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Val Garland
Tips, trends and beauty secrets. Spying on the make-up artist at the backstage of the fashion shows for F/W
Val Garland.
Her idea of make-up
Make-up should be absolutely perfect: she created a special glass through which she thoroughly checks if each single line is perfect. She's also famous for being a great innovator in terms of brushes.
People who love her
Kylie Minogue, Helena Christensen, Kate Moss, Björk, Gwyneth Paltrow, Gwen Stefani, Kate Winslet e Jennifer Lopez.
Her first steps
She grew up in Bristol and then moved to Sydney, Australia, where she trained as hair colorist. In the early 1980s she inaugurated Garland & Garland with her husband, a beauty salon for hairstyling, with paintings on the walls and lounge atmospheres which immediately became a "must" in the Australian city. Meanwhile she cultivated her passion for color and turned into a freelance make-up artist.
The turning point
In 1994 she moved back to the UK, to London. Her first project was with photographer Albert Watson for The Face. She entered a group of artists like Karl Templer, Eugene Souleiman, Nick Knight, Alexander McQueen, John Galliano and Guido Palau.
Val works with various magazines, such as Vogue, Dazed & Confused, i-D and Visionaire. She also collaborates with many photographers, like Nick Knight, Mario Testino, Mert Alas and Marcus Piggot, Richard Burbridge, Sølve Sundsbø and Steven Klein.
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Vittoria Mentasti - Dead Sea
Vittoria Mentasti's Dead Sea takes us to a place where the sky and the sea are one
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A chat with Kristin Prim, the founder of The Provocateur, the site that publishes letters written expressely by leading women addressing the whole female world. Vogue.it presents you an exclusive preview of the letter written by Dresden Dolls' Amanda Palmer
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Menswear and womenswear collections will walk together and will be on sale right after the show. These are the news from Burberry but the evolution is generalized: runway shows are changing


text: OverviewBack to top Maxi-Health Research Kosher Vitamins - Valerian Root and St. John`s Wort Liquid - 1 oz. Item# :56140UPC# :753406105014 Brand:Maxi-Health Research Kosher Vitamins Size/Form:1 oz. .8% Valerenic Acid, standardized extract Promotes relaxation during times of anxiety A mild sleep aid, a calmative and a stress buster Maxi Valerian is helpful as a calmative to support a healthy response to stress and frustration. It promotes and supports a normal, healthy mood during PMS and can be used as a mild sleep aid for mood support and for general relaxation. Great for soothing sleep due to occasional sleeplessness and for the temporary relief of leg cramps. Try it to see the results!

subset: commoncrawl


text:
- {{matchup.date.fullday}}{{matchup.date.month + ' ' + matchup.date.day}}
Sacramento Falls 97-93 to Cavaliers - Recap
Cleveland earned a 97-93 victory over Sacramento on Wednesday, getting 20 points from Ramon Sessions at Power Balance Pavilion.
The Cavaliers were a 9.5-point underdog in the win, and managed to turn a profit for their supporters. The combined score dipped UNDER the total, which closed at 215.5.
Cleveland got 17 points from J.J. Hickson and another 15 points from Luke Harangody. Ramon Sessions contributed 6 assists, while J.J. Hickson cleaned the glass with 8 rebounds.
Sacramento got 23 points from Marcus Thornton in a losing cause and another 16 points from Samuel Dalembert. Beno Udrih contributed 8 assists for the Kings, while DeMarcus Cousins had 16 rebounds.
The Cavaliers hit the break trailing 51-45 before taking care of business in the second half.
Sacramento had a 49-42 advantage in the rebounding department as they won the battle in the paint.
Next game, Cleveland takes its act on the road to face Portland looking for another win. For Sacramento, they head home to face Philadelphia.


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Cynthia S. Lohry wrote:
> Ingrid,
> I blame all my typos on the keyboard that the cats hve slept on too
> often and knocked to the floor too many times!
> Cindi
My study AND my green house are off-limits to my cats. Keeps my spelling
rather OK, and my cutting without tooth-marks!
Mimy Sluiter
cats: <http://welcome.to/Manx> mailto:email@example.com
politics: <http://welcome.to/d66.noordholland> mailto:email@example.com
phone & fax: +31-[0]35-6920501 / cellular phone: +31-[0]6-50278642


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Are you looking for Banquet Hall in ILLINOIS? Hotfrog showcases more than 100 popular businesses related to Banquet Hall in ILLINOIS! Find a specific region or suburb using the left navigation.
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Banquet hall for all occasions up to 600 guests.
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Joseph Academy is a school serving the needs of young people with severe behavioral, emotional, and learning disabilities We are pleased to announce that our Graduation Event will be taking place at The Diploma…
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Make Diamond Liquors your one stop for all your beverage needs We stock a large selection of wines, beers, and spirits
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HYSupplies Inc - We are proud of our long history of providing a quality collection of Salon towels, Table Skirts, Round Tablecloths, Bleach Proof Salon Towels, Bathrobes and Table Napkins at affordable prices
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Contact us at (708) 839-5820 in Willow Springs, IL, to host your next party. Our banquet hall and billiard club is the ideal place for any special event.
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Our elegant banquet hall in Fox Lake has three separate dining rooms to serve your needs, which can accommodate from 75 to 400 people We will be happy to help you plan your banquet or catered event with the most…
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Abbington Distinctive Banquets, the newest and finest banquet hall facility in Chicago offers the perfect venue for your Chicago wedding, event, meeting or conference
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text:
Swedish Pot Roast
|Chuck roast/Rump roast
|4 Pound
|1 Teaspoon
|1 Teaspoon
|Safflower oil
|3 Teaspoon
|2 Medium, sliced
|Anchovy paste
|1 Teaspoon
|Bay leaves
|2 Teaspoon
|2 Teaspoon
|Brown rice flour
|4 Teaspoon
|1⁄2 Cup (8 tbs)
Rub roast on all sides with salt and allspice.
Brown on all sides in oil.
Halfway through, add onions.
Stir in anchovy paste, bay leaves, vinegar, and molasses.
Reduce heat, cover, and simmer until meat is tender, 2-2 1/2 hours.
Remove meat to a warm platter.
Blend flour into the 1/2 cup water to make a paste.
Stir into pan juices and cook until slightly thickened.
Serve with roast.
Variations: If you can use corn, you can substitute 2 tsp cornstarch for the flour.
if you can use milk, you can use 1 c.
sour cream or yogurt instead of water.
if you can use wheat and gluten, you can use whole wheat flour instead of brown rice flour.
If you can use gluten but not wheat, you can substitute barley or oat flour for the brown rice flour.
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 2901 Calories from Fat 896
% Daily Value*
Total Fat 100 g153.8%
Saturated Fat 35.2 g176%
Trans Fat 0 g
Cholesterol 981.6 mg327.2%
Sodium 3367.4 mg140.3%
Total Carbohydrates 72 g23.8%
Dietary Fiber 9.5 g38.1%
Sugars 23.2 g
Protein 408 g816.7%
Vitamin A 3.3% Vitamin C 55.6%
Calcium 50.3% Iron 224.2%
*Based on a 2000 Calorie diet


text:
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PRI's The World
March 09, 2010 · 5:00 AM CST
Listen to the Story.
In Politics, Global Politics, Arts, Culture & Media, Lifestyle & Belief, Business, Finance & Economics and Science, Tech & Environment.
Tagged: Italy   Europe   government   history   work   business   Climate Change   taxes   pollution
February 27, 2017
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Women in the Ministry of Jesus
A Study of Jesus' Attitudes to Women and Their Roles as Reflected in His Earthly Life
By (author) Ben Witherington
Series edited by John Court
Format: Hardback
Normal Price: $210.00
Your Price: $189.00 AUD, inc. GST
Shipping: $7.95 per order
You Save: $21.00! (10% off normal price)
Plus...earn $9.45 in Boomerang Bucks
Availability: Available to Backorder, No Due Date for Supply
Women in the Ministry of Jesus by Ben Witherington
Book DescriptionWomen in the Ministry of Jesus is a study of both of Jesus' attitudes towards women as reflected in his words and deeds, and of the women who were part of his ministry, or who interacted with him according to the Gospel accounts. The book seeks to provide a balanced analysis of the relevant Biblical material, and also the historical background necessary to illuminate the setting of the Gospel events. Particular attention is given to related issues such as Jesus' views on marriage, the family and the single life, as well as his teaching on adultery, the laws of the clean and unclean and the sabbath. Witherington concludes that Jesus cannot be categorized neatly either as chauvinist or as feminist.
Buy Women in the Ministry of Jesus book by Ben Witherington from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9780521256582
(216mm x 138mm x 17mm)
Pages: 236
Imprint: Cambridge University Press
Publisher: Cambridge University Press
Publish Date: 3-May-1984
Country of Publication: United Kingdom
Other Editions...
Books By Author Ben Witherington
Isaiah Old and New, Paperback (February 2017)
Ben Witherington III offers pastors, teachers, and students an accessible commentary to Isaiah, as well as a reasoned consideration of how Isaiah was heard and read in early Christianity.
New Testament Theology and Ethics, Volume 1, Paperback / softback (June 2016)View all books by Ben Witherington
In this paperback edition of The Indelible Image, Volume 1, Ben Witherington III offers the first of a two-volume set on the theological and ethical thought world of the New Testament. This volume focuses on expositional samplings of the theology and ethics of New Testament writers in context.
» Have you read this book? We'd like to know what you think about it - write a review about Women in the Ministry of Jesus book by Ben Witherington and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a member - it's free to sign up!)
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M Suites Sorrento, Sorrento
- Free WiFi and free parking
Main amenities
- 3 apartments
- Train station pick-up service
- Terrace
- Air conditioning
- Garden
- Car rentals on site
- Self-serve laundry
- Barbecue grills
- Luggage storage
Feel at home
- Free cribs/infant beds
- Rollaway/extra beds (free)
- Sofa bed
- Kitchenette
- Cookware, dishware, and utensils
- Stovetop
What's around
- Heart of Sorrento
- Piazza Tasso (1.3 mi / 2.1 km)
- Marina Grande (2 mi / 3.1 km)
- Museo Correale di Terranova (1.1 mi / 1.8 km)
- Piazza Lauro (1.1 mi / 1.8 km)
- Frantoio Gargiulo (1.2 mi / 1.9 km)
Great views, accommodations good, a bit of a walk to central Sorrento.
The hotel is nice, you have a kitchen with a fridge and stove. They provide espresso,…
M Suites Sorrento, Sorrentofrom $134
- Apartment, 1 Bedroom, Bathtub, Sea View
- Apartment, 1 Bedroom, Jetted Tub, Sea View
- Apartment, 1 Bedroom, Sea View (shower)
More great choices
At a glance
Key facts
Hotel size
- This hotel has 3 rooms
- This hotel is arranged over 2 floors
- Check-in time 3:00 PM-5:30 AM
- Check-out time is 11:00 AM
- Express check-in/out
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Pets not allowed
- Specific rooms only *
- Free WiFi in public areas
- Free WiFi in rooms
- Train station pickup *
- Free self parking
- Free nearby parking
Nearby One Star Sorrento hotels
In the hotel
- Barbecue grills
- Limo or Town Car service available
- Laundry facilities
- Luggage storage
- Number of buildings/towers - 1
- Year Built 1954
- Garden
- Terrace
In the room
- In-room climate control (air conditioning)
- Air conditioning
- Espresso maker
- Coffee/tea maker
- Iron/ironing board (on request)
- Washer/dryer
- Sofa bed
- Sofa bed size queen
- Frette Italian sheets
- Individually decorated
- Individually furnished
- Separate dining area
- Separate living room
- Separate sitting area
- Furnished patio
- Private bathroom
- Shower/tub combination
- Rainfall showerhead
- Bidet
- Free toiletries
- Hair dryer
- Digital TV channels
- DVD player
- Desk
- Free WiFi
- Refrigerator
- Microwave (on request)
- Kitchenette
- Stovetop
- Cookware, dishware, and utensils
- Dishwasher
- Free bottled water
Top Sorrento hotels
Recently reviewed hotels in Sorrento
- Hotel MediterraneoFrom
"The staff at Hotel Mediterraneo went above and beyond in making our stay in Italy memorable. My husband is an above the knee amputee and Italy is not quite "handicap accessible".…"Jan 16, 2017
- Hotel PlazaFrom
"Great location, great quality of room and supreme service attitude. Unbeatable and want to repeat the experience. Thanks to Cynthia, Super Carlo at the Bar, Kind Marianne at…"Jan 16, 2017
- Eurostars Hotel ExcelsiorFrom
"Extremely beautiful and elegant hotel. The hotel and everything about it was near perfect. Only due to my personal preference, I found the bed and pillows a bit too firm. "Jan 16, 2017
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"Love it or hate it, one of Napoli's attractions is the controlled chaos on the streets, and there is no better time to experience that than during Christmas when we visited. Via…"Jan 15, 2017
Nearby hotels
Also popular with travelers from the USA
M Suites Sorrento, Sorrento's small print
Also known as
- M Suites
- M Suites Apartment
- M Suites Apartment Sorrento
- M Suites Sorrento
All guests, including children, must be present at check-in and show their government-issued photo ID card or passport.
Cash transactions at this property cannot exceed EUR 2999.99, due to national regulations. For further details, please contact the property using information in the booking confirmation.
Pet-friendly rooms can be requested by contacting the property at the number on the booking confirmation.
Only registered guests are allowed in the guestrooms.
This property does not have elevators.
For transfers, guests must contact the property before arrival at the number on the booking confirmation.
Mandatory fees
A tax is imposed by the city and collected at the property in cash. The tax applies to stays from 1 April to 31 October. This tax does not apply to residents of the city, or children under 18 years of age. Please note that further exemptions may apply. For further details, please contact the property using the information contained in the confirmation received after booking.
Optional extras
Self parking costs EUR 10 per day
Airport shuttle service is offered for an extra charge of EUR 100 per vehicle
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Excellent 4.5 /5 from 18 reviews
Our stay in M suites was pleasant. The area is nice. Close to center by car. It is not an easy walk down to bus stops. The street is uphill which provides a great view of the water from the apartment balcony. Parking was a bit difficult but we got lucky and found free parking. The beds were comfortable but the furniture needs a bit of an uplift. The owner was nice to leave us some bread, jam, juice and milk in the fridge. And provided us with tips to get around. since we had more than half day before going to the airport, they were nice enough to store our luggage for us until we were ready to leave.
Apartment itself was very nice with spectacular view but it was too far away from the places to eat and access to transportation. We left it too late when booking this part our itinerary, and we felt trapped when we were here. A more typical room in a closer location would have worked better for us as we did not have a car.
Superb apartment in a superb location just above Sorrento. Perfect for exploring the Amalfi coast, or Pompei. Close to amenities. You can even call in a meal to be delivered. The only complaint is the constant snail-like crawl of traffic along the Corso Italia. That isn't the apartment's fault. It just means you have to add 15 minutes to getting anywhere. And that was in November.
Excellent, would recommend
Is the description of this hotel not correct? Tell us


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Call us: 0121 356 1094
07718 425 452
Window Tinting
Shades Auto Tints - the car window tinting professionals in Birmingham
Contact us
Car window tinting you can trust
Here at Shades Auto Tints we have over twelve years of experience in the glass window tinting trade. If you need tinted windows for your car, Shades Auto Tints are the ones to call.
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Window Tinting
Benefits of window tinting for your car
Are you concerned about the security of your car? Or perhaps too much heat is coming through the car windows? If any of these problems sound familiar, contact Shades Auto Tints in Birmingham today. Our tinted windows have a range of benefits including:
Increased safety
Reduced UV rays
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All the work we carry out is backed up by a genuine lifetime guarantee and we offer a full comprehensive window tinting service which is second to none.
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Take A Look At Some Of Our Recent Work
To discuss reliable car tinting today call Shades Auto Tints in Birmingham today on
0121 356 1094
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Ann Sanner
Associated Press
COLUMBUS: The Ohio Senate has voted to reject nearly a quarter of outgoing Gov. Ted Strickland's appointments to state boards and commissions, in a move one fellow Democrat calls a stab in the back.
Democratic Sen. Nina Turner says Tuesday's 18-12 vote amounts to the largest rejection of a governor's appointments and is disrepectful to Strickland. Republican Senate President-elect Tom Niehaus said Republicans who lead the Senate thought carefully about the decision.
Seventy-eight of Strickland's 351 pending appointments were rejected. Another 273 appointees were poised to be approved or allowed to keep their seats without objection.
Of the rejections, more than half were submitted after Strickland lost the Nov. 2 election to Republican John Kasich.


text:
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- Map/Street View
- Things Nearby
Waiting for the right deal on a Brighton apartment or townhome Look no further! Greystone Apartments and Townhomes has you covered with weekly specials that will put a quick and happy end to your housing search. Starting at $814 per month for one bedroom apartments, this professionally managed and maintained → Read More
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The Oakland Raiders have long had one of the worst offensive lines in the NFL, a problem they have been trying to fix ever since drafting Robert Gallery way back in the 2004 NFL draft. Since taking over responsibilities for drafting as the Raiders general manager Reggie McKenzie has taken two offensive tackles in two consecutive drafts and neither one appears destined to anchor an end of the Raiders offensive line any time soon.
Both Tony Bergstrom and Menelik Watson have had injury issues and have not shown enough to earn starting spots, let alone much playing time with the team. Bergstrom, McKenzie's first ever draft pick with the Raiders may not make it through another season with the Raiders after failing to move up the depth chart at guard or tackle. And now, Watson, the British born basketball player with only a few years of experience playing football, may already be out of favor with the Raiders.
According to Scott Bair of CSN Bay Area, the Raiders coaching staff is concerned after just one season with the team that Watson "might not have it". This is rather big news since many had hoped Watson could be the answer the Raiders have been looking for at right tackle. The Raiders still need to re-sign left tackle Jared Veldheer, but assuming they do, they still need another book end to anchor the right side of the line.
If Watson is not that guy, it means the Raiders will have to add yet another piece to their long list of needs heading into this off season.


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Art: The Studio Experience FA1 (3)
Course Level: Undergraduate
This beginning studio course introduces students to painting, drawing, sculpture, and design combined with visual literacy. The course focuses on the interrelationship of hand, eye, and mind to create informed works of art that engage larger critical, formal, or cultural dialogues and relate basic visual language to analytic and creative processes of the artist. Usually offered every term.


text:
Hospice Maui is seeking a Clinical Director for our growing team of hospice and palliative care specialists. We provide our employees with opportunities for professional growth and competitive benefits. Join us in making a difference every day to patients and families coping with end-of-life illness.
In this leadership role, you will ensure quality patient care, direct, coordinate and control all aspects of the clinical functions, perform regulatory compliance, and manage staff. We are looking for someone who can build trust, is committed to the team, and holds themselves and others accountable. If patient care is your passion--we want to hear from you!
We hold sacred the work that we do: caring for the dying and their families with compassion and honesty. This is our core value. We seek a person who shares and embodies that perspective.
Our hospice program serves the uniquely culturally diverse and spiritually rich community of Maui. The right candidate for this position will hold the highest respect for the diversity of our community and of our workplace.
Minimum Qualifications for Director of Clinical Services:
BSN, Registered Nurse with a current and unencumbered license for the state of Hawaii
Proven effective managerial or supervisory experience to direct, train and develop a staff of clinicians to provide top level care to our patients
Understanding of business growth, financial management, personnel development
Strong clinical skills for mentoring, training and use in the field to ensure education of staff skills
Leadership qualities that include the ability to listen, inspire and motivate others, set expectations, empower others, lead a team to great results
Essential Functions for Director of Clinical Services:
Employ qualified personnel and ensure adequate staff education and evaluations; in collaboration with the CEO and Manager of Human Resources, determine the hiring, orientations, retention, evaluations, discipline, counseling or termination of the hospice's team associates
Work closely with the Medical Director to ensure quality patient care and staff competency
Work closely with the CEO, the Medical Director, the Spiritual Care staff, and others to deepen staff skills in the cultivation of compassion through self-awareness.
Adhere to budget requirements regarding labor, pharmacy, DME, and medical supply costs
Review all higher level of care patients including respite, general inpatient and continuous care
Serve as liaison to and conduit between the Administrator, Case Managers, clinical staff on his/her respective team, patients, their families, and the community
Benefits for Director of Clinical Services include:
Competitive compensation
This is a salary, exempt position.
If you meet the minimum requirements for Director of Clinical Services, please send your cover letter and resume with salary requirements to:
Required Experience:
Management: 2 years
Or mail to
Hospice Maui Inc.
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Jobs 2B DonePlumbing Plumbers
Woy Woy, NSW
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|Lucio Capuani <louis.capu...@gmail.com>
|Same (virtual) machines, very different behaviour
|Fri, 12 Jun 2009 13:01:01 GMT
Hello everybody and thanks for caring. I have an instance of Tomcat running into two Xen virtual machines. I have cloned one of the two virtual machines and I changed the IP address of the original. Now, the clone (the copy) still works fine. The original no more. Tomcat still start and works, but the startup time is endless (776637 ms, that's 12 minutes!). The big wait comes between these log lines: Jun 10, 2009 2:44:34 PM org.apache.catalina.core.StandardHost start and these ones (please notice the time stamp): Jun 10, 2009 2:57:30 PM org.apache.jk.common.ChannelSocket init INFO: JK: ajp13 listening on /127.0.0.1:8009 ...so it happens when it's about to opening the socket. On the cloned machine, this is the output: Jun 10, 2009 2:44:53 PM org.apache.catalina.core.StandardHost start INFO: XML validation disabled Jun 10, 2009 2:45:09 PM org.apache.jk.common.ChannelSocket init INFO: JK: ajp13 listening on /127.0.0.1:8009 there's a gap of one second among the two operations, which is of course fine. Please notice that all the differences between the hosts are in the IP address and in the fact that one's behind a firewall (the slow-to-start one) and the other is not. But I can't see how being behind a firewall can slow down opening a port on 127.0.0.1. That's the output I got with /usr/share/tomcat5.5/bin/catalina.sh debug Thanks so much! Louis Capuani --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: email@example.com
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Getting you more information on this room
Rooms outdated and worn. Only outdoor access to rooms. Vanity area light did not work. A different room was provided after informing clerk.
I stopped here in Dec with my dog & I asked for a ground floor room when I made the reservation & when I arrived that is what I got. The room is clean, wooden floors that are a lot better than carpet (especially in Florida) the shower was old & really should be replaced, otherwise everything was good.
I was traveling with my lil family & 2 of my siblings.it was very late & we were exhausted. Regardless of the new employee still in training, they were both very polite & quick to get us checked in
This days inn was terrible. 2 night there room was flooded from a over flowing toilet. Put in another room and the blankets and pillows smelled horrible. I don't recommand this hotel.
This was a one night stay in route to our Christmas Vacation trip. the staff was nice we checked in late after a long work week. The Hotel was clean bed was comfortable close to freeway breakfast was good.
"At back of hotel, very quiet"
"check the room before unloading your car"
"go somewhere else"
"Check the carpet before get the room."
"Stay at another hotel"


text:
Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis
DOI: 10.1186/ar3079
© Boettger et al.; licensee BioMed Central Ltd. 2010
Received: 23 April 2010
Accepted: 13 July 2010
Published: 13 July 2010
Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA.
Rats with AIA were either treated with sgp130 or saline intra-peritoneally or intra-articularly (each group n = 9). Then, pain-related and locomotor behaviour, as well as joint swelling, were measured during an observation period of 21 days, followed by histopathological end-point analysis for inflammatory and destructive changes.
A single intra-articular application of sgp130 at the time of AIA induction barely reduced the development of AIA, but significantly attenuated pain-related behaviour, that is, primary mechanical hyperalgesia in the acute phase of AIA. By contrast, repeated systemic application of sgp130 after onset of AIA only slightly attenuated pain at a late stage of AIA. None of the treatments reduced secondary hyperalgesia. Furthermore, in the present study joint destruction at 21 days was significantly attenuated after intra-articular sgp130 treatment, but not after systemic sgp130.
In addition to its role in chronic inflammation, IL-6 in the joint plays a significant role in the generation and maintenance of arthritic joint pain at acute and chronic stages of AIA. The particular effectiveness of intra-articular injection of sgp130 indicates, first, that IL-6/sIL-6R in the inflamed joint, rather than circulating IL-6/sIL-6R, is responsible for the generation of hyperalgesia, and, second, that early neutralization of IL-6/sIL-6R is particularly successful in producing antinociception. Furthermore, neutralization of IL-6/sIL-6R (and possibly other cytokines which use the transmembrane signal-transducing subunit gp130) directly at the site of joint inflammation seems to be effective in the prevention of joint destruction.
The cytokine interleukin-6 (IL-6) is thought to be a key player in systemic inflammation and arthritis [1], as shown, for example, by significantly attenuated antigen-induced arthritis in IL-6-deficient mice [2]. In a murine model of human tumour necrosis factor- (TNF) mediated inflammation, IL-6 was found to be particularly involved in inflammation-evoked osteoclast formation and bone erosion [3]. IL-6 signalling not only depends on the presence of IL-6 but also on various cofactors. IL-6 can bind to a membrane-bound IL-6 receptor (IL-6R) which acts in cooperation with the transmembrane signal-transducing subunit soluble glycoprotein 130 (gp130) [4, 5]. Alternatively, IL-6 can bind to a soluble IL-6 receptor (sIL-6R), and the IL-6/sIL-6R complex can bind to the transmembrane signal-transducing subunit gp130 of cells which do not express the membrane-bound IL-6R, thus leading to IL-6 transsignalling [5]. In fact, in the serum, synovial fluid and synovial tissue of rheumatoid arthritis patients the concentrations of both IL-6 [6, 7] and sIL-6R [8, 9] are elevated. While sIL-6R acts as an agonist, circulating soluble gp130 (sgp130) acts as an antagonist, because it binds IL-6/sIL-6R complexes and thus prevents transsignalling [4, 5]. In murine arthritis models, neutralization of IL-6 transsignalling by administration of sgp130 was shown to reduce inflammation [2, 10–12].
In addition, it has been suggested that IL-6 plays an important role in the generation of inflammatory pain. Using electrophysiological recordings from nociceptors of the rat knee joint, we recently found that the injection of IL-6 or of IL-6 together with sIL-6R into a normal knee caused a long-lasting sensitization of nociceptive C-fibres for mechanical stimuli applied to the joint [13]. This sensitization is likely to be caused at least in part by a direct effect on the nerve fibres, because most peripheral nerve fibres were shown to express the transmembrane signal-transducing subunit gp130 [14, 15]. The sensitizing effect of IL-6 was prevented by co-administration of sgp130 which binds and inactivates IL-6/IL-6R complexes [5]. Interestingly, however, sgp130 did not reduce the enhanced mechanosensitivity when it was administered into the joint one hour after IL6 or IL-6/sIL-6R [13] suggesting that IL-6 might induce a state of persistent hyperexcitability which is difficult to reverse. In line with this, it has been reported that 24 hours after the injection of IL-6 into skeletal muscle an additional injection of PGE2 into the muscle caused stronger nociceptive behaviour than under control conditions, and it was concluded that IL-6 caused long-term priming of nociceptive neurones [16].
While the available data suggest that IL-6 (trans)signalling may be important for pain and inflammation, no study has investigated how neutralization of IL-6 transsignalling affects pain in an arthritis model. Therefore, in the present study we explored in the rat the effect of neutralization of IL-6 transsignalling on pain-related behaviour and inflammation in the unilateral model of antigen-induced arthritis (AIA). In order to neutralize IL-6 transsignalling, we used sgp130 which has been employed in previous studies on inflammation [2, 11] and pain [13]. In the first approach, we repeatedly administered sgp130 intra-peritoneally during the course of AIA, starting six hours after arthritis induction. Employing such an approach, we previously found that the TNF-α neutralizing compounds etanercept and infliximab strongly reduced mechanical hyperalgesia at the inflamed knee joint and slightly but significantly decreased swelling at the inflamed joint [17]. In a second approach, we administered sgp130 into the knee joint together with the antigen upon arthritis induction. We analyzed pain-related and locomotor behaviour, knee swelling and, using histopathology, the severity of inflammation at the end of the observation period at 21 days after induction of arthritis.
Materials and methods
Antigen-induced arthritis (AIA)
Forty-five female Lewis rats (age six to eight weeks, weighing 160 to 180 g, Charles River, Sulzfeld, Germany) were used. All experiments were approved by the Thuringian state authorities and complied with EC regulations (86/609/EEC). AIA was induced as reported previously [18, 19]. In brief, 500 μg methylated bovine serum albumin (m-BSA; Sigma, Deisenhofen, Germany) in saline emulsified with 500 μl Freund's complete adjuvant (Sigma; supplemented with 2 mg/ml Mycobacterium tuberculosis strain H37RA; Difco, Detroit, MI, USA) were injected sub-cutaneously (s.c.) twice during a one week interval for immunization. After another two weeks, m-BSA (500 μg in 50 μl saline) was injected into the left knee joint cavity to induce monoarticular AIA.
Treatment protocols
We used recombinant human soluble gp130 (sgp130, R&D Systems, Minneapolis, MN, USA) which is effective in different species [2, 4, 13]. Nine animals received sgp130 intra-peritoneally (i.p.) (1 μg dissolved in 200 μl saline starting six hours after induction of AIA and on every third day until Day 12 after induction). Another nine rats were treated with sgp130 intra-articularly (i.a., 100 ng in 50 μl), which was injected simultaneously to m-BSA application. Data were compared to those from animals receiving saline i.a. (50 μl injected together with m-BSA at the time of arthritis induction), saline i.p. at the same time points as i.p.-sgp130 treatment was performed (0.9% NaCl, volume 200 μl), and to animals that were immunized, but in which no arthritis was induced (controls, each n = 9).
Behavioural experiments
Pain-related behaviour
In this calculation, an antinociceptive effect of 0% means a reduction in thresholds to the same extent as in saline-treated animals, while 100% would indicate a complete return to baseline values on all testing days.
Pain-related guarding behaviour was assessed by quantification of weight bearing towards the non-inflamed hindlimb using an incapacitance tester (Linton Intrumentation, Norfolk, UK). Animals were placed in a plastic cage with both hindpaws resting on scales. The weight force on both scales was obtained and averaged for three seconds and values from three consecutive measurements were obtained for every testing day. From these values, the relative weight resting on the inflamed hindlimb was calculated as described previously [20].
Secondary hyperalgesia was assessed at sites remote from the inflamed joint, the paw and the contralateral knee joint. Mechanical secondary hyperalgesia at the contralateral knee joint was assessed as described above. In addition, secondary mechanical hyperalgesia was obtained from the paw using a dynamic plantar aesthesiometer (Ugo Basile, Comerio, Italy) as previously described [21]. This device reflects an automated form of von Frey hair testing with a blunt filament touching the paw on the plantar surface while the animal rests on a mesh floor. Then, pressure is increased until the animal withdraws its limb, and the weight force needed to elicit this response can be read out in grams. In this study, 50 g were defined as cut-off and a ramp speed of 2.5 g/s was chosen according to the procedure previously reported [22]. After allowing the animals to habituate to the device for 30 minutes, measurements were taken in triplicate over a period of approximately half an hour and means were taken as secondary mechanical hyperalgesic thresholds. Thermal secondary hyperalgesia at the hindpaws was assessed with an algesimeter (Ugo Basile, Comerio, Italy) as described previously [23, 24].
Gait analysis
Paw prints were obtained as described previously (see [19, 25]). From these prints, the distance between a print from the left (inflamed) paw and a consecutive print from the right (non-inflamed) paw (left-right-distance), mainly indicating pain [19], and the angle between consecutive paw prints, which has been associated with joint destruction [19], were assessed. For each animal and testing day, at least five gait cycles were analysed. In addition, a guarding score was assessed: 0: no guarding, 1: guarding of the hindlimb after a defined brief noxious compression of the knee, 2: visible limping during walking without previous pain stimulus, 3: no use of the hindlimb with the arthritic knee.
Joint swelling
Histopathological grading of joint inflammation and destruction
Histology of the knee joints was assessed on Day 21 after AIA induction as described previously [17, 19]. Under deep anesthesia with sodium thiopentone rats were perfused with PBS and 4.0% phosphate-buffered formalin. Knee joints were removed, skinned, post-fixed in formalin, decalcified in 7% AlCl3, embedded in paraffin, cut into 5 μm thick frontal sections and stained with hematoxylin-eosin. Two independent observers (MG, RB) unaware of the treatment scored the sections for cellular infiltration and hyperplasia (0: no, 1: mild, 2: moderate, 3: severe alterations), cartilage destruction and bone erosion (0: no erosion, 1: erosion of < 10%, 2: of 10 to 25%, 3: of 25 to 50%, and 4: of > 50% of cartilage and bone).
Statistical Analyses
For statistical analyses, SPSS for Windows was used (version 17.0). Data were tested for normal distribution applying Kolmogorov-Smirnov-test. Behavioural data were compared between groups using repeated measures ANOVAs with the between-subjects factor treatment (sgp130 i.a., sgp130 i.p., saline i.a., saline i.p.) and the within-subjects factor time (baseline, Days 1, 3, 7, 14 and 21 after induction of arthritis for all parameters except those from paw print analyses, that is, left-right distances and angles between paws, for which baseline and Days 7, 14 and 21 were included). Differences between treatment groups (sgp130 i.a. versus sgp130 i.p.; sgp130 i.a. versus saline i.a.; sgp130 i.p. versus saline i.p.) were analyzed for each testing day applying post-hoc t-tests.
For comparison of histological scores between groups, one-way ANOVAs were employed, followed by post-hoc t-tests. Antinociceptive and anti-inflammatory effects were compared between i.a.- and i.p.-sgp130-treated animals using unpaired two-sided t-tests. Significance was assumed for P < 0.05.
In the text, results from statistical analyses are displayed as values from multivariate testing, while figures and tables show results from post-hoc t-tests.
Behavioural assessment
Pain-related behaviour
Measures of secondary hyperalgesia and weight bearing
Day 1
Day 3
Day 7
Day 14
Day 21
Weight bearing [% on inflamed hindlimb]
Saline i.p.
49.7 ± 0.7
23.5 ± 3.1
27.0 ± 1.1
31.6 ± 2.4
40.0 ± 2.6
50.3 ± 2.1
Sgp130 i.p.
49.8 ± 0.6
27.0 ± 2.6
25.3 ± 2.5
26.1 ± 3.3
40.8 ± 2.5
46.4 ± 1.7
Saline i.a.
51.1 ± 0.6
30.6 ± 3.8
30.3 ± 1.5
33.6 ± 2.8
39.2 ± 2.4
45.5 ± 1.0
Sgp130 i.a.
50.6 ± 0.8
32.4 ± 0.8 *
38.0 ± 1.7+,**
43.2 ± 1.3 +,**
44.2 ± 1.2
48.4 ± 2.5
Mechanical thresholds paw [g]
Saline i.p.
26.2 ± 2.9
16.6 ± 1.7
12.5 ± 1.5
12.2 ± 1.3
12.3 ± 1.0
14.6 ± 1.9
Sgp130 i.p.
24.6 ± 3.0
14.2 ± 2.4
16.7 ± 1.9
14.0 ± 1.1
12.3 ± 1.8
13.3 ± 1.7
Saline i.a.
22.9 ± 2.1
14.5 ± 3.7
12.8 ± 1.8
9.8 ± 2.6
9.0 ± 2.4
12.3 ± 2.4
sgp130 i.a.
24.4 ± 1.6
15.5 ± 2.0
14.5 ± 2.2
12.7 ± 1.8
15.1 ± 2.6
14.7 ± 2.1
Thermal withdrawal thresholds paw [s]
Saline i.p.
15.3 ± 0.8
10.3 ± 0.9
10.3 ± 0.9
8.7 ± 0.8
8.4 ± 0.9
9.3 ± 0.9
sgp130 i.p.
14.9 ± 0.7
10.2 ± 0.8
11.3 ± 1.4
8.2 ± 1.3
9.4 ± 1.0
10.2 ± 0.9
Saline i.a.
14.9 ± 0.6
9.8 ± 0.8
9.5 ± 0.8
9.3 ± 1.1
10.1 ± 0.9
10.3 ± 1.3
sgp130 i.a.
13.4 ± 0.7
9.4 ± 0.7
10.7 ± 0.8
10.0 ± 0.7
10.5 ± 1.2
12.4 ± 1.0
By contrast, measures of secondary hyperalgesia assessed at the paw revealed no significant time × treatment interaction for mechanical thresholds (F(15,78) = 1.333; P = 0.218, see Table 1) or for thermal withdrawal thresholds (F(15,78) = 1.328; P = 0.206, see Table 1).
Locomotor behaviour
Furthermore, angles between paws indicating joint destruction [19] were significantly different between groups (F(9,71) = 2.047; P = 0.046). Again, i.a. treatment with sgp130 attenuated the inflammation-related gait changes (Figure 2d, f), while i.p.-sgp130 application was not different from i.p.-saline treatment (Figure 2e). On Days 14 and 21, significant differences could further be obtained between sgp130-i.a.- and sgp130-i.p.-treatment (P = 0.012 and P = 0.022, respectively).
For all objective gait parameters, only Days 7 to 21 were analyzed, since only few AIA animals utilized their inflamed hindlimb in the acute phase on days 1 and 3 (saline i.a. n = 3; saline i.p. n = 3; sgp130 i.a. n = 6; sgp130 i.p. n = 4).
Measurement of inflammation
In this study, we show that a single injection of sgp130 into the knee joint at the time of arthritis induction caused a significant long-term antinociceptive effect, although acute arthritis per se was barely attenuated. Antinociception is expressed as an increase of mechanical thresholds at the knee joint (reduction of hyperalgesia) and a faster normalization of pain-related gait disturbances. By contrast, repeated i.p. injection of sgp130 in the course of AIA reduced mechanical hyperalgesia only weakly, at a time point where AIA is already in the process of remission. Swelling was only weakly reduced by sgp130, but the effect of i.a. sgp130 was significantly greater than the effect of i.p. sgp130 on Day 7 of AIA. Histopathological scoring of inflammation did not show an effect of sgp130 upon either i.a. or i.p application but i.a. sgp130 produced a significant reduction of the score of cartilage and bone destruction.
The previous electrophysiological recordings from joint afferents revealed that injection of IL-6, and in particular injection of IL-6 together with its soluble receptor into the normal joint induces long-lasting sensitization for mechanical stimuli [13]. The significant antinociceptive effect of the intra-articular injection of sgp130 in the present study suggests that endogenous IL-6/sIL-6R indeed plays a significant role in the generation of arthritic joint pain. As a caveat it should be noted that sgp130 is not only restricted to sIL-6R signalling, as sgp130 also regulates the IL-6-related cytokines leukemia inhibiting factor (LIF) and oncostatin M (OSM) [5]. However, sgp130 has a lower affinity for LIF and OSM than for the IL-6/sIL-6R complex [5]. While in mice a prominent role of IL-6 in the AIA model has been established [2, 26, 27], the putative role of LIF and OSM in AIA is unknown. Furthermore, sgp130 is thought to prevent mainly transsignalling by IL-6/sIL-6R complexes and not to inhibit the classical IL-6 pathway [5]. Therefore, the magnitude of effects of IL-6 neutralization may be underestimated in the present study.
Both the long-lasting antinociceptive effect upon a single intra-articular injection at the time of arthritis induction and the very weak and only late effect of systemic sgp130 are remarkable. The greater effectiveness of i.a. sgp130 indicates that IL-6/sIL-6R in the joint is more important than circulating IL-6/sIL-6R. Although the dose ratio between i.a.- and i.p.-applied sgp130 was performed according to the same criteria as for etanercept in previous studies, where systemic application showed a beneficial effect [17], we cannot completely exclude that the i.p. sgp130 was underdosed and produced for this reason a less pronounced, yet detectable effect. It was pointed out that sgp130 may be present as an endogenous antagonist in the circulation and that "a molar excess of sgp130" leads to competitive inhibition of the IL-6/sIL-6R response [5]. However, not only the site of intervention (i.a. versus i.p.) may be crucial but also the timing of injection of sgp130. While the intra-articular injection of sgp130 was performed simultaneously with the injection of the antigen into the knee joint and can therefore be considered as pre-treatment, systemic sgp130 was administered for the first time six hours after induction of inflammation, that is, as post-treatment (same treatment regime as for etanercept and infliximab). These findings should be seen in the context of the effect of sgp130 on the IL-6-induced hyperexcitability. The intra-articular injection of sgp130 prevented the IL-6- or the IL-6/sIL-6R-induced sensitization upon pre-treatment but sgp130 did not reverse the IL-6- or IL-6/sIL-6R-induced hyperexcitability when it was applied after the establishment of hyperexcitability. These data suggest, therefore, that IL-6 generates a type of hyperexcitability, which is long-lasting and difficult to reverse (see Introduction).
We observed some reduction of swelling after i.a. sgp130 which may correspond to effects in previous studies in mice which showed a pronounced effect for inhibition of IL-6-transsignalling by sgp130 or splice variants thereof when applied once intra-articularly together with the antigen at the time of AIA induction [2, 11]. However, histopathological scoring did not reveal a significant reduction of the inflammatory process by Day 21. By contrast, the destruction was significantly reduced which is in line with a recent study in a murine model of human TNF-mediated inflammation in which the blockade of IL-6 receptors impaired osteoclast formation and reduced bone loss, while the inflammatory process per se was not influenced by IL-6R-blockade [3]. This effect might even be pronounced in repeated inflammatory states. In this respect, in mice it was found that AIA can be rekindled by further injections of the antigen into the joint, and with each flare-up reaction joint destruction becomes more severe (unpublished observations).
The present and previous data show differences between the treatment with sgp130 and TNF-α-neutralization by etanercept and infliximab. First, systemic etanercept and infliximab clearly reduced mechanical hyperalgesia as well as secondary hyperalgesia at the paws at the early and late stage of AIA whereas [17, 19] systemic sgp130 had only a late and weak effect. Second, injection of etanercept into the inflamed knee joint significantly reduced responses of nociceptive fibres within one hour [17], and etanercept also reduces sensitization of joint afferents by intra-articular TNF-α injection (unpublished observations) whereas intra-articular injection of sgp130 reduced the IL-6/sIL-6R-induced mechanical sensitization only in a pre-treatment approach [13]. Thus, we believe that the effects of TNF-α might overall be more reversible than those of IL-6. This might be due to its manifold putative sites of action when interfering with the pain system, that is, locally at the nerve endings [17], at the dorsal root ganglia [28], or on the spinal level [29].
In addition to its pathogenetic role in chronic inflammation and bone destruction, IL-6 in the joint plays a significant role in the generation and maintenance of arthritic joint pain at acute and chronic stages of arthritis. The particular effectiveness of the intra-articular injection of sgp130 indicates that IL-6/sIL-6R (and possibly other cytokines which use the transmembrane signal-transducing subunit gp130) in the inflamed joint, rather than circulating IL-6/sIL-6R, is responsible for the generation of hyperalgesia. Furthermore, early neutralization of IL-6/sIL-6R is particularly successful in producing antinociception. The induction of pain by IL-6 or IL-6/sIL-6R is likely to result directly from an action at peripheral neurones because most peripheral nerve fibres were shown to express the transmembrane signal-transducing subunit gp130 [14, 15]. Similar conclusions on the importance of the neuronal target were drawn in a study on the role of IL-6 on the generation of pathophysiological heat hyperexcitability [30]. Concerning the success of systemic treatment, we would expect that neutralization of IL-6/sIL-6R is less antinociceptive than the neutralization of TNF-α because systemic sgp130 reduced mechanical hyperalgesia much less than systemic etanercept or infliximab [17]. Finally, early neutralization of IL-6/sIL-6R by sgp130 directly at the site of joint inflammation was much more effective in the prevention of joint destruction than systemic sgp130. It may be useful, therefore, to explore clinically the effect of intra-articular injection of IL-6/sIL-6R-neutralizing compounds.
antigen-induced arthritis
analysis of variation
area under the curve
- gp130:
glycoprotein 130
- i.a.:
- i.p.:
interleukin-6 receptor
leukemia inhibiting factor
- m-BSA:
methylated bovine serum albumin
oncostatin M
- s.c.:
- sgp130:
soluble glycoprotein 130
- sIL-6R:
soluble form of IL-6R
- TNF-α:
tumour necrosis factor-α.
The authors would like to thank Renate Stöckigt and Cornelia Hüttich, Institute of Pathology, for technical assistance with behavioural experiments and joint histology. This study was funded by Deutsche Forschungsgemeinschaft (SCHA404/13-1).
Authors' Affiliations
- Fonseca JE, Santos MJ, Canhao H, Choy E: Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev. 2009, 8: 538-542. 10.1016/j.autrev.2009.01.012.View ArticlePubMedGoogle Scholar
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- Richards PJ, Nowell MA, Horiuchi S, McLoughlin RM, Fielding CA, Grau S, Yamamoto N, Ehrmann M, Rose-John S, Williams AS, Topley N, Jones SA: Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum. 2006, 54: 1662-1672. 10.1002/art.21818.View ArticlePubMedGoogle Scholar
- van den Berg WB: Lessons from animal models of arthritis over the past decade. Arthritis Res Ther. 2009, 11: 250-10.1186/ar2803.View ArticleGoogle Scholar
- Brenn D, Richter F, Schaible HG: Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain. Arthritis Rheum. 2007, 56: 351-359. 10.1002/art.22282.View ArticlePubMedGoogle Scholar
- Obreja O, Biasio W, Andratsch M, Lips KS, Rathee PK, Ludwig A, Rose-John S, Kress M: Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. Brain. 2005, 128: 1634-1641. 10.1093/brain/awh490.View ArticlePubMedGoogle Scholar
- Segond von Banchet G, Kiehl M, Schaible HG: Acute and long-term effects of IL-6 on cultured dorsal root ganglion neurones from adult rat. J Neurochem. 2005, 94: 238-248. 10.1111/j.1471-4159.2005.03185.x.View ArticleGoogle Scholar
- Dina OA, Green PG, Levine JD: Role of interleukin-6 in chronic muscle hyperalgesic priming. Neuroscience. 2008, 152: 521-525. 10.1016/j.neuroscience.2008.01.006.PubMed CentralView ArticlePubMedGoogle Scholar
- Boettger MK, Hensellek S, Richter F, Gajda M, Stöckigt R, Segond von Banchet G, Bräuer R, Schaible HG: Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum. 2008, 58: 2368-2378. 10.1002/art.23608.View ArticlePubMedGoogle Scholar
- Griffiths RJ: Characterisation and pharmacological sensitivity of antigen arthritis induced by methylated bovine serum albumin in the rat. Agents Actions. 1992, 35: 88-95. 10.1007/BF01990957.View ArticlePubMedGoogle Scholar
- Boettger MK, Weber K, Schmidt M, Gajda M, Bräuer R, Schaible HG: Gait abnormalities differentially indicate pain or structural joint damage in monoarticular antigen-induced arthritis. Pain. 2009, 145: 142-150. 10.1016/j.pain.2009.06.006.View ArticlePubMedGoogle Scholar
- Whiteside GT, Harrison J, Boulet J, Mark L, Pearson M, Gottshall S, Walker K: Pharmacological characterisation of a rat model of incisional pain. Br J Pharmacol. 2004, 141: 85-91. 10.1038/sj.bjp.0705568.PubMed CentralView ArticlePubMedGoogle Scholar
- Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, Rondelli I, Chamiot-Clerc P, Simonato M, Barbieri M: Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. J Pharmacol Exp Ther. 2003, 306: 804-814. 10.1124/jpet.103.050039.View ArticlePubMedGoogle Scholar
- Boettger MK, Weber K, Gajda M, Bräuer R, Schaible HG: Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis. Brain Behav Immun. 2010, 24: 474-485. 10.1016/j.bbi.2009.12.002.View ArticlePubMedGoogle Scholar
- Boettger MK, Üceyler N, Zelenka M, Schmitt A, Reif A, Chen Y, Sommer C: Differences in inflammatory pain in nNOS-, iNOS- and eNOS-deficient mice. Eur J Pain. 2007, 11: 810-818. 10.1016/j.ejpain.2006.12.008.View ArticlePubMedGoogle Scholar
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- Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O: Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine. 1999, 11: 1057-1064. 10.1006/cyto.1999.0502.View ArticlePubMedGoogle Scholar
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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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Woah, I'm on a bit of a roll at the moment, so many ideas so little time. This one is set later than my other one shots. I was unsure of what genre to put it in, towards the end it does get fairly serious but there is some humour in it (I hope) ;L
Anyway, enjoy and let me know what you think!
I don't own Doctor Who. HOWEVER, I do own some posters and a cat.
Grown up talk
The Doctor strolled into the kitchen, intending to make himself some breakfast. River and their eldest daughter were sat at the table, engaged in what looked like a rather uncomfortable conversation – at least on Amelia's part. He wasn't really paying attention so he sat down and helped himself to some toast when he caught a snippet of their conversation ''Oh sweetie, don't worry it happens. In fact just the other day, your father was a bit too keen and it pained me to walk for days!'' the Doctor's head snapped up, half a piece of toast hanging from his mouth,
''Mum, I really did NOT need to know that!'' Amelia cringed at her words and the Doctor's eyes widened – surely River was not talking about what he thought she was talking about, and at the breakfast table no less!
''What the heck are you two talking about!''
''Stuff that mum really doesn't need to tell me-,''
''Sex'' River cut in chirpily. The doctor spat out his tea, spraying it all over the table,
''River!'' he choked ''she's far too young to be getting involved in that sort of thing!''
''Bit late for you to be worrying about ''that'' now dad...'' she made quotation marks with her fingers. If the situation was any different, she would have found it highly amusing that her father could not bring himself round to say the word 'sex'.
More choking.
''WHAT!'' he almost fell out of his chair.
''Sweetie, she's seventeen. That's two years older than I was when I fir-,''
''Alright mum, no need''
''River, that's not the point! This is completely different!'' his eyes darted between his wife and daughter, not quite believing what he was hearing, perhaps his ears were deceiving him
''How is it? She's of age and Daniel's such a lovely boy'' Amelia rolled her eyes, knowing what was coming next,
''Sorry,'' more spluttering ''did you just say Daniel? As in Daniel from the space station Daniel!''
''Yes'' River sighed and the Doctor jumped up, causing the table to shift by a good few inches.
''He's almost twenty! TWENTY!''
''Oh, you're' one to talk!'' Amelia laughed ''how old are you, nine hundred and something? And how old is mum, 41. Talk about cradle snatcher much''
''Yes, but that's different'' he was struggling for something to say now, nothing he could think of seemed justifiable at the moment.. ''we got married!'' he blurted
''Oh, stop being so dramatic. It's not like they're not being careful'' she turned to their daughter ''you are being careful aren't you sweetie?''
The doctor looked like he was about to pass out ''..Oh my god..''
''Yes mum! Bloody hell, I'm going to leave now'' she got up quickly, intending to get out of the before it got any more uncomfortable
''Oh no you don't. You stay right where you are young lady, and you'' he pointed to River ''shouldn't encourage her!.. And most certainly shouldn't be telling her about what we do when, you know..'' his hands flew pointlessly in the air for a moment ''adult-y stuff…'' he grumbled.
It was silent for a while, River was staring at the table cloth, Amelia was looking everywhere except for her father and the Doctor was glaring at his daughter. The atmosphere was just plain awkward.
''Amelia'' he spoke a little more quietly, ''I forbid you to see that boy ever again-,''
''Sweetie, that's not fair'' River said curtly
''You can't stop me from seeing him!'' she shrieked also standing up to try and match her father's intimidation
''I'm your father, I'll think you'll find I can'' he said in a dangerously low voice that she had only heard a few times before and it had never been directed at her..
''Go to your room sweetheart, we'll talk about this later'' River rose from her chair looking serious but giving her a small smile at the same time,
''Now.'' She snapped, pointing to the kitchen door. Amelia stomped to her room, her angry footsteps echoing through the TARDIS corridors followed by a loud SLAM of her bedroom door.
In the kitchen, the Doctor slumped back into his chair, shoulders hunched, head in his hands, ''sweetie, she's not a child anymore'' River squeezed his shoulder gently and he sighed
''I know.. It's just she'll always be a little girl to me..''
''But she's not though, she's seventeen and you've got to let her make her own choices''
The Doctor took in a slow breath ''I just don't want her to grow up too fast or get all.. corrupted..''
River chuckled softly, ''oh my love, she's far more sensible than I was at that age and I turned out alright, huh? Not too 'corrupted''' they both laughed this time and the Doctor looked up at her grinning,
''No, just psychotic''
''Oi!'' she nudged his shoulder playfully ''I'm being serious, you've got to let her grow up, you know, make her own decisions, learn from her own mistakes''
''…I know, your right''
''Of course I am love, I'm always right''
''You should talk to her''
The Doctor groaned ''Ohh, can't you talk to her instead? You're her mother, you talk to her about woman-y things and what not''
''No, I can't. You made her angry. It's you she's mad at not me'' she grabbed his arm and started pulling him up towards the door ''besides I'm always the one that talks to our children about this sort of thing. It's your turn now''
He huffed, putting all his weight on his heels ''yes but you don't find it all awkward..'' she raised an eyebrow at him and give him her 'oh just do it' look and he agreed ''Fine, but if she starts shouting at me again you can deal with her''
''Okay, just go'' she pushed him out the door ''If you hurry up, we can re-enact what I was on about earlier'' he immediately picked up his pace and glided down the corridor, grinning like an idiot.
I wrote the last few paragraphs pretty quickly so I hope it still reads well! :)


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John Barrowman talks about the new season of Torchwood: Miracle Day, saying "I'm naked in one episode – I
am full-on naked. I am bumping and grinding in this one. I am having man sex.
The true die-hard fans know Jack is omnisexual – he likes men and women. People
who tune into this series will just think Jack is gay, because he just has
full-on man sex. It was really fun. One day, I get to shoot a helicopter and
save the world, and a couple of days later, I get to have sex with a
24-year-old. It's the most perfect job in the world."
At a fundraiser last night in New York City, President Obama said that marriage should be left to the states. So much for his opinion "evolving." I can't begin to express how offended I am that a man whose own parents' interracial marriage was made possible by a federal court ruling is taking the Tea Party route on the issue.. I can't
begin to express how offended I am that a man whose own parents' marriage was
possible thanks to a federal court takes the Tea Party route on the issue.
JK Rowling has
unveiled Pottermore. It's as confusing as it is revolutionary. Basically, it's
an ebook store, with Rowling selling her own works via ebook, with no publisher
in between. No DRM, just trust. There's also a social experience around the
books, with the ability to join Hogwarts houses, get original content, and
interact with other Potter fans. Some people think it could change the face of
Aaron Sorkin and John Krasinski are teaming up to develop a mini series about the legendary Chateau
Marmont, home and party palace for everyone from Jean Harlow to Lindsay Lohan.
Lindsay Price is pregnant. If you're going "Who?" like I was,
she's the fortunate soul that gets to sleep with celebrity chef/hunk Curtis Stone.
Over at E! they're voting for the Best Kiss of the last television season, and
you can vote for the kiss that almost caused me to wreck the car when my phone
nearly exploded – Kurt and Blaine.
For an outside perspective on my favorite new website, Animals Being Dicks,
we get ANIMALNewYork, who loves it, with this qualifier: "So, let's make a quick
distinction here. Dogs are hilarious jerks. Cats are just assholes. Oh yeah, I
went there."
Will Smith is reportedly courting Emma
Thompson to adapt Annie as a starring vehicle for his
daughter Willow.
The Great Speedup is going on all around you, particularly in the United
States. You're now doing the jobs that used to take several people, but you're
not being paid more. And you're not really good at it, but you're good enough
to up corporate profits. How did we get here?
The Williams Institute is chewing its way through the 2010 Census Data on same-sex
couples on a state-by-state basis (trust me, they send a LOT of press
releases). But it is fascinating to see how many are raising children, and how
it seems more common in more rural areas.
In news that I totally missed, and shocked me, Here! has announced new television development, including a new
eight episode season of Dante's Cove called Dante's
Cove: Book of Tresum, set to debut late fall. Now if only my cable
system still carried Here!
True Blood's Ryan
Kwanten says he doesn't work out for the show – he works out to
stay sane. He's always been active, and as one of three boys, was always on the
move, even the time he got gummed by a shark.
Cory Monteith had a wild youth that included a lot of drugs, and stealing
from his family to pay for the habit. Some tough love and rehab set him
straight though, and it's how he got into acting.
Sofia Vergara has had to drop out of The Paperboy with Matthew McConaughey, Zac Efron and Tobey Maguire because the camera couldn't handle all the beauty.
No, seriously, the dates slipped and she has to get back to Modern Family,
which is for the best.
So Justin Bieber was at Macy's launching a fragrance just before Johnny Weir's appearance. And this picture happened, and the pop culture universe may have imploded.
Filed under "didn't expect that to happen"
I haz cheeseburger!
Spy hunk Eddie McClintock brings out the big guns for the new season of Warehouse 13 – literally! The Tesla rifle.
But we need to assess the moobs for the new season, so doff the shirt!
Presenting without comment. Or awareness.
Anderson Cooper was in a wetsuit today. That is all.
Pixar finally released character sketches for Brave . I think I'm going to like the blue-faced dude.
Logo's own Jonathan D. Lovitz is in Houston to be the Grand Marshall of Pride. And they gave him a medal – for being gay! Who knew you could win the gold for that?
Seriously, I'd have to be a platinum award winner at this point.
Here's the first picture of Bilbo Baggins from The Hobbit. I used to hit Bilbo Baggins restaurant for the gayest, highest calorie brunch when I lived in Old Town Alexandria. Fabulous place. I wonder if it's still around?
I may have gotten off topic there for a bit.
Neil Gaiman is a bit of an odd creature. Quite British, he's been in America for nearly 20 years, and he's still fascinated by how strange we are. It's what inspired American Gods, which is now celebrating it's 10th anniversary. So what's strange about America?
I'll just admit it – I've always had a bit of a crush on Drake Bell. He's a hot little dude, and he's got some talent, musically. Here's the new video for his song "Terrific" which is not what I'd expect from a Nickelodeon star.
So Target has put out an It Gets Better video. The cynic in me says this is about damage control, and the cynic is probably right. But why the company produced it is less important than the message from the employees, and I have to admit, these are good messages. While I'm still not shopping at Target, I'm glad this is out there. Also – is the blond in the plaid single?
This is a goose parade. Why they're on parade I don't know. Perhaps Goose Pride? I've heard that this is in Belgium, but can't confirm that. Can any of my European readers explain this to me?
This is a Literal Drug Commercial, and it's brilliant. Why do we allow drug companies to advertise in the United States? Are consumers qualified to "ask our doctor?"
This is a trailer for Killer Elite, and it has Robert De Niro, along with Jason Statham beating up Clive Owen. I think the idea is a battle between hitmen, but that's just a loose premise to string together action scenes
This is the trailer for Football Cops, by DirectTV. It stars Eli and Peyton Manning, and I'm unclear if they actually intend to make this into something for the fall, or if it's pure spoof
Watch closely, because these surfers are not alone in the water.
I really don't know what to make of this. I'm certainly fond of Thundercats, and I do get it if they had to make a living between the old series and the upcoming show, so I can't judge how they did that. But seriously – Panthro has a cabaret act?


text:
I can't figure out how replicate the error, and the script it occurs in is 1,400 lines long, but has anybody else run into this when creating a task in javascript? If so, would you be kind enough to share your wisdom?
Just found a solution, but I haven't figured out the specific reason why it works. I tracked the error down to a line that sends the compile message to another jsui object. Further clarification on how a task could get created without a context frame & exactly what a context frame is would still be appreciated.
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text:
Camphor Cleansing Milk...
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Cleanses deeply... thoroughly... gently.
Unlike most standard anti-bacterial cleansers, Reviva Labs Camphor Cleansing Milk does not "over-dry" oily skin.
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Apply with fingertips or on moistened cotton... on entire face and neck. Rinse thoroughly with warm water, followed by a cool water rinse.
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Water, vegetable oil, stearic acid, cetyl alcohol, glyceryl stearate, camphor, menthol, potassium sorbate, sodium benzoate, citric acid, color, lavender oil.


text:
Speech and Hearing Research Group ,Department of Computer
Science ,
Regent Court ,
phone: (44) 114 22 21828 fax: (44) 114 22 21810 email: firstname.lastname@example.com
Semester 1 of COM2001, Advanced Programming Techniques – Functional Programming
Semester 2 of COM1005, Machines and Intelligence – AI Techniques.
All my teaching materials are now on MOLE.
Professor, Department of Computer Science, University of Sheffield (from October 1999)
Head of Department (Sept 2004-Dec 2008)
Auditory Scene Analysis and Speech Recognition in Noise Can sound-source segregation techniques, based on auditory processing, be used as a front-end to provide evidence for recognition?
Missing Data Speech Recognition: Can speech recognition techniques be adapted to handle incomplete evidence, for instance provided by auditory scene analysis? Theoretical analysis of and practical solutions to this problem (with Jon Barker and Ning Ma).
Clinical Applications of Speech Technology Training and Recognition aids for disordered speech - the Stardust, VIVOCA, REDRESS, DISARM and homeService projects (with Robin Hofe and Heidi Christensen).


text:
CLOSED: Jays Pure Vegetarian Restaurant
547 Kingsbury Road, Kingsbury, North West London, England, NW9 9EL
Indian meals and snacks. Dairy is used, so vegans should specify. Can make mild or spicy upon request. Fast service. Located near the station with limited parking. SEP 2016 REPORTED SHUT.
Category: Lacto, Ovo, Indian, Take-out, Indo-Chinese
Reviews (1)First Review by dinitro
Indian vegetarian bites - Edit
Jays is in Kingsbury near the station and so parking can be difficult, however if timed before 8 there usually is no problem.
We order the bites and do not go for the main meals.
Bites include Chilli Paneer, Chilli mogo, Masala Dosa, Crispy Bhajia, Crispy mushrooms, Bhel poori.
Drinks we choose usually are salted Lassi or falooda.
Service is very good, price is very good, when ordering they take notice of our requirements (kids like milder food!).
They did not take credit cards when we last visited due to a defective machine, however this was no problem.
Food was excellent, not overly spicy or hot and not over salted. A thoroughly recommended restaurant.
Pros: excellent food, friendly staff, fast service
Cons: cold wind by door
Link to this page from your site.
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Return to North West London Vegetarian Restaurants & Health Food Store Listings
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If you are trying to make a grand impression or let someone know that you truly care, this assortment will surely fit the bill! Each unit is hand packed to ensure absolute freshness!
If you would like all of the cookies to be Chocolate Chip, please make a Note when placing your order.
Massive Cookie and Candy Container Massive Three Gallon Cookie and Candy Container is filled with over six (6) pounds of delicious, individually wrapped, assorted cookies and topped with an array of wrapped candies and snacks. This is truly an impressive gift offering. If you are
- Price: $115.00


text:
Joining Google
So, it's official. As of July this year I'll be joining Google. Why Google? Why now? Well, it's sort of a long story. I co-founded Onsite Solutions back in 1999 while I was still CTO for Scandianvia Online (SOL). After we got tired of working in an increasingly corporate environment, and wanting to get our hands dirty and to develop some great software again. Great Software And we did ; We created a great web application framework, much like Ruby on Rails, with Ajax and a universal Object/DOM structure (that didn't suck). All well before any of these where invented (remember, this is still 1999/2000). In addition - we created a real time analytics software, capable of scaling to accommodate some of the largest sites in world, with real time reporting, 11 years before Google Analytics could do the same. (Both of the products are alive and kicking today.) IT Bubble And then the IT bubble hit. We where about 15 people when it hit the hardest. We had to l


text: Being the Boss Means Getting The (Second To) Last CookieEsther Inglis-Arkell8/12/14 10:20amFiled to: psychologycookiespower dynamicsscience422EditPromoteShare to KinjaToggle Conversation toolsGo to permalink Finally, there is an experiment that can fill me with ambition. A group of workers was given an insufficient cookie supply. (I know. Disgusting. It's like a crummier version of the Stanford Prison Experiment.) And guess who got more than their share. Advertisement In an experiment about power dynamics, researchers split students into groups of three and had them work together on a technical paper. Although all three students were working, one was labeled as the "boss." And here's where it gets twisted. Someone brought in a plate of cookies that could not be divided evenly. Five cookies were supplied for three people. Everyone took a cookie. There were no fools in those groups. It was rare for anyone to eat the last cookie, as to eat that cookie was to deny one person in the group the pleasure of eating a second cookie. The conventional polite thing to do is to deny two people the pleasure of eating a second cookie, by leaving the last cookie on the plate. However, there is no convention against eating the second-to-last cookie. The only question is, who would get to it first? Advertisement The researchers found that, most of the time, the "boss" would eat that second cookie. Not only that, but the boss would eat it in a "disinhibited" way - mouth relatively open, making relatively loud smacking noise, eyes gleaming with malicious pleasure. I may be making that last one up. The point is, power corrupts. And in corrupts in such a way that the powerful one gets the last (actually edible) cookie. So I'm for it.[Via The Cookie Experiment.]Reply42 repliesLeave a reply


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CDH Hotel Villa Ducale, Parma
- Free hot/cold buffet breakfast, free WiFi, and free parking
Main amenities
- 113 guestrooms
- Restaurant and bar/lounge
- Free airport shuttle
- Fitness center
- Conference center
- 24-hour front desk
- Coffee/tea in a common area
- Air conditioning
- Daily housekeeping
- Garden
- Computer station
- Front desk safe
For families
- Free cribs/infant beds
- Rollaway/extra beds (surcharge)
- Private bathroom
- Garden
- Daily housekeeping
- Laundry facilities
What's around
- Palazzo della Pilotta (1.5 mi / 2.3 km)
- Galleria Nazionale (1.5 mi / 2.4 km)
- Ducale Park (1.5 mi / 2.4 km)
- Museo Archeologico Nazionale (1.5 mi / 2.5 km)
- Museo di Glauco Lombardi (1.6 mi / 2.6 km)
CDH Hotel Villa Ducale, Parmafrom $52
- Standard Room
- Standard Double or Twin Room
- Family Room
- Classic Double Room
- Standard Single Room
- Standard Double or Twin Room
- Quadruple Room
- Triple room
- Executive Single Room
- Quadruple Room
- Classic Single Room
- Classic Triple Room
- Junior Suite
- Executive Double room
- Classic Double Room Single Use
More great choices
At a glance
Key facts
Hotel size
- This hotel has 113 rooms
- This hotel is arranged over 5 floors
- Check-in time 2 PM-midnight
- Check-out time is 11 AM
- Express check-in/out
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Children (6 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- Pets allowed
- Restrictions apply *
- Free WiFi in public areas
- Free WiFi in rooms
- Free airport shuttle (available on request) *
- Free self parking
- Free RV/bus/truck parking
Nearby Four Star Parma hotels
In the hotel
- Free hot/cold buffet breakfast daily
- Restaurant
- Bar/lounge
- Room service (during limited hours)
- Coffee/tea in a common area
- Fitness facilities
- Number of meeting rooms - 4
- Conference space
- Conference center
- Computer station
- 24-hour front desk
- Tours/ticket assistance
- Laundry facilities
- Luggage storage
- Multilingual staff
- Porter/bellhop
- Number of buildings/towers - 1
- Elevator/lift
- Safe-deposit box at front desk
- Garden
- Television in common areas
- Accessible bathroom
- Roll-in shower
In the room
- In-room climate control (air conditioning)
- Air conditioning
- Minibar
- Private bathroom
- Satellite TV channels
- Desk
- Free WiFi
- Daily housekeeping
- In-room safe
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"Room was spacious and clean. Staff was friendly and helpful. And the breakfast was excellent. It's a 15 minute walk to city center; we didn't mind the walk."Oct 30, 2016
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Also popular with travelers from the USA
Special features
DiningVilla Ducale Restaurant - This restaurant serves breakfast, lunch, and dinner. Guests can enjoy drinks at the bar. Open select days.
CDH Hotel Villa Ducale, Parma's small print
Also known as
- CDH Hotel
- CDH Hotel Villa Ducale
- CDH Hotel Villa Ducale Parma
- CDH Villa Ducale
- CDH Villa Ducale Parma
- My 1 Hotel Villa Ducale
- My One Hotel Ducale
All guests, including children, must be present at check-in and show their government-issued photo ID card or passport.
Cash transactions at this property cannot exceed EUR 2999.99, due to national regulations. For further details, please contact the property using information in the booking confirmation.
Pet-friendly rooms can be requested by contacting the property at the number on the booking confirmation.
Guests under 16 years old are not allowed in the fitness facility.
For transfers, guests must contact the property 72 hours prior to arrival at the number on the booking confirmation.
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A tax is imposed by the city: EUR 3.00 per person, per night. This tax does not apply to children under 12 years of age.
Optional extras
Rollaway beds are available for EUR 20 per night
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Excellent 4.1 /5 from 84 reviews
Restaurant was great also!
It was a decent hotel. Not much in the a the area.
A good hotel for the money. Clean, good service, great for a stay outside of town and free parking. Need a car to stay at this hotel, no public transport after 8PM. Very hard to find even with a GPS, no clear sign for the hotel.
hotel was a little old and needs a little tlc; staff nice and helpful; close to Parma and main road; good breakfast
Very suitable for an overnight stay when you want to be close to Parma but not in town. Clean, comfortable, black out drapes. Good sleep.
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