text:
Posts Tagged 'Downey'
Posted: June 5, 2012 in Entertainment, Movies
Tags: 2012, 3, 3dd, 7, 9, a, Abraham, Adam, age, ages, Alec, alien, aliens, amazing, America, and, andy, animated, armor, article, Asgard, back, bad, Baldwin, banner, batman, battleship, bear, beautiful, beginning, billy, black, blog, bomb, book, box, boy, brave, brolin, Bruce, budget, burton, captain, Carell, cartel, carter, Catwoman, CGI, change, Channing, Charlize, cheesy, Chloe, Chris, City, classic, Clint, comic, comics, coming, commissioner, Connors, continental, criminal, cruise, curt, dance, dancing, dark, date, dead, death, del, delay, delayed, Dennis, Depp, digital, director, district, Downey, drift, dwarfs, Dwayne, effects, Emma, end, Evans, explosions, fail, failure, family, fiction, film, films, finding, for, friend, fury, GI joe, Gilmore, good, Gordon, Gotham, grease, guns, guy, gwen, happy, hate, hawkeye, Hayek, Heath, helicarrier, hulk, hunter, huntsman, ice, in, inc, incredible, invasion, iron, Jackson, jaxx, John, Johnny, Johnson, jones, josh, Joss, jr, kiera, Kirsten, Kitsh, knight, knightly, kunis, Kyle, l, Leary, ledger, lee, Lincoln, list, lizard, Loki, loss, love, Madison, man, mark, marvel, marvels, McFarlane, men, Michael, Milan, monsters, movie, movies, musical, my, Natasha, Nemo, new, nick, of, office, old, Oliver, origin, original, over, overrated, Parker, Peter, piranha, Pixar, pot, practical, prequel, preview, Prometheus, pushed, rated, ray, reboot, recap, release, remake, rest, retaliation, review, revolution, ridley, rises, roadblock, Robert, robin, rock, Rogers, Romano, ruffalo, sad, Samberg, Samuel, Sandler, savages, Scarlett, Sci-Fi, science, scifi, Scott, seeking, Selina, Selma, sequel, Seth, seven, shadows, shield, short, Shreks, skree, skull, slacker, smith, Snl, Snow, songs, soon, special, spider-man, spiderman, Stacie, Stacy, star, stark, starring, step, Steve, Stewart, stone, story, stuffed, success, suit, summer, tatum, Taylor, Ted, thanos, that's, the, The avengers, Theron, Thor, thriller, Tim, time, Timur, Tom, tommy, tony, toro, toy, trailer, trailers, travel, Travolta, trilogy, troll, twilight, up, upcoming, vampire, vampires, venom, wahlberg, wall-e, wanted, Wayne, what, what's, whedon, when, where, white, who, why, widow, will, Willis, witch, world, x-men
This is a pretty big year for movies so I figured I'll do a rundown of a bunch of flicks headed to the theaters until the end of the year. Let me just point out before we get started that I didin't mention every single movie that's coming out, I'm just going through the major ones and the ones that fought my eye and I feel like thu deserve your attention (and ones that don't). Frankly, if it doesn't interest me then I'm not going to mention it and before I start to ramble on, let me just get into the meat and potatoes of the article. I'll do it month by month, in the order of the release date
"The Avengers" Trailer
Now I realize this has already come out, but since we're still in about the middle of May, I'll include the movies that have come out this month. If you haven't already heard, The Avengers is a huge success and it deserves every single record it has broken because the movie is absolutely incredible. Joss Wheadon, the director of The Avengers and the creator of such TV gems as Buffy: The Vampire Slayer and Firefly, had a huge task in front of him and he pulled it off flawlessly. This is by far one of the most entertaining things he has ever created and I truly belive the reason The Avengers is as good as it is because of Wheadons background as a comic book writer. He has a knack for being able to juggle and mix different personalities within a team and making it work, jut look at his run on The Astonishing X-Men to see how great he is at how skillfully he is at working with team work dynamics. He balances every member of The Avengers with art-like precision and the end product is a perfect balance of drama, humor and action. It never feels like its an Ironman movie, a Captain America movie or a Thor movie, it just feels like an Avengers movie. The scenes with the Hulk completely out shine the previous two movies the green Goliath previously starred in and Whedon makes The Black Widow's storyline play out so perfectly that fans are already clamping for a solo movie starring the Russian assassin who is played to perfection by the big boobied Scarlet Johanson (we were all thinking it, I just said it). Do yourself a favor, see the movie in the theaters in IMAX and if you feel like you wasted your money I'll buy you lunch
"Men in Black 3" Trailer
Loved the first one, disliked the second one and don't really care about the third one. Look, when MIB came out in the late 90s it was fresh, Will Smith as as an actor was new and the special effects were pushing the boundaries of those times. The script was original (even tho it was based on a comic book) and everybody fell in love with it, besides, how could you forget the theme song performed by the fresh prince himself? When MIB2 came out, it was a natural response to the success of the first movie. MIB made a huge impact at the box office and people loved it and wanted more so the studio did exactly what a studio does in that scenario, they rushed the sequel out sacrificing quality in order to get it out sooner. Did MIB2 make money? Of course it did, but not as much as the first one and it wasn't as well liked as the first one. Now this is what gave the studio pause on the third film: Although MIB2 made its money back, the fact that not as many people liked it increased the risk of people not seeing the third one, therefore making it a financial loss. Basically, the cons outweighed the pros and the third flick was never made. Fast forward to about 10 years later, this time the studio is betting on the nostalgia factor and the return of Will Smith after a 4 year absence from the theaters to help out with the gross of the movie, but count me out. I've always felt like this was a one movie premise, the whole point being someone who has no idea that this stuff exists being thrown into a world full of it. The sequels are unneeded and uninspired so the only way I'll see this in on HBO in about 18 months
"Dark Shadows" Trailer
Yet another movie starring Johnny Depp and directed by Tim Burton….color me unimpressed. Don't get me wrong, Depp is a great actor and Burton a pretty good director, but it seems like they are both stuck in the same place when they get together. It just seems to me like all their movies look and feel exactly the same, with Depp playing the weird, quirky character and Burton shooting everything to look like an Emo kids dream. It's just that after "Edward Scissorhans"', "Sweeny Todd", "Alice in Wonderland" and now "Dark Shadows", Burton and Depps collaborations feel stagnant. Scorsese knew when to bail on De Niro, Burton should know its time to bail on Depp.
"Snow White and the Huntsman" Trailer
As soon as I saw the trailer for this a few months back I knew I would be seeing this in the theater. I love movies that are filled with visual flair and imagination going wild, and this film definitely hits those spots. The special effects seem incredible, and the dark twist on an old story seems to work (although purists will know that the original Snow White story is even darker and more sinister then this). I know that all the twilight haters will refuse to see this because Bella is the main character, and admittedly I am one of those haters I'm willing to give the girl a chance. Thor's in this as well wielding an axe instead of a hammer and the film also stars some of my favorite actors form the UK as the dwarfs. The directing seems really good, the score is amazing, the……..who am I kidding? I'm on board because Charlize Theron is in it. I am absolutely in love with her, like not healthy in love with her. I could watch her reading a phone book and it would be the most entertaining thing I've ever seen. Wanna hear something gross? ……I'm not going to tell you but for all the guys reading this: Watch the trailer again. You know the scene with Charlize? What would a perv say about that? Yeah…..that what I was going got write.
Piranha 3DD
"Piranha 3DD" Trailer
I love movies that fall into the category of "So Bad it's Good", even more so I love "So Bad it's Good" movies that know that they fall into that category and embrace it. I didint see the first "Piranha 3D" until it showed up on HBO, and even then i only saw it at my friends urging. I expected it to be bad, but I didint expect it to know it was bad and that's what made it so great. The creators behind this knew that all people were expecting when they saw this was boobies, blood and killer fish and that's exactly what they gave us and for that they are geniuses. I truly belive that it's harder to make a "So Bad it's Good" movie than an actual good movie, there's a by fine line you have to walk, a perfect balance you have to hold between cheesy and serious. You don't want to go too cheesy because then it will just become a parody, and you don't want to go too serious because then the movie will go from "So Bad it s Good" to just plain old bad. I can't wait to see this sequel, although I won't waste $13 on a theater ticket I might be willing to drop $4 on it when it shows up onDemand.
"Prometheus" Trailer
Let me just say this right off the bat since a lot of people seem to still be in the dark about this fact: "Prometheus" is a prequel to "Alien". In the original movie, the crew of Nostromo received an SOS signal and went to help which is what started the whole thing. The ship that sent the SOS signal was Prometheus. I really can't write a lot about this movie because I have purposefully kept myself in the dark as not to get spoiled on anything and to be totally surprised when I see it in the theaters. I did see a couple of trailers for it, and I just have to say that I love the vibe of the movie, it has that 80s vibe. Aside from "District 9", we really haven't had a good Sci-Fi movie in a long time, I guess we had "Star Trek" a few years ago but I don't consider that Sci-Fi, it's too well know and too ingrain in our pop culture. A true Sci-Fi movie should be very unfamiliar, when you enter the theater you should have that "into the unknown" feeling and Prometheus has it and that's why I've avoided spoilers like e plague. The late 1970s and the 1980s were the prime of Sci-Fi movies with classics like "Mad Max", "The Terminator", "Escape From New York" and "Blade Runner". Ever since CGI became more affordable then practical effects, Sci-Fi movie have been slowly diluted into all out action extravaganzas. With a few exceptions like "District 9", Sci-Fi became and excuse to blow stuff up in cool ways by cool characters, like "Transformers". They became a perfect example of style over substance, they all became action movies at their core without any effort to use the technology if CGI to make an interesting story. For example, if you took out CGI and could only use practical effects (ie. puppets, miniatures etc) how do you think any of the "Transformers" movies would have turned out? They would be horrible because they are all about the special effects. Now on the other hand take "District 9", even without the special effects it would have been a great movie because they storyline is exceptional. That's what I'm hoping "Prometheus" is; an amazing movie with amazing special effects.
"That's My Boy" Trailer
A lot of people have been disappointed with Adam Sandler in the past few years, and yes, I somewhat do fall into that category although not as deep as others do. Obviously, his first movies were the best, "Billy Madison" and "Happy Gilmore" are classics and "Big Daddy" was great, but movies like "Mr. Deeds", "50 First Dates", "Anger Management" and "The Longest Yard" are utterly forgettable. I think around the Zohan movie is when most of his fans gave up on him, and you can include me in that category. However, about a year ago I was channel surfing and happened upon "Grown Ups" on HBO (yes, I watch HBO a lot) and found myself laughing, I realized that Adam Sandler hasn't really changed since "Billy Madison". His comedy stayed the same throughout all these years and it was me who has gotten older and doesn't find that kind of humor hilarious anymore, funny but not hilarious. I watched "Billy Madison" recently and recognized the fact that if it came out yesterday I might have not even seen in. I find it hilarious because when I was a kid watching it I found it hilarious, I guess you could call it nostalgic humor; finding something funny because you used to think it was funny. There's still some missteps once in a while like "Jack and Jill", which I don't think I'll see unless it's free on cable and I'm drunk, but the recent "Just Go With It" wasn't as bad as critics made it out to be. Anyway, I'm looking forward to "That's My Boy" because I like Andy Samberg and it seems like a return to an R rated comedy for Sandler which I can't wait to see.
"Rock of Ages" Trailer
Go ahead, laugh at me if you wish, but I'm a sucker for a good musical and I'm not ashamed to admit it. "Grease" is one of my all time favorite movies and the 1980 are one of my favorite periods in musical history, a movie that combines the two cant go wrong in my book. I'm usually not a fan of the "Glee" type of a musical were they take great original songs and give it a tweak here and there. The song was great for a reason so why the hell are you changing it? I'm also not a fan of musicals not having their own material and using existing songs,(one of the reasons I love "Grease" do much is because all their songs were original and they were all great) but I'm willing to give "Rock of Ages" a pass since it would be damn hard to recreate incredible songs like Bon Jovi's "Wanted Dead or Alive". I'll most likely not see this in the theaters' either out of embarrassment or the fact it's so expensive to see a movie nowadays, but I'll definitely catch in on DVD or onDemand. It's a musical based in the 1980s with licensed music starring Tom Cruise, it's going to be like a 90 music vide with a storyline and great tunes….how can you go wrong?
"Abraham Lincoln: Vampire Hunter" Trailer
If you don't roll your eyes after reading or hearing the title of this movie I'm pretty sure theres something wrong with you. I mean, seriously? Honest Abe hunting vampires? I know it's a movie, I know it's based on a really good comic book and I know that vampires a "in" these days but COME ON! If the title of a movie makes you laugh and it's not a comedy, you have a serious problem on your hands. When I first heard of this I honestly though it was a joke, and to be perfectly frank, I still kind of do. I'm not sure why Timur Bekmambetov agreed to do this movie after his success with "Wanted" because he could have picked any action movie he wanted. I'm familiar with his previous work in Russia, and for any film fan out there that doesn't mind reading subtitles I highly recommend "Daywatch" and "Nightwatch", he is truly a skilled director but his choice to do this movie baffles me. I'll tell you right now: this movie will be a massive flop. I know that it only cost $70 million but I doubt that in a summer of blockbusters people will want to spend their money on something that makes them scratch their head and think to themselves "Is this Serious?"
"Brave" Trailer
In my humble opinion, an opinion that is absolutely not shared in the movie geek community, PIXAR and their films are extremely over rated. The "Toy Story" films were good with only "Toy Story 3" getting into the great category. "Finding Nemo", " The Incredibles", "Monsters Inc" and "Ratatouille" were entertaining, both "Cars" films were terrible and "Wall-E" and "Up" we're so unjustifiably praised that it makes me question people's sanity. I mean for a kids movie, "Up" was so depressing that it would give "Requiem for a Dream" a run for its money. I find myself enjoying the Dreamworks animated films, like "How to Train Your Dragon" and all the "Ice Ages" and "Shreks" more then the Pixar animated outings. It's like Dreamworks makes these movies for kids with multiple tongue in cheek references for adults while Pixar makes these semi-kid/ semi-adult movies that are not really sure who their audience is. Reading this, you probable already know my view on "Brave" but I'll say it anyway: I'll wait to watch 15 minutes of it on cable in 5 years.
A lot of people don't know about this movie, at least not yet, and it's totally justifiable. It's one of those major studio productions that tries to any it off as an independent movie to make the audience think that it's some fancy art house film. If you're one of those people, the basic plot outline is that the world is about to end and Steve Carell is looking for someone to enjoy his last moments with. I love Steve Carell but I hope this isn't one of those roles where he is playing it straight and realistic because after years of seeing him as Michael Scott on "The Office" and Rick in "Anchorman" I can't take him as a serious actor. I hate to pigeonhole an actor into one type of role, but he played Michael Scott so well for so many years that whenever I see him in something serious all I can think of is him calling Dwight an ignorant slut. Aside from Steve Carell, this cast includes a whole lot of funny guys like Rob Huebel and Rob Corddry and I'll hold my judgement on this movie until I know more about it but I'll have a feeling I'll avoid this one just like I did with "Dan in Real Life" and "Little Miss Sunshine"' the latter, by the way, being the most over rated movie of the last 10 years in my personal opinion.
"GI Joe: Retaliation" Trailer
When I originally started working on this blog "GI Joe 2" was still scheduled to be released in July of this year, however around 3 weeks ago Paramount Pictures pushed the movies release date all the way back to summer of 2013. They said the reason for the change was to give the special effects team more time to convert it to 3D, but over the last couple of weeks various sources have come out and said that when the movie was shown to test audiences the results were very negative. Apparently the reason for that being is that Channing Tatum's character dies in the first 10 minutes of the sequel and the test audience wasn't a very big fan of that. The problem is that this move is going to cost Paramount a huge amount of money since not only will they have to add an additional year of shooting which includes paying much more money to the actors and crew, but also in terms of marketing. Paramount has spent tens of millions of dollars advertising the movie with the release date of 2012 and now all that money has gone down the drain. Basically if you break it down it goes like this: Officially the budget for the movie is $125 million and that's not including the marketing budget. It's usually a pretty safe bet to estimate the marketing budget and around half of the production budget, in this case let's say $50 million and that brings us to around $175 million before this faux pas. Let's just say that the additional year of filming is going to run them $35 million, and that's me being very generous since its probably closer to $60 million. Now, they are going to have to market the movie from scratch so there goes another $50 million, so now were adding a total of $85 million to the budget that was originally green lighted for only $175 million and this brings us to a total budget of $260 million. Budgets like that are usually reserved for guaranteed hits, movies like "The Avengers" or "Transformers" not semi-successful, barely-made-their-money-back movies like the original "GI Joe". This is a huge risk for Paramount and they stand to loose a huge amount of money if this film is incredibly successful when it's finally released which I really doubt it will.
"The Amazing Spider-man" Trailer
One of the most annoying trends going on in Hollywood right now is the remake trend, taking basically every movie from before the year 2000 and giving us a remake of it or a really crappy sequel (I'm looking at you "Live Free or Die Hard"). Making remakes of older movies is one thing, but taking a movie from 2002, a movie that we all saw and remember very well, and remaking it is really pushing it. If it was at least a semi-sequel like "The Incredible Hulk", were it kind of follows the original but not really, that would be fine but Sony decided the go full remake on old web head, treating it like its a brand new movie. I'm a huge comic book fan and Spidey is one of my favorites, I make sure I see all the comic book movies out there but I refuse to sit through another movie of his that spend half of its running time explaining his origins. Everybody and their mom saw the original "Spiderman", when it came out it held the record for the biggest opening weekend of all time, we don't need another explanation of how he got his powers. He got bitten by a radioactive spider, even if you never read a comic book you know that, spidermans origin is part of pop culture. Aside from that, just looking at the trailers makes me think that this is aimed at the twilight crowd which is basically the opposite of the comic book crowd this movie should be for. The director, Marc Webb (I swear that's his real name) only has one semi big budget movie under his belt and its "500 Days of Summer" which is a teen romance movie. I think I'm going to sit this movie out and wait for the DVD unless I hear it's amazing from my fellow geeks.
"Savages" Trailer
Not many people know about this movie and I don't blame them, the movie has kept a very low profile and the expectations for this one are very low. If you don't know, the plot centers about two California marijuana growers who battle it out with a Mexican cartel when one of their girlfriends is kidnapped. The way I see it, this movie is going to either be terrible or very good and I'm basing that simply on the director and the cast. When it comes to me, Oliver Stone is a hit or miss type of guy and so is John Travolta, Benicio del Toro and Selma Hayek. If they pull it off this could be a fun action thriller, the sort we have sorely missed the last couple of years. Aside from that I kind of feel bad for Taylor Kitsh who is the lead in this one, so far the guy has been the lead in two major productions: "John Carter" and "Battleship". Both of those movies have been complete and utter failures, literally costing the studios that produced them millions and millions of dollars. If Kitsh doesn't get a hit on his resume soon he's going to be viewed as box office poison and his next starring role will be in "Do You Want Fries With That?".
"Ted" Trailer
Finally, after spending more the 10 years of making America laugh on the small screen, Seth McFarlane is bringing his type of humor to the big screen, how awesome is that?….If you couldn't tell, I was being sarcastic in the previous sentence. I haven't watched "Family Guy" or any of McFarlane's othe animated shows in years. I found the one note, one joke premise of his style of comedy played during the 4th season of "Family Guy", but I'm not judging those who do. After all, I am the guy who still finds "The Simpsons" and "Seinfeld" funny although I've seen every episode at least twice, all I'm saying is that's just not my brand of humor. However, I can't say I'm not intrigued by what McFarlane is going to do on the big screen, I'm not expecting much but I hope to be pleasantly surprised. The premise of the movie is the same as his TV shows with a kind of a dumb slacker being best friends with a talking pot head animal that no one finds weird it can talk. Well, I guess there is a difference because this time the animal is a stuffed bear!!! I know I sound like a hater here, but I'm really not, I just think its fun to laugh at a lack of creativity displayed in everything McFarlane does, but I can't say I blame the guy. He found something that works and is running with it. Also, from what I've seen from the trailers, the movie might be kind of funny and I'm hoping for the best since this summer is seriously lacking any high profile comedies.
"Ice Age: Continental Drift" Trailer
I mentioned before, when I was talking about Pixar's "Brave", that I wasn't a huge fan of the Pixar animated movies, but in all honesty that's not really true. I'm not really fan of many animated movies, especially most of the animated features that are released these days. I'm not sure whether it's just me getting older, It's just I don't feel the same about animated movies like a did years ago, but if you were to throw "The Lion King" in the DVD player I'd sit there and love every minute of it. I know that it takes the same amount of work to make a computer generated image as it does to draw one, perhaps even more, but I just can't connect to the characters the same way. There's just something special to me about drawing artists slaving over hundreds of pieces of papers, drawing a two hour movie frame by frame. I'm getting way off topic here so let me just double back, although I prefer classic animation to CGI I still enjoy the current trend of animated films. If I had to make a choice, I'd go with "Ice Age" rather then any of the Pixar film (except for "Toy Story 3"), it just seems to me like Pixar tries too hard and Dreamworks has fun with it.
FYI: Just for you guys, this is a secret "Dark Knight Rises" poster that you will only see here…..and most other movie sites, but it will take a lot of effort so….enjoy.
"The Dark Knight Rises" Trailer
Much like "Prometheus" I've kept myself in the dark about the upcoming Batman threequel, and yes that is an actual word. No matter how hard you try tho, with a movie of this proportions, with this much hype and popularity you're bound to find out more than you'd like. Before you continue reading, I just want to let you know that I have no real (read:confirmed) spoilers for this movie, but I do have some plot and character details that I will go into here so if you want to go into the movie completely in the dark STOP READING NOW! Is everybody gone? OK, let's continue. We know that this is the last "Batman" movie for Christopher Nolan and its the end to his batman trilogy. What I mean by the end is that this batman, in this universe, is finished after this one. Whether that means that Bruce Wayne dies or retires is still a well guarded secret by the production team. This time old Bats is squaring off against Bane, a very formidable villain in the comics,and from what it looks like, as well as onscreen. We get the addition fans have been clamoring for since Nolan started with the Bat-films and that is adding Catwoman to the cast, but I have come to find out she is never referred to as "Catwoman" in the film. The new cast member whose presence is puzzling every fan out there is the role Joseph Gordon-Levitt plays. All we know is that Appearantly he plays some sort of law enforcement agent by the name of John Blake, a character that has never existed in the comics. Now Nolan went on record many years ago that he will never have a "Robin" in his batman movies, but (and this is fan speculation only) there are people out there that belive Bruce Wayne will die in this one only to have the mantle of the Bat taken over by John Blake. All of this is simply fanboy speculation and nobody will know exactly what happens until the movie is released, Nolan is good like that when it comes to keeping the plot under wraps. All we know for sure is when this movie hits, it's going to hit hard and I believe box office records broken by "The Avengers" will be broken again. Nolan is coming off a string of super successfull films (Batman Begins, The Dark Knight, Inception) and because of how good his previous Batman film was, the anticipation for this one is sky high.
"The Watch" Trailer
Before I start on this, you guys want to hear another example of political correctness going to far in America? OK. "The Watch" used to be called "The Neighborhood Watch"' but because of the whole Trayvon Martin case they changed it because it might offend people. Yes, unfortunately we live in a time and place where stuff like this happens but enough about the name change and let's talk about the movie. The movie stars Ben Stiller, Vince Vaughn Jonah Hill as a group of dads that start a neighborhood watch group and fight off an alien invasion. I had no idea about the alien angle until I saw a trailer for this a few weeks back, I just thought this was a run of the mill comedy where they'll end up fighting a cartel or something. I was pleasantly surprised by the alien reveal, but also a little worried because mixing Sci-Fi and comedy is much tougher then it looks. I really hope they can pull it off and I really hope the stars of this flick step up to the plate, because when it comes to the two main actors in this they really need to prove they still have it. Stiller used to be funny (check out "The Ben Stiller Show") but he hasn't made a good movie in years and in my eyes, Vaughn was never really a comedy genius. He pretty much played the same cynical asshole in everything he's ever been in, but if you make his character feel like he belongs in said world he'll at least be entertaining.
Step Up: Revolution
"Step Up: Revolution" Trailer
I'm not really sure why I'm including this movie on this list, the target audience that reads this is definetly not the same target audience that goes to see Step Up movies. Honestly, I beg you (and I'm 100% serious about this), if you're planning on seeing "Step Up: Revolution" please leave a comment on here because I would love to have proof that you exist. I'm not sure what I can say about this movie because the deciding factor of you seeing it is very simple: Do you like dancing? Then go see this movie. If I may just give you a warning, because it happened to me a couple years back, if you're going to see this movie in 3D with a girl make sure that the theater has a 3D screen before you purchase you tickets. Otherwise, you might be stuck like I was, watching "Step Up 3D" without the "D".
Thank you very much for reading part one of "2012 and the Rest of it's Movies (PART1)". Part 2 will be up shortly.


Prior to joining Foundry Commercial, formerly CNL Commercial Real Estate, ranked the highest producing broker for the entire state of Florida for more than 10 consecutive years.
Investor customers include Archon Group, Principal Financial Group, Prudential Insurance, various Trammell Crow entities and joint venture partners; and P. Barnett Construction.
Investment and disposition projects include more than 1.3 million SF.
Has represented corporate users such as Danka Business Systems, Cott Beverages, Chase Manhattan Mortgage Corp., Progressive Insurance, American Express, Bank of America and Fidelity Investments.


text:
Home Latest Oshiomhole: Celebrating a Labour Activist and Political Leader at 67
Oshiomhole: Celebrating a Labour Activist and Political Leader at 67
Adams-Oshiomhole
By Simon Ebegbulem
Human epochs are replete with great men and women in the various fields who defined and continue to define their peculiar histories with the magnitude of their accomplishments. Comrade Adams Aliyu Oshiomhole, mni, CON, national chair of the governing All Progressives Congress (APC) is one member of that tribe. It is on this score that it becomes apposite to celebrate the former president of the Nigeria Labour Congress (NLC) and former governor of Edo state who turns 67 today (April 4, 2019).
Comrade, as he is popularly referred to by associates and devotees, happened on the national stage in 1999 when he emerged as the 4th president of the NLC. As someone who restlessly craves the institution of legacies for posterity, he immediately set out and committed himself to building an independent, militant and socially responsive fighting organisation. To be sure, the independent, militant and socially-responsive dispositions were not for gratuitous appropriation of the spoils of office.
He deployed the powers of his NLC presidency in becoming the number one defender of the rights and welfare of the working people. He provided leadership by staying in the frontline in resisting arbitrary increases in the prices of petroleum products. The NLC on his watch was a nemesis of the Olusegun Obasanjo administration on its harsh fuel pricing policy as well as other socio-economic policies that were injurious to the wellbeing of Nigerians.
Combating arbitrary increases in fuel pump prices was one turf of policy antagonism; the other turf was the battle for salary increases for workers. He secured significant salary increases for workers, the last being the 15 percent increase across board. Under his presidency, the NLC became the most popular and influential non-State actor in the country, which provided effective opposition to then ruling Peoples Democratic Party (PDP).
For his courage, tenacity and single-minded devotion to labour issues, he earned himself such monikers as "Hurricane Adams" and "Adamant Adams". But the workers and masses loved to refer to him as the "People's President" (which was eventually as the title of a book written on his eight-year robust leadership of the NLC that was publicly presented in Abuja on 10 February, 2011).
In April 2007, he was overwhelmingly elected governor of Edo state on the platform of the Action Congress (AC) but his mandate was stolen, thus precipitating an intense legal struggle to reclaim his mandate. The Edo State Election Petition Tribunal restored the mandate, which was re-affirmed on November 11, 2008 by the Court of Appeal. On November 12, 2008, he was formally sworn in as governor of Edo state.
As governor, Oshiomhole adopted what is now popularly referred to as participatory, people-driven and bottom-up approach to governance. This is based on his well-advertised campaign slogan, that is: "Let the People Lead." He shunned the bogus title of "Executive Governor" and did not tolerate the pretentious appellation of "His Excellency." To Edo people, Oshiomhole was simply and truly the comrade-governor, people's governor or just simply, comrade.
A foremost apostle of "one man, one vote" and the most methodical visionary and transformer that the Edo people have seen in this generation, Oshiomhole was rewarded with a resounding victory for a second term in office in the governorship election that was held on 14 July, 2012. For the first time in Edo state, Oshiomhole won election in the entire 18 Local Government Areas.
He was a national phenomenal figure whose wisdom was required by the Federal Government in conflict resolutions. For instance, the late President Umaru Musa Yar'Adua requested him to negotiate and resolve the stalemate that led to a three-month strike by the Academic Staff Union of Universities (ASUU). Comrade did not fail to deliver.
Oshiomhole shattered the assumption, prior to his emergence as governor that labour leaders don't do well in public offices, by delivering the goods in Edo state. Having inherited a state with decayed infrastructure, a state that was held hostage by powerful cabal in the PDP, he did not despair but rather rose to the occasion by confronting the problems head-on. He did not complain but rather he started the battle by ensuring that his party, the then ACN got the majority in the state House of Assembly and eventually took over the leadership of the House.
Oshiomhole strategically embarked on massive construction of roads across the state, commenced what was referred to as the red roof revolution in both primary and secondary schools through the construction of red roof schools equipped with modern teaching facilities in all the local governments and 192 wards in the state.
In addition, he embarked on a N30-billion Benin water storm project which had effectively checked the menace of flooding in Benin City and its environs. His administration also built a state-of-the-art Benin Central Hospital, which was geared towards bolstering the health needs of the people of the state and the South-south zone.
Even out of office, Oshiomhole is widely known as the father of modern Edo State. And one unique thing that endeared him to the people while he was governor was his penchant for inspecting projects even at nights. He constructed solid roads with walk ways and street lights across the state. He provided water especially in Edo central senatorial district, an area where it was earlier believed that it was difficult to extract water.
Oshiomhole was adored in Edo state due to his uncommon humility, service to humanity, protection of the poor and his demystification of governance. Today, elders, youths and women cast their votes for Oshiomhole's party in every election. That was why he has become a thorn in the flesh of the PDP leaders.
Associates and devotees celebrate the transformation of Oshiomhole into an aficionado of politics, whose moves have become a veritable bugaboo to his opponents. Many, who earlier questioned his political sagacity, have done so to their own peril. A Majority of such people have been victims of Oshiomhole's dexterous politics.
Some politicians who started well did not end well when it has to do with enthroning a successor. But Oshiomhole is not in that category. He used his political foot soldiers – the good, the bad and the ugly – to deliver the incumbent governor, Mr. Godwin Obaseki, who was the Chairman of the state's Economic and Strategic Team, as his successor
Despite several efforts by his adversaries to muddy his good name, Oshiomhole has continued to soar higher politically. On the 23 of June, 2018, he was unanimously elected as the national chair of the APC and promised to embark on reforms that would shape the future of the party and he has not looked back since then.
Observing that some powerful individuals within the APC had hijacked the party, Oshiomhole promised to return the party to the members who overwhelmingly voted for President Muhammadu Buhari in 2015. He commenced the direct primary mode of selecting candidates for the party so that all members of the party would be part of the process of electing their leaders unlike when it was done through few delegates.
For the first time in the history of the politics of the nation, a presidential candidate of a party, in the person of President Muhammadu Buhari, emerged through direct primary election. That paid off as the president garnered overwhelming victory across the nation in the just-concluded presidential election. When he accepted the job of national chairman, Oshiomhole made it clear that the national working committee (NWC) would embark on reforms that might not be easy but that such reforms would make the party much stronger and people-oriented. He had pointedly indicated his readiness to wield the big stick where necessary.
According to him, "It will no longer be business as usual in party affairs. From membership, discipline, funding, party management and respect for party constitution to conduct of party members in the arms of government; working with the president, we shall reinvent the ability to reward positive conduct and sanction recalcitrant, anti-party conduct. My task is to work with Mr. President, governors, leaders of the party at all levels and other stakeholders to pull our members together to build a strong and united party.,,,"
Oshiomhole has not deviated from his promises ten months after he stepped in the saddle. For instance, through his reforms, ministers who were not at home with the party or their people were disqualified from participating in the primary election.. Governors who played gods in their various states against the party's interest, including alleged involvement in anti-party activities, were either suspended from the party or queried. For Oshiomhole's NWC, supremacy of the party is paramount. Whether you like him or not, under his leadership, President Buhari was re-elected. The APC is on the path of nicking the leadership of the 9th National Assembly where it enjoys overwhelming majority just as it maintains a majority control in the states. Happy birthday to a dogged fighter and reformer.
Ebegbulem is Chief Press Secretary to Comrade Adams Oshiomhole
Previous articleNAPTIP Convicts 379 Traffickers in 16 Years, Says Director
Next articleBuhari to Attend WEF in Jordan, Investment Summit in Dubai
Atiku Decries Rising Debt Profile, Says Debt Now N24.3trn
editor - July 10, 2019 5:19 pm
NCC Remits N51.3bn to FG's Consolidated Revenue Account
Strengthening SEC's Market Development Role

redpajama_set_name: RedPajamaCommonCrawl


text:
Casino Apps – iPhone Versus Android
Melvin Guillard (Esther Lin/MMA Fighting)
Melvin Guillard Pulled from WSOF 20, Lucas Montoya Named Replacement Against Ozzy Dugulubgov
News, Spotlight, WSOF
Earlier this week World Series of Fighting announced that it has pulled Melvin Guillard from his scheduled WSOF 20 co-main event matchup with Ozzy Dugulubgov after failing to deliver his required medical results by the April 6 deadline.
As a result of Guillard's disappearance, the promotion has replaced him with the streaking Lucas Montoya, who was originally slated for preliminary card action.
"We are disappointed that we are in a position where we have to pull Melvin from this event but, given the fact that he did not turn in his required medical exam results by this morning's deadline, we were left with no other choice but to do so," stated WSOF President Ray Sefo. "Melvin and his camp were reminded more than once about the hard deadline. Yet they failed to deliver what was necessary in order for him to compete."
Montoya (8-3) of Layton, Utah will enter the cage on a four-fight win streak, with three of the four victories having come by way of TKO or submission.
His opponent, Dugulubgov (6-2) is looking for his second straight win after delivering a thunderous KO (punch) on Keon Caldwell at WSOF 13 on Sept. 13, 2014.
The lightweight matchup between Nick Newell (11-1) and Joe Condon (12-7) has also been named the new WSOF 20 co-main event. Montoya's original opponent, Abdula Dadaev, will no longer compete on the card, but will receive his fight purse.
WSOF 20 is expected to air on April 10 liveF from oxwoods Resort Casino in Mashantucket, Conn. In the main event, David Branch (15-3) and Ronny Markes (15-3) will collide in a contest that represents the second matchup in the WSOF multi-event tournament that will crown its winner the inaugural WSOF world light heavyweight champion.
Lucas MontoyaMelvin GuillardOzzy DugulubgovWSOFWSOF 20
A Gambler's Guide to UFC Fight Night 64
Dustin Poirier vs. Yancy Medeiros Added to UFC Fight Night 68
Bellator 171: Guillard vs. Njokuani Live Weigh-ins
WSOF 32 Weigh-ins & Prelim Live Stream


text:
Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study
M. N. Olesen1, 13, 7,
K. Soelberg2, 8, 14,
B. Debrabant3,
A. C. Nilsson4,
S. T. Lillevang4,
J. Grauslund5, 6,
I. Brandslund7, 8,
J. S. Madsen7, 8,
F. Paul9, 10,
T. J. Smith11,
S. Jarius12 and
N. Asgari1, 13, 14Email authorView ORCID ID profile
Journal of Neuroinflammation201916:59
Accepted: 22 February 2019
Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS.
Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19–41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2–38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms.
CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77–1] and 0.86 [0.74–0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms.
CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.
Optic neuritis (ON) is an inflammatory optic neuropathy, which may occur as an early manifestation of multiple sclerosis (MS) [1]. ON is believed to be immune-mediated and results from the destruction of the myelin sheath and nerve fibers, resulting in impaired vision or blindness [2]. Antibodies with specificity for myelin oligodendrocyte glycoprotein (MOG) are implicated in ON, as well as in ON associated with neuromyelitis optica spectrum disorder (NMOSD) in cases where immunoglobulin (Ig) G antibodies against the water channel aquaporin-4 are undetectable [3–6]. The predilection for the optic nerve in MS may be explained by regional differences in blood-brain barrier (BBB) permeability. Significant risk factors for the transition of ON to MS routinely used in clinical practice are the presence of brain lesions on MRI and cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs). These represent intrathecally produced IgG of unknown specificity [7, 8]. Apart from OCBs, alterations of the levels of interleukin (IL)-10 produced by naïve and/or regulatory B cells and the chemokine, CXCL13, which is a key regulator of B cell recruitment, have been reported in MS patients [9–11]. These findings suggest that B cells play a role in the pathogenesis of MS, although their importance in MS development has not yet been determined.
Neurofilament light chain (NF-L) is a major structural component of neurons. Increased levels of NF-L in CSF have been suggested to be a marker of axonal damage in MS [12]. The implications of early changes of NF-L levels in acute ON and its potential predictive value for the subsequent conversion to MS are unexplored. Furthermore, the relation between intrathecal inflammation and neurodegeneration in acute ON is incompletely understood. We propose that markers of inflammation and of neurodegeneration (a) may differ between patients with MS-related ON and patients with ON unrelated to MS and (b) may predict development of MS in patients with acute ON.
Study design and patients
Patients with acute ON originated from a population-based prospective study with clinical follow-up performed 2014–2016 in the Region of Southern Denmark [13, 14]. The diagnosis of ON was obtained by independent neurological and ophthalmological examination as previously described based on a uniform algorithm [13, 14]. The neurologist and ophthalmologist were masked to results from autoantibody and cytokine/chemokine analysis, and the laboratory analyses were performed blinded to the clinical status of patients [14]. Patients were excluded if they had been diagnosed previously with MS or NMOSD. AQP4-IgG was measured with a recombinant immunofluorescence assay using HEK293 cells transfected with recombinant human full-length AQP4 gene and re-evaluated by means of an in-house cell-based assay [14]. MOG-IgG was determined by two cell-based assays employing fixed and live HEK293 cells, respectively, transfected with full-length human DNA [3, 6]. MS was diagnosed according to the 2010 MS criteria [8]. Forty patients presenting with acute ON prior to treatment and a median follow-up time after onset of 29 months (range 19–41) were included in the study. We tested and found no indication of immunological differences between males and females (not shown).
CSF samples were collected from 12 age-matched subjects assessed because of sudden transient headache without trauma or infection and where all subsequent investigations were normal. These individuals were considered healthy controls (HC) [15].
Sample storage and handling
Venous blood and CSF from 40 patients were collected within 38 days of ON onset (median, 14 days; range 2–38). For IgG and albumin ratios, EDTA plasma was prepared and analyzed directly. CSF was sampled and stored according to international research standards [1]. Briefly, for quantification of IL-1β, IL-6, IL-10, IL-17A, tumor necrosis factor (TNF)-α, and TNF-related apoptosis-inducing ligand (TRAIL), CSF was collected, centrifuged immediately, cooled to 4 °C for 2 h, and stored at − 20 °C for up to 1 month and then at − 80 °C until analysis. Serum was isolated following clot formation at ambient temperature and frozen as described for CSF.
Interferon (IFN)-α, IFN-β, and CXCL13 concentrations were determined on an aliquot of the CSF and serum that had been frozen at − 80 °C immediately following centrifugation. Samples were thawed once for aliquoting prior to analysis, except for CXCL13 (one additional thawing cycle).
Immunochemical and cytological parameters
Routine diagnostic analyses were carried out at the Department of Biochemistry and Immunology, Vejle Hospital, being accredited by Danish Accreditation Fund (DANAK) according to the ISO 15189 standard that specifies requirements for quality and competence in medical laboratories. IgG and albumin were measured on a Cobas 8000C instrument (Roche, Basel, Switzerland), oligoclonal bands (OCBs) on a Hydrasys instrument (Sebia, Surrey, UK), and leukocytes on a Sysmex XN-9000 instrument (Sysmex Europe, Norderstadt, Germany).
Immunoassay measurements
IL-1β, IL-6, IL-10, IL-17A, TNF-α, TRAIL, and NF-L were measured using Simoa HD-1 digital enzyme-linked immunosorbent assay (ELISA) (Quanterix, Lexington, MA, USA).
CXCL13 and INF-α/β concentrations were determined using ELISAs (Euroimmun, Lübeck, Germany and PBL Assay Science, NJ, USA, respectively) in the Department of Clinical Immunology, Odense University Hospital, also accredited according to the ISO 15189 standard. Lower cutoff sensitivity of the CXCL13 assay was set to 10 pg/ml, according to the manufacturer's instructions [16].
Association analysis
Prism 7 (GraphPad Software, La Jolla, CA) was used for generating comparisons and correlation analyses with a significance level of 5%. Fisher's exact test was used to test for differences regarding frequency distributions (sex and OCBs). Continuous variable data was analyzed using the nonparametric Kruskal-Wallis test. Results described in the text are given as "median [25th–75th percentiles]" unless otherwise clearly stated. CSF-to-serum ratio of cytokines was normalized to albumin ratio and similarly compared by the Kruskal-Wallis test. To account for multiple testing, these analyses were followed by false discovery rate adjustment (alpha = 0.05) of p values, and corresponding q values were reported unless clearly stated [17]. Spearman correlations were estimated and tested for being identical to 0 without further p value adjustment. This approach for reducing false positives was chosen due to the explorative nature of the study.
Predictive modeling
R version 3.3 (R Core Team at R Foundation for Statistical Computing, Vienna, Austria) was used for extended analyses of the conversion of isolated optic neuritis (ION) to multiple sclerosis in relation to optic neuritis (MS-ON). Here, logistic regression modeling was performed, including receiver-operating characteristic (ROC) area under curve (AUC) calculations. For uni- and multivariate model assessment, we reported on likelihood ratios, overall p values, and McFadden's adjusted R2, and for multivariate models also the Hosmer-Lemeshow's goodness-of-fit test is reported. Since prediction performance measures such as AUCs are overly optimistic when calculated for the same sample population as used for model fitting, we also applied a bootstrap optimism correction based on 500 bootstrap samples. This is an internal validation method for assessing the optimism bias of prediction models when no validation cohort is available, i.e., when a model is fitted and tested on the same dataset. The approach calculates AUCapparent − Optimism = AUCcorrected, and is described in detail by Steyerberg [18]. When applying this approach, we did however not account for potential preselection of variables before inclusion in our multivariable prediction models, in which case the actual optimism will likely be larger than estimated. Nomograms as graphical output representations of the logistic regression models were made using R, and calibration plots showing observed versus expected proportions were used to assess calibration of the prediction models.
Cohort characteristics
All 40 patients with acute ON were Caucasians with a female to male ratio of 2:1 and a median age of 36 years (range 16–66 years). A total of 12 patients (30%) were diagnosed with MS (MS-ON) at the acute stage of ON (< 2 months), and four additional patients developed MS within the first year of follow-up (giving a total of 16 patients, 40%, with MS-ON) [14]. The remaining 24 patients had a final diagnosis of isolated ON (ION). None of the patients had detectable AQP4-IgG according to two cell-based assays performed at two independent laboratories. MOG-IgG was detected in one patient at a titer of 1:1280 [19]. There were no significant differences between the ION and MS-ON patients as to age, gender, or follow-up time. Median follow-up time was 30 months (range 21–41) for ION, and 28 months (range 19–38) for MS-ON (Table 1).
Distribution of age, sex, and follow-up time in the patient groups
f/m
Years of age, median (range)
Follow-up time, median (range)
48.0 (16–63)
MS-ON
p value versus
n.a. not applicable
Routine CSF biomarkers are increased in MS-ON patients and distinguish MS-ON from ION
CSF biomarkers were assessed at the time of the acute ON event. ON patients were stratified based on prospective diagnosis into ION and MS-ON and compared to HC. As a whole, MS-ON patients showed increased levels of CSF leukocytes (median [25th–75th percentiles] 18 [4–44.5] versus 2.5 [1–4.8] cells/μl, respectively, q = 0.0007), they exhibited OCB positivity more frequently than ION patients (13/16 positive versus 6/24, respectively, q = 0.0021), and had a higher IgG index (1.1 [0.56–1.82] versus 0.52 [0.49–0.59], respectively, q = 0.0052; Fig. 1a–c). Two MS-ON patients but none with ION had albumin ratios above the threshold of [age]/25 + 8 proposed by Hegen and colleagues [15]. The findings suggest higher immune reactivity in the CSF of MS-ON patients.
Routine cerebrospinal fluid findings differentiate patients who later converted to multiple sclerosis at onset of optic neuritis. a Cerebrospinal fluid (CSF) leukocyte count, b distribution of oligoclonal band (OCB) positivity and negativity and c IgG index in multiple sclerosis (MS)-related optic neuritis (ON) (MS-ON), isolated ON (ION), and healthy controls (HC). Open circles indicate four patients that were diagnosed with MS 3 to 12 months after ON onset
High intrathecal IL-10, TNF-α, and CXCL13 are associated with a diagnosis of MS
When comparing cytokine/chemokine protein levels, we found higher CSF levels of IL-10, TNF-α, and CXCL13 in MS-ON than in ION (IL-10, respectively, 0.27 [0.11–1.26] vs 0.083 [0.043–0.12] pg/ml, q = 0.004, TNF-α 0.37 [0.21–0.43] vs 0.16 [0.13–0.24] pg/ml, q = 0.021, and CXCL13 28.9 [10–75.4] vs 10 [10] pg/ml, q = 0.0006; Fig. 2a). No differences could be detected in serum (Fig. 2b). This indeed suggests that, although clinically indistinguishable, patients destined to develop MS have a distinct CNS immune phenotype relative to ION patients.
Intrathecal levels of TNF-α, IL-10, and CXCL13 distinguish patients who develop multiple sclerosis. Cytokines and chemokines as denoted in a cerebrospinal fluid and b serum. Open circles indicate patients that were diagnosed with multiple sclerosis 3 to 12 months after optic neuritis onset
IL-1β, IL-6, IL-17A, and TRAIL could be detected in all CSF samples except IL-1β and IL-17A that were undetectable in two samples, and levels appeared similar between the two patient groups (Fig. 2a, b). IFN-α was detected in serum and CSF from one ION patient while IFN-β could be detected only in CSF from one other ION patient (not shown).
We calculated the cytokine-specific CSF/serum ratios normalized to albumin ratio, e.g., ([IL-10]CSF/[IL-10]serum)/albumin ratio, to indicate whether cytokines were synthesized intrathecally. Both IL-10 and TNF-α showed significantly higher indices in MS-ON compared to ION before false discovery rate adjustment (p = 0.036 and 0.048, respectively). For CXCL13, only one patient with MS-ON had detectable levels in both serum and CSF. The seven other MS-ON patients and two ION patients with detectable CXCL13 in CSF had undetectable levels in serum. These findings argue in favor of intrathecal cytokine synthesis.
Testing for correlations between intrathecal markers for inflammation in MS-ON disclosed increased CSF levels of IL-10, TNF-α, and CXCL13 that failed to correlate with the albumin ratio, suggesting that cytokine levels did not reflect blood/CSF barrier disruption (Fig. 3a). In contrast, a strong correlation between each of these cytokines and CSF leukocyte counts (Spearman r ≥ 0.69 for all, p = 0.0042, p < 0.0001, and p = 0.002, respectively; Fig. 3b) and IgG index could be detected (Spearman r ≥ 0.55 for all, p = 0.001, p = 0.037, and p = 0.003, respectively; Fig. 3c). IL-17A exhibited a similar pattern of correlation, although not differentially expressed in MS-ON (Fig. 2a).
Intrathecal immune activity in patients who develop multiple sclerosis. Cerebrospinal fluid levels of TNF-α, IL-10, IL-17A, and CXCL13 in patients who develop multiple sclerosis (MS-ON) and their correlation with a albumin ratio, b leukocyte count, and c IgG index. Open circles indicate patients that were diagnosed with MS 3 to 12 months after ON onset
Similar correlations were also found in ION patients but were less strong (Spearman r between 0.48–0.53 and p > 0.024 for all; Additional file 1: Figure S1), suggesting that CNS immune processes in MS-ON are distinct from those in ION.
CSF NF-L levels are increased in acute ON and progress in MS-ON
Quantification of NF-L in CSF revealed higher levels in all 40 acute ON patients compared to 11 HC (451 [224–947] pg/ml vs 229 [161–346] pg/ml, respectively, q = 0.0324). When stratified based on subsequent (prospective) diagnosis, these elevations in NF-L were restricted to MS-ON patients (q = 0.0077, Fig. 4a). Moreover, when considering all ON patients (disregarding the prospective MS-ON or ION diagnosis), patients with CSF NF-L higher than the median (> 450 pg/ml) had more abundant CSF leukocytes than ON patients with NF-L < 450 pg/ml (10.5 cells/μl [3–42.2; n = 18] versus 2.0 [1–7.5; n = 17], p = 0.011, not shown). There was no correlation with other inflammatory markers. In MS-ON, but not in ION patients, a gradual increase in CSF NF-L levels was observed in the period between 7 and 14 days after disease onset (Spearman r = 0.73, p = 0.0065, Fig. 4b).
Increased cerebrospinal fluid neurofilament light chain (NF-L) levels in patients who progress to multiple sclerosis. a Levels of intrathecal NF-L and b significant correlation of NF-L levels in multiple sclerosis (MS)-related optic neuritis (ON) patients with cerebrospinal fluid (CSF) sampling delay from symptom onset. Open circles indicate patients that were diagnosed with multiple sclerosis 3 to 12 months after optic neuritis onset. Excluded from analysis are two samples due to few data points in this time interval
Modeling of conversion of ON to MS
To assess whether it is possible to predict development of MS-ON in the cohort of patients with ON, we employed logistic regression utilizing one or more possible predictor variables. Regression models based on individual parameters were tested first, and optimal cutoffs for each univariate prediction model were calculated according to the Youden method (Additional file 2: Table S1). ROC curves for single predictors are shown in Additional file 3: Figure S2.
Next, the predictive performance of two different combined models was tested. The model entitled "routine biomarkers" comprises parameters distinguishing ION from MS-ON in Fig. 1. The second, "candidate biomarkers", contains parameters based on findings in Figs. 2 and 4. TNF-α was not included because screening sets of variables indicated that it explained the same variation as IL-10 and thus did not add additional information. However, both IgG index and OCB were included in the routine biomarker model even though the ROC curve for leukocytes and OCB showed AUC equivalent to that of leukocytes and IgG index (Additional file 4: Figure S4 and Additional file 5: Figure S5) because of the face validity (i.e., biological relation to MS-ON), thus potentially providing predictive information. Routine biomarkers comprised OCB, leukocyte count, and IgG index, while candidate biomarkers included CSF IL-10, CXCL13, and NF-L. These biomarker cohorts yielded AUC of 0.86 [0.74–0.98] and 0.89 [95% C.I.: 0.77–1], respectively (Table 2 and Fig. 5; cf. Additional file 6: Figure S5 for calibration plots). Combining these two models with six predictors did not significantly improve AUC (0.90; 95% CI: 0.78–1), and thus this aggregate was felt to be too cumbersome for the clinical setting. For all three models, Hosmer-Lemeshow's goodness-of-fit test supported that the prediction models fitted the data.
Multivariate logistic regression modeling for the candidate and routine biomarkers and a combined biomarker model, which combines candidate and routine biomarkers into one model
Number of observations
Likelihood ratio χ2
Adjusted McFadden R2
Hosmer-Lemeshow's p value
Area under ROC curve
AUC 95% CI
Experimental biomarkers
NF-L
CXCL13
Routine biomarkers
IgG index
Full model
Receiver-operating characteristic (ROC) for models predicting the conversion of optic neuritis to multiple sclerosis. ROC curves showing the discriminative performance of our prediction models. ROC curves for logistic regression models comprising levels of IgG index, cerebrospinal fluid (CSF) leukocytes, and oligoclonal band status, denoted as "routine biomarkers" (green) and CSF IL-10, CXCL13, and NF-L, denoted as "candidate biomarkers" (apricot). Given is area under curve (AUC) and 95% confidence intervals
Because the two predictor models were generated and tested on the same dataset, they are inherently optimistic. Therefore, the optimism of each model was estimated to obtain an optimism-corrected estimate of the AUC. This reduced their AUC to 0.83 (routine) and 0.87 (candidate).
MS risk assessment via nomograms based on CSF findings
Two nomograms were developed as predictive tools based on levels of CSF biomarkers (routine and candidate models) useful for the estimation of a given patient's risk of developing MS after presenting with acute ON (Fig. 6a, b). For each, three single predictor variables were combined into a multivariate logistic model. This model was finally visualized in a nomogram. Instructions on how to use the nomograms are described in the Appendix.
Nomograms for a routine and b candidate biomarker prediction models for estimation of the patient-specific risk of multiple sclerosis. Each of the nomograms can estimate a patient's risk of multiple sclerosis (MS) diagnosis. Instructions for use (here exemplified for the "routine model"): Locate the patient's IgG index value on the "IgG index" scale and find the corresponding point score straight above on the "Points" scale. Do this for the other axes and sum the total point score. Locate the total score on the "Total Points" axis and draw a line straight down on the "Risk for MS" axis: This is the patient's estimated risk of MS diagnosis within the first year from onset of optic neuritis (ON). Risk of MS should be considered with an uncertainty of up to ± 10% for the "routine biomarker" model, and ± 15% for the "candidate biomarker" model according to calibration plots (Additional file 3: Figure S3). Example of patient from this study: a A patient had no OCBs, 3 leukocytes/μl, and an IgG index of 0.48, giving a score on the "routine biomarker" nomogram of 0, 1, and 9 points, respectively (10 in total). This corresponds to approximately 13% risk of developing MS. b This same patient had CSF measurements of 0.16 pg/ml IL-10, ≤ 10 pg/ml CXCL13, and 229 pg/ml NF-L. This scored 6, 0, and 2 points, respectively, and 18 in total on the "candidate biomarker" nomogram. Such a score corresponds to circa 19% risk of MS. This patient indeed had ION by the end of the follow-up period
Intrathecal biomarkers for inflammation and neurodegeneration may become useful for predicting the diagnosis of MS at onset of acute ON, an early inflammatory event. Moreover, they may provide a better understanding of MS pathogenesis. In this prospective population-based cohort study of acute ON with a longitudinal clinical follow-up, we aimed to determine the predictive value of such potential biomarkers. The main finding was that at acute onset of ON and prior to treatment, patients who later receive a diagnosis of MS (i.e., MS-ON) had a significantly different intrathecal inflammatory profile compared to patients who remained as ION. MS-ON patients showed higher levels of CSF leukocytes and higher IgG index, both correlated with CSF IL-10, TNF-α, CXCL13, and IL-17A levels, and these patients more frequently had OCBs.
Moreover, patients developing MS-ON had progressively increasing levels of NF-L, a marker of neuronal damage. These data suggest that dynamic immune processes are evolving in these patients at ON onset. Potentially, these early indicators can be used to predict development of MS. Furthermore, the relatively high predictive power of routine biomarkers (OCB, CSF leukocytes, and IgG index, optimism-corrected ROC area of 0.82) and candidate biomarkers (CSF IL-10, CXCL13, and NF-L, optimism-corrected ROC area of 0.87) suggests these combinations may differentiate MS-ON from ION. To provide a diagnostic tool, nomograms for estimation of a patient's specific risk of MS diagnosis based on the CSF routine or candidate biomarkers were developed. Such calculations suggest a potential usefulness of composite indices to advance diagnosis, which could be implemented in clinical practice. The potential for identifying those patients who later develop MS would facilitate timely treatment and thus prevent or minimize disability and other consequences of delayed diagnosis.
CSF examination is invaluable in the diagnostic work-up of patients with suspected MS. The recent 2017 MS criteria include the presence of CSF-restricted OCBs in patients presenting with a clinically isolated syndrome (CIS) together with MRI lesions disseminated in space [7, 20]. CSF-restricted OCBs substitute for the requirement of additional symptoms (a second clinical event) or lesions disseminated in time to confirm the diagnosis of MS, based on evidence that these CSF-restricted OCBs are an independent risk factor for the development of MS [20, 21]. CSF examination may identify new biomarkers that predict MS at an early clinical presentation. In the current study, we evaluated CSF cytokine/chemokine levels and routine biomarkers in the acute phase of ON before treatment with corticosteroids. Our findings are congruent with the recent attention directed toward importance of CSF examination, including assessment of the leukocyte numbers and IgG index. We did not find additional predictive value of an abnormal CSF leukocyte count and IgG index. However, in the absence of OCBs, which in general occurs in a limited proportion of cases, IgG index may be of value as a parameter for intrathecal antibody synthesis [7]. Besides their clinical implications, the findings here are of biological relevance since they suggest areas for further interrogation into disease mechanisms. Elevated CSF levels of CXCL13 in MS-ON compared to ION and controls, together with OCB positivity and IgG index, strongly suggest B cell activity in the CNS [22]. Increased IL-10, an important anti-inflammatory and immunosuppressive cytokine, plays an important role in many inflammatory diseases [23, 24]. However, it is unclear what specific role IL-10 plays in MS. Some aspects of IL-10 actions are relevant to B cell behavior in MS, but its involvement may be through other cell types as well [25, 26]. TNF-α is also upregulated in MS-ON. It possesses pro-inflammatory properties and is dysregulated in many systemic and neurologic autoimmune diseases. In MS, TNF-α is upregulated in active brain lesions and in CSF [27]. Although TNF-α is generally considered pro-inflammatory and thus intuitively detrimental in MS, its impact depends on the particular receptor with which it interacts. Two TNF-α receptors (TNFR1 and TNFR2) are expressed by neurons directly and seem to mediate largely opposing effects with respect to direct de- and re-myelination of neurons [27]. Thus, it may represent a double-edged sword in the context of MS due to multiple mechanisms of action.
NF-L levels in CSF are used as an indicator of neuronal damage in the CNS [28]. We found NF-L levels in CSF to be increased in acute ON patients. This finding suggests that damage of neuronal tissues occurs closely to clinical onset [29]. Moreover, NF-L levels significantly increased over time in MS-ON patients between days 7 and 14 after ON onset, suggesting that neuronal damage develops progressively over days or weeks in patients who later develop MS. Collectively, CSF biomarkers reflect immune dysfunction in MS and in this manner predict the development of MS.
Risk evaluation is crucial for the selection of therapy at an early stage of MS. Few studies have evaluated CSF biomarker profiles at the acute onset of ON to attempt prediction of risk for subsequent development of MS. In the current study, we developed two nomograms as predictive tools based on levels of CSF biomarkers (routine or candidate models) which may be useful in estimating this risk (Fig. 6a, b). For each, three single predictor variables were compiled into a multivariate logistic model. This study was based on a small cohort; nonetheless, this cohort was pre-defined from an epidemiological study with a natural history and longitudinal follow-up of patients. The proposed nomograms may benefit from validation in large, multicenter trials.
A notable strength of this study design is the diagnostic algorithm used to prospectively assess a population-based cohort of ON with a high representativity, which has been characterized extensively [14]. Laboratory investigations were performed using largely automated techniques, which strengthen data reliability. To our knowledge, this is the first study quantifying an array of CSF cytokines on the ultra-sensitive Simoa™ platform, which added high resolution in the low-expressing individuals (limit of detection in the range of ~ 0.01–0.002 pg/ml).
In conclusion, we determined the predictive value of CSF biomarkers for MS development in this prospective population-based study of acute ON. We found a potential for routine as well as candidate model biomarkers to differentiate individuals, who would subsequently develop MS-ON from those who continued to manifest ION during follow-up. These findings suggest that MS-ON patients had strong and highly orchestrated immune processes occurring in the CNS associated with early neuronal damage. We took advantage of both routine and candidate biomarkers to generate two nomograms as tools for predicting a patient's specific MS risk after onset of acute ON. Additional studies with larger, well-designed cohorts including differential diagnoses and other ethnicities will be needed for validation preferably at multiple centers.
AUC:
BBB:
CSF:
HC:
Healthy controls
IFN:
ION:
Isolated optic neuritis
MOG:
Myelin oligodendrocyte glycoprotein
MS:
MS-ON:
Multiple sclerosis in relation to optic neuritis
NF-L:
Neurofilament light chain
NMOSD:
Neuromyelitis optica spectrum disorder
OCBs:
Oligoclonal bands
Receiver-operating characteristic
The authors thank Professor Brian G. Weinshenker and Professor Trevor Owens for suggestions and advice for the study design; Sara Egsgaard, Camilla Davidsen, and Dorte Aalund Olsen, Department of Biochemistry & Immunology, Vejle Hospital, for their technical expertise and assistance; the Autoimmunity Lab at Department of Clinical Immunology, Odense University Hospital, in particular Lis Rasmussen, for technical assistance.
The study was funded by The Region of Southern Denmark, The University of Southern Denmark, The Danish Multiple Sclerosis Society, Lillebaelt Hospital Research Foundation and Næstved, Slagelse and Ringsted Hospital Foundation.
MNO contributed to the study design, acquisition of the data, statistical analysis, interpretation of the results, and drafting and revising the manuscript. KS contributed to the acquisition of data, interpretation of the results, and revising the manuscript. ACN contributed to the acquisition of the data, interpretation of the results, and revising the manuscript. BD contributed to the statistical analysis, and revising the manuscript. SJ contributed to the acquisition of the data, interpretation of the results, and revising the manuscript. JG contributed to the interpretation of the results, and revising the manuscript. TJS contributed to the study design, interpretation of the results, and revising the manuscript. FP contributed to the study design, interpretation of the results, and revising the manuscript. IB contributed to the interpretation of the results, and revising the manuscript. JSM contributed to the interpretation of the results, and revising the manuscript. STL contributed to the study design, interpretation of the results, and revising the manuscript. NA contributed to the study concept and design, acquisition of the data, interpretation of the results, revising the manuscript, and was the study supervisor. All authors read and approved the final manuscript.
The Research Ethical Committees in the Region of Southern Denmark approved the study protocol (ref. no. S-20130137) as did the Danish Data Protection Agency (ref. no. 14/26345). All patients gave written consent to participate after being presented verbal and written descriptions of the study. Data were processed in accordance with the European Union General Data Protection Regulations.
F. Paul serves on the scientific advisory board for Novartis; received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck, Serono, Alexion, Chugai, MedImmune, and Shire; he is an academic editor for PLoS ONE; is an associate editor for Neurology® Neuroimmunology & Neuroinflammation; was consulted for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion, and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis of the USA. T.J. Smith patents on the therapeutic targeting of the insulin-like growth factor I receptor and the clinical assay development of anti-IGF-IR antibodies in autoimmune diseases. I am funded by National Institutes of Health grants EY008976 and 5UM1AI110557, Center for Vision core grant EY007003 from the National Eye Institute, unrestricted grants from Research to Prevent Blindness and the Bell Charitable Foundation. All other authors declare that they have no competing interests.
Instructions on how to use nomograms are provided in the Fig. 6 legend.
As an example, using the "candidate biomarker" nomogram, one patient had 0.40 pg/ml IL-10, so draw a line straight up onto Points axis (top axis) to find the patient's point. As located on the IL-10 axis, the patient will receive 20 points. Repeat this procedure for the CXCL13 and NF-L: Based on the CXCL13 level of 79.2 pg/ml and NF-L of 698.4 pg/ml, the patient will receive 14 and 8 points, respectively. The reader may then sum the points achieved for each biomarker, which in this case is 20 + 14 + 8 = 42 points, and locate this sum on the Total Points axis (second from the bottom). Draw a line straight down from the Total Points axis to "Risk for MS" scale (bottom) to find the patient's risk for MS. Here, 42 points correspond to 0.85, so this patient's estimated risk of MS is 85% (Fig. 6).
The same patient was OCB positive and had 51 leukocytes/μl and IgG index of 1.3. On the routine biomarker nomogram, this would give 22, 22, and 24 points, respectively, and 68 in total on the Total Points axis. This corresponds to circa 83% risk of MS. This patient indeed was diagnosed with MS closely after acute ON.
Additional file 1: Figure S1. Correlation between intrathecal markers in isolated optic neuritis. This figure depicts the same, albeit much weaker or even absent correlations as shown for patients who later converted to multiple sclerosis (MS-ON) in Fig. 4. (PDF 123 kb)
Additional file 2: Table S1. Logistic regression analyses for single predictors. Highlighted in bold are p values for which the odds ratio (OR) confidence interval do not overlap the value of 1, as an indicator of association between the highlighted markers and MS-ON. The optimal cutoff value and corresponding sensitivity/specificity is also given. (DOCX 17 kb)
Additional file 3: Figure S2. Receiver-operating characteristic (ROC) curves for the six individual predictors that were unified in two models in Fig. 5. (PDF 142 kb)
Additional file 4: Figure S4. Receiver-operating characteristic (ROC) for models predicting the conversion of optic neuritis to multiple sclerosis (here for leukocytes and OCBs). Area under ROC curve = 0.8620. (PDF 38 kb)
Additional file 5: Figure S5. Receiver-operating characteristic (ROC) for models predicting the conversion of optic neuritis to multiple sclerosis (here for leukocytes and IgG index). Area under ROC curve = 0.8423. (PDF 38 kb)
Additional file 6: Figure S3.(A + B) Calibration plots for the prediction models presented as nomograms. The calibration plots assess the agreement between observations and predictions. For a well-calibrated prediction model, if a 10% risk for MS is predicted, the observed frequency of MS should be close to 10% amongst all patients with the same prediction. The apparent calibration curve relies on our original data and a bias-corrected (=optimism-corrected) curve was based on 500 bootstrap samples. (PDF 81 kb)
Department of Neurology, Slagelse Hospital, Slagelse, Denmark
Department of Internal Medicine, Slagelse Hospital, Slagelse, Denmark
Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark
Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
Department of Ophthalmology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Immunology and Biochemistry, Lillebælt Hospital, Vejle, Denmark
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
Clinical and Experimental Multiple Sclerosis Research Center and NeuroCure Clinical Research Center, Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, Berlin, Germany
Departments of Ophthalmology and Visual Sciences and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
Institutes of Regional Health Research and Molecular Medicine, University of Southern Denmark, Winsloewsvej 25.2, 5000 Odense C, Denmark
Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
Petzold A, Wattjes MP, Costello F, Flores-Rivera J, Fraser CL, Fujihara K, et al. The investigation of acute optic neuritis: a review and proposed protocol. Nat Rev Neurol. 2014;10(8):447–58.View ArticleGoogle Scholar
Toosy AT, Mason DF, Miller DH. Optic neuritis. The Lancet Neurology. 2014;13(1):83–99.View ArticleGoogle Scholar
Pache F, Zimmermann H, Mikolajczak J, Schumacher S, Lacheta A, Oertel FC, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. J Neuroinflammation. 2016;13(1):282.View ArticleGoogle Scholar
Sato DK, Callegaro D, Lana-Peixoto MA, Waters PJ, de Haidar Jorge FM, Takahashi T, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82(6):474–81.View ArticleGoogle Scholar
Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, George J, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276–83.View ArticleGoogle Scholar
Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflammation. 2016;13(1):279.View ArticleGoogle Scholar
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology. 2018;17(2):162–73.View ArticleGoogle Scholar
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.View ArticleGoogle Scholar
Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol. 2007;178(10):6092–9.View ArticleGoogle Scholar
Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P, Ransohoff RM, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain J Neurol. 2006;129(Pt 1):200–11.View ArticleGoogle Scholar
Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, Fallon PG. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun. 2015;6:5997.View ArticleGoogle Scholar
Matute-Blanch C, Villar LM, Alvarez-Cermeno JC, Rejdak K, Evdoshenko E, Makshakov G, et al. Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Brain J Neurol. 2018;141(4):1085–93.View ArticleGoogle Scholar
Soelberg K, Skejoe HPB, Grauslund J, Smith TJ, Lillevang ST, Jarius S, et al. Magnetic resonance imaging findings at the first episode of acute optic neuritis. Mult Scler Relat Disord. 2017;20:30–6.View ArticleGoogle Scholar
Soelberg K, Jarius S, Skejoe H, Engberg H, Mehlsen JJ, Nilsson AC, et al. A population-based prospective study of optic neuritis. Mult Scler. 2017;23(14):1893–901.View ArticleGoogle Scholar
Hegen H, Auer M, Zeileis A, Deisenhammer F. Upper reference limits for cerebrospinal fluid total protein and albumin quotient based on a large cohort of control patients: implications for increased clinical specificity. Clin Chem Lab Med. 2016;54(2):285–92.View ArticleGoogle Scholar
Asgari N, Voss A, Steenstrup T, Kyvik KO, Stenager E, Lillevang ST. Interferon alpha association with neuromyelitis optica. Clin Dev Immunol. 2013;2013:713519.View ArticleGoogle Scholar
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.Google Scholar
Steyerberg EW. Clinical prediction models: a practical approach to development, validation, and updating: Springer; 2009.Google Scholar
Jarius S, Paul F, Aktas O, Asgari N, Dale RC, de Seze J, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation. 2018;15(1):134.View ArticleGoogle Scholar
Arrambide G, Tintore M, Espejo C, Auger C, Castillo M, Río J, et al. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain J Neurol. 2018;141(4):1075–84.View ArticleGoogle Scholar
Tintore M, Rovira A, Rio J, Otero-Romero S, Arrambide G, Tur C, et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain J Neurol. 2015;138(Pt 7):1863–74.View ArticleGoogle Scholar
Kowarik MC, Cepok S, Sellner J, Grummel V, Weber MS, Korn T, et al. CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation. 2012;9:93.View ArticleGoogle Scholar
Nakashima I, Fujihara K, Misu T, Okita N, Takase S, Itoyama Y. Significant correlation between IL-10 levels and IgG indices in the cerebrospinal fluid of patients with multiple sclerosis. J Neuroimmunol. 2000;111(1):64–7.View ArticleGoogle Scholar
Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut. 2013;62(12):1795–805.View ArticleGoogle Scholar
Ries S, Hilgenberg E, Lampropoulou V, Shen P, Dang VD, Wilantri S, et al. B-type suppression: a role played by "regulatory B cells" or "regulatory plasma cells". Eur J Immunol. 2014;44(5):1251–7.View ArticleGoogle Scholar
Li R, Rezk A, Healy LM, Muirhead G, Prat A, Gommerman JL, et al. Cytokine-defined B cell responses as therapeutic targets in multiple sclerosis. Front Immunol. 2016;6:626.View ArticleGoogle Scholar
McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008;5:45.View ArticleGoogle Scholar
Zetterberg H. Fluid biomarkers for microglial activation and axonal injury in multiple sclerosis. Acta Neurol Scand. 2017;136 Suppl 201:15–7.View ArticleGoogle Scholar
Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflammation. 2015;2(3):e102.View ArticleGoogle Scholar


Coal Prep is the ONLY annual trade show and conference in the United States that is solely dedicated to coal preparation and processing. This year's event will be held in Louisville, KY at the Kentucky Exposition Center, April 25-27. Altra Industrial Motion will feature high and low speed backstops from Formsprag & Marland Clutch, couplings and sheaves by TB Wood's, and caliper brakes from Twiflex Limited & Svendborg Brakes. Visit Altra at Booth #1019!


The Founder and and President of National Access Design, Cheryl White grew up in a family owned and operated traffic door manufacturing environment. Now in business for over four years, National Access Design has grown from a garage based business to a 10,000 square foot manufacturing plant. The employees of National Access Design bring more than 100 years of cumulative industry experience.
The manufacturing facility is located in Cincinnati, Ohio with nationwide and international product distribution. Please contact us for more information.
Rigid, Flexible, Frames, PVC Strip Doors, Industrial Curtains, Dock Seals, Blast Cell Doors, Cold Storage, FRP Doors, Hollow Metal Door, Air Curtains.


Why did you decide to pursue a career in interior design?
I worked in media planning and advertising in London for four years, and despite enjoying it, I always knew I wanted to do something that would creatively challenge me. I decided to take the plunge and leave my job to chase the interior design dream. I applied for KLC's 12-week Full Time Certificate course because the school offered an amazing fast track course allowing me to hit the ground running in the world of interior design as soon as possible. The way the course was structured enabled me to learn a lot about the industry in a short period of time.
What did the course at KLC teach you?
I learnt the confirdence to express my creative ideas, as well as a lot of technical skills and processes, which have been invaluable in the real world of interior design. We had brilliant and talented tutors, and I loved learning about the history of design through the KLC guided talks around the V&A.
And what about after the course?
The KLC careers service put me forward for an internship at Studio Reed - it was a great learning experience where I was able to pick up lots ideas around materials and colour. My first paid job was at Carden Cunietti, where I worked on a range of residential projects in London as well as Los Angeles, the South of France and Ibiza. I learnt a lot about furniture and fixtures and travelled with the studio to Maison & Objet in Paris and the Salone Del Mobile in Milan. I spent just over two years at Carden Cunietti, before moving to Suzy Hoodless' studio last June. We are very busy with a range of wonderfully unique projects; I am workig on two residential homes in London, as well as the development of the Television Centre in White City.
Definitely the design and development of the residential amenities at the Television Centre in White City. We have worked on all the communal areas from screening rooms to huge outdoor terraces.
The fact I am always learning. It is also incredibly rewarding to see all your hard work and ideas come to life.
To win a place on KLCs Professional Certificate in Interior Design Course, worth £8,995, head to our competition page.


text:
RDI bought a key strategic asset in the city centre on Albion Street in 2016. We worked closely with them and Derby City Council to identify potential regeneration opportunities for the street and how to integrate their asset into those plans. US-owned TK Maxx was keen to bring a new store to the city centre (a second in the city) subject to several complicated conditions. Working in partnership with Derby City Council, we were able to help RDI secure the lease to TK Maxx of 15,000 sq ft over three floors which opened in February 2018, creating 35 new jobs.
""Marketing Derby played a key role in what was a complex letting to TK Maxx. They were proactive and helpful in overcoming obstacles in the process and we look forward to working with them again in the future.""
— Sarah Jones, Senior Asset Manager, RDI REIT


It's been quite the twelve months for screenwriter Ryan Sprague. His book Somewhere In The Skies: A Human Approach To The Alien Phenomenon is a very different beast to the usual UFO abduction books in that, as the title suggests, it focusses on the human aspects. What Ryan did is unique. Rather than stick to the tried and tested, and tired, clinical approach to the abduction phenomena he explored the emotional after-effects on the abductees with astounding and at times heartbreaking effect.
Not content with solely promoting the book though, he decided to launch his own complementary podcast radio show Somewhere In The Skies. Going from strength to strength and having clocked up a further 36 episodes since April at the time of writing, Ryan is primed to be one of the hottest new radio hosts in the alternative community.
SOYM: Let's start with the book, what was the inspiration that compelled you to write 'Somewhere In The Skies…' from a human perspective?
Ryan Sprague: Endless books about UFOs have covered a UFO event, the time it happened, the place, and what the other proposes it may have been. I wanted to do something vastly different and actually contribute to progressing the UFO conversation. So I took a very personal approach. While I related UFO events, I focussed more on the individual having the experience. I wanted to know how the event was perceived by them, and how it affected their life in every way possible. Whatever is happening in our skies, it starts, and in my opinion, ultimately ends with the observer and experiencer. The human aspect of the UFO question should not be ignored, and can lead to some amazing discoveries. And perhaps equally as important; new questions being asked.
For the full interview read the issue here.


LEXINGTON (AP) A Virginia jail's former superintendent and head nurse are facing federal charges.
The federal indictment unsealed Aug. 16 alleges that 61-year-old John Higgins violated inmates' civil rights, media outlets reported. It's alleged he failed to protect inmates at Rockbridge Regional Jail from physical abuse or to provide medical treatment. He's charged with four counts of deprivation of rights.
The grand jury also indicted former jail head nurse 58-year-old Gary Hassler on two counts of falsifying documents. It's alleged Hassler falsely reported on jail medical logs that an inmate refused to take his medication. He's also accused of falsifying an incident report from March 2017.
The Roanoke Times reported that Higgins had no comment and that McGinn did not reply to requests for comment.


During divorce proceedings, property which was acquired during your marriage will be inspected and divided up according to a formula that is outlined in law. If you want to prevent being taken advantage of during this process, then you need to work with a Dallas family law attorney from our firm. At the Mathur Law Offices, P.C., we are dedicated to helping clients maintain the rights to their own property. We are also able to assist clients whose property is threatened by any legal action generated by their spouse.
Community property is defined as the property other than separate property which was acquired during the course of the marriage. Even if the asset is in only one person's name, it is still considered community property at the time of the divorce if it was acquired during the marriage. Salary, cars, retirement savings, and more are all subject to community property laws and if you do not have an attorney to protect your assets, you may lose half of your ownership.
Property is divided into two main categories regarding divorce property settlement. One category is community property and the other category is separate property. Separate property is property which was owned before the marriage took place, property in the form of an inheritance or gift, compensation recovered by the marriage partner from a case, or anything which is exchanged for property which falls under these headings.
Community property can be anything which does not fall under the above categories. A Dallas community property attorney can be of great importance in providing evidence to show that an asset is actually separate property. Ensure that you notify your lawyer early on in the divorce process if you own separate property or believe your spouse owes you a reimbursement. Certain factors influence the division of community property such as the income of each spouse, whether or not one brought about the divorce, and what kind of property is involved. Contact a Dallas divorce attorney today and find out how you can be assisted in retaining your property.


London's Camden Underground club hosts this triple-threat punk party featuring Captain Everything! from Watford, England; Divit, from California's East Bay; and Belvedere, hailing from Calgary, Canada. Songs include "Problem with Numbers" and "The Cheesiest Line" by Captain Everything, "Misunderstanding Maybe" and "In Slow Forward Motion" by Divit, and "Not My Problem" and "Slaves to the Pavement" by Belvedere.