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Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian movement disorder. This study will determine the role of specific genetic, occupational and environmental components in the development of PSP by evaluating patients with this disorder and age and gender matched controls.
This proposal will determine: (1) if there is an association between PSP and specific genes of interest; (2) if there is an association between PSP and occupational and/or environmental chemical exposures functionally or structurally similar to known parkinsonian toxicants; and (3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP, this case-control multicenter study involves 500 PSP cases, 500 age/gender matched primary controls, and 500 secondary controls for genetic confirmation. Understanding the etiology of PSP may also help explain the causes of other related diseases such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists, epidemiologists, geneticists, biostatisticians, industrial hygienist and toxicologist is well suited to unravel the etiology of PSP.
Observational Model: Case Control, Time Perspective: Prospective
Progressive Supranuclear Palsy
University of Alabama, Birmingham
United States
University of Louisville
Published on BioPortfolio: 2014-08-27T03:40:18-0400
Extension Study of BMS-986168 in Patients With Progressive Supranuclear Palsy Who Participated in CN002003
The purpose of this study is to evaluate the long-term safety and tolerability of multiple intravenous (IV) infusions of BMS-986168 in patients with Progressive Supranuclear Palsy (PSP). T...
A Molecular Anatomic Imaging Analysis of Tau in Progressive Supranuclear Palsy
This study is designed to learn more about overall tau burden in the brain of patients with Progressive Supranuclear Palsy (PSP).
Effects of Coenzyme Q10 in Progressive Supranuclear Palsy (PSP)
The clinical syndrome of PSP responds poorly to all available forms of therapy used in Parkinson's Disease (PD). Currently, no effective treatment exists. Coenzyme Q10 in high doses has b...
Safety, Tolerability, and Pharmacokinetics of C2N-8E12 in Subjects With Progressive Supranuclear Palsy
This study will evaluate the safety and tolerability (maximum tolerated dose (MTD) within the specified dosing range) of single intravenous (IV) infusion of C2N-8E12 in patients with prog...
Trial of Valproic Acid in Patients With Progressive Supranuclear Palsy
Progressive Supranuclear Palsy (PSP) is a relentlessly progressive neurodegenerative disorder, clinically characterized by parkinsonism with prominent axial involvement and postural instab...
Paraneoplastic syndrome mimicking progressive supranuclear palsy.
Paraneoplastic syndrome presenting with progressive supranuclear palsy (PSP) phenotype is extremely rare. We report a patient who presented with features of rapidly progressive parkinsonism similar to...
123I-FP-CIT and 99mTc-HMPAO in Pathologically Confirmed Progressive Supranuclear Palsy.
Molecular brain imaging I-FP-CIT SPECT is an important tool in evaluation of patients with parkinsonism. However, various neurodegenerative etiologies cannot be differentiated by I-FP-CIT SPECT alone....
(18) FAV-1451 tau positron emission tomography in progressive supranuclear palsy.
The [(18) F]AV-1451 positron emission tomography ligand allows the in vivo assessment of tau proteins in the brain. It shows strong binding in Alzheimer's dementia, but little is known about how it pe...
Rest-activity rhythm disruption in progressive supranuclear palsy.
The brainstem is among the first regions affected in progressive supranuclear palsy (PSP) and is part of the sleep/circadian regulation network. In two small studies, blood pressure and core body temp...
Diagnostic value of blink reflex in multisystem atrophy, progressive supranuclear palsy and Parkinson disease.
Abnormal blink reflex (BR) is a result of reticular brainstem pathways dysfunction and seems to be one of the features of brain degenerative disorders. The aim of the study was to estimate the diagnos...
Neurodegenerative disorders involving deposition of abnormal tau protein isoforms (TAU PROTEINS) in neurons and glial cells in the brain. Pathological aggregations of tau proteins are associated with mutation of the tau gene on chromosome 17 in patients with ALZHEIMER DISEASE; DEMENTIA; PARKINSONIAN DISORDERS; progressive supranuclear palsy (SUPRANUCLEAR PALSY, PROGRESSIVE); and corticobasal degeneration.
Supranuclear Palsy, Progressive
A degenerative disease of the central nervous system characterized by balance difficulties; OCULAR MOTILITY DISORDERS (supranuclear ophthalmoplegia); DYSARTHRIA; swallowing difficulties; and axial DYSTONIA. Onset is usually in the fifth decade and disease progression occurs over several years. Pathologic findings include neurofibrillary degeneration and neuronal loss in the dorsal MESENCEPHALON; SUBTHALAMIC NUCLEUS; RED NUCLEUS; pallidum; dentate nucleus; and vestibular nuclei. (From Adams et al., Principles of Neurology, 6th ed, pp1076-7)
Motor Neuron Disease
Diseases characterized by a selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In AMYOTROPHIC LATERAL SCLEROSIS there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes (see MUSCULAR ATROPHY, SPINAL) the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy (BULBAR PALSY, PROGRESSIVE), the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation. (Adams et al., Principles of Neurology, 6th ed, p1089)
Bulbar Palsy, Progressive
A motor neuron disease marked by progressive weakness of the muscles innervated by cranial nerves of the lower brain stem. Clinical manifestations include dysarthria, dysphagia, facial weakness, tongue weakness, and fasciculations of the tongue and facial muscles. The adult form of the disease is marked initially by bulbar weakness which progresses to involve motor neurons throughout the neuroaxis. Eventually this condition may become indistinguishable from AMYOTROPHIC LATERAL SCLEROSIS. Fazio-Londe syndrome is an inherited form of this illness which occurs in children and young adults. (Adams et al., Principles of Neurology, 6th ed, p1091; Brain 1992 Dec;115(Pt 6):1889-1900)
Multiple Sclerosis, Chronic Progressive
A form of multiple sclerosis characterized by a progressive deterioration in neurologic function which is in contrast to the more typical relapsing remitting form. If the clinical course is free of distinct remissions, it is referred to as primary progressive multiple sclerosis. When the progressive decline is punctuated by acute exacerbations, it is referred to as progressive relapsing multiple sclerosis. The term secondary progressive multiple sclerosis is used when relapsing remitting multiple sclerosis evolves into the chronic progressive form. (From Ann Neurol 1994;36 Suppl:S73-S79; Adams et al., Principles of Neurology, 6th ed, pp903-914)
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Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of affected individuals. Symptoms can range from mild breathles...
Anxiety Disorders
Anxiety is caused by stress. It is a natural reaction, and is beneficial in helping us deal with tense situations and pressure. It is deterimental when is becomes an excessive, irrational dread of everyday situations. The most common types of anxiety di...
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Have you ever heard of Dr. Temple Grandin? She is not a medical doctor, but a doctor of animal behaviour. She is famous not only for her brilliant mind and her insight into animal behaviour but also because she has autism. Or, as her official description puts it:
"Internationally Renowned Livestock Behaviourist, Autism Advocate and Outstanding Person of Our Times"
On May 8, 2015, Dr. Grandin spoke at our local agricultural college as a benefit for 4H, and the Mister decided to get tickets for me and our seven-year-old son to attend.
I was doubtful that he would get anything out of it, but in the end, I'm glad he came.
Most people know who Dr. Grandin is, either through her work in animal sciences as "the woman who thinks like a cow", her work in autism activism as a very successful woman with Aspergers, or through the movie that was made about her, called, simply enough, Temple Grandin.
The Cowboy
At the beginning of the talk, a young man of about 18 introduced her.
He said his nickname was Cowboy … Ben? Bill? I'm embarrassed to admit that I only remember the "cowboy" part and his white ten-gallon hat.
He spoke about living with autism and how much working with 4H had helped him grow, and then he said how proud he was to be introducing his hero, Dr. Temple Grandin.
Dr. Grandin
As she began her talk, Dr. Grandin expressed how much she loved 4H. As an autistic child growing up, 4H was one of the few places where she was accepted and not badly teased. She says that when 4H asks her for a favor, she does it.
Dr. Grandin spoke about Low Stress Handling of Livestock – and it was a lot more interesting than the title might make it sound!
The basis point of the talk was that animals that are not stressed – who are with familiar people, in familiar settings, doing familiar things – provide better milk and meat, but they also cooperate better and are therefore safer and easier to work with.
Some of the points she made were, in retrospect, quite obvious. However, the fact that she has needed to tell people these things over and over again for the past forty years, tells us that the obvious is not always …. well, obvious!
Training an animal to remain calm when it sees a bright orange tarp will do nothing to calm it when it sees a blue and white umbrella.
She talked about how animals who fear people are less productive. People have argued with her that using the word "fear" is not appropriate because fear is a human emotion.
Dr. Temple insisted that fear is certainly the proper scientific term and that it is used in animal neuroscience literature.
Fearful sows produce fewer piglets.
Fearful dairy cows have lower conception rates. However, cows that willingly approach humans have lower somatic cell counts. (Low quality milk with a lot of pathogens has a high somatic cell count.)
Dr. Temple is in favour of measuring good performance, stating that "You manage what you measure". Maintaining high standards requires constant measurement, preferably with an objective numerical scoring system, to prevent bad from becoming normal.
My Son
The highlight of the evening, for me and our son, however, came during the question and answer period.
Our 7 year old, A, has a mild form of autism generally called Aspergers, much like Dr. Grandin. He is a wonderful, highly intelligent and lovable boy, and I was eager to show him a woman who had succeeded in life because of – and not in spite of – her autism.
Although I suspected the talk would be above his head (since a lot of it was above mine), I hoped he would enjoy it.
And he did.
When they began to bring around the microphone for questions after the talk, he said to me "I want to ask her something." So we practiced quietly until he had a concise, clear question to ask. Finally, we had the microphone. I showed him how to hold it, covered it up and had him practice his question one more time.
And then, it was his turn and … he froze.
Now, that's partly seven year old stage fright and it's partly the autism, but he completely froze. Eyes wide, staring at me, he couldn't get a word out. I knew how disappointed he'd be if I couldn't get him to speak, but it's very difficult to break him out of that trance.
Finally I spoke, "I'm sorry, Dr. Grandin. He's seven, has Aspergers and he got shy."
People started to cheer him and clap for him, until Dr. Grandin snapped "Stop! And hush!"
She then spoke for a bit about how dogs, horses and children are similar in that they need encouragement but they also need space and safety.
While she talked, I tried to get him to speak. I could hear her talking about how important it was for parents of autistic children to push them out of their comfort zones, to help them grow and experience new things.
Nothing I said to him, though, could turn off that glazed stare.
Suddenly there was someone beside me. "Would it help if you wore my hat?" A white cowboy hat was being held toward us.
My son suddenly grinned, put it on his head, turned to the stage and said, just as clear as a bell, "Hello, Dr. Grandin. How many years did you go to school to learn all this stuff?"
Well, I'm sure she answered, but I don't know if anyone heard.
The room erupted in cheers and clapping for two brave and wonderful autistic boys.
Recommended Reading – Books By Dr. Grandin
The Autistic Brain: Helping Different Kinds of Minds Succeed
How To Teach Life Skills to Kids With Autism or Asperger's
The Unwritten Rules of Social Relationships
Temple Grandin: How the Girl Who Loved Cows Embraced Autism and Changed the World

subset: commoncrawl


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Student Bodies
Student Bodies centers around the students and staff of Lamab High, as one by one they are picked off by The Breather. The Breather is a galoshes wearing killer with a bizarre choice of weapons and apparently a bad case of asthma. The movie starts out on Friday the 13th and jumps right into the action as promiscuous teens are picked off with everything from paper clips to horse head bookends and including an eggplant. There is an on screen death count just to help viewers keep track of the action and also a nifty arrow that helps viewers realize when a door is left unlocked or a window opened. My favorite moment of the show though, hands down is the breakaway to a news desk where the movie s R rating is discussed and then earned. The cast is full of campy actors who specialize in cheese and do great in keeping the bad jokes and sight gags flowing throughout the movie. There is one character named Malbert who is honestly a human cartoon. The guy is probably 7 foot tall and has to weigh less than 100 pounds. He contorts his limbs throughout the movie in ways that had me doing a double take as it didn't seem humanly possible. In the credits the actor is listed as The Stick so I have no idea of his real name.
Product Details
Actors: Joe Flood, Matthew Goldsby, Jerry Belson
Directors: Mickey Rose
Format: Blu-ray, Widescreen
Language: English
Region: Region A/1 (Read more about DVD/Blu-ray formats.)
Number of discs: 1
Rated: R
Studio: Olive Films
DVD Release Date: August 25, 2015
Run Time: 86 minutes


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Toucan play at that game - big bird branding for Brazil green group
With a timely nod to the fact that there are more aspects to Brazil than football, we take a look at the branding for environmental organisation IBRA
With a timely nod to the fact that there are more aspects to Brazil than football, we take a look at the branding for environmental organisation IBRA
Wondering why you've got Photoshop CC and Photoshop CC 2014 on your computer? You're not alone.
Check out our pick of the best design and illustration from CSM 2014 grad show.
Check out these amazing poster designs from the 24th International Poster Biennale in Poland.
Adobe has released new versions of all of its Creative Cloud tools, plus free apps, iPad accessories and more.
Squad rebrands a Cumbrian roadside institution opening a new catering enterprise far from its roots
Discover a new way to cut-out or select parts of images based on focus.
In Soccer Knights, Man-Tsun has represented three of his footballing heroes – Lionel Messi, Ronaldhino, Zinedine Zidane – with Manga knights acting as their totems.
The Formica Envisualizer is a free online pattern design tool created by the company whose patterned laminates are synonymous with the kitchens of the 1950s and 60s.
Win a Wacom Cintiq Companion – plus come to the Digital Arts HQ to learn how to use it.
The Abertay Honours graduate uses digital paper to evoke appreciation for hand-crafted arts in an interactive medium
Check out this year's winners: including Monument Valley, Day One, Blek and Threes.
Discover what really matters to you from iOS 8 and Mac OS X Yosemite.
Check out our Show Your Creativity content, in association with Wacom.
The RSA Student Design Awards are 90 this year and we've got the winning entries to share with you.
The 10 best quotes from the Creativity in Conversation: Youthful Thinking discussion at the Apple Store last night.
London Design Festival 2014 features a huge work by Barber Osgerby and a drone aviary
We get insider info from Cognitive on how the forthcoming Ideas In Profile animated ebooks were created
At last you can use Comic Sans with impunity for this Cancer Research poster project.
The London Design Festival 2014 features hundreds of exhibitions, conferences, installations, talks and more this September.


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For those that do not understand why a company would sell their consoles at a lose look up the Razor-Razor Blade business model.
Consoles = Razor
Games and accessories = Razor Blades
In the past most companies sold their consoles at a loss (except Nintendo) at launch but this time around it looks like only Sony is actually making a profit on each console. People buying multiple games plus extra controllers and such makes a much higher profit than the $20-$50 they lose on the console itself. So having more consoles in more peoples hands makes the most sense.
Originally posted by lizardbonesLol, in the time it took me to write mine, there is a good pit of clarification to my question/point. And very nice, I didn't know they lowered the price for the low end models. Cool deal. At $399 I may get a PS4.
Originally posted by Daranar
Originally posted by lizardbones Sony stated that they are not selling their consoles at a loss. Some people are even saying that Sony will turn a profit on each one shipped. Not much profit, but $25 to $55 per unit shipped isn't chump change. http://www.playstationlifestyle.net/2013/06/11/pachter-sony-almost-certainly-making-a-profit-on-399-ps4/
This makes sense to me. Hardware was more expensive when the last generation released. It seems that if you could build a cheaper PC then the console hardware costs to Sony and Microsoft would be even lower. It only makes sense, given the price point, that the new consoles are paying for themselves.
The old business adage is: "You make money on the blades, not the razors.".
It's been said to apply to videogames as well.
edit: Apparently I should have read the whole thread. I've been beaten to the punch.
I want a mmorpg where people have gone through misery, have gone through school stuff and actually have had sex even. -sagil


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Jamie Varner talks with Iris Garcia following his huge TKO win over formerly unbeaten Edson Barboza at UFC 146. He also gives some insight into his focus for training and also give a shoutout to mom. watch video >>
PLEASE SUBSCRIBE & CHECK OUT MORE VIDEOS at http://www.mmainterviews.tv Get 25% off at http://www.Proboxingsupplies.com if you call and mention MMAinterviews! Get $10 off preworkout supplements Bod watch video >>
Check out what CB had to say following his big win over Jason Mayhem Miller at UFC 146.. watch video >>
MMA H.E.A.T.'s Karyn Bryant talks with Paul Sass after his win over Jacob Volkmann at UFC 146. Paul talks about his preparation, his standing in the lightweight division and what he plans to do to c watch video >>
http://www.MMAWeekly.com brings you Paul Sass at the UFC 146 Press Conference (Post-Fight) from Las Vegas, NV. This was after Sass defeated Jacob Volkmann at UFC 146. watch video >>
Paul Sass talks about his submission victory over Jacob Volkmann at UFC 146, fighting on the Facebook prelims, where he stands in the lightweight division and more with MMA Fighting's Ariel Helwani.S watch video >>
For more log onto http://www.fighthubtv.com Like us:http://on.fb.me/xWRC1f follow us:http://bit.ly/wACkIv videos uploaded daily! Subscribe: http://goo.gl/vnzIb in association with http://www.lowkick watch video >>
Dana comments on UFC 146, the Jon Jones DUI situation, and gives his opinion on who's the greatest MMA fighter of all time.. watch video >>
HeavyMMA's Megan Olivi catches up with Stefan Struve, who picked up a quick first-round submission victory over Lavar Johnson at UFC 146 on Saturday. watch video >>
Here is Iris Garcia's Interview with Urijah Faber during the UFC 146 festivities. Here he talks about his upcoming Bout with Renan Barao, the Dominic Criz fallout, his time coaching TUF, and also his watch video >>


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Web design required. for a game
This project was awarded to sujaykar for $400 USD.Get free quotes for a project like this
Project Budget$250 - $750 USD
Total Bids11
Project Description
I need new design for my site sguwars.com.
basiclly remake the hole design of the site.
I dont need new html/css code just the photoshop psd files with layers comps.
I need home page design,base page design tables design, 7 planets designs, and one additional page.
so its 3 pages, 7 planets and design for all game tables, Input fields and buttons.
Anyway I am searching for the top quality work.
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Will graphics be important to you for Camelot Unchained?
If so what kind of graphics would you like to see? would it be more DAoC style? WoW style? Warhammer style?
A more fluid updated version of DAOC before they added the stupid new models ( catacombs? or NF? or whatever it was )
Something like the screenshots i see of TESO
Ozek - DAOC
Niix - Other games that sucked
Camelot Unchained Backer
DAOC [retired]: R11 Cleric R11 Druid R11 Minstrel R9 Eldritch R6 Sorc R6 Scout R5 Healer
Originally posted by meddyck
Yes. It's not 2005 or 2008. The game needs to look at least a little better than DAOC and WAR. But it also can't have such great graphics that you need a $5,000 computer to get good framerates during huge fights.
Mark Jacobs
CEO, City State Entertainment
The game needs to look good. I believe it should have a graphical overhaul every year.
I like to use eve as an example. It didn't get to look as good as it does now in one giant patch, every year they've made graphics updates here and there.
I hope that if they keep the art assets tied to only RvR and maybe 4 RvR dungeons, keeping the scope on content small, but reinventing, improving, and updating that content again and again.
Of course graphics matter. Beauty is on the outside. That other thing people say is just so ugly games will feel better about themselves.
"You are all going to poop yourselves." BillMurphy
"Laugh and the world laughs with you. Weep and you weep alone."
Yes and no, graphics should be at least 2005 level for a low budget and everything in the world should look natural, for higher budgets minimum goes up to 2006 and max 2008. Anything before 2005 and you get the polygons of death a la SWG and we need the world to look natural so it does not break immersion. Flashy graphics =/= good game so it should not be the focus.
Note: the above is stated in general terms, I do not have any feelings for or against Unchained, good luck to them and hope you guys enjoy the final product.
The graphics depend on the engine itself, but overall.. I hope they use high polygon models baked on low poly models with LOTS of hand painted textures for a stylized look on the characters.
I'd love to see high resolution, photo realistic/stylized textures on major environmental objects such as keeps and towers, but regular hand painted textures on minor environmental objects like trees, crates, tents, etc.
To coin a phrase I'd rather have an ugly cow that produced delicious milk than a pretty cow that produced spoiled milk.
Yes, good graphics matter.
DO graphics trump game play? NO.
but it's a close second IMHO>
Originally posted by Xobdnas
To coin a phrase I'd rather have an ugly cow that produced delicious milk than a pretty cow that produced spoiled milk. Moo
Or since we're the ones genetically manipulating the cow from inception, we can get one that does exactly what we want...
This is easy .Yes.
I don't expect it to be at the same level of visual flufiness of,let's say GW2,
but it has to look great.
And it also has to run nice in mid and low range machines.
And no cartoony WoW stuff please.
Wildstar does that and it already looks 8 years old.
I feel that the graphics aren't soo important for me however, I must say I don't care for the cartoonish ones like WoW. I would much rather take DAoC-like graphics, it just feels so surreal to me. I don't care for warhammer graphics too much but it is somewhat of a blend between cartoony and real. Just my preference though
Graphics AND animations matter, at least to me.
For example, I was interested in Salem, upcoming hardcore PvP MMORPG with some interesting ideas.
But the moment I saw those ridiculous player characters with enormous heads and the whole artstyle (which I believed it must be a joke at first), I completely wiped it of my "watch" list.
Gameplay > Graphics
However, if the game is hideously outdated you're going to have issues garnering a fanbase.
Bear "replicant" Powell
"I am Shaolin-Style!"
Gameplay is of course the main part about any game it it needs to look good as well.
If they come out and say its going to be Cartoon wow style graphics i wont be happy at all... i want it to be age of conan gritty if you know what i mean and it needs to look good s well..
Originally posted by CyborWolfTK
Yes, good graphics matter. DO graphics trump game play? NO. but it's a close second IMHO>
Gameplay is vital. Great graphics are fine, but I'll take a fun game over a pretty game any day of the week.
For me, even though gameplay, depth of the storyline and complexity of the mechanics are the "most important" aspects of a game, graphics that are subpar to what's generally being put out in games, is a big turnoff. I've tried going back and playing old games, EQ is one I looked at a couple of years ago and MAN were the graphics terrible! Lol. I remember when EQ first came out I spent days just being amazed at how good the game looked having come from 2D graphical MUD's, but after games like Skyrim, old games are pretty much unplayable to me.
I would definitely prefer graphics like Warhammer as opposed to cartoon graphics like Wow. Hugely oversized armor and weapons are massive turnoffs for me. I love the realistic character models Warhammer had with the scars and generally "rough" looking character models. To me Wows cartoon characters have an appearance that evokes a "for children" feeling, a few other games I've seen look the same, Tera is believe is another that uses huge weapons and oversized characters.
I've always been of the performance > pretty school, at least as far as pvp goes.
But the edges do keep getting pushed back. Update the graphics to just-a-few-years-ago, should be a good compromise.
Or hell, give me everything you've got, as long as uncheck-it control exists. Does your engine let me choke particle counts? Kill shadows, minimize reflections, nuke the pretty-water? If so, we'll be happy together.
Self-pity imprisons us in the walls of our own self-absorption. The whole world shrinks down to the size of our problem, and the more we dwell on it, the smaller we are and the larger the problem seems to grow.


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Varsity Chili for Hot Dogs
Total Time
Prep 20 mins
Cook 8 hrs
Lots of Atlantans have fond memories of trips downtown that include chili dawgs from The Varsity! Here's the chili recipe.
Ingredients Nutrition
- 4 lbs lean ground beef
- 1⁄2 onion, chopped fine
- 1 -2 teaspoon salt
- 2 tablespoons ground cumin
- 6 tablespoons chili powder
- 2 cups water
- 1 (1 1/4 ounce) package chili seasoning mix
- Brown ground beef in skillet and drain fat.
- Add all ingredients and combine in crockpot, stirring to mix thoroughly.
- Cook on high for 2 hours.
- Stir well, reduce heat to LOW and continue cooking for 6-8 more hours.
- Enjoy!
Most Helpful
I have to second this -- I went to school at Georgia Tech, and I practically lived off the Varsity. All I need now is a recipe for Varsity Whipped Oranges!
Having moved away from Atlanta, I dearly miss the Varisty and all of the greasy wonderful food they serve up. This tasted exactly like the real deal!! Thanks so much for sharing!!!!!
First off, born and raised in Atlanta and am VERY familiar with our Varsity restarant chains. It's un-American NOT to be in Georgia. We were all raised with those delicious chili dawgs and every chance we get to go back and visit family, the Varsity is the first place we stop at to indulge and re-hash memories. Living in DFW area, Varsity is a little too far to indulge in whenever we get the "urge" but....while this chili for hot dogs recipe isn't EXACTLY like our beloved Varsity...........it's as close as we can get while at home............and it is pretty darn good. This will be a keeper for us that are just too far away to enjoy our beloved Varsity at will.


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Metallica's Master of Puppets on a half-day Wednesday in September 1987; Masters of Reality's The Blue Garden on a Friday night in February 1989; Red House Painters' Down Colorful Hill on a rush hour train in the summer of 1993 – we all have special moments when those touchstone records came into our lives. On a wet evening in May Mississippi-born Murry's debut joined the list and, like the rest, the years ahead will be the better because of it.
This is both a classic example of how our worst enemies are ourselves and a reminder that you can climb back out of the hole you've dug, Murry recounting addiction, the filling of voids, the hustles of false dawns and the ghosts we all live with like a master storyteller who's been around a lot longer than 34 years. One ragged 'glory' follows another, with Murry's rough-and-ready guitar playing the perfect foil for the sadness of his Southern drawl. And if you find a better song this year than his piano-driven OD odyssey Little Coloured Balloons, it will more than likely be somewhere on this album too. Like the man himself sings: "It all comes pouring out in these startling melodies."
Definitely the kind of beauty that is not natural in age like this.
Harry Guerin


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How-To Geek
How to Find The Best Wi-Fi Channel For Your Router on Any Operating System
Choosing the best Wi-Fi channel on your router helps to reduce interference and improve your WI-Fi signal. These tools will help you identify the least congested Wi-Fi channel in your area.
Wi-Fi channels overlap with nearby channels. Channels 1, 6, and 11 are the most frequently used for 2.4 GHz Wi-Fi. These three channels are the only ones that don't overlap with each other.
Android – Wifi Analyzer
The easiest-to-use application we've found for this is Wifi Analyzer on Android. Just install the free app from Google Play and launch it. You'll see an overview of the wireless networks in your area and which channels they're using.
Tap the View menu and select Channel rating. The app will display a list of Wi-Fi channels and a star rating — the one with the most stars in the best. The app will actually tell you which Wi-Fi channels are better for your Wi-Fi network, so you can go straight to your router's web interface and choose the ideal one.
iOS – Jailbreakers Only
This isn't possible on iPhones and iPads. Apple restricts apps from accessing this Wi-Fi data directly from the hardware, so you can't get an app like Android's Wifi Analyzer on Apple's App Store.
If you jailbreak, you can install an app like WiFi Explorer or WiFiFoFum from Cydia to get this functionality on your iPhone or iPad. These tools moved to Cydia after Apple booted them from the official App Store.
You probably wouldn't want to go through the trouble of jailbreaking just for this, so use one of the other tools here instead.
Windows – NirSoft WifiInfoView
We previously recommended inSSIDer for this on Windows, but it's become paid software. You probably don't want to pay $20 just to figure out which Wi-Fi channel is ideal, so use a free tool instead.
Xirrus Wi-Fi Inspector is very powerful, but it's a bit overkill for this. We liked NIrSoft's WifiInfoView instead — its simple interface does the job and it doesn't need any installation. Launch the tool, locate the Channel header, and click it to sort by Wi-Fi channel. Here, we can see that channel 6 looks a bit cluttered — we might want to switch to channel 1 instead.
Linux – The iwlist Command
You could use a graphical app like Wifi Radar for this on Linux, but you'd have to install it first. Instead, you might as well just use the terminal. The command here is installed by default on Ubuntu and other popular Linux distributions, so it's the fastest method. Don't fear the terminal!
Open a Terminal and run the following command:
sudo iwlist wlan0 scan | grep \(Channel
Read the output of the command to see which channels are the most congested and make your decision. In the screenshot below, channel 1 looks the least congested.
Mac OS X – Wireless Diagnostics
Mac OS X actually has this feature integrated. To access it, hold the Option key and click the Wi-Fi icon on the menu bar at the top of your screen. Select "Open Wireless Diagnostics."
Ignore the wizard that appears. Instead, click the Window menu and select Utilities.
Select the Wi-Fi Scan tab and click Scan Now. The "Best 2.4 GHz Channels" and "Best 5 GHz" Channels" fields will recommend the ideal Wi-Fi channels you should be using on your router.
How to Change Your Router's Wi-Fi Channel
Actually changing your router's Wi-Fi channel should be simple. First, log into your router's web interface in your web browser. Click over to the Wi-Fi settings page, locate the "Wi-Fi Channel" option, and choose your new Wi-Fi channel. This option may be on some sort of "Advanced Settings" page, too.
If there are too many other nearby networks interfering with your signal, try getting a router that supports 5 GHz — you'll need devices that support 5 GHz, too. However, you can get "dual band" routers that have both 2.4 GHz and 5 GHz radios for maximum compatibility. 5 GHz Wi-Fi channels are farther apart and won't interfere with each other as much.


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Hotfrog SouthAfrica provides information regarding Witbank Management Services Witbank, Mpumalanga in Witbank Mpumalanga. Witbank Management Services Witbank, Mpumalanga is located at 37 President Ave, Witbank Mpumalanga 1034 and provides Management services. Contact them on 013 656 2267.
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McKay Commission: What is the West Lothian question?
25 March 2013 Last updated at 08:35 GMT
Welsh, Scottish and Northern Irish MP's could see their role in the House of Commons limited in the future if recommendations to give English MPs a greater say in laws affecting England are implemented.
That is one of many conclusions of the McKay Commission, set up to by the UK government last year to examine the so-called West Lothian question.
Hazel Morgan, who lives in Cardiff now but is originally from Edinburgh, gives a guide to the West Lothian question.
Role of Welsh MPs may be limited


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Elevated signal transducers and activators of transcription 1 correlates with increased C-C motif chemokine ligand 2 and C-X-C motif chemokine 10 levels in peripheral blood of patients with systemic lupus erythematosus
DOI: 10.1186/ar4448
© Dominguez-Gutierrez et al.; licensee BioMed Central Ltd. 2014
Received: 23 April 2013
Accepted: 14 January 2014
Published: 23 January 2014
The present study examines the levels of recently reported biomarkers, adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine 10 (CXCL10), signal transducers and activators of transcription 1 (STAT1), and miR-146a in systemic lupus erythematosus (SLE) patients over multiple visits.
Peripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, 60 of whom had samples from 2 or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real time PCR assays. Relative expression of I-IFN signature genes, chemokines, and miR-146a were determined by the ΔΔCT method. Results were correlated with clinical data and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher's exact test.
Levels of ADAR, CCL2, CXCL10, and STAT1 in SLE were significantly elevated compared with the healthy controls (P <0.0001). ADAR, CCL2, and CXCL10 showed significant correlation with IFN score in both healthy donors (P <0.0033) and SLE patients (P <0.0001). In SLE patients, miR-146a level was not significantly different from healthy controls nor correlated to the IFN score. Two STAT1 populations were identified: a low STAT1 and a high STAT1 group. High STAT1 patient visits displayed higher (P ≤0.0020) levels of CCL2 and CXCL10 than the low STAT1 patient visits. STAT1 levels correlated with IFN score in low STAT1 group but not in high STAT1 group. More importantly, high STAT1 levels appeared as an enhancer of CCL2 and CXCL10 as indicated by the significantly stronger correlation of CCL2 and CXCL10 with IFN score in high STAT1 patient visits relative to low STAT1 patient visits.
Our data indicate a novel role for STAT1 in the pathogenesis of SLE as an expression enhancer of CCL2 and CXCL10 in SLE patients with high levels of STAT1. Future study is needed to examine the exact role of STAT1 in the etiology of SLE.
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by periods of increased disease activity, referred to as flare-ups, and periods of remission. Several genetic and environmental factors have been implicated in SLE etiopathogenesis, but in recent years increased type I interferon (IFN-I, IFNα and IFNβ) expression has been discovered to play a key role in the majority of SLE patients, despite being known for over 30 years that it is elevated in SLE patients[1–4]. Because of the technical challenges in measuring the numerous isoforms of IFNα, one common way to evaluate IFN-I expression is to examine the levels of common IFN-inducible genes, such as 2′,5′-oligoadenylate synthetase (OAS1), myxovirus resistance 1 (MX1), and lymphocyte antigen 6 complex locus E (LY6E); the mRNA levels of these IFN-I-inducible genes are then used to calculate the IFN score[1, 5–7]. Another interferon inducible gene that plays an important antiviral and immunomodulatory function is the adenosine deaminase acting on RNA (ADAR). ADAR is an enzyme that catalyzes the conversion from adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) substrate[8, 9], with an impact on RNA at different levels, such as mRNA splicing and degradation[10, 11]. Furthermore, ADAR1 has been observed to suppress interferon regulatory factor (IRF)3 and protein kinase RNA-activated (PKR) and therefore blocking IFN induction[12–14]. The ability of ADAR1 to respond and regulate IFN-I production makes it an intriguing IFN-I-inducible gene to examine in SLE. Up to now, ADAR1 expression has only been observed in T-cells of SLE patients, as shown in a limited number of studies[15–17]. In fact, Laxminarayana et al. showed that ADAR1 is upregulated approximately 3-fold in SLE patients[15]. The same group later observed the increased editing of ADAR2 by ADAR1 in T-cells of SLE patients[16]. Additionally, due to increased ADAR1 in SLE patients, Orlowski et al. observed an increase of phosphodiesterase 8A1, which participates in the termination of cyclic nucleotide signaling by hydrolyzing cAMP and cGMP and is activated by IFN and enhances T-cell adhesion[17].
Other IFN-I-inducible genes include signal transducers and activators of transcription (STAT)1 and 2. STAT1 is involved in type I, II, and III IFN signaling and has been observed to be elevated in SLE[18]. In response to type I IFN, STAT1 causes IFN receptor (IFNAR)1 and 2 dimerization, activation and phosphorylation of IFNAR by Tyk2 and Jak1, and thus docking and phosphorylation of STAT1 and STAT2[19]. The heterodimer STAT1-STAT2 is then translocated into the nucleus where it can bind specific promoters playing a key role in IFN signaling and production[20].
Besides STAT1 and ADAR, IFN-regulated chemokines have become another important topic of research in recent years[21]. Two of these chemokines have been shown to be SLE biomarkers, and they are called C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10)[22]. CCL2, formerly referred to as monocyte chemotactic protein-1 (MCP-1), is a potent recruiter of monocytes, T-cells, basophils, and dendritic cells to the site of infection or tissue damage, but it has no effect on neutrophils or eosinophils unless the N-terminus of CCL2 is cleaved[18, 23]. Some cell types such as monocytes, macrophages, and dendritic cells can primarily secrete CCL2, which signals via the cell surface receptors CCR2 and CCR4 and is upregulated by IFNα and IFNβ[24, 25]. The role of CCL2 is beneficial in clearing pathogens, but it has also been involved in some pathological processes. In a glomerulonephritis mouse model, CCL2 plays a role in crescent formation and interstitial fibrosis supported by the observation that anti-CCL2 antibodies can reduce crescent formation, renal impairment, and scarring, as well as T cell and macrophage infiltration[26]. CCL2 has been observed in the recruitment of T cells and monocytes/macrophages in lupus nephritis and blockade of CCL2 ameliorates lupus nephritis in MRL-(Fas)lpr mice[23, 27]. In a serologic proteome study by antibody microarray in SLE, CCL2 was identified as one of the twelve upregulated proteins; furthermore CCL2 was one of three chemokines that would precede lupus flare, indicating that they are good predictors of increased SLE activity[21].
CXCL10, also known as IFN gamma-induced protein 10 (IP-10), is a chemokine of the C-X-C motif family. Similar to CCL2, CXCL10 is a potent attractor of monocytes, macrophages, T-cells, natural killer (NK) cells, and dendritic cells to sites of tissue damage and infection[28, 29]. CXCL10 is an IFN-response cytokine that binds its CCL3 receptor and acts via Jak/STAT pathway activation[30–32]. Even though CXCL10 is a potent immune responder for bacterial and viral infections and a critical biomarker for organ transplant rejection, its role in the pathogenesis of autoimmune diseases is not clear[33, 34]. Furthermore, the combination of CXCL10 and CCL2 protein levels could be useful as prediction factor for upcoming flares[22].
The reason behind upregulation and control of IFN in SLE is not known, but some studies have recently focused on the possible role played by selected microRNAs (miRNAs). MiRNAs are small non-encoding 20- to 23-nucleotide-long RNAs, that regulate their target mRNA by binding to the 3′ UTR, causing translational repression and/or degradation of targets. miR-146a is one of the most significant miRNAs in regulating innate immune response and tolerance[35] and it was first shown to be involved in toll-like receptor (TLR) regulation through the nuclear factor (NF)-кB pathway[36]. miR-146a would function to attenuate the immune response and regulate inflammation in normal immune response and autoimmune disorders, and it is also a critical regulator of endotoxin-induced tolerance and cross-tolerance[37–39]. To date, miR-146a has been found in association with autoimmune diseases such as Sjögren's syndrome[40], psoriasis[41, 42], and rheumatoid arthritis[43–45].
Tang et al. reported that miR-146a was under-expressed in peripheral blood mononuclear cells (PBMCs) of Chinese SLE patients[46]. miR-146a was significantly lower in patients with active SLE with proteinuria compared to those with inactive SLE[46]. Additionally, SLE patients displayed an inverse correlation between miR-146a expression and IFN score[46]. Tang et al. also demonstrated that reduction of miR-146a may enhance the signaling due to elevated levels of STAT1 and IRF5 which leads to increased production of IFN[46]. The reduced levels of miR-146a observed in Chinese SLE patients could potentially explain elevation of IFN by loss of regulation of STAT1 expression.
Our present study evaluates the interaction among STAT1, ADAR, CCL2, CXCL10, and miR-146a in SLE patients and healthy controls, demonstrating that all except for miR-146a correlate with IFN score in both SLE patients and healthy donors.
Healthy donors' and SLE patients' demographic data
Demographic data of SLE patients and healthy donors
Number of cases
Number of visits (2 or more)
180 (60)
65 (0)
Mean age, years (range)
44 (25–68)
33 (19–59)
Sex, female/male/unknown, n
Race, AA/EA/LA/AsA/IrA/unknown1, n
Race by visit (AA/EA/LA/AsA/IrA/unknown)1, n
Active/inactive by SLEDAI, number of patients
Main clinical features, number of patients
Malar rash
Discoid lesions
Oral ulcers
Leukocytes and RNA purification
Peripheral blood leukocytes were collected from whole blood using Ambion LeukoLOCK kit (Ambion, Austin, TX, USA). LeukoLOCK filters were washed twice with 3 ml of PBS and stabilized with 3 ml of RNAlater solution. Stabilized filters were stored for a minimum of 24 h at −80°C before collecting total RNA. Total RNA, including small RNAs, was collected using the "Alternative Protocol" (version 0602, Ambion) for the extraction of RNA from cells captured on LeukoLOCK filters using TRI reagent.
mRNA and microRNA quantitative RT-PCR
OAS1 (Hs00973637_m1), MX1 (Hs00895608_m1), LY6E (Hs00158942_m1), STAT1 (Hs01013996_m1), CCL2 (Hs00234140_m1), CXCL10 (Hs00171042_m1), ADAR (Hs00241666_m1), TNFα (Hs00174128_m1), and pri-miR-146a (Hs033303259_pri) levels were analyzed by TaqMan mRNA assay primers (Applied Biosystems, Foster City, CA, USA). mRNA qRT-PCR was performed as a duplex with 18S rRNA assayed as the normalizer. mRNA was transcribed to cDNA using the TaqMan High-Capacity cDNA Reverse Transcription Kit followed by quantitative (q)PCR using TaqMan Fast Advance PCR Master Mix (Applied Biosystems). miR-146a (000468; Catalogue # 4427975) was analyzed by miRNA qRT-PCR using the TaqMan MicroRNA Reverse Transcription Kit, TaqMan Fast Advance PCR Master Mix, and TaqMan MicroRNA primers (Applied Biosystems). All reactions were analyzed using StepOne Real-Time PCR System (Applied Biosystems).
Anti-dsDNA ELISA
After the collection of leukocytes with the LeukoLOCK filters, the leukocyte free blood was transferred to 10 ml Vacutainer SST plus blood-collection tubes (BD, Franklin Lakes, NJ, USA). Blood was centrifuged at 1,000 g for 20 minutes. The plasma was transferred to a 15-ml conical tube and stored at −20°C. Anti-dsDNA ELISA was performed as previously described[48]. In brief, anti-human IgG secondary antibody was used and samples were considered positive when the absorbance was greater than the mean plus three SD from the healthy controls.
Complement levels
C3 and C4 complement levels were obtained from clinical data. C3 levels lower than 90 mg/dl and C4 levels less than 15 mg/dl were considered as low complement levels in the analysis.
IFN score and SLE activity
The expression of three known type-I IFN signature genes, MX1, OAS1, and LY6E, was z-transformed into IFN score as previously shown[1, 49]. The SLE disease activity index (SLEDAI) was used to classify the patients into active (SLEDAI >4) or inactive (SLEDAI ≤4) at the time of the visit (Table 1)[50, 51].
Cell culture and innate immune ligand stimulation
Human THP-1 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). THP-1 cells were maintained in RPMI containing 10% (v/v) FBS (Mediatech, Manassas, VA, USA) and 100 U/ml penicillin-streptomycin (Mediatech). For analysis of THP-1 monocyte response to ligand in vitro, log-phase cells were seeded at 5 × 105 cells/ml in a 24-well plate. Cells were stimulated with the following agonists: 1,000 ng/ml of lipopolysaccharide from S. enterica serotype Minnesota Re595 (LPS Se, TLR4 ligand, Ultrapure grade, Sigma-Aldrich Corp. St. Louis, MO USA), 0.10 and 1.0 ng/ml IFNα2 (PBL Interferon Source, Piscataway, NJ, USA), and 0.10 or 1.0 ng/ml IFNβ (PBL Interferon Source). TLR4 ligands were reconstituted in endotoxin-free water and used at concentrations as reported before[38]. IFNα2 and IFNβ were reconstituted in endotoxin-free PBS with 1 mg/ml BSA to make 5-μg/ml stocks stored at −80°C.
Data analysis
The copy number of miR-146a was normalized to total loaded RNA, whereas mRNA levels were normalized to 18S RNA. The copy number of miR-146a was determined using a standard curve with synthetic miR-146a (Integrated DNA Technologies Inc., Coralville, IA, USA)[52]. Relative expression of mRNA compared to controls was determined by the ΔΔCT (cycle threshold) method[53]. Analyses were performed using SAS version 9.2 and JMP Genomics version 5 (SAS, Cary, NC, USA). The Wilcoxon/Kruskal-Wallis test was used to evaluate significance between groups, whereas the Wilcoxon signed rank test for matched pairs was used to evaluate SLE patients with two visits. P-values <0.05 were considered significant. Before applying ordinary linear regression analyses, the distributions of datasets were confirmed for normality. The coefficient of determination (r2) was used to determine linear correlation. Significant differences between slopes was evaluated by analysis of covariance (ANCOVA). The Generalized Estimating Equation (GEE) model for Repeated Measures was used to account for possible with-in subject effects from patients with multiple visits[54].
Expression of candidate biomarkers in the SLE cohort
The influence of race in anti-dsDNA, IFN score, STAT1, CCL2, and CXCL10 were also examined. African Americans (AA) and European Americans (EA) contributed to 83.3% of the visits, followed by Latin Americans (LA) and Asian Americans (AsA) for 15%, and interracial Americans (IrA) for less than 2% of patient visits (Table 1). Due to the small sample size, IrA were excluded in all subsequent analyses. In general, results show that higher levels of anti-dsDNA, IFN score, STAT1, CCL2, and CXCL10 were observed in all race groups analyzed (Additional file1: Figure S1). The lack of statistically significant differences between SLE and HD in certain groups, such as LA, might be due to the smaller sample sizes.
By comparing patients of different race (Additional file1: Figure S2), the levels of the parameters examined were all higher in AA than EA, LA, and AsA. In particular, AA had significantly higher SLEDAI (P = 0.024), anti-dsDNA level (P = 0.044), IFN score (P = 0.0005), STAT1 (P = 0.0011), CCL2 (P = 0.0004), and CXCL10 (P = 0.0004) than EA. Furthermore, AA had significantly (P ≤0.014) higher IFN score, STAT1, CCL2, and CXCL10 than LA (Additional file1: Figure S2B-F). Also in this case, the lack of additional statistically significant results for LA and AsA might be due to the small sample sizes. However, AA clearly displayed increased biomarker levels more than any other race.
Biomarker interrelationship in SLE patients with return visits
SLE patients who had decreasing IFN score by at least 50% between first and second visit (N = 32; P <0.0001, Figure 3C) displayed a significant decrease in STAT1 (P = 0.0002) and CXCL10 (P = 0.0002), but not in CCL2 and miR-146a. Similarly, SLE patients with decreasing STAT1 (n = 13; P = 0.0001, Figure 3D) had significant decrease in IFN score (P = 0.0001) and CXCL10 (P = 0.0004), whereas no significant changes in CCL2 and miR-146a were observed. By ranking patients according to decreasing IFN score or STAT1, the reversal of the results from ranking by increasing IFN score or STAT1 should ideally have been observed. Interestingly, the exception was observed only for CCL2 and miR-146a (Figure 3C, D).
Relationship of IFN score to other biomarkers
STAT1 levels correlate with SLE activity
To determine whether ethnicity could be a confounding factor for the effects of high and low STAT1, IFN score, CCL2, and CXCL10 levels were segregated based on ethnicity and high and low STAT1 (Additional file1: Figure S3A-C). Overall, high STAT1 patient visits did not show a significant difference among AA, EA, and LA. However, low-STAT1 AA patients showed significantly higher IFN score, CCL2 and CXCL10 compared to other groups (Additional file1: Figure S3). These results indicated that high- and low-STAT1 groups were identified essentially in all ethnicities, and differences in IFN score, CCL2, and CXCL2 levels were observed among low-STAT1 groups but not among the high-STAT1 groups.
STAT1 influences the covariance of IFN score with ADAR, CCL2, and CXCL10
The slope of the linear regression represents the rate of change of ADAR, CCL2, and CXCL10 per unit of change in IFN score. This led to the intriguing possibility that patient visits with high STAT1 have a higher slope than those with low STAT1. ANCOVA was used to test if the slopes were significantly different (Figure 7). ADAR/IFN scores were not significantly different between high- and low-STAT1 patients (Figure 7A, blue versus red line, P-value not shown), but CCL2/IFN score and CXCL10/IFN score slopes were significantly higher in the high-STAT1 (HS) patients compared to the low STAT1 (LS) patients (Figure 7B, C, blue versus red line). This suggests that high STAT1 levels may enhance CCL2 and CXCL10 expression potentially induced by IFN.
Next, we studied whether ethnic background could influence the association of IFN score with CCL2 and CXCL10 and altered the effects of high and low STAT1 (See Additional file1: Figure S4). Influence of ethnic background appeared to be minimal on CCL2 in high-STAT1 patient visits. CCL2 in high-STAT1 AA, EA, and LA displayed very good linear correlation (r2 >0.59, P ≤0.0018) with IFN score (See Additional file1: Figure S4A, C, E). Low-STAT1 EA and LA also showed good linear correlation (r2 ≥0.16, P ≤0.039, red, Additional file1: Figure S4C, E); however, low-STAT1 AA did not display a linear correlation between CCL2 and IFN score (See Additional file1: Figure S4A).
CXCL10 had a significant correlation (r2 >0.24, P ≤0.032) with IFN score for high-STAT1 AA and EA (See Additional file1: Figure S4B, D); however, CXCL10 had significant correlation (r2 >0.25, P ≤0.0002) with IFN score for low-STAT1 EA and LA (See Additional file1: Figure S4A, D, F). AsA could not ascertain significant correlations for CCL2/IFN score and CXCL10, probably due to the small sample size (data not shown).
Induction of STAT1, CCL2, and CXCL10 in THP-1 cells with type I IFN
Interestingly, whereas LPS displayed a gradual, long-term increase of CCL2 and CXCL10, IFNα2 and IFNβ treatments displayed rapid increases followed by decreases of CCL2 and CXCL10. After LPS stimulation, STAT1 did not increase till 4 h and reached its peak expression at 8 h (Figure 8B); however in THP-1 cells stimulated with IFNα2 or IFNβ, STAT1 increased at 2 h, peaking at 8 h (Figure 8G, L). CCL2 increased at 2 h in LPS-treated THP-1 cells and continued to increase during the 24-h period (Figure 8C); however this was not until after maximum expression of STAT1 was reached (Figure 8B), and CCL2 began to rapidly increase (Figure 8C). CCL2 increased at 2 h in 0.1 and 1.0 ng/ml IFNα2-treated as well as 0.1 ng/ml IFNβ-treated THP-1 cells, but it peaked at 4 h and began to decrease rapidly (Figure 8H). For 1.0 ng/ml IFNβ treatment of THP-1 cells, the peak was shifted by 2 h so that CCL2 peaked at 2 h and began to rapidly decrease (Figure 8M). CXCL10 displayed a trend similar to CCL2 for 1.0 ng/ml IFNα2-treated and 0.1 ng/ml IFNβ-treated THP-1 cells (Figure 8I, N). In 1.0 ng/ml IFNβ treatment of THP-1 cells, CXCL10 continued till 8 h (Figure 8N). These results indicated that CCL2 and CXCL10 rapidly responded to IFNα2 and IFNβ stimulation whereas TLR4 stimulation appeared to induce a slow gradual increase, but then a rapid increase after STAT1 reached its maximum expression.
miR-146a appeared to differ in its response from the other biomarkers. LPS upregulated miR-146 3-fold and it rapidly reached a peak of an 11-fold increase at 12 h (Figure 8E). miR-146a in IFNα2- or IFNβ-treated cells showed a modest of 3- to 4-fold peak at 8 h, potentially indicating that IFN-I did not induce significant production of miR-146a (Figure 8J, O).
In this study, expression of previously identified SLE biomarkers was examined and correlation tested with demographic and clinical parameters, focusing on the analysis of a possible correlation among them. The primary analyses used ordinary linear regression, even for data from multiple visits, as reported in Figures 4,5, and7. Alternatively, the GEE model for repeated measures was also used to account for possible within-subject effects from patients with multiple visits[54]. When we compared the parameters (slope and significance) from the GEE and ordinary linear regression, the results were practically identical (data not shown). It is known that unless the vast majority of the samples have repeated measures (patients with multiple visits), the ordinary linear regression is expected to closely approximate the GEE model[64]. Furthermore, even if there was strong correlation between visits of patients, ordinary linear regression would underestimate the correlation because it assumes that the visits are independent; therefore, the correlations of ordinary linear regressions are more stringent than those of GEE[64]. In addition, we also assessed the normality of each dataset before applying linear regression. With the exception of STAT1, the IFN score, ADAR, CCL2, and CXCL10 resembled normal distributions (data not shown). In most cases when dealing with such large datasets, even moderate deviations from normalcy are not critical due to the central limit theorem[65]. For these reasons, we decided to report ordinary linear regression rather than the more complex GEE model for repeated samples.
Biomarker assessment
Our results show that ADAR, STAT1, CCL2, and CXCL10 levels were significantly elevated in the SLE cohort as expected. This is in part validated by previously published results showing increased levels of these biomarkers and their correlation to IFN-I production in SLE patients[1, 2, 6, 21, 22, 66]. Furthermore, our study shows that THP-1 cells treated with IFNα2 or IFNβ display up to 18-fold increase of STAT1, 25-fold increase of CCL2, and 700-fold increase of CXCL10, confirming that these genes respond to IFN-I stimulation.
Tang et al. reported miR-146a under-expression in SLE PBMCs[46], whereas we did not observe a decrease or a difference between patients with active or inactive SLE for miR-146a expression in peripheral blood leukocytes of SLE patients in our cohort. Luo et al.[67] hypothesize that a functional variant in the miR-146a promoter may be responsible for decreased levels of miR-146a in SLE, so the pri-miR-146a levels should be decreased in our population; however, no significant differences in pri-miR-146a expression were observed in our population. Furthermore, Tang et al. reported inverse correlation between miR-146a and IFN score in their SLE cohort, while we did not observe a significant correlation in our cohort. A significant increase in miR-146a was observed only in SLE patients with increasing IFN score between the initial and the second visit[36]. Other possible explanations for the discrepancy between the two datasets could be the difference in cell populations and racial composition in our cohort versus the one examined by Tang et al. and Luo et al.[46, 67]. As for the THP-1 monocyte cell model, IFN-I weakly stimulated miR-146a expression compared to LPS. All these results suggest that the role of miR-146a in regulating IFN-I in our cohort of SLE patients may have been limited.
Biomarker connections
Previous reports have demonstrated the involvement of ADAR mRNA and CCL2 and CXCL10 protein in SLE[15–17, 22]. In published literature, ADAR mRNA and CCL2, CXCL10 protein levels displayed a positive association with IFN score[11, 21, 22, 68]. Similarly in our cohort, directly correlation between IFN score and mRNA levels of ADAR, CCL2, and CXCL10 was observed. This was observed not only in SLE but in HD as well, potentially indicating that these genes are responding normally to IFN even when at levels aberrantly elevated. Unlike reports from previous studies, STAT1 did not correlate well with the IFN score in the SLE patient population[69, 70]. Instead, patients with low-STAT1 SLE and HD with low-STAT1, the expression was associated with IFN score. Patients paired by two visits that were ranked by increasing IFN score demonstrate strong covariance with STAT1, but the covariance between IFN score and increasing STAT1 appeared to be weaker. In paired SLE patient visits, decreasing IFN scores or STAT1 level is accompanied by a decrease of the other biomarkers suggesting that STAT1 and IFN-I may be driving factors.
When SLE patient visits are grouped into high and low STAT1, high-STAT1 SLE patient visits showed significantly higher levels of CCL2 and CXCL10. After grouping by high and low STAT1, the high-STAT1 patient visits showed a significantly increased slope for CCL2/IFN and CXCL10/IFN scores compared to low-STAT1 SLE patient visits. This enhanced response by CCL2 and CXCL10 to IFN-I in high-STAT1 patients may be due in part to the role of STAT1 in activation of CCL2 and CXCL10[71–73]. Hence, STAT1 levels appear to be enhancing chemokine response to IFN-I.
Furthermore, THP-1 cells treated with IFNα2, IFNβ, or even LPS, demonstrated that IFN score, STAT1, CCL2, CXCL10 and miR-146a were upregulated in a time-dependent manner. IFNα2 or IFNβ treatment of THP-1 cells shows that cells expressed decreased levels of CCL2 and CXCL10 shortly after reaching their peak expression, whereas LPS treatment displayed a steady increase of CCL2 and CXCL10 with a less rapid induction compared to their expression after IFNα2 or IFNβ stimulation. After STAT1 peak expression in LPS-treated THP-1 cells, CCL2 and CXCL10 expression rapidly accelerated. On the contrary, IFNα2 and IFNβ treatment of THP-1 cells shows that CCL2 and CXCL10 both started decreasing after reaching their peak expression, whereas STAT1 continued to increase with IFNα2 or IFNβ stimulation. These results indicate that CCL2 and CXCL10 respond differently to TLR4 stimulation compared to IFN signaling. It also indicates that CCL2 and CXCL10 response to IFN-I is rapid but short compared to TLR signaling, as IFN score correlates with greater increase of CCL2 and CXCL10 in the high-STAT1 patients than in low-STAT1 patients. The results of TLR4 stimulation suggest that at least in the high-STAT1 patient population CCL2 and CXCL10 are being driven by TLR signaling rather than IFN-I directly since IFN-I stimulation caused a rapid increase followed by an equally rapid decrease of CCL2 and CXCL10 independent of STAT1 expression.
It is unclear why STAT1 was elevated to such high levels in some of the SLE patients and HD. One possibility is from TLR activation as seen in the LPS stimulations. Another possibility is impairment in the expression of miR-146a, which is known to target STAT1[46]. In the paired SLE-patient visits, miR-146a might be increased as a response to STAT1 increases, but it is unable to downregulate STAT1. One potential reason that miR-146a is unable to downregulate STAT1 is due to alternative splicing. STAT1 exists as a long form (STAT1a) and short form (STAT1b). According to the miRNA target prediction site, TargetScan.com, STAT1b has a shorter 3′ UTR compared to STAT1a 3′ UTR. The shorter 3′ UTR in STAT1b lacks miR-146a binding sites, which would prevent miR-146a downregulation of STAT1b. Several HD also displayed very high STAT1 levels, however CCL2 and CXCL10, even though elevated compared to low-STAT1 HD, were significantly lower than in SLE patients. A potential reason is that IFN-I drives CCL2 and CXCL10 expression, and high STAT1 primes the immune system to amplify CCL2 and CXCL10 expression when IFN-I is present. Without IFN-I, the high STAT1 levels may still prime the immune system but they lack the ignition to drive the process forward.
The results of this study show that STAT1 mRNA expression in PBMCs from lupus patients and healthy controls is segregated into high- or low-STAT1 groups. STAT1 may be an important driver of lupus pathogenesis with STAT1 serving as an expression enhancer of CCL2 and CXCL10 in patients with high levels of STAT1.
African Americans
American College of Rheumatology
adenosine deaminase acting on RNA
antinuclear antibody
analysis of covariance
- AsA:
Asian Americans
bovine serum albumin
C-C motif chemokine ligand 2
C-X-C motif chemokine 10
- dsDNA:
double-stranded DNA
- dsRNA:
double-stranded RNA
European Americans
enzyme-linked immunosorbent assay
fetal bovine serum
healthy donors
interferon receptor
type I interferon
- IgG:
immunoglobulin G
- IrA:
interracial Americans
interferon regulatory factor
Latin Americans
lymphocyte antigen 6 complex locus E
- miRNA:
myxovirus resistance 1
2′,5′-oligoadenylate synthetase
optical density
peripheral blood mononuclear cells
phosphate-buffered saline
protein kinase RNA-activated
systemic lupus erythematosus
systemic lupus erythematosus disease activity index
signal transducers and activators of transcription
toll-like receptor
tumor necrosis factor
untranslated region.
Supported in part by a grant from the Lupus Research Institute and the National Institutes of Health grant Al47859. PRDG was supported by NIH training grant T90/R90 DE007200. We thank all the staff at the Division of Rheumatology for collection of blood and clinical information.
Authors' Affiliations
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Clayton Hotel Silver Springs, Cork
- Free WiFi and free parking
Main amenities
- Restaurant and bar/lounge
- Indoor pool
- Breakfast available
- Free children's club
- Indoor and outdoor tennis courts
- Spa services
- Conference center
- 24-hour front desk
- Daily housekeeping
- Garden
- Computer station
- Lobby fireplace
For families
- Playground on site
- Babysitting or childcare (surcharge)
- Children's club (free)
- Connecting/adjoining rooms available
- Private bathroom
- Free toiletries
What's around
- Cork City Hall (2.6 mi / 4.2 km)
- St. Anne's Shandon Church (2.8 mi / 4.6 km)
- Bells of Shandon (2.8 mi / 4.6 km)
- Holy Family Church (2 mi / 3.3 km)
- Military Museum Collins Barracks (2.1 mi / 3.4 km)
Clayton Hotel Silver Springs, Corkfrom $73
- Executive Queen or King Room
- Superior Double or Twin Room, 1 Queen Bed, City View
- Superior Double Single Room
- Deluxe Double Room
- Deluxe Double Room Single Use
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- Family Room
- Deluxe Twin Room
More great choices
At a glance
Key facts
Hotel size
- This hotel is arranged over 6 floors
- 24-hour check-in
- Check-out time is noon
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 18
Travelling with others
- Children (2 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- Babysitting/childcare *
- Free children's club
- No pets or service animals allowed
- Free WiFi in public areas
- Free WiFi in rooms
- Free self parking
Other information
- Smoke-free property
Nearby Four Star Cork hotels
In the hotel
- Children's club (free)
- Full breakfast daily (surcharge)
- Restaurant
- Bar/lounge
- 24-hour room service
- Free reception
- Indoor pool
- Health club
- Indoor tennis court
- Spa services on site
- Spa tub
- Playground on site
- Racquetball/squash on site
- Free use of nearby fitness center
- Outdoor tennis court
- Steam room
- Tennis on site
- Sauna
- Number of meeting rooms - 9
- Meeting rooms 9
- Conference space size (feet) - 25177
- Conference space size (meters) - 2339
- Conference center
- Computer station
- 24-hour front desk
- Dry cleaning/laundry service
- Laundry facilities
- Free newspapers in lobby
- Luggage storage
- Wedding services
- Number of buildings/towers - 2
- Year Built 1964
- Elevator/lift
- Garden
- Fireplace in lobby
- Accessible bathroom
- In-room accessibility
In the room
- Coffee/tea maker
- Iron/ironing board
- Hypo-allergenic bedding available
- Blackout drapes/curtains
- Private bathroom
- Shower/tub combination
- Free toiletries
- Hair dryer
- Flat-screen TV
- Desk
- Free WiFi
- Phone
- Daily housekeeping
- In-room safe (laptop compatible)
- Connecting/adjoining rooms available
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Special features
DiningGrill - This lobby lounge serves breakfast, lunch, and dinner. A children's menu is available. Open daily.
On Site
- Health club
- Indoor tennis court
- Outdoor tennis court
- Sauna
- Spa tub
- Steam room
- Tennis on site
- Playground on site
- Racquetball/squash on site
Clayton Hotel Silver Springs, Cork's small print
Also known as
- Hotel Moran Silver Springs
- Clayton Hotel Silver Springs
- Clayton Silver Springs Cork
- Clayton Silver Springs
- Hotel Silver Springs Moran
- Moran Silver Springs
- Moran Silver Springs Hotel
- Silver Springs Moran
- Silver Springs Moran Cork
- Silver Springs Moran Hotel
- Silver Springs Moran Hotel Cork
- Silver Springs Hotel Cork
- Clayton Hotel Silver Springs Cork
This hotel reserves the right to pre-authorize credit/debit cards for any bookings where payment for the stay will be made onsite instead of at the time of booking. Should a valid card not be provided by 2 PM on the day of arrival, the hotel reserves the right to cancel a reservation. For more details, please contact the office using the information on the reservation confirmation received after booking
The property has connecting/adjoining rooms, which are subject to availability and can be requested by contacting the property using the number on the booking confirmation.
Reservations are required for massage services and spa treatments and can be made by contacting the property before arrival at the number on the booking confirmation.
Optional extras
Full breakfast is offered for an extra charge of EUR 12.50 for adults and EUR 6.50 for children (approximately)
Babysitting/childcare is available for an extra charge
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Good 3.9 /5 from 241 reviews
Great value. Thank you.
The staff was friendly and the restaurant convenient. We enjoyed our quick stay at Claytin Springs.
Nice hotel on the outskirts of Cork. The hotel exterior was undergoing renovation but the inside was nice. The buffet breakfast was great. The staff was friendly, wifi was good, and there was plenty of parking. Great hotel unless you want to experience downtown Cork.
A lot of flies near the windows in my room, like 10+ of them. Windows were not closed properly. The lobby was nice but rooms were old.
My friends and I stayed here for two nights and were very pleased overall. The hotel is about 7-10 minutes / 10 euro cab ride to city center. There is a bus stop just up the street which will also take you to city center. If you like to walk, the walk is beautiful and takes about 30 minutes. The staff is very friendly and there is a great bar in the lobby - good beer selection. Rooms were spacious, bathroom was huge and everything was clean!! The only bad thing I can say about this place is that the breakfast buffet was not worth the money. With all the good restaurant options in town, do yourself a favor and skip the buffet.
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