democracy, it needs to be helped to keep its freedom. Free peoples must come to one another's aid.
If China wants to invade Taiwan, they likely will succeed. But the CCP needs to know that the resulting damage to China and China's economy will be sufficient to make the CCP's continued rule untenable. Keeping Taiwan militarily strong helps to ensure that. It is worth the cost.
Abraham Lincoln is an american hero because he kept together the union. Eradication of slavery was a rather second goal for him, and he even wanted to move all the freed blacks in latin america or somewhere else. However the truth, I don't think the situation between US in 1860 is comparable with the China/Taiwan situation now. US wanted to keep the union and free the slaves, while China wants to keep a united China at the expense of Taiwan's fledgeling democracy.
I am Romanian and my country experienced a division due to soviets twice, last time in 1941 and the part taken from is now the Republic of Moldova. I do not think that the two parts should be again united if people from Moldova do not really wanted. Romania got first united by popular referendums.
I do not think that any authoritarian or democratic regime has any rights to impose to another party what to do against their will. I seay Taiwan should stay free!
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My cat chewed through the power cord of the Airport base station. Does anyone know if a replacement can be purchased separately from the base station
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The question of whether torture 'works' was settled by interrogation experts long ago. But, the fact that it even comes up says that we are willing to be part of a society that tortures people---sad to say. The world has plenty of experience with torture and any decent human being should regard it as evil.
DICK CHENEY et al justify the use of "enhanced interrogation" on the grounds that it produced some high-value information. That begs the question of whether other techniques might have yielded the same high-value information, as many professional interrogators claim, but it is at least a morally serious case.
But what happens if one of the main drivers of the enhanced interrogation policy was the desire to prove a non-existent connection between al Qaeda and Saddam Hussein? That surely changes the moral calculation completely. The administration was not just trying to prevent a future attack, but also to justify its case for going to war with Iraq; it was not just trying to elicit information, but also to get detainees to confess to something it presumed to be true.
Here are the first three paragraphs from a McClatchy news report this morning:
The Bush administration applied relentless pressure on interrogators to use harsh methods on detainees in part to find evidence of cooperation between al Qaida and the late Iraqi dictator Saddam Hussein's regime, according to a former senior U.S. intelligence official and a former Army psychiatrist.
Such information would've provided a foundation for one of former President George W. Bush's main arguments for invading Iraq in 2003. In fact, no evidence has ever been found of operational ties between Osama bin Laden's terrorist network and Saddam's regime.
The use of abusive interrogation — widely considered torture — as part of Bush's quest for a rationale to invade Iraq came to light as the Senate issued a major report tracing the origin of the abuses and President Barack Obama opened the door to prosecuting former U.S. officials for approving them.


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Issue 174/2015
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MSBuild is now just another GitHub project as Redmond continues its path to the light.
Researchers Demonstrate Hack by Heat
Malware could pass data and commands between disconnected computers without leaving a trace on the network.
Kernel Developers Adopt Code of Conflict
New rules emphasize collegiality in coding.
Ubuntu Switches to systemd
Upstart lands in the dust bin as a new era begins for Linux.
Old Vulnerabilities Are Kept Alive Through Bad Configuration
HP's annual Cyber Risk report offers a bleak look at the state of IT.
Linus Torvalds Announces Linux 4.0
But what do the big numbers really mean?
Microsoft Frees CoreCLR
.NET Core execution engine is the basis for cross-platform .NET implementations.
New Trojan Attacks Linux Servers
The Xnote trojan hides itself on the target system and will launch a variety of attacks on command.
Cisco Releases Annual Security Report
Spammers go low-volume, and 90% of IE browsers are unpatched.
Zero Day Exploits Target Flash
Adobe scrambles to release patches for vulnerable Flash Player.