text:
McLagan is the financial services industry's leading compensation consulting, productivity and performance benchmarking firm. More information about our firm is available at www.mclagan.com.
McLagan has an opening for a full-time Senior Compensation Analyst in our Bloomington, MN office.
Job Responsibilities:
-Coordinate key compensation survey processes for national banking compensation survey, including data collection, data review, systems setup, client communication, and delivery of reports
-Independently work with clients over the phone and, in some instances, on client visits as part of the survey production process
-Participate in moderately complex client engagements including data analysis, report creation, and client meetings
-Research and analyze executive and director compensation data from public financial institutions for use in client projects
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-One to three years of experience in the analysis, design, and/or administration of compensation programs
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-Ability to organize and prioritize work and handle multiple projects simultaneously
-Strong verbal and written communication skills
-Bachelor's or Master's degree in any field with proven academic excellence
-Willingness to reside in the Greater Twin Cities area
*The title of the position will either be an Analyst or Sr. Analyst predicated on the experience level.
Please email your resume and cover letter to Rebecca Pelton at firstname.lastname@example.com
Job number: 49732
Category: Consulting
Location: United States, US, Minnesota (MN)
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September 28, 2014 8:40 pm US resumes supply of Hellfire missiles to Israel Tank rounds and other weapon deliveries had also been temporarily halted by review process By Times of Israel staff
August 29, 2014 1:44 pm US missiles to be released 'soon' — whatever the Hellfire that means Delay in arms shipment to Israel may – or may not – end in coming days, but Obama administration will continue increased scrutiny By Rebecca Shimoni Stoil
August 21, 2014 9:17 pm Hold up of US missile shipment to Israel reportedly resolved TV report quotes Israeli official saying blocked transfer of Hellfires was 'just bureaucratic', but no word on when delivery expected By Times of Israel staff and Rebecca Shimoni Stoil
August 15, 2014 1:46 am The new US-Israeli quarrel. How bad is it, really? The withholding of a missile shipment is nothing to worry about, an ex-defense minister says. Others call it a 'very serious rupture' By Raphael Ahren

subset: commoncrawl


text:
LONDON -- The lawyer for a British hacker wanted in America for breaking into sensitive computer networks at U.S. military and space installations says that officials will rule on the case by next month.
U.S. authorities have been seeking Gary McKinnon's extradition ever since he went on an electronic rampage between 2001 and 2002, carrying off what one prosecutor described at the time as "the biggest hack of military computers ever."
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The 46-year-old, who claims he had accessed the computers to hunt for evidence of extraterrestrial life, has been fighting extradition ever since.
McKinnon's lawyer, Karen Todner, said in a statement Thursday that British Home Secretary Theresa May would rule on her client's case by Oct. 16.


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> Post a job: < Rates: $100 - One job posting - displayed for one month
Fujifilm has launched the latest addition to its J-series digital cameras; the FinePix J250. Discover stunning image quality - the essence of the FinePix brand - with a fun and easy to use camera that will fit any budget. In addition to its image quality and appealing style, the FinePix J250 offers 10 Megapixels, a wide-angle Fujinon 5x optical zoom lens and a large 3.0" LCD screen. Users will also enjoy its small design giving you the ability to carry the camera in your pocket or bag and take it wherever you go.
Dual Image Stabilization
Offering consumers exceptional value for their money, the FinePix J250 features Fujifilm's highly effective Dual Image Stabilization technology - a first in J series cameras - which combines CCD shift technology with high ISO settings to achieve blur free images.
NEW Intelligent Scene Recognition (SR Auto)
The FinePix J250 offers an impressive feature set, including Intelligent Scene Recognition (SR Auto) and Face Detection Technology with auto red-eye removal. SR Auto makes it quick and easy to take great shots. All users have to do is frame the shot, and SR Auto automatically recognizes the scene (Portrait, Landscape, Night, Macro, Backlit Portrait, Night Portrait) and selects the ideal settings automatically. The J250 also features Face Detection technology with Auto red-eye removal for perfect people pictures every time.
Wide-Angle Fujinon 5x Optical Zoom Lens
The FinePix J250 also has a high-quality wide-angle Fujinon 5x Optical Zoom Lens (28-140mm). The versatile zoom range of this camera makes it ideal for a range of subjects, from family group shots and sweeping landscapes to dramatic close-ups and action shots.
Appealing Design
In addition to the high quality features, the J250 has a classy brushed metallic finish and a diamond cut FinePix logo. With its pocket-sized dimensions, stylish looks and impressive feature set, the FinePix J250 can be taken anywhere and everywhere and will look as good as the pictures it takes.
The FinePix J250 is expected to be available to Canadian consumers in April 2009 at a suggested retail price of CDN $219.99 and will be offered in Black with a 2 Year Canadian Warranty.
Features at a glance:
10 Megapixels Wide-Angle Fujinon 5x optical zoom lens High Resolution 3.0" LCD screen Dual Image Stabilization NEW Intelligent Scene Recognition (SR Auto) Face Detection with Auto red-eye removal High Sensitivity up to ISO 3200 (at 3MP)
Source: FUJIFILM Canada
Other IT news about FUJIFILM Canada / Fujifilm
Thanks to the success of their crowd funding efforts - quadrupling their initial goal and raising over $450,000 in one month on IndieGogo - DreamQii announces that they will be bringing the PlexiDrone to market in the spring. The small, sophisticated and easy-to-use drone is operated by a smart phone or tablet and allows users to capture breathtaking aerial photography with unprecedented ease. The device is the first of its kind to be designed and manufactured in Canada.


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LPL Financial, the independent broker-dealer serving some 11,890 independent advisors, has launched a program called ClientsFirst to help FAs attract, convert and retain new clients....
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World Cup
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Swine flu claims 36 more lives, toll rises to 1,040, over 19,000 affected
11 hours 52 minutes ago
New Delhi: Swine flu has claimed 36 more lives raising the toll to 1,041 even as the number of people affected by the H1N1 virus in the country breached the 19,000 mark on Saturday. As per data collated by the Health Ministry, the total number of deaths due to swine flu...
Rail budget is dedicated to infrastructure: Rajasthan BJP
3 days ago
Jaipur: Terming the rail budget as the "first rail budget dedicated to infrastructure", the ruling BJP in Rajasthan on Thursday said it was focused on facilities of people even as the opposition Congress described it as a "hollow budget with no vision". "Security of women passengers, ease in ticket availability, safety...
Swine flu claims 21 more lives, toll reaches 833
5 days ago
New Delhi: Swine flu claimed the lives of 21 more people as the toll reached 833 across the country while the number of persons affected by H1N1 virus breached the 14,000 mark. According to Health Ministry figures, the total number of persons who have died of the disease till February 22...
Mother Teresa's service was motivated by conversion to Christanity, says RSS chief Bhagwat
6 days ago
Bharatpur: Conversion to Christianity was the main objective behind Mother Teresa's service to the poor, RSS Chief Mohan Bhagwat said on Monday. "Mother Teresa's service would have been good. But it used to have one objective, to convert the person, who was being served, into a Christian," he said while speaking...
Swine flu claims 38 more lives, death toll now 812
6 days ago
New Delhi: Swine flu claimed 38 more lives in the country taking the death toll to 812 with Rajasthan and Gujarat among the worst hit states with 212 and 207 fatalities respectively, as the total number of affected crossed 13,000. According to Health Ministry figures released on Sunday, the total number...
Government battles swine flu outbreak, over 10,000 infected with deadly virus
February 19, 2015
Swine flu scare continues to spread across the country with 663 people having lost their lives in 2015 and more than 10,000 people having tested positive. On Wednesday, 12 people died in Gujarat taking the death toll in the state to 167 while 3 people succumbed to the deadly virus...
Swine flu scare: As death toll constantly rises, chemists report shortage of medicines
February 18, 2015
New Delhi: Chemists are reporting a shortage of swine flu medication at a time when 39 people have died in the country over the last 24 hours and 624 people have lost their lives due to the deadly H1N1 virus in less than two months. However, the government is claiming...
PM Modi to launch scheme for analysing soil of farms
February 17, 2015
Jaipur: Prime Minister Narendra Modi will launch a nationwide scheme to analyse the soil of farms in the country scientifically, on February 19 from Sriganganagar district of Rajasthan. The 'Soil Health Card' scheme will be launched in a rally from Suratgarh town of Sriganganagar under which farmers of the country will...
Over 596 dead due to swine flu, Centre orders additional stocks of medicines
February 17, 2015
New Delhi: The death toll due to swine flu is increasing with each passing day and has claimed over 596 lives this year. Altogether 8,423 people have contracted swine flu this year with Rajasthan, Gujarat, Madhya Pradesh and Maharashtra are the worst-affected states with their respective tolls standing at 176,...
100 more deaths in 3 days, swine flu toll jumps to 585
February 16, 2015
New Delhi: The death toll from swine flu in 2015 has soared to 585 with 100 more casualties reported across the country in three days since February 12, prompting the Centre to order additional stocks of medicines and diagnostic kits. While the total number of swine flu deaths had stood at...
Rajasthan, Maharashtra tourism face Rs 5,500 crore loss due to swine flu
February 15, 2015
Mumbai: The outbreak of swine flu in Rajasthan and Maharashtra is expected to result in a loss of Rs 5,500 crore to tourism and aviation industries, according to an Assocham assessment. The outbreak of swine flu in Rajasthan and Maharashtra must be dealt with on a war-footing both by the...
Swine flu outbreak: 12 more die in Rajasthan, toll climbs to 142
February 14, 2015
Jaipur: Swine flu has claimed twelve more lives in parts of Rajasthan in the last 48 hours, raising the toll due to the H1N1 virus to 142 this year, a senior official of the Medical and Health Directorate said. Three persons on Saturday succumbed at SMS hospital, two died in...
Is the government prepared to tackle Swine Flu?
February 13, 2015
Swine Flu has now claimed 407 lives this year, 216 in the first 10 days of February itself. Most deaths have occoured in Rajasthan and Gujarat but cases are being reported from across the country. Tami Flu the vaccine needed to cure the virus is running short in most places. ...
Swine flu menace continues, 216 cases registered throughout the country
February 12, 2015
New Delhi: The Health Ministry has stated that around 216 swine flu deaths have been registered throughout the country in just the first 10 days of February. But, the ministry has assured that there is adequate stock of medicines in most states. Five more people succumbed to swine flu in...
High Court relief for Rajasthan Cricket Association office-bearers
February 11, 2015
Jaipur: The Rajasthan High Court on Wednesday granted relief to the office-bearers of the Rajasthan Cricket Association (RCA) by quashing the no-confidence motion by which a faction of the RCA had removed president Lalit Modi and a couple of other office bearers. Announcing the decision and questioning the legalities of the...
Swine flu outbreak: 12 more die in Rajasthan, toll crosses 100
February 10, 2015
Jaipur: Swine flu has claimed 12 more lives in parts of Rajasthan in the last 48 hours, taking the death toll to 104 this year, an official of state Medical and Health Department said on Tuesday. Two persons each succumbed to H1N1 virus in Jodhpur, Sikar, Nagaur districts while one...
Eleven more die of swine flu, toll climbs to 92 in Rajasthan
February 9, 2015
Jaipur: With eleven more persons succumbing to swine flu in parts of Rajasthan in the last 24 hours, the death toll has climbed to 92 in the state in 2015. Out of the 897 people tested positive for the H1N1 virus, 92 have died in the state from January 1 to...
Disgruntled Uttarakhand volleyball team withdraws from National Games
February 9, 2015
Thiruvananthapuram: The Uttarakhand volleyball team on Monday withdrew from the ongoing 35th National Games owing to a dispute with the national federation over the players' participation in the upcoming National Club Volleyball Championships (NCBC). Scheduled to play Rajasthan in a preliminary match, players from the north Indian state of Uttarakhand decided...
Rajasthan: Swine flu death toll goes up to 62, state faces shortage of tamiflu tablets
February 4, 2015
Jaipur: The swine flu death cases across the country has now crossed 100 in 2015. The death toll alone in Rajasthan has gone up to 62, with the state facing a shortage of 'tamiflu' tablets. One swine flu death has been reported in Goa and another from Jalandhar in Punjab....
Is the opposition to Surya Namaskar in schools justified?
February 3, 2015
After Madhya Pradesh made Surya Namaskar voluntary in schools, another BJP-ruled state has gone a step further. The Rajasthan government has made it mandatory for school students to meditate and perform the Surya Namaskar. ...
Rajasthan Home Minister tests positive for swine flu
February 2, 2015
Jaipur: After former chief minister Ashok Gehlot, Rajasthan Home Minister Gulab Chand Kataria on Monday tested positive for swine flu. Kataria tested positive for the H1N1 virus in Udaipur and is convalescing at his residence in that city, his personal secretary said. Kataria had gone to Udaipur a day back after...
Former Rajasthan chief minister Ashok Gehlot tests positive for Swine flu
February 1, 2015
Jaipur: Former chief minister Ashok Gehlot has been tested positive for Swine Flu in preliminary reports and samples have been sent to Delhi for further tests. Gehlot on Sunday tweeted that he went for timely treatment and there's improvement in his condition now but he has slammed the BJP state government...
As it happened: Ranji Trophy 2014-15, Round 8, Day 3
January 31, 2015
(For Live updates, scroll down to the bottom of the page.) Day 2 Round-up: Seen as a future India Test regular, Young Lokesh Rahul on Friday cracked a memorable triple century - the first from Karnataka to achieve the feat in Ranji Trophy as well as first-class cricket - guiding his...
Overlooked but not overworked, Pankaj Singh still a romantic figure
January 28, 2015
When Pankaj Singh stood at the top of his run up at the Rose Bowl in Southampton on Test debut against England in July last year, he not only had the experience of having taken 300 first-class wickets from ten hard-toiling seasons to dig into, but also carried the wishes...
MiG 27 fighter aircraft crashes in Barmer in Rajasthan, no casualty
January 27, 2015
Barmer: A MiG 27 fighter aircraft crashed in Barmer in Rajasthan on Tuesday. No casualties have been reported in the mishap as of now. Air Force sources said the crash occurred at about 3:10 PM. The pilot ejected safely, a defence spokesperson said in New Delhi. The aircraft, which is used for...
Ranji Trophy, Rd 7, Group B wrap: Rajasthan run through Odisha for bonus point win
January 23, 2015
Balangir: Rajasthan romped past Odisha by 10 wickets to win with a bonus point on Day 3 on Friday. Odisha, starting the day at 144 for nine, failed to add to their first innings total before being bowled out for 199 with Rajasthan enforcing the follow-on. Rajasthan had made 305 in...
SC verdict will impact all sports bodies: Justice Mukul Mudgal
January 22, 2015
New Delhi: Welcoming the Supreme Court verdict barring N Srinivasan from contesting any BCCI election on grounds of conflict of interest, head of IPL-6 spot-fixing and betting probe committee Justice Mukul Mudgal today said that it will have far reaching ramifications as it will also impact on all sports bodies. Delivering...
IPL verdict: SC says high probability Srinivasan involved in corruption; Meiyappan, Kundra guilty
January 22, 2015
The Supreme Court on Thursday brought the hammer down on the Indian Premier League spot-fixing case, ruling Gurunath Meiyappan and Raj Kundra guilty of betting on IPL matches but sparing N Srinivasan on allegations of cover-up but not on the issue of conflict of interest. The apex court read...
Ranji Trophy, Rd 7, Group B wrap: Saxena, Bist save Rajasthan blushes with fighting fifties
January 21, 2015
Balangir: Vineet Saxena (87) and Chetan Bist (51) saved the day for Rajasthan by striking fighting unbeaten half-centuries as the visitors ended the day one at 191 for five against Odisha on Wednesday. Put into bat, Rajasthan were off to a poor start as opener Pranay Sharma (0) left without bothering...
Musical session marks the beginning of Jaipur Literature Fest
January 21, 2015
Rajasthan Chief Minister Vasundhara Raje inaugurated the Jaipur Literature festival on Wednesday. A host of writers, poets, Nobel laureates and celebrities have descended in Jaipur for the festival. ...
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Very cute!! I love the ducks. TFS
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Top Trojans sleepers
These recruits didn't enter with the hype but exited having made their mark at USC
Updated: February 3, 2012, 1:31 PM ET
Greg Katz | WeAreSC.com
LOS ANGELES -- One was signed as a kicker and turned into an All-American wide receiver. Another was signed because a respected uncle thought he could compete at USC's level. Still another originally came in as a walk-on and was selected to his third consecutive NFL Pro Bowl while already sporting a Super Bowl ring.
It's hard to fathom that Erik Affholter, Troy Polamalu, and a former walk-on named Clay Matthews, were once considered afterthoughts on signing day, and they certainly didn't generate Cardinal and Gold excitement like Wednesday's signatures of All-America prep linemen Zach Banner, Max Tuerk, and Jordan Simmons.
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Robert Riger/Getty ImagesHe arrived as a placekicker recruit in 1984. When he finished his career four years later, Erik Affholter was an All-America wide receiver.
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Welcome, Sign In
Mom and Pop Start-Ups Rev Up in Silicon Valley
Description:A long-shunned Silicon Valley technology sector - consumer-electronics start-ups - is showing some surprising signs of life. One San Francisco couple is making a $359 kitchen appliance dubbed Nomiku, which people can use to "sous-vide" food. Jessica Vascellaro has details on The News Hub. Photo: Alison Yin for The Wall Street Journal. (4:06)
Source: WSJLive
Tags: Pop Start-Ups Rev Up in Silicon Valley , mom and pop startup , silicon valley trends , social media stock plummet


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Who here loves the office? I have netflix and have been watching all the seasons up to 4 im getting through season four now and I happen to love the show its the funniest show I've seen in a long, long time
Results 1 to 25 of 43
Thread: WHo here loves the Office?
03-18-2009 #1
WHo here loves the Office?
03-18-2009 #2
I would saying, and hope, that anyone with even a morsel of humor would enjoy The Office.
03-18-2009 #3
I enjoy watching The Office, I think it is a great comedy series comprising non-sensical humour.
"Go Hard or Go Home"
03-18-2009 #4
03-18-2009 #5
Nah I think currently they are airing season 5 or 6 or are about to start airing 6. And the first four are available on Netflix.
03-18-2009 #6
It's right up there with those Kiwi comedic legends from Flight of the Concords.
03-18-2009 #7
03-18-2009 #8
I enjoy watching The Office I just hate when people start quoting it. Which my wife and her co-workers do all day long.
03-19-2009 #9
It's very funny and one of the best TV shows currently on. It's a gem of a show amidst all the trash. I really liked the hour long episode after the Superbowl, the beginning was classic (where Dwight sets a garbage can on fire and causes a huge panic).
The Office that had two seasons was the British version I think.
03-19-2009 #10
03-22-2009 #11
British version yes, American version -meh not as much.
03-22-2009 #12
03-22-2009 #13
I loved the UK version but I wasnt much of a fan of the US version, it made me laugh but not as much as the UK one. I didnt know it was going on for so long though, must be pretty popular!
03-29-2009 #14
Both UK and US versions are god awful if you ask me.
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03-29-2009 #15
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03-29-2009 #16i5-2500k @3.3Ghz, Gigabyte GA-Z68XP-UD4, Crucial 4GB 1333Mhz RAM,
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03-29-2009 #17
03-30-2009 #18
03-30-2009 #19
both are GREAT shows
people who hate on the american one usually dont give it a chance...
it is great... and IMO better... mainly because everyone is really funny, where in the british one only about 3 people were funnyLove United
03-30-2009 #20
I love the US show, and I definitly think it is the best comedy series on TV. Season 5 has been a little slow because the lack or a big story arc, but that has changed recently and it is great.
03-30-2009 #21
The Office is amazing. It's gotten a lot better lately.
04-12-2009 #22
I greatly prefer the British show. With everyone not being funny, it adds to it in my opinion, as not everyone is hilarious in an office. The thing is meant to be a parody, that at times makes you forget its not a documentary.
In general, the US aren't very good a adapting British shows. Red Dwarf is a typical example. Just imagine how awful they'd make Dr Who.
Similarly, if there was a British version of Scrubs or House, they wouldn't be as great.
04-12-2009 #23
i prefer the British version (original) i think gervais is hilarious. however i liked the first season of teh American one, but i haven't seen any of the others. watched teh first online and wasnt reli bothered for the others.
04-13-2009 #24
To all the British Office fans, why did their series end so soon while the American one has been continuing far past the British one?
04-13-2009 #25
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Brittish: Yes!
American: Noooooooooooooooooooooooo......................... ......
Most TV shows in Brittan are short and sweet, most series consist of 8+ episodes. In America TV series run around the 22 mark. I guess the British one is short because Ricky Gervaise couldn't be bother played that character anymore and went on to write and star in 'Extras' which is an equally funny show.
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Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.
Research Article
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate
Article first published online: 31 AUG 2006
DOI: 10.1002/art.22033
Copyright © 2006 by the American College of Rheumatology
Additional Information
How to Cite
Maini, R. N., Taylor, P. C., Szechinski, J., Pavelka, K., Bröll, J., Balint, G., Emery, P., Raemen, F., Petersen, J., Smolen, J., Thomson, D. and Kishimoto, T. (2006), Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis & Rheumatism, 54: 2817–2829. doi: 10.1002/art.22033
Publication History
- Issue published online: 31 AUG 2006
- Article first published online: 31 AUG 2006
- Manuscript Accepted: 11 MAY 2006
- Manuscript Received: 5 OCT 2005
Funded by
- Chugai Pharmaceuticals Ltd.
- Abstract
- Article
- References
- Cited By
To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).
The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.
A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.
These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.
Interleukin-6 (IL-6) is a proinflammatory cytokine that is abundantly expressed in patients with rheumatoid arthritis (RA) and is detectable in the joints and circulation of such patients during active phases of the disease (1–4). IL-6 binds to its soluble and membrane-bound receptors, and their interaction with gp130 transduces intracellular signals that mediate gene activation and a wide range of biologic activities (5). Preclinical and human studies have demonstrated IL-6 activities relevant to RA. These include the differentiation of B cells into immunoglobulin-secreting plasma cells, activation of T cells, induction of acute-phase proteins by hepatocytes, and production of platelets (6–9). IL-6 induces the recruitment of chemokines and leukocytes (10) and has been shown to induce proliferation of synovial fibroblasts (11). In addition, IL-6 has a profound effect on bone and can induce osteoclast differentiation and activation in vitro (12). IL-6 appears also to be involved in damage to cartilage, by decreasing aggrecan protein and type II collagen production by chondrocytes (13). The inflammatory destructive effects of IL-6 have been validated, with data in animals suggesting an important role of IL-6 in the induction and maintenance of chronic synovial inflammation (14–16). IL-6 gene–knockout mice have been demonstrated to be protected from arthritis (17). Because of the key role played by IL-6 in several phenomena typical of RA, IL-6 is a candidate target for therapeutic inhibition as a novel approach to the treatment of RA.
Monoclonal antibodies (infliximab and adalimumab) and a soluble tumor necrosis factor (TNF) receptor fusion protein (etanercept), which inhibit another proinflammatory cytokine TNF, have become established as effective options for the treatment of RA, especially in patients who experience an inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX) (18). The efficacy of anti-TNF therapy is increased by concomitant treatment with MTX (19, 20). Nonetheless, 20–40% of patients have an inadequate response to such treatment, and there is an unmet need for new therapeutic interventions with new modes of action for the treatment of RA.
Tocilizumab (previously known as MRA) is one of the molecules in development that offers a new mechanism of action. Tocilizumab, a humanized anti-human IL-6 receptor antibody of the IgG1 subclass, was developed collaboratively by Osaka University and Chugai Pharmaceutical Company Ltd (Japan). Tocilizumab is humanized by the grafting of complementarity-determining regions of a mouse anti-human IL-6 receptor monoclonal antibody onto human IgG1, using recombinant DNA technology. Tocilizumab has been shown to compete for both the membrane-bound and soluble forms of human IL-6 receptor, thus inhibiting the binding of IL-6 to its receptors and its proinflammatory activity. Short-term clinical trials of tocilizumab in adult-onset RA and systemic-onset juvenile idiopathic arthritis have demonstrated acceptable safety and significant efficacy (21–24).
The objective of this multicenter randomized clinical trial (the Chugai Humanized Anti-Human Recombinant Interleukin-6 Monoclonal Antibody [CHARISMA] study) was to establish the safety and efficacy of repeat infusions of tocilizumab, alone and in combination with MTX, in patients with established RA in whom the response to MTX was inadequate and who had continuing disease activity. Tocilizumab was used either as monotherapy (by discontinuation of MTX) or concomitantly with MTX therapy and compared with placebo infusions in patients who continued to receive a fixed dose of MTX during this 20-week study.
Role of the funding source.
Chugai Pharma Europe (a member of the Roche Group) provided funding for the trial and was responsible for supply of the study medication (active and placebo), for data processing and management, statistical analysis, and consulting via a clinical research organization (Covance), for ongoing medical safety reviews, and for reporting of serious adverse events. Dr. Maini was responsible for the trial design and manuscript preparation. Both Chugai and Roche Pharmaceuticals checked and approved the submitted manuscript.
Patient and treatment protocol.
In this randomized, double-blind, controlled trial, the study group comprised 359 patients fulfilling the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) revised criteria for a diagnosis of RA (25); all patients had active disease, had experienced an inadequate response to MTX, and had been stabilized on their current dose of MTX for at least 4 weeks before randomization. Three groups of patients received intravenous infusions of tocilizumab (2 mg/kg, 4 mg/kg, and 8 mg/kg, respectively) every 4 weeks, plus MTX placebo once weekly. Another 3 groups of patients received intravenous infusions of tocilizumab (2 mg/kg, 4 mg/kg, and 8 mg/kg, respectively) every 4 weeks, plus MTX once weekly. A control group received placebo infusions every 4 weeks and MTX once weekly. Thus, all patients received a total of 4 infusions of tocilizumab or tocilizumab placebo once every 4 weeks, together with 10–25 mg of MTX or MTX placebo each week. End point efficacy evaluations were performed at week 16; followup evaluations for safety were performed at week 20, after which patients were no longer monitored. A total of 359 patients from 57 rheumatology centers in Europe were randomized to participate in this study. Members of the CHARISMA Study Group and the European countries involved are shown in Appendix A.
Randomization was performed centrally. When a patient was eligible for randomization into the study, an interactive voice response system was used to allocate treatment, by determining inclusion into the group that would minimize any imbalances between MTX dose level at baseline and between patients from a center. All patients and investigators were blinded to the study treatments.
Tocilizumab or placebo (an aqueous solution of sucrose and polysorbate 80, resembling the active treatment) was diluted in normal saline and administered by intravenous infusion over 1 hour. Pre-prepared capsules containing 10-mg, 12.5-mg, 15-mg, 17.5-mg, 20-mg, 22.5-mg, and 25-mg doses of MTX were blinded by over-capsulation using a lactose filler; the matching placebo capsules contained only filler.
The MTX dose remained unchanged for at least 4 weeks prior to baseline and throughout the study. Patients at all centers were supplied (separately, from the same source) 5 mg of folic acid weekly, for the duration of the study. Patients randomly allocated to receive tocilizumab monotherapy were switched to MTX placebo on day 0.
Inclusion criteria were a diagnosis of RA according to the ACR revised criteria (25), disease duration of at least 6 months, active disease (defined as ≥6 tender joints and ≥6 swollen joints, based on a 28-joint count), an erythrocyte sedimentation rate (ESR) ≥28 mm/hour, and/or a C-reactive protein (CRP) level ≥1.0 mg/dl. Patients must also have shown an inadequate response to MTX or a disease flare while receiving MTX (at a dosage of 10–25 mg weekly) during a minimum of 6 months of therapy. An inadequate response was defined as the presence of active disease, as described above, despite MTX therapy. If patients required concomitant treatment with nonsteroidal antiinflammatory drugs and/or oral steroids, the dose must have been stable for at least 4 weeks prior to study entry and during the course of the study (for steroids, ≤10 mg prednisolone or equivalent).
Exclusion criteria included leukopenia (white blood cell count <4.0 × 109/liter, absolute neutrophil count <2.0 × 109/liter) and/or thrombocytopenia (platelet count <150 × 109/liter), any hepatic dysfunction as shown by aspartate transaminase (AST) and alanine transaminase (ALT) levels >1.5-fold the upper limit of normal or significant renal impairment (serum creatinine level >1.5-fold the upper limit of normal). Patients who received DMARDs (excluding MTX) within 4 weeks prior to the start of the study were excluded, as were patients who received anti-TNF agents within 12 weeks or leflunomide within 6 months of infusion of study medication.
Ethical approval was obtained from the appropriate authorities in each country, and each patient gave informed consent. The first patient was enrolled on May 14, 2001, and the final patient exited the study on September 3, 2002.
Efficacy assessments.
The primary clinical end point was the percentage of patients who achieved improvement of 20% according to the ACR criteria (ACR20 response) at week 16; secondary end points included the ACR50 and ACR70 responses (26). For the analysis of efficacy (i.e., the ACR20 response at 16 weeks), all patients who withdrew before the week 16 assessment because of lack of efficacy were included in the analysis as nonresponders, as per protocol. For patients who withdrew for other reasons, the last recorded assessment of the ACR20 response was carried forward.
Other secondary end points included percent and absolute change from baseline in individual disease activity measures (swollen joint count, tender joint count, physician's global assessment of disease activity, patient's global assessment of disease activity, patient's pain score, ESR, CRP level, and Health Assessment Questionnaire [HAQ] score), as well as changes in the duration of early morning stiffness, and the Disease Activity Score in 28 joints (DAS28) (27). In this study, the DAS28 was calculated using the ESR, according to a previously described formula (28). Remission was defined according to the European League Against Rheumatism (EULAR) definition of a DAS28 score <2.6 (29).
Safety assessments.
Safety assessments included physical examinations, pre- and postdose electrocardiograms, and laboratory analyses of hematology, serum biochemistry, coagulation, immunologic parameters, and urine. Adverse events were recorded throughout the study. A treatment-emergent adverse event was defined as any adverse event that occurred after commencement of allocated treatment or an adverse event that occurred prior to the allocated treatment but worsened in severity after commencement of the allocated treatment. A treatment-related adverse event was defined as any adverse event whose relationship to the study drug was described as possible, probable, or definite, as documented in the case report forms.
Statistical analysis.
The primary efficacy end point was the ACR20 response at week 16, using an intent-to-treat full-analysis set. All patients who were allocated to receive study medication, had received at least 1 dose, and had postrandomization efficacy data available were included in the full-analysis set. All patients who withdrew because of lack of efficacy before the week 16 assessment were included in the analysis as nonresponders. For patients who withdrew because of other reasons, the last recorded assessment of the ACR20 response was carried forward. Differences between treatment groups in the proportion of responders were assessed using logistic regression. A model was fitted for the treatment groups to which patients were assigned in a center and the stratification of weekly doses of MTX. Analyses similar to the primary efficacy analysis were performed for the secondary efficacy end points.
Treatment groups were formally compared at the week 4, week 8, week 12, week 16, and week 20 assessments, separately; changes from baseline to each assessment were analyzed using analysis of covariance, with an effect for treatment, center, and the respective baseline value fitted as a covariate. The P value for the overall test of difference between treatment groups from this model was determined. If results of the overall test of difference between treatment groups from this model were statistically significant, the linear and quadratic components of the dose-response relationship were assessed. P values for linear, quadratic, and average dose effect were determined for the groups receiving monotherapy and the groups receiving combination therapy.
Baseline characteristics and patient flow.
Three hundred fifty-nine patients were randomly allocated to the 7 treatment groups. Patient flow through the trial and randomization to each treatment arm are shown in Figure 1. Approximately equal numbers of patients were randomly allocated to each arm of the study. During the trial, 60 patients withdrew (34 patients withdrew due to adverse events and/or possible drug-related toxicity). Of the 359 patients randomized to receive study medication, all were included in the safety population, and 354 patients were included in the full-analysis set (5 patients were excluded from the full-analysis set because of a protocol violation). The baseline demographics of the treatment groups were similar, and no statistically significant differences were observed (Table 1).
Characteristic | MRA monotherapy | Combination therapy, MRA plus MTX | MTX (n = 49) | All groups (n = 359) | ||||
2 mg/kg (n = 53) | 4 mg/kg (n = 54) | 8 mg/kg (n = 52) | 2 mg/kg (n = 52) | 4 mg/kg (n = 49) | 8 mg/kg (n = 50) | |||
| ||||||||
Age, years | 52.2 | 49.3 | 50.1 | 49.2 | 50.2 | 50.1 | 50.9 | 50.3 |
No. of men/no. of women | 9/44 | 13/41 | 14/38 | 7/45 | 12/37 | 11/39 | 11/38 | 77/282 |
Duration of RA, months | 9.19 | 9.79 | 9.21 | 9.33 | 7.82 | 10.62 | 11.24 | – |
Tender joint count (28 joints) | 15 | 15 | 15 | 15 | 13 | 15 | 16 | 15 |
Swollen joint count (28 joints) | 11 | 11 | 12 | 11 | 11 | 11 | 12 | 11 |
ESR, mm/hour | 39† | 41 | 39‡ | 45§ | 40 | 39¶ | 43 | 41 |
C-reactive protein, mg/liter | 26† | 19 | 22‡ | 28§ | 31 | 24¶ | 32 | 27 |
Rheumatoid factor positive, no. | 44 | 39 | 43 | 46 | 38 | 40 | 47 | – |
MTX dose* | ||||||||
Low | 20 | 20 | 19 | 19 | 17 | 18 | 17 | – |
Medium | 25 | 25 | 24 | 25 | 24 | 24 | 24 | – |
High | 8 | 9 | 9 | 8 | 8 | 8 | 8 | – |
Patient's assessment of pain | 58.9† | 62.2 | 58.5‡ | 59.7§ | 60.2 | 57.0¶ | 63.8 | – |
Duration of MTX therapy, mean ± SD months | 33.0 ± 25.5 | 34.1 ± 26.5 | 40.0 ± 30.5 | 38.8 ± 27.1 | 29.0 ± 17.7 | 40.4 ± 32.7 | 33.3 ± 27.8 | 35.5 ± 27.3 |
Patient's global assessment of disease activity | 62.0† | 63.6 | 60.7‡ | 62.3§ | 60.9 | 62.1¶ | 68.8 | – |
Physician's global assessment of disease activity | 61.3† | 62.1 | 59.5‡ | 59.2§ | 59.5 | 61.3¶ | 66.0 | – |
Duration of early morning stiffness, minutes | 90.0† | 110.0 | 120.0† | 110.0§ | 90.0 | 120.0¶ | 90.0 | – |
All patients had previously been treated with DMARDs, the most common of which was MTX. The mean duration of prior MTX treatment varied across the groups, with the longest duration recorded in the group receiving 8 mg/kg of tocilizumab plus MTX (40 months), and the shortest duration recorded in the group receiving 4 mg/kg of tocilizumab plus MTX (29 months). Most patients had previously been treated with 1–3 different DMARDs, although several patients had previously received more than 5 different DMARDs. Cyclophosphamides had been taken by 1.4% of patients, leflunomide by 6.4%, sulfasalazine by 53.5%, azathioprine by 6.7%, cyclosporine by 20.3%, etanercept by 2.8%, auranofin by 2.8%, chloroquine by 23.4%, gold by 3.1%, hydroxychloroquine by 12.0%, penicillamine by 7.2%, and sodium aurothiomalate by 21.2% of patients. Fifty patients had received TNF inhibitors (infliximab or etanercept) prior to study enrollment. A high proportion of patients in each treatment group was serum rheumatoid factor positive (overall mean 82.7%), and the proportion was highest in the group receiving placebo plus MTX (95.9%).
Primary efficacy end point.
The primary end point of the study, an ACR20 response at week 16, was achieved by 61% and 63% of the patients receiving monotherapy with 4 mg/kg and 8 mg/kg of tocilizumab, respectively, compared with 41% of patients receiving placebo plus MTX (P < 0.05). The responses of the group receiving tocilizumab at a dose of 2 mg/kg were not significantly different from those of the group assigned to receive placebo plus MTX (Figure 2). The ACR20 responses among patients receiving combination therapy with tocilizumab (2 mg/kg, 4 mg/kg, and 8 mg/kg) plus MTX exceeded those among patients receiving placebo plus MTX (64%, 63%, and 74%, respectively, versus 41%; P < 0.05, P < 0.05, and P < 0.001, respectively) (Figure 2).
Secondary efficacy end points.
The ACR50 and ACR70 response rates at week 16 were measured, as shown in Figure 2. Only combination therapy with 8 mg/kg of tocilizumab plus MTX was significantly better than placebo plus MTX in terms of both the ACR50 and the ACR70 (P < 0.05). There was a similar pattern of change in DAS28 scores, showing a clear dose response with tocilizumab and significant differences from week 4 onward, except in the group receiving monotherapy with 2 mg/kg of tocilizumab. The maximum reduction in the DAS28 was achieved with the 8-mg/kg doses. Among patients assigned to the 8-mg/kg dose of tocilizumab in combination with MTX, the mean DAS28 at 16 weeks was 2.9. All groups receiving tocilizumab, alone or in combination with MTX (except for the group assigned to monotherapy with 2 mg/kg of tocilizumab), showed a greater decrease in the DAS28 by week 16 than did the group receiving placebo plus MTX (for combination therapy with 8 mg/kg of tocilizumab and monotherapy with 8 mg/kg of tocilizumab, P < 0.001; for combination therapy with 4 mg/kg of tocilizumab, P < 0.05 versus placebo plus MTX) (Figure 3).
A further analysis was performed to calculate the percentage of patients who achieved remission according to the DAS, in the group receiving 8 mg/kg of tocilizumab plus MTX, the group receiving 8 mg/kg of tocilizumab as monotherapy, and the group receiving placebo plus MTX. The analysis showed that the rate of remission was 34% among those assigned to 8 mg/kg of tocilizumab plus MTX, 17% among those receiving 8 mg/kg of tocilizumab as monotherapy, and 8% among those receiving placebo plus MTX. Among patients responding to tocilizumab treatment, a response was observed by week 4, and this was maintained during the course of the study. The slope of the graph suggested that a peak response had not been reached by the end of the study, and that further improvement could be attained.
Each of the individual clinical components of the ACR response assessment (swollen joint count, tender joint count, physician's global assessment of disease activity, patient's global assessment of disease activity, patient's pain score, and HAQ score), as well as the duration of morning stiffness, showed an improvement at doses of tocilizumab ≥4 mg/kg. However, comparison with the placebo plus MTX control group at week 16 consistently showed that monotherapy with 2 mg/kg of tocilizumab performed less well than did placebo plus MTX. For the swollen joint counts, the mean reduction observed among patients receiving 8 mg/kg of tocilizumab, alone and in combination with MTX, was statistically significant compared with the reduction in the group assigned to placebo plus MTX (P = 0.01 and P < 0.001, respectively). Additionally, the mean reduction in the tender joint count in the group receiving combination therapy with 8 mg/kg of tocilizumab plus MTX was statistically significantly superior compared with the mean reduction in the group assigned to receive placebo plus MTX (P = 0.009).
The mean CRP level and the mean ESR showed a marked decrease over time in all of the patients receiving tocilizumab except those assigned to 2 mg/kg as monotherapy (both the ESR and the CRP level) and those receiving 4 mg/kg as monotherapy (the CRP level only), while placebo plus MTX had little effect on these laboratory parameters (Figure 4). Especially in the groups receiving 4 mg/kg of tocilizumab, as monotherapy or combination therapy, there was a sawtooth pattern, with a decrease in these parameters 2 weeks after dosing (maximum observed biologic effect) and an increase prior to the next infusion. The 8-mg/kg dose of tocilizumab produced a more sustained decrease. The mean CRP level normalized after the first infusions of 8 mg/kg of tocilizumab (as both monotherapy and combination therapy) and 4 mg/kg of tocilizumab as combination therapy, while the mean ESR normalized after the third infusions of tocilizumab at a dose of 8 mg/kg (as both monotherapy and combination therapy). The comparison between 8 mg/kg of tocilizumab, as monotherapy or combination therapy, and placebo plus MTX showed the most significant differences (P ≤ 0.001) at week 16. The mean ESR and the mean CRP level returned toward baseline values within 4–8 weeks after the last infusion of tocilizumab.
Other direct and indirect laboratory markers of inflammation that returned toward baseline levels after tocilizumab treatment included serum ferritin, serum amyloid A, C4 complement, fibrinogen, neutrophils, platelets, and hemoglobin.
In general, tocilizumab was well tolerated in this trial (see Table 2). Approximately half of the patients experienced adverse events after treatment, the majority of which were mild or moderate in intensity, and only one-fourth of which were judged to be treatment-related. The most frequent treatment-emergent adverse events were infections (mixed viral and bacterial), musculoskeletal disorders (all of which were compatible with RA), gastrointestinal disorders (a variety of minor disorders, the incidence of which was higher among those receiving tocilizumab compared with those receiving placebo plus MTX), skin rash, pruritus, and erythema.
MRA monotherapy | Combination therapy, MRA plus MTX | MTX (n = 49) | |||||
2 mg/kg (n = 53) | 4 mg/kg (n = 54) | 8 mg/kg (n = 52) | 2 mg/kg (n = 52) | 4 mg/kg (n = 49) | 8 mg/kg (n = 50) | ||
| |||||||
Patients with ≥1 treatment-emergent AE | 30 | 27 | 31 | 30 | 19 | 27 | 23 |
Patients with ≥1 treatment-related AE | 13 | 14 | 15 | 12 | 9 | 14 | 9 |
Patients who discontinued due to an AE | 4 | 5 | 5 | 3 | 6 | 6 | 4 |
Patients with ≥1 serious treatment-emergent AE | 8 | 5 | 3 | 4 | 1 | 7 | 2 |
Patients with ≥1 serious treatment-related AE | 5 | 2 | 1 | 2 | 0 | 4 | 0 |
Serious treatment-emergent infections† | 4 | 0 | 0 | 0 | 0 | 3 | 0 |
Serious treatment-emergent anaphylactic reaction/shock‡ | 3 | 1 | 0 | 0 | 0 | 0 | 0 |
There was no clear pattern of occurrence of adverse events by dose group, except for serious adverse events (Table 2). Thirty patients experienced 35 treatment-emergent serious adverse events. The incidence of treatment-emergent serious adverse events was highest in the group receiving 2 mg/kg of tocilizumab as monotherapy and lowest in the group receiving 4 mg/kg of tocilizumab plus MTX (Table 2). The most common treatment-emergent serious adverse events were aggravated RA (2 cases in the group receiving low-dose combination therapy and 1 case in the group receiving placebo plus MTX), 4 infections in 3 patients in the 2-mg/kg monotherapy group (1 patient with a limb abscess and osteomyelitis and 2 patients with respiratory infections), 3 infections in the 8-mg/kg plus MTX group (including 1 patient with infective arthritis and 2 with sepsis not otherwise specified), and anaphylactic shock/reaction and hypersensitivity (4 cases in the 2-mg/kg monotherapy group and 1 case in the 4-mg/kg monotherapy group). Of the 2 patients for whom sepsis was reported as a serious adverse event, septicemia developed in 1 patient following a Staphylococcus aureus–infected skin wound; in the other patient, septicemia was diagnosed, but there were no signs of focal infection and no organisms were isolated on blood culture, and pyelitis was suspected. That patient had a history of streptococcal septicemia due to a dental abscess (10 months previously).
Additionally, 2 cases of nonserious anaphylactic reactions and hypersensitivity were reported (1 in a patient receiving monotherapy with 4 mg/kg of tocilizumab, and 1 in a patient receiving combination therapy with 2 mg/kg of tocilizumab). Overall, anti-tocilizumab antibodies developed in 25 patients, all of whom were in the groups receiving either 2 mg/kg or 4 mg/kg of tocilizumab as monotherapy; anti-tocilizumab antibodies developed in none of the patients receiving treatment with 8 mg/kg of tocilizumab, as either monotherapy or combination therapy. No cases of reactivation of tuberculosis were seen, and no opportunistic infections were observed in this study.
Liver function test changes.
During the dosing period of this trial, the mean ALT level and, to a lesser extent, the mean AST level increased in all patients receiving tocilizumab, following a sawtooth pattern (rise and fall) between infusions (Figure 4). This increase was tocilizumab-related but was accentuated in patients receiving tocilizumab in combination with MTX (>3-fold the upper limit of normal in 2% of the patients receiving combination therapy). All of the mean values returned to near-baseline values within 8 weeks of the final infusion. The mean ALT level increased in a dose-related manner in the groups receiving tocilizumab monotherapy; the maximum increase from baseline at week 2 (45%) was observed in the group receiving 8 mg/kg of tocilizumab. Larger dose-related increases in the ALT level occurred in the combination-therapy groups; the maximum increase from baseline at week 2 (88%) was observed in the group receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. No increase in the mean ALT level was observed in the group receiving placebo plus MTX. A similar pattern of changes in the mean AST level was seen, but these changes were of lesser magnitude.
Certain patients showed marked but reversible increases in the level of transaminases, which in some cases led to discontinuation of the study treatment. Five patients who had ALT levels >100 IU/liter were withdrawn from the study; all of these patients were in the groups receiving tocilizumab plus MTX. In 4 patients, the ALT level returned to a level within the normal range within 4 weeks of withdrawal. Overall, 127 patients treated with tocilizumab experienced an ALT level greater than the upper limit of normal during the study; 35 of these patients had mildly abnormal ALT values at baseline, compared with 12 patients who were treated with MTX alone. In 112 tocilizumab-treated patients, the ALT level returned to near-baseline values by the time of the followup visit. Eighteen patients had ALT values >100 IU/liter during the study, and all of these patients had been treated with tocilizumab.
Mean total bilirubin values increased gradually during the study period in tocilizumab-treated patients, but this increase was not exacerbated by the addition of MTX. Among the groups receiving tocilizumab monotherapy, the maximum increase from baseline in mean total bilirubin levels was 83% at week 16; this was observed in the group receiving 8 mg/kg of tocilizumab. Among patients receiving combination therapy, the maximum increase in bilirubin levels (59%) was observed at week 14 in the group receiving 4 mg/kg of tocilizumab plus MTX. Again, values had largely returned to normal by the followup visit, and the group receiving placebo plus MTX was unaffected. Twenty-one patients had bilirubin levels >21 μmoles/liter during the study, but these patients had high total bilirubin levels when they entered the study (mean 17 μmoles/liter, which is the upper end of the normal range) and demonstrated predominantly unconjugated hyperbilirubinemia. In 86% of this subgroup, total bilirubin levels returned to near-baseline values by the time of followup. No relationship between elevated ALT levels and elevated bilirubin levels was observed. No individual patient experienced significant elevations in both the ALT level and the bilirubin level simultaneously.
Lipid changes.
During the study period, moderate but reversible increases in the mean levels of nonfasting total cholesterol, high-density lipoprotein cholesterol, and triglycerides were seen in the groups assigned to receive treatment with tocilizumab. The levels increased initially and then stabilized and did not continue to increase during the treatment period (Figure 4). Importantly, the mean atherogenic index remained largely unchanged despite some rise and fall between infusions in the higher-dose groups. In both of the groups receiving 8 mg/kg of tocilizumab, the atherogenic index was reduced to below its initial level by the 20-week followup visit. Again, certain individuals experienced abnormally high lipid levels, but in the majority of these patients the levels were high at study entry and showed a relatively small increase during treatment.
There was a general dose-dependent reduction in the neutrophil count following treatment with tocilizumab, but the neutrophil count recovered when tocilizumab was withdrawn (Figure 4). Forty patients experienced neutropenia during treatment with tocilizumab. Reductions in the neutrophil counts of 47% and 43%, respectively, were seen at week 14 in patients receiving 8 mg/kg of tocilizumab as monotherapy and in those receiving 8 mg/kg of tocilizumab plus MTX. Of the 13 patients who experienced grade 2 neutropenia (between 1,000 and 1,500 neutrophils/mm3) or grade 3 neutropenia (between 1,000 and 500/mm3) during the dosing period excluding baseline, all had received higher doses of tocilizumab, with or without MTX. The addition of MTX did not seem to exacerbate the effect, based on the relative incidence of neutropenia in the groups receiving tocilizumab as monotherapy or combination therapy. Infections were not associated with reduced neutrophil counts. The lowest neutrophil count observed was 0.88 × 109/liter at week 8 (in patients receiving 8 mg/kg of tocilizumab), and no clear pattern in the occurrence of neutropenia was observed across study visits. Some patients experienced neutropenia after the first infusion of tocilizumab, and some patients experienced neutropenia after later infusions, and there was no evidence that continued dosing worsened the effect. The neutrophil count returned to the normal range by the followup visit in all except 1 patient, in whom the count was abnormally low at baseline.
The number of patients with low neutrophil counts was related to the dose of tocilizumab administered (0, 5, and 14 patients in the 2-mg/kg, 4-mg/kg, and 8-mg/kg tocilizumab groups, respectively). The proportion of patients who experienced infections was no different between those with low neutrophil counts (7 of 40 patients) and those with normal neutrophil counts (62 of 359 patients).
Previously, a monoclonal antibody to the IL-6 molecule was shown to induce improvements in patients with RA. However, the effects were short-lived, and neutralizing antibodies developed against this murine antibody (30). Clinical studies in Japan, in which tocilizumab was used as monotherapy (4 mg/kg or 8 mg/kg) in adults who had previously received DMARDs (including MTX at a dosage less than 8 mg/week) (22, 23), and a dose-ranging study in Europe in which patients received a single dose of either 0.1 mg/kg, 1 mg/kg, 5 mg/kg, or 10 mg/kg of tocilizumab (21) have provided proof of concept that IL-6 blockade by tocilizumab is efficacious in the treatment of RA. Based on these data and those from our study, it may be concluded that IL-6 is an important driver of inflammation in RA. The blockade by tocilizumab of the membrane-bound as well as the soluble IL-6 receptor thus appears to be a direct and manipulable method for achieving the target of reducing the pathologic effects of excess IL-6.
The results of this study clearly show that infusions of tocilizumab every 4 weeks, with or without background MTX therapy, can produce marked and dose-related improvement in RA disease activity as measured by ACR20, ACR50, and ACR70 responses and clinically meaningful changes in the DAS28. The study also showed that the 4-mg/kg and 8-mg/kg doses of tocilizumab were associated with high percentages of ACR50 and ACR70 responses after only 4 infusions (the difference between patients receiving placebo plus MTX and those receiving 8 mg/kg of tocilizumab in combination with MTX was statistically significant) (Figure 2). Assessment of efficacy over time showed continued improvement in all dose groups. This improvement was seen up to the end of the 16-week trial, and there was an indication that maximum efficacy may not have been achieved in this short-term study.
The mean DAS28 among patients receiving combination therapy with 8 mg/kg of tocilizumab plus MTX approached the EULAR criteria for remission (DAS28 <2.6). The primary and secondary efficacy end points for tocilizumab therapy at the highest dose demonstrate that the efficacy of this therapy is in the same range as that of the currently available anti-TNF therapies (18). Thirty-seven percent of the patients in this high-dose group also achieved an ACR70 response, and 34% achieved EULAR-defined remission based on the DAS28.
One feature of note in this study is that a relatively high proportion of patients in the group receiving placebo plus MTX also continued to respond. The ACR20 response rate of 41% in this study contrasts with a rate of 11% among placebo-treated patients in the Japanese study (23). Because the Japanese study compared a placebo infusion with treatment that commenced after a DMARD washout period, and patients in our study received a placebo infusion during continuation of MTX therapy, the high response rate associated with placebo likely indicates that our patients were not MTX nonresponders, but rather that they had not yet fully responded to MTX at the time of trial entry. In the current study, the response to placebo plus MTX was high, and a better control group might have been produced if the period of time during which controls received stable doses of MTX prior to trial entry had been longer than 4 weeks. The study design required that background MTX be withdrawn abruptly at the start of the study in the groups receiving tocilizumab monotherapy, thus placing these groups at a relative disadvantage in terms of efficacy in a population of incomplete MTX responders. This may have contributed to the negative comparison between the group receiving 2 mg/kg of tocilizumab and those receiving placebo plus MTX and to the apparent superiority of combination therapy over monotherapy at each dose level. However, the unexpectedly high rate of ACR20 responses in the group of patients who received MTX alone has no effect on the numbers of patients who achieved ACR50 or ACR70 responses while receiving tocilizumab plus MTX.
The durability of the response to tocilizumab was not investigated in this study; however, data from a phase II study performed in Japan demonstrated that with continued treatment, efficacy (as measured by ACR20, ACR50, and ACR70 responses) was maintained at least until week 72 (22). These data were obtained from an open-label extension study in which patients received tocilizumab at a dosage of 8 mg/kg every 4 weeks for an unrestricted period of time (22).
The most important safety signals in this study were related to changes in the results of liver function tests and serum lipid levels. A dose-related increase in the mean serum transaminase level was seen during tocilizumab treatment. This change appeared to be drug-related, due to the sawtooth pattern of rise and fall between infusions, most of which were observed after the first infusion of tocilizumab. More importantly, certain individuals experienced clinically significant increases in the transaminase level. The addition of MTX appeared to accentuate this effect. Mean bilirubin levels showed a gradual elevation over the study period. It is clear that the pattern of change for the mean bilirubin level was not the same as that for the mean transaminase level, and larger individual rises in the bilirubin level were not observed in the same patients as those experiencing rises in the levels of transaminases or lipids. Also, the total bilirubin elevations were mild (<3-fold the upper limit of normal). In a retrospective analysis of 8 patients with high levels of bilirubin, the increase appeared to be primarily in the unconjugated bilirubin fraction and possibly associated with underlying Gilbert's syndrome. Hemolysis may possibly have contributed to the bilirubin level, but there are no data supporting this hypothesis, which needs to be investigated in the future.
There was no evidence of frank clinical hepatitis or predictors of the occurrence of hepatitis in any of the patients who had elevated levels of ALT and bilirubin. Based on a review of individual patients at each time point, there was no temporal correlation between ALT, total bilirubin, and cholesterol and clinical symptoms consistent with hepatitis. No patient had any 2 of the 3 laboratory abnormalities at the same time. In the Japanese extension study, bilirubin levels did reach a plateau in patients treated for up to 72 weeks.
Treatment with tocilizumab also resulted in an increase in the total cholesterol level as well as an increase in the level of triglycerides and HDL cholesterol (in this study, low-density lipoprotein cholesterol was not measured). At the same time, the mean atherogenic index was unchanged. As with bilirubin, changes in the cholesterol level were not temporally related to changes in the ALT level; however, there was a temporal correlation between total cholesterol levels and the CRP levels (CRP levels were dramatically reduced). The degree of elevation of the cholesterol level may be related to the degree of suppression of inflammation (31). It has also been observed that use of the anti-TNF monoclonal antibody infliximab to treat RA leads to an elevated cholesterol level (32). Increases in plasma lipid levels and/or CRP levels are associated with an increased risk of cardiovascular events (33, 34), and a major cause of death in patients with RA is heart disease (35). The significance of the increases in lipid levels and the decreases in CRP levels observed in this study is unclear (especially because the lipid samples were nonfasting), and further studies are clearly indicated to investigate the clinical significance of these effects on the morbidity and mortality associated with ischemic heart disease. In addition, the mechanism of this lipid level elevation following DMARD treatment in general and tocilizumab in particular is unclear and should be further evaluated.
Favorable effects of tocilizumab were also demonstrated by other direct and indirect laboratory indicators of inflammatory disease (levels of serum ferritin, serum amyloid A, complement C4, fibrinogen, rheumatoid factor, and serum albumin, the neutrophil count, the platelet count, and the hemoglobin concentration), suggesting that suppression of inflammation by tocilizumab is not associated with only a few of the markers of inflammation.
A small number of patients in whom the neutrophil count was normal at the start of the study (unlike the majority of the study population) experienced neutropenia when treated with tocilizumab at a dose of 8 mg/kg. An increased incidence of infections, including life-threatening conditions, has been observed with other monoclonal antibodies targeting the components of the immune system. In this study, serious infections were seen in the group receiving combination therapy with 8 mg/kg of tocilizumab plus MTX, as might be expected with the combination of 2 potentially immunosuppressant drugs, although serious infections were also seen in the group receiving monotherapy with 2 mg/kg of tocilizumab. As the most clinically effective dose, 8 mg/kg of tocilizumab may be considered the optimal therapeutic dose. Although the evidence clearly is not conclusive, IL-6 is known to demarginate neutrophils (36), and inhibition of IL-6 function could be expected to marginate neutrophils, thus showing a decrease in the number of circulating neutrophils. Larger studies in which the period of exposure to the study drug is longer will be required to accurately assess the risk of serious infection associated with tocilizumab treatment.
Anaphylaxis and anaphylactoid reactions are also expected and serious adverse events associated with treatment with humanized monoclonal antibodies. In the case of tocilizumab, as with infliximab, such reactions occurred only at low doses and in the absence of MTX, against a background of "insufficient" immunosuppression, or high-dose antigen–induced immunologic tolerance may have occurred to prevent formation of anti-tocilizumab antibodies (19). Among patients in whom anti-tocilizumab antibodies developed, the number was highest in the groups receiving monotherapy, which suggests that MTX provides some protection against anti-tocilizumab antibody production. This trend is also seen when MTX is given in combination with infliximab (19).
The highest responses to tocilizumab monotherapy have been achieved using the 4-mg/kg (minimally efficacious) and 8-mg/kg (optimally efficacious) doses; therefore, those doses are proposed for use in future clinical studies. Monthly administration of 8 mg/kg of tocilizumab is proposed as the highest dosage, because in this study both efficacy and safety appeared to be dose-related, and increasing the dose beyond 8 mg/kg may increase the possibility that adverse events will occur. Combination therapy with tocilizumab plus MTX demonstrated superior efficacy compared with tocilizumab monotherapy.
In conclusion, the results of this study indicate that targeted blockade of IL-6 is a highly efficacious and promising means of decreasing disease activity in patients with RA, and that tocilizumab treatment (as monotherapy or in combination with MTX) is well tolerated in the majority of cases, having a safety pattern consistent with that of other biologic and immunosuppressive therapies. Large-scale phase III studies are currently ongoing in an attempt to validate the encouraging hypothesis generated in this and other studies, and to investigate the potentially beneficial radiographic outcomes related to treatment with tocilizumab in patients with RA.
We thank David Andrews for assistance with preparation of the figures and manuscript.
- 1Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 1988; 18: 1797–801., , , , , , et al.
- 2Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988; 31: 784–8., , , , .
- 3Synovium as a source of interleukin 6 in vitro: contribution to local and systemic manifestations of arthritis. J Clin Invest 1989; 83: 585–92., , , , .
- 4Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993; 52: 232–4., , , .
- 5 .
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- 7B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med 1989; 557: 417–35., , , , , , et al.
- 8Interferon β 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A 1987; 84: 7251–5., , , , .
- 9Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci U S A 1989; 8: 3546–9., , , , , .
- 10Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 6: 315–25., , , , , , et al.
- 11Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol 1995; 34: 321–5., , , .
- 12Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996; 11: 88–95., , , , , , et al.
- 13JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes: association with a down-regulation of SOX9 expression. J Biol Chem 2003; 278: 2903–12., , , .
- 14Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998; 187: 461–8., , , , , , et al.
- 15Involvement of IL-6, apart from its role in immunity, in mediating a chronic response during experimental arthritis. Am J Pathol 2000; 157: 2081–91., , , .
- 16Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 2004; 114: 582–8., , , , , , et al.
- 17Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine 1999; 11: 1057–64., , , , .
- 18Anti-TNF α therapy of rheumatoid arthritis: what have we learned? [review]. Annu Rev Immunol 2001; 19: 163–96., .
- 19Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: 1552–63., , , , , , et al.
- 20TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675–81., , , , , , et al, and the
- 21Therapeutic benefit of blocking interleukin-6 activity with an anti–interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 2002; 46: 3143–50., , , , , , et al.
- 22Long-term safety and efficacy of anti–interleukin 6 receptor antibody (MRA) in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2003; 48 Suppl 9: S126., , , , , , et al.
- 23Treatment of rheumatoid arthritis with humanized anti–interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 50: 1761–9., , , , , , et al.
- 24Therapeutic efficacy of humanized recombinant anti–interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2005; 52: 818–26., , , , , , et al.
- 25The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–24., , , , , , et al.
- 26American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727–35., , , , , , et al.
- 27Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44–8., , , , , .
- 28Provisional guidelines for measuring disease activity in RA clinical trials [editorial]. Br J Rheumatol 1992; 31: 793–4..
- 29Remission in a prospective study of patients with rheumatoid arthritis: American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 1996; 35: 1101–5., , , , , .
- 30Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol 1993; 20: 259–62., , .
- 31Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation. Rheumatol Int 2005; 25: 241–5., , , , , , et al.
- 32Short term effects of infliximab on the lipid profile in patients with rheumatoid arthritis. J Rheumatol 2005; 32: 252–5., , , , , , et al.
- 33Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis 2005; 64: 303–5., , , , , , et al.
- 34Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351: 2599–610., , , , , , et al.
- 35The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum 2005; 52: 412–20., , , , , , et al.
- 36Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol 2000; 279: H2954–60., , , .
Members of the CHARISMA Study Group, in addition to the authors of this article, are as follows: Dr. S. Augustinova (Czech Republic), Dr. R. Bernstein (UK), Dr. M. C. Boisier (France), Dr. B. Bourke (UK), Dr. S. Bowman (UK), Dr. H. Brabcova (Czech Republic), Dr. F. C. Breedveld (The Netherlands), Dr. G. R. Burmester (Germany), Dr. E. Choy (UK), Dr. L. Czirjak (Hungary), Dr. J. P. Devogelaer (Belgium), Dr. C. Edwards (UK), Dr. A. Geusens (Belgium), Dr. H. Haentzschel (Germany), Dr. M. Hakala (Finland), Dr. P. J. Hedin (Sweden), Dr. K. Horslev-Petersen (Denmark), Dr. I. L. Johannesen (Denmark), Dr. J. Kalden (Germany), Dr. B. B. La Cour (Denmark), Dr. M. Leirisalo-Repo (Finland), Dr. T. Lorenzen (Denmark), Dr. M. Malaise (Belgium), Dr. K. Mikkelsen (Norway), Dr. N. D. Peters (Denmark), Dr. P. Prouse (UK), Dr. J. Sany (France), Dr. M. Schattenkircher (Germany), Dr. M. Schou (Denmark), Dr. P. Sheldon (UK), Dr. S. Sierakowski (Poland), Dr. K. Sirova (Czech Republic), Dr. A. K. L. So (Switzerland), Dr. H. Sorensen (Germany), Dr. Z. Szekanecz (Hungary), Dr. L. Szcezpanski (Poland), Dr. G. Thamsborg (Denmark), Dr. W. Tlustochowicz (Poland), Dr. H. P. Tony (Germany), Dr. D. Walker (UK), Dr. R. Westhovens (Belgium), Dr. J. Wojtulewski (UK), Dr. E. Veys (Belgium), Dr. P. Vitek (Czech Republic), Dr. R. Van Vollenhoven (Sweden), Dr. D. Zarowny (Poland).


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The Perky-Pet Lantern Hummingbird Feeder features a bright red base to attract hummingbirds and a clear, shatter-proof plastic reservoir to make it easy to monitor nectar levels. The reservoir unscrews from the feeder base for quick cleaning and filling, and the lantern-shaped feeder holds up to 18 oz. of nectar with 4 feeding ports for plenty of enjoyment.
Assembled Depth (in.) | 4.33 in | Assembled Height (in.) | 9.00 in |
Assembled Width (in.) | 4.33 in | Product Depth (in.) | 3.48 in |
Product Height (in.) | 10.24 in | Product Width (in.) | 3.5 |
Bird Feeder Type | Hummingbird Feeder | Color Family | Red |
Material | Plastic | Nectar Capacity (oz.) | 18 oz |
Product Weight (lb.) | .392 lb | Returnable | 90-Day |
Squirrel Guard | Yes | UV Resistant | No |
Standard Shipping includes delivery by small parcel service. Processing time varies by product.
Orders for this item may be expedited for an additional fee.
Other Delivery Options:
Express and Expedited shipping options are also available. Estimated arrival times are available in checkout.
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byRobert Westervelt on
2. Identity Management, Access Control
Solution providers told CRN in July following EMC's acquisition of Aveksa that the market for identity management and access control platforms is in flux. The news of Snowden's apparent widespread access to systems, combined with ongoing password theft and other high-profile data breaches has prompted a look at tighter access control measures, including multifactor authentication, provisioning and reporting. Solution providers say the latest behavioral analytics can identify if someone is attempting to log into systems from an unusual location or at an unusual time, and challenge them with additional measures before validating and authorizing access to corporate resources.
As solution providers position themselves for growth, the pressure is on vendors and distributors to meet their partners' needs. Here CRN presents the 2015 Channel Chiefs, our annual look at the executives responsible for running channels at today's IT vendors.
Here are 10 recent searches by CRN visitors.
Cloud 100


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Md.mosheur R.
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I am highly interested to work for you for Search Engine Optimization (SEO) and Search Engine Marketing (SEM) of your website, so that it gets Google HIGHER PAGE RANK, ALEXA Lower Website RANK and better Search Engine Ranking Position (SERP), that will ultimately drive traffic to your website and generate revenue by sales.
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96 |
Internet Marketing Test |
55 |
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Current local time in Girdwood: 13:45
Coordinates of Girdwood: Longitude: 149° 9' 59" West Latitude: 60° 56' 33" North Find Girdwood on MapQuest |
AlaskaMart Cams - Several webcams, including Downtown Anchorage, the airport and Mount McKinley at the bottom of the page. Operator: ALASKAMART.COM |
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Cybersecurity & Privacy
Financial institutions instructing law firms to beef up cybersecurity
For corporations such as financial companies that deal with highly sensitive information, ensuring privacy includes protecting information in closely-related hands as well.
FCC imposes first cybersecurity fine
The Federal Communications Commission (FCC) has become the latest to join the ranks of regulators imposing fines for data negligence on companies, announcing on Oct 24 that it will impose its first fine related to data security on phone providers TerraCom Inc and YourTel America Inc. The FCC is asking...
Best practices for efficiently and effectively settling data breach claims
By creating the proper settlement process and securing court involvement early on, these claims can be resolved efficiently and effectively.
Allstate's Steve Ihm addresses e-discovery strategy and proposed FRCP changes
Recently, InsideCounsel had an opportunity to speak with Steve Ihm, vice president and assistant general counsel at Allstate, about the approaches he takes to e-discovery and how he sees changes to the FRCP effecting corporate litigation.
Businesses can actually learn from hackers
Rather than corporations getting angry at hackers and cyber-criminals who break into their networks, they may want to learn some of their methods and strategies in order to improve their own cyber protection.
Navigating the highway of employee privacy concerns
OCR is beginning its "Phase 2" series of audits. A much-larger number of entities will be considered for an audit. Many expect some employer-provided health plans to be targeted.
Considerations in exiting outsourcing deals
The key to successfully exiting an outsourcing agreement starts with proper planning to assess all the activities and timing necessary to transition the services to a new provider.
Banks identify suspicious activity related to credit cards recently used at Staples stores
According to a post on the blog KrebsonSecurity, several banks indicated that an unidentified entity has gained access to customer credit card information from multiple Staples regional subsets in the Northeast
Cyber liability insurance at heart of new lawsuit
After Chang's filed its claim, Travelers stated that the restaurant does not have cyber liability coverage in the policy it purchased.
Rightside Group released two new web domains for legal community
The newly launched .ATTORNEY and .LAWYER can now be used by legal professionals looking to create a larger and more advanced online presence


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Fukushima nuclear plant still leaking radioactive water, operator reveals - video
The operator of Japan's tsunami-crippled Fukushima nuclear power plant confirms that 300 tonnes of highly radioactive water have leaked from one of the storage tanks, and is still leaking. Tepco's spokesman, Masayuki Ono, said the water had seeped into the ground after breaching a concrete and sandbag barrier around the tank. The leak is the worst such incident since the March 2011 meltdown


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New Hanover done with Irene clean-up
Submitted by WWAY on Fri, 10/14/2011 - 2:30pm.READ MORE:
It's been nearly two months, but New Hanover County is finally done cleaning up from Hurricane Irene.
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» UNCW designated bicycle-friendly campus
Submitted by Marcy Cuevas on Fri, 10/14/2011 - 2:24pm.READ MORE:
The effort to go green is paying off at UNC Wilmington. The university is just one of 26 in the nation to be designated a "Bicycle Friendly University."
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» UNC hires new Athletic Director from Tulsa
Submitted by WWAY on Fri, 10/14/2011 - 9:12am.READ MORE:
North Carolina has hired Tulsa athletic director Bubba Cunningham as the school's next AD.
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» City schedules meeting on downtown sign rules
Submitted by WWAY on Fri, 10/14/2011 - 8:07am.READ MORE:
In the wake of public outcry over an ordinance restricting signs at downtown businesses, the City of Wilmington has called a public meeting.
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» Sixth rabies case found in New Hanover County
Submitted by WWAY on Fri, 10/14/2011 - 7:52am.READ MORE:
Another raccoon has tested positive for the rabies virus after the animal tangled with two dogs in the dog owner's yard. Animal Control officers were called to a Johns Creek Road residence on Wednesday.
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» Meet the Seahawk women's basketball team
Submitted by John Rendleman on Thu, 10/13/2011 - 10:41pm.READ MORE:
Practice has been underway for nearly two weeks for the UNC Wilmington women's basketball team. They were more than willing to stop bouncing the round ball on Thursday in order to take part in Seahawk women's basketball media day.
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» Laney soccer is a kick this year
Submitted by John Rendleman on Thu, 10/13/2011 - 10:38pm.READ MORE:
Laney High School entered Thursday's soccer game against New Hanover sporting a ten game winning streak. That makes the Bucs the hottest team in the region, but can they beat the Wildcats for the second time this season?
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» 5th Quarter: Week 9 High School Football preview
Submitted by John Rendleman on Thu, 10/13/2011 - 10:35pm.READ MORE:
Week number nine of the high school football season kicks off on Friday night. Jesse Jones has a preview of Friday's action. It's highlighted by the Laney-New Hanover game that will be played at Laney High School on Friday night.
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» FIRST ON 3: Ticket info announced for "An Evening with One Tree Hill"
Submitted by WWAY on Thu, 10/13/2011 - 10:35pm.READ MORE:
Organizers have announced ticket info for "An Evening With One Tree Hill," a Q&A session with members of the cast and the show's creator, at UNCW.
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» Wrightsville Beach pondering a skate park
Submitted by Cliff Pyron on Thu, 10/13/2011 - 10:10pm.READ MORE:
A group of skateboarders on Wrightsville Beach have been pushing the town for a skate park for quite some time. They are now one step closer as the Board of Aldermen decided Thursday night to allow them to work out details and further questions with the town staff.
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