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Quick Answer: What Causes Dementia To Worsen?
How do you stop dementia from getting worse?
What are the first signs of your body shutting down?
How rapidly does dementia progress?
What should you not say to someone with dementia?
What causes dementia to progress quickly?
What happens when dementia gets worse?
What stage of dementia is incontinence?
At what point do dementia patients need 24 hour care?
Is it normal for someone with dementia to sleep a lot?
At what stage of dementia do hallucinations occur?
Can dementia get better?
Does sugar make dementia worse?
Can dementia get worse suddenly?
What are the signs that someone with dementia is dying?
Why do dementia patients get up at night?
How long does the aggressive stage of dementia last?
What foods are bad for dementia?
How can you reverse dementia naturally?
What is the last stage of dementia?
How does peanut butter detect Alzheimer's?
What medications make dementia worse?
However, there are actions that one can take to reduce the risk for dementia and, in some cases, slow the progression of the disease….These factors include:Physical Exercise.Healthy Diet.Heart Healthy Behaviors.Avoiding Head Injury.Mental Activities.Socializing..
You may notice their:Eyes tear or glaze over.Pulse and heartbeat are irregular or hard to feel or hear.Body temperature drops.Skin on their knees, feet, and hands turns a mottled bluish-purple (often in the last 24 hours)Breathing is interrupted by gasping and slows until it stops entirely.
Rapidly progressive dementias (RPDs) are dementias that progress quickly, typically over the course of weeks to months, but sometimes up to two to three years. RPDs are rare and often difficult to diagnose. Early and accurate diagnosis is very important because many causes of RPDs can be treated.
"The development of this list has sometimes been taken the wrong way by family care partners.Don't say 'but you don't look or sound like you have dementia'.Don't tell us 'we are wrong'.Don't argue with us or correct trivial things.Don't say 'remember when…'.More items…•
Most cases of sudden confusion and rapidly progressing dementia in an elderly person are due to delirium caused by infection. Urinary infections and pneumonia can trigger acute confusion that comes on quickly, causing people to be incoherent, muddled and disorientated.
Moderate dementia increasing confusion or poor judgment. greater memory loss, including a loss of events in the more distant past. needing assistance with tasks, such as getting dressed, bathing, and grooming. significant personality and behavior changes, often caused by agitation and unfounded suspicion.
Incontinence is a symptom that develops in the later stages of dementia. About 60 to 70 percent of people with Alzheimer's develop incontinence. But it's not a defining trait.
During the middle stages of Alzheimer's, it becomes necessary to provide 24-hour supervision to keep the person with dementia safe. As the disease progresses into the late-stages, around-the-clock care requirements become more intensive.
It is quite common for a person with dementia, especially in the later stages, to spend a lot of their time sleeping – both during the day and night. This can sometimes be distressing for the person's family and friends, as they may worry that something is wrong.
Both hallucinations and delusions in people with Alzheimer's often occur in the late-middle to later stages of the disease.
Treatment of dementia depends on its cause. In the case of most progressive dementias, including Alzheimer's disease, there is no cure and no treatment that slows or stops its progression. But there are drug treatments that may temporarily improve symptoms.
A study that was recently published in the New England Journal of Medicine found that even without having the pre-existing condition of diabetes, sugar and dementia are still directly correlated and that a blood sugar level above normal (numbers vary, due to your unique activity level and weight, among other things) …
Vascular dementia causes problems with mental abilities and several other difficulties. The symptoms can start suddenly or gradually. They tend to get worse over time, although treatment can help slow this down.
Tips for managing dementia end-of-life signs. These signs may include moaning or yelling, restlessness or an inability to sleep, grimacing, or sweating. This may also signal that it's time to call hospice or a palliative care team to help with the pain management.
Dementia and sleep problems: causes Less exposure to sunlight, which affects the sleep cycle. Physical or mental exhaustion at the end of the day. Chronic pain. An environment that is inadequate for sleep, such as a noisy or bright room before bedtime.
It may be too difficult to walk, and extensive help is needed for daily living activities, including personal hygiene and eating. At the end of this stage, the individual will most likely be bedridden. This severe stage of dementia lasts approximately 1 to 3 years.
The MIND diet specifically limits red meat, butter and margarine, cheese, pastries and sweets, and fried or fast food. You should have fewer than 4 servings a week of red meat, less than a tablespoon of butter a day, and less than a serving a week of each of the following: whole-fat cheese, fried food, and fast food.
We now know otherwise. Similarly, dementia can be reversed if caught early enough and by attending to all the factors that affect brain function – including diet, exercise, stress, nutritional deficiencies, toxins, hormonal imbalances, and inflammation. To do this is, in fact, quite simple.
A person with later stage dementia often deteriorates slowly over many months. They gradually become more frail, and will need more help with everyday activities such as eating, dressing, washing and using the toilet. People may experience weight loss, as swallowing and chewing become more difficult.
The researchers discovered that those who had an impaired sense of smell in the left nostril had early-stage Alzheimer's. They noted that the participants needed to be an average of 10 centimeters closer to the peanut butter container in order to smell it from their left nostril compared to their right nostril.
Medications: Some Drugs Make Dementia WorseBenadryl, found in cough syrups and over-the-counter allergy and sleeping pills such as Tylenol PM®. … Bladder pills such as Tolterodine/Detrol®, Oxybutynin/Ditropan. … Tropsium/Sanctura®, do help when patients need to urinate often.More items…
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Quick Answer: What Is The Month Of Nutrition?
What is the theme of WHO 2020? 2020: Support Nurses
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Do referees get Super Bowl rings? While much attention
Quick Answer: Why Are My Teeth Yellow When I Brush Them Everyday?
Is it true banana peels whiten teeth? Unfortunately
What Is A Chronic Injury?
What is a chronic overuse injury? Chronic injuries
What Make You Taller?
Does sleep affect height? But over the long term, a
Question: What Is The Most Famous Tribe In Africa?
What is the most dangerous tribe in Africa?


Artist Talks occur on the first Monday of each session at 5:30 PM at The Pines Community Center Whyte Hall.
BOFFO Teas are hosted every Monday at 6:30 PM at The Blue Whale.
Movie Nights are hosted every Wednesday at 8:30 PM at the Pool Deck.
Children's Workshops are lead by the artist in residence and take place on Sundays on the beach at Beach Hill. To register, send an email to .
Please register your children in advance by sending their names and ages along with the dates to .
Miguel Gutierrez, a 2010 Guggenheim Fellow in choreography, lives in Brooklyn and makes performances. He is currently created a series of queer pieces in three parts called Age & Beauty. Part 1 premiered in the 2014 Whitney Biennial, Part 2 premiered in American Realness 2015, and Part 3 will premiere at the Fisher Center for the Arts at Bard College in September 2015. Other recent work includes Storing the Winter (with Mind Over Mirrors), And lose the name of action, and HEAVENS WHAT HAVE I DONE. His work is presented frequently in NYC, across the country and internationally at venues and festivals such as the Brooklyn Academy of Music and Dance Theater Workshop, On the Boards In Seattle, Walker Art Center in Minneapolis, TBA/PICA in Portland, Pompidou Centre in Paris, ImPuls Tanz in Vienna and many others. He has been an artist-in-residence at Bard's Fisher Center, MANCC, LMCC and CCN Montpellier. He has received fellowships from from Foundation for Contemporary Art, United States Artists, Lambent Foundation, New York Foundation for the Arts and support from MAP Fund, National Dance Project, National Performance Network, Jerome Foundation and Creative Capital. He has created commissions for BalletLab in Melbourne, The Fondue Set in Sydney, Movement Forum in Salt Lake City, and Fauxnique in San Francisco. He has choreographed music videos for Diane Cluck, Holcombe Waller and Le Tigre, has released an EP as The Belleville, has performed frequently at Joe's Pub and has sung with Antony and the Johnsons, Justin Vivian Bond, Nick Hallett and My Robot Friend. He teaches at Hollins University and Movement Research. His book WHEN YOU RISE UP is available from 53rd State Press and he maintains a blog at Stargayze.com. His work is discussed in Jenn Joy's recent book The Choreographic. He invented the absurdist workout DEEP AEROBICS, most recently used to warm up audiences for The Knife's tour, and he is training to become a Feldenkrais Method practitioner. He studies singing with Barbara Maier.
Anna Betbeze's work approaches painting with rigorous and alchemical experimentation that index action in relation to sensation and pleasure. Her most notable body of work to date engages wool flokati carpets as a ground for color saturation, physical distress, and natural processes to manipulate the surface. The shaggy reliefs hover between the visceral and the pictorial,painting and sculpture, and locate paradoxes such as the simultaneity of beauty and abjection.
Betbeze was born in 1980, grew up in Columbus, GA and currently lives and works in New York, NY. Betbeze has held solo exhibitions at Kate Werble Gallery, New York, NY; Massachusetts Museum of Contemporary Art, North Adams, MA; University of the Arts, Philadelphia, PA Lüttgenmeijer, Berlin, DE; and François Ghebaly Gallery, Los Angeles, CA. Her work has been exhibited at venues including Musée d'Art Moderne de la Ville de Paris, Paris, FR; Power Station of Art, Shanghai, CN; MoMA PS1, Long Island City, NY; Johnson Museum of Art at Cornell University, Itahaca NY; Galerie Perrotin, Paris, FR; Mitchell-Innes & Nash, New York, NY; Tonya Bonakdar Gallery, New York, NY; and Ramiken Crucible, New York, NY.
Betbeze is a recipient of the 2013-2014 Rome Prize and is Senior Critic at Yale University School of Art.
Jacolby Satterwhite's video works bring together 3-D animation, drawings, and live performance to construct utopian digital worlds. Within this uncharted digital architecture, Satterwhite explores personal history, identity and memory. Satterwhite often incorporates personal sources such as his mother's drawings, which he hand-traces and imports into 3D animation programs to build lush, computer-generated landscapes. Into these digital realms he inserts multiple elaborately costumed avatars, whose kinetic gestures compose a sensual physical choreography. Fusing pop culture, subculture, and art history in his video work and performance, Satterwhite creates visually dazzling tableaux that reflect the changing spatial and bodily anxieties and desires of the digital world. Satterwhite's computer-generated realms densely layered with proliferating drawings, objects and performances encompass animated narratives of personal memory and identity.
Jacques Servin is an internationally known media artist and writer, and co-founder and co-director of the Yes Men and the Yes Lab. His last position was as Visiting Associate Arts Professor at NYU, where he also directs the Critical Tactics Lab. Servin is the author of two collections of short stories, and has published numerous articles and stories internationally; his software art pieces have been featured in numerous exhibitions. As Andy Bichlbaum of the Yes Men, he has starred in the documentary hit The Yes Men, and co-wrote, co-directed, co-produced, and co-starred in the award-winning feature documentaries The Yes Men Fix the World and The Yes Men Are Revolting (debuting theatrically at IFC on June 9). Servin's individual and collective work with the Yes Men has appeared in the Whitney Biennial, the Venice Biennale, ARS Electronica, and many other art venues. In 2013, Servin designed and co-launched the Action Switchboard, a platform to facilitate creative activist projects worldwide.
Rashaad Newsome's work is hinged on the sampling and the recontextualizing of contemporary cultural elements in traditional frameworks. Using the equalizing force of sampling, he crafts compositions that frequently surprise in their associative potential and walk the tightrope between identity politics and abstraction. Newsome's collages, videos, sculptures, performances, and sound pieces work to oppose cultural essentialisms. They lead us into a realm of uncertainty, in which the symbols presented lose significance, but are nonetheless made comprehensible. Newsome earned his BFA from Tulane University in his native New Orleans, Louisiana. He participated in the 2010 Whitney Biennial, Greater NY 2010, Performa 2011, and the 2011 Venice Biennale. Newsome has exhibited at The Drawing Center, New York, NY; MoMA PS1, New York, NY; The New Museum, New York, NY; The Studio Museum in Harlem, NY; the New Orleans Museum of Art, New Orleans, Louisiana; and the Centre Pompidou, Paris, France. His work is included in such public collections as the Brooklyn Museum, the San Francisco Museum of Modern Art and the Whitney Museum of American Art. He has been the recipient of such awards and residencies as The Louis Comfort Tiffany Foundation Award, New York, NY; The Headlands Center for the Arts, Sausalito, California; and the McColl Center for Visual Art, Charlotte, North Carolina, among others.
Xavier Cha's performance-based work revolves around modes of accessibility, exchange, and hierarchies of space and perception. Collaboration is often at play in her performances: Xavier has invited actors, dancers, musicians, programmers, cults, and clowns, among many other non-artist performers, to not only participate in her projects, but also to become protagonists in the work. Through these events, Cha formalizes subjectivity within contemporary culture, isolating elements of production, perception and communication into bare, abstract and often illogical experience. In stripping away extraneous content, Xavier reveals phantasmic qualities of consumption, trends, and cultural engagement. Her work has been exhibited at the Whitney Museum of American Art, the New Museum, Kunsthalle Düsseldorf, the Institute of Contemporary Art, Philadelphia, de la Cruz Collection Contemporary Art Space, The Kitchen, Museum of Contemporary Art North Miami, Contemporary Art Museum St. Louis, Northern Gallery for Contemporary Art (UK), the Sculpture Center, Asia Society Museum, and the Hammer Museum, among other galleries and museums throughout the United States and Europe.
Multi-instrumentalist and composer, Tara Jane ONeil creates melodic and experimental music under her own name and in collaboration with artists of all disciplines. As a solo artist TJO has released 7 full length albums internationally. JMY JAMES KIDD designs dances, clothing, and community spaces as James Kidd Studio.
Tara Jane and JMY live and work together in Los Angeles. Since 2102 Oneil and Kidd have been exploring notions of somatic listening, to develop a body of work which encourages complementary vibrational parallels. The work is both music and dance, it uses intention and receptivity to weave the air of space. Their wild and ecstatic pieces have been performed at the New Museum, New York, NY; the Hammer Museum, Los Angeles, CA; High Desert Test Sites, Joshua Tree, CA; REDCAT, Los Angeles,CA; Honor Fraser Gallery, Los Angeles, CA; the Skirball Center, Los Angeles, CA, and many other natural and theatrical venues.


Welcome to week one of our blog series aimed at helping you make the most of the camera you already carry with you everywhere you go. If you missed our article last week introducing this series, take a moment and check it out. This series was inspired by a mildly caustic article we shared a few weeks ago, Don't Buy a Camera, where I tried to save you some money on something you weren't likely to use anyway.
Well, here we are in week one of our, possibly, never-ending semi-monthly series. This series will be light on 'technical aspects' of photography (yes, even smart phone photography has technical aspects) but there are some things we should discuss before we get to anything really 'actionable'. I don't want to just start spitting how-to advice at you that lacks a larger context; I want you to have the option of back tracking through this series and filling in knowledge gaps, if you choose.
So, I want to lay some 'ground rules' and set some expectations for thinking about and acting on the coming advice. As long as you take this in, and remember it, the tips, tricks, strategies and skills won't be so frustrating. The fact of the matter is, your not suddenly going to turn into the next Ansel Adams. You're probably not even going to suddenly turn into that person you so admire on Instagram. You could, but that's not our goal here. Instead, our goal is to make everyday photography more rewarding and less frustrating. And, if you're so inclined, give you a realistic and affordable (you already own the equipment) launching point to experience photography as a more serious hobby.
As we progress through this series, I'll do my best to source the knowledge I'm dolling out with more technical learning resources. Lets jump in.
This wasn't always such a complicated question to answer. At one point, photography was prohibitively expensive, brutal and unforgiving. At one time, a 'snapshot' may have taken a lifetime to master. The term 'photographer' was aptly applied to those people. Things are messier today. Given virtually everyone takes photos, 'photographer' and 'person' are practically synonyms. Hell, even monkeys have been known to take some photos, now and again. In other words, without some qualifying definition, the term 'photographer' is almost meaningless.
I think a more useful definition—and the one I'll be using in this series—is someone who takes pictures purposefully, and who wants to enjoy (or wants others to enjoy) the aesthetic quality of the images they create. By this definition, the chief difference between a 'photographer' and a 'professional photographer' is simply how seriously they pursue those goal (and yes, whether they get paid to do so).
There's a blurry line here that we won't attempt to clarify. In fact, unless you fancy yourself an artist, or an enthusiastic and serious appreciator of art, it really doesn't matter.
When I hear people talk about wanting to take better photos, I frequently perceive a certain kind of insecurity. They frequently use qualifying terms—like they really want me to know they don't think they're an artist, as if that's a badge of honor thats difficult to affix. Or, maybe they're afraid of being labeled a 'bad artist'.
Whatever the case, wanting to take better photos doesn't mean you're an artist. It doesn't mean you want to be an artist. It doesn't mean you suddenly have to analyze every aspect of a picture you take, and it doesn't mean every picture you take has to be layered over and over with social or personal meaning. All it really means is that you want to enjoy this thing you do all the time, and want to get more enjoyment from the results.
I touched on this in the series introduction. Here's what is critical you understand: reading this article isn't going to help your photography any more than an unused camera sitting in a bag in your closet will. Reading every book about photography on Amazon is not going to make you good at taking pictures. That's just not how this works.
There is no way around this—practice is the only path to improving your photography skills. But, the good news is that if you practice with your smart phone, those skills will translate almost seamlessly to every other camera you'll ever use. Maybe you never move onto more specialized equipment, or maybe you do. Either way, the practice is indispensable.
You might want to consider giving yourself a personal challenge which forces you to practice a little every day. "Take at least one photo of your kids every day", "take at least one photo in the office, every day", "take at least one photo every time your family goes out together". It could really be almost anything, but it should be something. And, bonus points if you keep up with this series and make your practice each week reflect the skills we talked about.
Practice is the only way to get better at anything, and photography is no exception.
Join us next week when we'll demystify some of the basic, unavoidable photographic 'technicalities' I promised we would steer clear of. We'll try and get those out of the way early so we can move onto more practical information. Is there something you'd like us to cover in this series? Tweet your questions at us, or just leave a comment! We'd also love to see your progress, so don't be shy! Share and subscribe to join us on this journey!


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Springfield Armory's Hellcat (CCW Game Changer)
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Company Co-Founded by Pelosi's Son, Charged W/ Securities Fraud & Connected to Ukraine
By Raymond Draper	 On Dec 1, 2019
Opinion| By HJIC A little context to former Vice President Joe Biden's son Hunter Biden's Ukraine-China scandal that's unfolding thanks to an investigation by President Trump's attorney Rudy Giuliani:
Another prominent Democrat's child was implicated in a different form of corporate corruption, in 2014, and, and was later tied to Ukraine, in 2017. That was the son of the House Minority Leader and current Speaker of the House.
Reporting by The Washington Free Beacon The Securities and Exchange Commission (SEC) charged a company co-founded by Paul Pelosi Jr. with fraud on Wednesday after learning that two convicted criminals were running the business.
Paul Pelosi Jr., the son of House Minority Leader Nancy Pelosi (D., Calif.), was the president and chief operating officer of Natural Blue Resources Inc., an investment company he cofounded that focuses on "environmentally-friendly" ventures.
The SEC charged four individuals with fraud, including former New Mexico Gov. Toney Anaya, and suspended trading in the company's stock. Pelosi owned over 10 million shares in the company in 2009.
The SEC said Wednesday the company was "secretly controlled" by James E. Cohen and Joseph Corazzi, both of whom had previous fraud convictions.
The SEC suspended trading in Natural Blue stock. A notice filed in the Federal Register on Wednesday by Jill M. Peterson, assistant secretary of the SEC, revealed that the company has not filed any periodic reports, which are required by law, with the SEC in four years.
"It appears to the Securities and Exchange Commission that there is a lack of current and accurate information concerning the securities of Natural Blue Resources, Inc. because it has not filed any periodic reports since the period ended September 30, 2010," Peterson said, in the order announcing suspension of trading.
The Free Beacon reported that Pelosi was still listed with The New Mexico Office of the Secretary of State Business Service Division as the president of Natural Blue at the time it filed the report.
The New Mexico Office of the Secretary of State Business Service Division had designated Natural Blue as a company "not in good standing."
Also, the now-defunct Mountain View Telegraph also cited Pelosi as Natural Blue's president in an article that ran the previous year.
Hunter Biden partnered with the nephew of mobster Whitey Bulger. Now we learn that Paul Pelosi partnered with James E. Cohen and Joseph Corazzi, both of whom had previous fraud convictions.
And then there's this…
(Nationalfile.com) House Speaker Nancy Pelosi's son Paul Pelosi Jr. visited Ukraine in 2017 to meet with government officials in connection to a business initiative. Now, unearthed records reveal that Paul Pelosi Jr. was an executive of a gas industry company that did business in Ukraine – and his mother Nancy Pelosi was featured in one of the company's promotional videos.
BOOM: Nancy Pelosi's son Paul Pelosi Jr. (who went to Ukraine in 2017) was a board member of Viscoil and executive at its related company NRGLab, which DID ENERGY Business in UKRAINE!
And Nancy Pelosi appeared in a promotional video for the company!https://t.co/wlndLhPqLe
— Patrick Howley (@HowleyReporter) October 3, 2019
If this report proves to be true, it adds to the growing suspicion that Ukraine was viewed as a piggy bank by powerful Democrats during the Obama administration.
Nutso Nancy Pelosi Chases Congressman Across House Floor: WATCH VIDEO
It's still the talk of the town…and beyond – Nancy Pelosi's unhinged "how dare you" display on the floor of the House. Confronting, then chasing down a congressman who had the you-know-whats to criticize Pelosi's leadership on immigration reform and border security.
The Cali Queen of Mean lost it!
In an unusual breach of decorum, even for the divided Congress, House Minority Leader Nancy Pelosi chased Rep. Tom Marino across the House floor, taking offense at comments by the Pennsylvania Republican during debate on the border funding bill.
That congressman who was the target of nutty Nancy's wrath, Tom Marino (R-PA), later described to Fox News what happened, and how Pelosi angrily insulted him and his constituents, calling him "insignificant" several times.
After Marino concluded his remarks and as many Republicans applauded their colleague, Pelosi crossed the chamber again in view of cameras, enraged, pointing and sticking her finger at Marino.
She then followed Marino up a Republican aisle, gesturing and arguing with him. Lawmakers on the GOP side gathered in dismay as one spoke out to tell the chair that the House was not in order, in an effort to halt the bickering.
According to Pelosi spokeswoman Evangeline George, "Leader Pelosi just wanted to remind the Congressman that House Democrats had the courage to pass the DREAM Act – and have the courage to stand up for what the American people want: bipartisan, comprehensive immigration reform."
George added that "Pelosi accepted the Congressman's apology."
But Marino's chief of staff, Bill Tighe, stressed that Marino did not apologize to Pelosi, and will not apologize.
"[Rep. Marino] did not apologize to Leader Pelosi and does not intend to do so as he has nothing to apologize for. She was entirely out of line in approaching him while he was recognized and delivering remarks on the Floor," Tighe wrote in an email. "Her staff's comment in your story about her accepting his apology is simply not true."
What Did Pelosi Say About Trump That Made Maxine Waters Become Unhinged???
it was one small phrase that made Aunt Maxine almost spit her coffee!
She called Trump, President George Bush!
Pelosi has had a large number of appearances in the last few years where she seems dazed and confused, but this one is very telling! This is at LEAST the third time she has called President Trump, 'President Bush'!
But the reaction it made Maxine Waters have will have you watching the video over and over!
During an appearance at The Commonwealth Club in San Francisco, Nancy Pelosi had also called President Trump 'President Bush' and then could not remember 'President Trump'!
"They do not believe in it," Pelosi said. "And a lot of those people voted for George— for, what's his name?" she asked.
During an April appearance on "This Week" today, Pelosi did the exact same thing…
"I'm so sorry, President Bush," Pelosi said, "I never thought I would pray for the day that you were president again."
This latest gaffe would be hilarious if it was not so serious for our leaders to be of sound mind.
During a press briefing last week, the House Minority Leader criticized the president's choice of visiting Saudi Arabia first during his inaugural foreign trip.
She actually complained about the 'alphabetical' order in which President Trump is visiting other countries.
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'You're A Damn Liar, Man!': Joe Biden Snaps At Voter During Iowa…
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Fotolia pictures are shown in the editor with watermark and low resolution. Of course the later printings contain no watermark and are well resolved according to the high-class index of the editor.
Pattern Designs are shown in the editor with watermark and low resolution. Of course the later printings contain no watermark and are well resolved according to the high-class index of the editor.
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Seriously, don't you watch phone in bed! This tune sounds familiar? When night fell, the sleeping when they lying in bed browsing Facebook, may also encounter one or two as you can't sleep with teammates. You also notice, until one o'clock in the morning it was also posted on Facebook. Until the next day when I was awakened by my alarm clock and don't know how to fall asleep last night.
This is not the life of a small group, but many people in the State! This is a sociologist could not bear to look directly at the phenomenon and even Internet addiction symptoms. Recently, a 9,846 16-19 young people, continuing a two-year study has confirmed that the phone's screen effects on sleep. The study published Monday in the medical journal BMJ Open top.
Researchers recorded the sleep of teenagers and the equipment used, and focuses on an hour before going to bed. Study results showed that sleep has a relationship with equipment using time: the longer the device, face higher risk of insomnia.
One researcher said, almost all of the teenagers used an hour before going to bed one or more electronic devices. Prolonged use of electronic equipment and sleep latency (SOL) and lack of sleep were significantly positively correlated, the use of longer, a sleep latency and sleep deprivation symptoms more severe. Sleep time was negatively correlated with electronic devices, using the longer and shorter sleep time.
So why, exactly, the phone's screen will let us sleep? Early research indicates that LED screens, Blu-ray will interfere with the brain and sleep-related hormone: melatonin. This may explain why twilight shimmer eye application software (Twilight) to protect the eyes, do not interfere with sleep. This is because the software can be automatically adjusted according to the ambient light intensity and Blu-ray. The application on Google app store with more than 74,000 more praise.
But this thing is so over it? Oh, no! The team also made a factor affecting sleep: electromagnetic radiation. We watch phone in bed position, usually bow posture leads to headaches and muscle aches. This does not include the impact of the explosion of Internet information on the brain.
The study also pointed out that there are a lot of theories to explain the relationship between electronic equipment and sleep. And the use of social media will also directly affect sleep. Because these social media takes up a lot of our time, or through physiological and psychological arousal interferes with normal sleep rhythms. Simply put, you compare used gun artifact and philosophy reading applications, which affect sleep?
In fact, sleep affects not just because you are using the phone, but you use your phone is doing things! All the important social news (such as divorce) and social media are all over your brain, even a legend like candy crushed hand, also makes you raise your heart rate, leading to highly nervous state.
Of course, it will take more research to determine the electronic equipment and the relationship between, because now science can't yet complete solution of intelligent mobile phone insomnia cause.
But we can do some basic protection measures, such as proper dozed off or slow down the reading speed. If you need to read on the screen, do not blindly believe the Kindle or iBooks application. Of course, the best on a mobile phone or Tablet is not too long to read. Because your brain to contact these devices have generated some excitement. Whenever in the usual mobile phone, you can adjust the brightness. Of course, you can try to wear blue glasses to read mobile phone, so that you can screen all of the absorbed blue light (this is a joke).
In fact, very simple, brush less tweets, friends or other social media, then you will sleep well.
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text:
Frontiers in Immunology
Viral Immunology
Linda F. Van Dyk
University of Colorado Denver, United States
Sarah Rowland-Jones
Nuffield Department of Medicine, Medical Sciences Division, University of Oxford, United Kingdom
Pilar Perez-Romero
National Center of Microbiology, Instituto de Salud Carlos III, Spain
Open Supplemental Data
Front. Immunol., 24 April 2019 | https://doi.org/10.3389/fimmu.2019.00898
Cytomegalovirus Infection May Trigger Adult-Onset Still's Disease Onset or Relapses
Jinchao Jia1†, Hui Shi1†, Mengguo Liu2, Tingting Liu1, Jieyu Gu1, Liyan Wan1, Jialin Teng1, Honglei Liu1, Xiaobing Cheng1, Junna Ye1, Yutong Su1, Yue Sun1, Wen Gong1, Chengde Yang1* and Qiongyi Hu1*
1Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
Previous studies have revealed that several micro-organisms, especially DNA viruses, have been associated with adult-onset Still's disease (AOSD). However, there are no studies on the relationship between the presence of viral infections in AOSD patients with disease occurrence and reactivation. In the present study, we aimed to investigate the presence of antibodies against virus, virus DNA load and nucleic acid sensors in AOSD patients. Anti-viral antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in plasma samples from 100 AOSD patients and 70 healthy controls (HCs). The copy number of cytomegalovirus (CMV) DNA in 100 AOSD patients was detected by PCR. The expression levels of nucleic acid sensors interferon gamma-inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) in peripheral blood mononuclear cell (PBMC) and skin from AOSD patients and HCs were analyzed by PCR and immunohistochemistry. The levels of antibodies against CMV were significantly higher in AOSD patients compared to HCs. Moreover, the level of anti-CMV IgM antibody was significantly increased in patients with fever, sore throat, arthralgia and rash. CMV DNA was found in plasma of AOSD patients with disease new-onset and relapse. Furthermore, the copy number of CMV DNA significantly increased in patients with fever, sore throat, arthralgia and rash. And the significant associations of the CMV DNA level with the levels of leukocytes, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were observed. Moreover, we found an upregulation of cytoplasmic DNA-sensing receptor IFI16 and AIM2 in PBMC and skin from AOSD patients. In conclusion, our results showed that CMV infection may play a role in the initiation or amplification of inflammatory responses in AOSD.
Adult-onset Still's disease (AOSD) is a rare but clinically well-known systemic inflammatory disease. It is typically characterized by a high spiking fever, evanescent skin rash, arthralgia, sore throat and neutrophilia (1–3). Even though the etiology of AOSD remains unknown, there is evidence that it's triggered by environmental factors with genetic predisposition (4). It has long been suspected that viral infections might contribute to the onset and relapse of AOSD, although definitive evidence has not been presented.
The link between an infectious agent and the development of AOSD has long been discussed (5), and in 1988 research reported that evidence of viral infections was acquired in three of five patients with AOSD, including echovirus 7 and rubella virus (6). Since then, several researchers have reported the occurrence of AOSD after viral infections, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6, influenza virus, parainfluenza viruses, or coxsackie virus (7–9). In addition, AOSD patients often present with high fever, sore throat and rash, just before the initiation of the disease or the relapse. These manifestations were similar to viral infections with infectious danger signal to trigger inflammatory response (10). Studies during the past decade have emphasized the importance of viral infections to AOSD onset, while data available were based on some cases, and a cohort study to determine the existence of viral infections in AOSD is still lacking (11). Therefore, more evidences need to be provided to explore the relationship between viral infections and onset of AOSD with a cohort study.
The cytokine storm of AOSD is critical to the pathogenesis of AOSD, which is activated by innate immune cells. Over-production of pro-inflammatory cytokines is found in AOSD, including TNF-α, interleukin (IL)-1β, IL-18, and IL-6 (2). The starting point of cytokine storm is probably from specific viral danger signals. Host defense against viruses relies partly on receptors that monitor the presence of non-self nucleic acids associated with viral infection (12). Most of the nucleic acid receptors majoring in inducing pro-inflammatory transcription factors have been identified. The RIG-I-like receptor family of RNA sensors include retinoic acid inducible gene I (RIG-I; also known as DExD/H-box helicases 58, DDX58) and melanoma differentiation associated gene 5 (MDA5; also known as IFIH1, interferon induced with helicase C domain 1). The DNA sensors include AIM2 and cyclic GMP-AMP synthetase (cGAS) (13). RIG-I-like receptors detect RNA molecules that are absent from the uninfected host (14). DNA receptors alert the cell to the abnormal presence of non-self nucleic acids in the cytosol (15). The signaling pathways triggered by RNA and DNA receptors can activate NOD-like receptor protein 3 (NLRP3) inflammasome, produce pro-inflammatory cytokines and chemokines (16). To date, the virus signaling pathway in AOSD has not been assessed.
In the present study, we aimed to investigate the association of CMV, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2) and EBV with clinical manifestations by measuring anti-viral IgG and IgM antibodies in plasma from 100 AOSD patients and 70 matched healthy controls. And we determined the relationship between appearance of CMV DNA and disease onset and relapses. Finally, we identified the expression pattern of DNA-sensing receptors in AOSD patients. Our results provided further insight into the role of viral infection in the pathogenesis of AOSD.
AOSD Patients and Healthy Controls Subjects
A total of 100 AOSD patients (69 active and 31 inactive AOSD patients) and 70 HCs were included in the present study. All patients fulfilled Yamaguchi's criteria after exclusion of those with infectious, neoplastic and autoimmune disorders (17). Patients were considered as having active AOSD if they had fever and/or arthralgia/arthritis and/or any suggestive skin lesions and/or sore throat. New-onset patients were defined as newly diagnosed AOSD patients with the first appearance of the signs or symptoms and no previous treatment of steroid or synthetic disease-modifying antirheumatic drug. All HC subjects were recruited from age- and sex-matched volunteers with no history of autoimmune, rheumatic, or other diseases. Information on demographic and clinical data was entered into a database together with the laboratory test results. The AOSD disease activity of each patient was assessed using a modified Pouchot score (18). The experimental design was approved by the Ethics Committee of Shanghai Jiao Tong University (identifier 2016-62), and all the participants provided informed consent. All plasma and serum samples were stored at −80°C immediately after collection.
Detection of Anti-viral IgG and IgM Antibodies in Plasma by ELISA
Anti-viral (CMV, HSV1, HSV2, EBV) antibodies in plasma were analyzed by ELISA kits (Trinity Biotech, New York, USA) according to the manufacturers' instructions. The 96-well plates were incubated with human plasma (1:81) at 37°C for 2 h and washed five times with PBS plus 0.05% Tween-20. The negative control, positive control, standards were added to confirm the validity of the experiment. Secondary horseradish peroxidase (HRP)-conjugated goat anti-human IgM or IgG monoclonal antibodies were added to each well. After five washes with PBS plus 0.05% Tween 20, 100 μL of tetramethybenzidine substrate solution (TMB) was added, and the samples were incubated at room temperature. The reaction was terminated by the addition of 100 μL of 2 N H2SO4/well, and optical density (OD) was measured at 450 nm. The cutoff values were equal to the average OD value of standards multiplied by the cutoff factor.
Real-Time PCR for CMV Viral Load Measurements
DNA from 50 μL plasma was amplified using the Real-time PCR system instrument with Human Cytomegalovirus Nucleic Acid Quantitative Detection Kit (DAAN Gene Co., Ltd., China) according to the manufacturers' instructions. Fifty microliter plasma samples were mixed with nucleic acid extraction solution to purify CMV DNA. Two microliter CMV DNA standard or DNA sample as well as 3 μL Taq DNA polymerase were mixed with 40 μL HCMV-PCR reaction solution for viral DNA amplification and quantitation. CMV-positive and negative controls were run in each PCR assay. The enzyme was activated at 93°C for 2 min, followed by 40 cycles at 93°C for 5 s and 57°C for 45 s. The viral load of CMV was expressed with copies/mL.
Determination of DNA-Sensors
Detection of DNA-Sensors Expression Using Quantitative PCR (qPCR)
Venous blood samples were obtained from untreated, active and hospitalized AOSD patients who had available samples at the time of inclusion (N = 20) and healthy controls (N = 21). Briefly, PBMC was isolated by density gradient centrifugation on Lymphoprep (Axis-Shield, Dundee, UK) according to the manufacturer's instructions (19). The collected cells were used for RNA extraction using RNAeasy columns (Qiagen, Hilden, Germany), and cDNA was prepared by PrimeScript RT Master Mix transcription kit (TaKaRa, Tokyo, Japan). The mRNA expression levels of DNA-sensors expression were determined by SYBR green master mix (Takara). To standardize mRNA expression levels of DNA-sensors, the mRNA levels of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were also determined in parallel for each sample. Relative mRNA expression was calculated as described previously.
Detection of IFI16 and AIM2 Expression by Immunohistochemical Analyses
Skin biopsies from AOSD patients with typical skin rash during fever spikes (N = 4) and healthy controls (N = 4) were analyzed for protein expression (see Supplemental Files for detailed protocol) by immunohistochemistry using the following antibodies: rabbit anti-IFI16 (CST, USA) and rabbit anti-AIM2 (CST, USA). The reaction was then visualized under light microscopy (BX51 Olympus, Japan).
MSD for Detecting TNF-α, IL-1β, IL-6, and IL-18
Serum TNF-α, IL-1β, IL-6, and IL-18 were measured by the Meso Scale Discovery electrochemiluminescence assay (MSD, Rockville, MD, USA) according to manufacturer's instructions.
All data were statistically analyzed using the SPSS version 20.0 software (SPSS Inc., Chicago, IL, USA). Quantitative data are expressed as the means ± SD. Data between two groups with a Gaussian distribution were analyzed using an unpaired t-test, while non-parametric data were assessed using the Mann-Whitney U test. Data among three groups or more were analyzed using one-way analysis of variance (ANOVA) or Wilcoxon rank-sum test. Spearman correlation analysis was performed to test whether anti-CMV antibody levels and the copy number of CMV DNA are correlated with clinical variables. P-values <0.05 were considered statistically significant.
Higher Antibody Levels Against Cytomegalovirus (CMV) in AOSD
In order to determine whether AOSD patients have an immune response to DNA virus, including CMV, HSV-1, HSV-2, and EBV, which were the relatively common DNA viruses in clinical practice, we next employed ELISA to test. Plasma from 100 AOSD patients (69 active and 31 inactive patients) and 70 healthy controls (HCs) were collected. The clinical characteristics of these subjects in each group are detailed in Table 1.
Table 1. Demographic and clinical characteristics of individuals with AOSD.
Among the 69 active AOSD patients, common manifestations included spiking fever (62, 89.9%), evanescent rash (60, 86.7%), sore throat (46, 66.7%), and arthralgia (55, 79.7%). Hepatomegaly, splenomegaly and lymphadenopathy were noted in 10 (14.5%), 26 (37.7%), and 26 (37.7%) patients, individually. There were no significant differences in terms of mean age or sex distribution between the AOSD patients and HCs (P = 0.9338 and P = 0.6690).
As shown in Figure 1A, the antibody levels of anti-CMV IgM and IgG were significantly higher in AOSD patients than in HCs (both P < 0.0001). The positive rate of anti-CMV IgM antibodies was 5% in AOSD patients, 0 in healthy controls. And the positive rate of anti-CMV IgG antibodies was 93% and 90% in AOSD patients and HCs. Moreover, the levels of anti-virus antibody against HSV1, HSV2, and EBV were up-regulated in AOSD patients compared to HCs, though there was no significant difference (Figures 1B,C). These results suggest that AOSD patients have more enhanced immune response to CMV with higher levels of anti-CMV IgG and IgM antibodies.
Figure 1. Anti-virus antibody levels in AOSD patients (N = 100) and HCs (N = 70). (A) Comparison of antibody levels of anti-CMV IgM and IgG in AOSD patients and HCs. (B) Comparison of IgM and IgG antibody levels against HSV1 and HSV2 in AOSD patients and HCs. (C) Comparison of anti-EBVCA IgM, anti-EBVCA IgG, anti-EBNA IgG, and anti-EAD IgG levels in AOSD patients and HC. Each symbol represents an individual patient with AOSD and a HC. The data represent the mean ± SD by Student's t-test. CMV, Cytomegalovirus; HSV, Herpes simplex virus; EBVCA, Epstein-Barr virus capsid antigen; EBNA, Epstein-Barr virus nuclear antigen; EAD, Epstein-Barr virus early antigen diffuse.
Higher Levels of Anti-CMV Antibodies in Active AOSD
Furthermore, we assessed the levels of anti-CMV antibody in AOSD patients with diverse disease activity. Remarkably, the plasma levels of anti-CMV IgM and IgG antibodies were significantly up-regulated in AOSD patients with active disease (N = 69) compared to those with inactive disease (N = 31) (Figure 2, P = 0.0112 and P = 0.0355). Moreover, anti-CMV IgM and IgG levels differed significantly, with higher antibody levels detected in patients with active AOSD compared to HCs (Figure 2, both P < 0.0001). And the levels of anti-CMV antibody were also significantly higher in inactive AOSD compared to HCs (Figure 2, P = 0.0105 and P = 0.0167). Taken together, our data indicate that both IgM and IgG antibodies against CMV are associated with the disease activity of AOSD.
Figure 2. Anti-CMV antibody levels in AOSD patients with diverse disease activity and HCs. (A) Plasma levels of anti-CMV IgM antibody in active AOSD (N = 69), inactive AOSD (N = 31) and HCs (N = 70). (B) Plasma levels of anti-CMV IgG antibody in active AOSD, inactive AOSD and HCs. The data represent the mean ± SD by Student's t-test.
Anti-CMV Antibodies in AOSD Were Associated With Clinical Manifestations
We next assessed the correlations between the levels of anti-CMV antibody and clinical manifestations. Compared with AOSD patients without high spiking fever, the levels of anti-CMV IgM and IgG antibody were significantly higher in AOSD patients with fever (Figures 3A,B, P = 0.0022 and P = 0.0411). In addition, our results showed that patients with sore throat had higher level of anti-CMV IgM and IgG antibody (Figures 3C,D, P = 0.0015 and P = 0.0141). And in the presence of sore throat, the level of anti-CMV IgM antibody was significantly increased in AOSD patients (Figures 3E, P = 0.0283). The level of anti-CMV IgG tended to be higher in AOSD patients with sore throat (Figure 3F). Furthermore, the level of anti-CMV IgM antibody was significantly higher in patients with arthralgia than in patients without arthralgia (Figure 3G, P = 0.0231). In AOSD patients with arthralgia, the level of anti-CMV IgG antibody didn't show significant difference compared with those without arthralgia (Figure 3H). Moreover, the difference of anti-CMV antibody in patients with other clinical manifestations, including pneumonia, pleuritis, pericarditis, hepatomegaly, splenomegaly, lymphadenopathy and myalgia didn't reach statistic difference (Supplementary Figure 1). Taken together, AOSD patients have an immune response to CMV, leading to the onset and relapses, as Yamaguchi's criteria includes the clinical manifestations of high spiking fever, skin rash, arthralgia and sore throat.
Figure 3. Comparison of the anti-CMV antibody levels in AOSD patients with different clinical manifestations. The levels of anti-CMV IgM and IgG antibody in AOSD patients with or without fever (A,B), rash (C,D), sore throat (E,F), and arthralgia (G,H). The data represent the mean ± SD by Student's t-test.
CMV Viral Load Was Higher in Reactive AOSD
Due to the high level of anti-CMV antibodies in AOSD patients, we further aimed to detect the copy number of CMV DNA in 100 AOSD patients. To exclude the influence of treatment on CMV viral load, 69 active AOSD patients were stratified into 38 new-onset patients and 31 reactive patients. Compared with inactive AOSD patients (N = 31), significantly higher copy number of CMV DNA in plasma was observed in new-onset patients (N = 38) (Figure 4A, P = 0.027). Further comparison was performed between AOSD patients with inactive and reactive disease. Remarkably, compared with AOSD patients with inactive disease, there was significantly more copy number of CMV DNA in plasma in reactive disease (N = 31) (Figure 4A, P = 0.0014), indicating the presence of CMV infection in AOSD patients with higher disease activity. And then we investigated whether high copy number of CMV DNA was associated with increased systemic score. It revealed that the copy number of CMV DNA was positively associated with systemic score, with a low correlation coefficient (Figure 4B, r2 = 0.2152, P = 0.0383). In conclusion, CMV infection was more frequent in AOSD patients with disease onset and exacerbation.
Figure 4. Detection of CMV DNA copy number in AOSD patients. (A) Comparison of CMV DNA copies in patients with inactive (N = 31), new onset (N = 38) and active AOSD (N = 31). (B) Correlation between CMV DNA copy number and AOSD disease systemic score. The data represent the mean ± SD by Student's t-test in (A). The correlations were evaluated with Spearman's non-parametric test in (B). p < 0.05 represents a significant difference.
CMV Viral Load Was Associated With Clinical Manifestation
Due to high level of anti-CMV IgM antibody in AOSD patients with fever, rash, sore throat and arthralgia, we further analyzed the difference of CMV DNA copy number in patients with and without these clinical manifestations. As shown in Table 2, higher copy number of CMV DNA was observed in patients with fever (P = 0.0039), rash (P = 0.0462), sore throat (P = 0.0006) and arthralgia (P = 0.0156). And the difference of CMV viral load in patients with other clinical manifestations, including pneumonia, pleuritis, pericarditis, hepatomegaly, splenomegaly, lymphadenopathy and myalgia didn't reach statistical difference. Thus, CMV infections would be related with AOSD as Yamaguchi's criteria includes the clinical manifestations of high spiking fever, arthralgia, sore throat and arthralgia.
Table 2. Comparison of CMV DNA copy number according to disease manifestations in 100 patients with adult-onset Still's disease.
We next measured the correlation coefficient of CMV DNA levels with inflammatory index, including leukocytes, ESR, and CRP. The copy number of CMV DNA were positively associated with leukocytes (Figure 5A, r2 = 0.3642, P = 0.0005) and ESR (Figure 5B, r2 = 0.2657, P = 0.0146), as well as CRP (Figure 5C, r2 = 0.3456, P = 0.0021). Furthermore, the significant association was found between the CMV DNA copy number and TNF-α levels (Figure 5D, r2 = 0.2265, P = 0.0338). We found that CMV DNA copy number showed no significant correlation with IL-1β, IL-6, and IL-18 in AOSD patients (data was not shown). Taken together, the results indicate that CMV DNA may play a role in the inflammatory response in AOSD.
Figure 5. Correlation between CMV DNA copy number and inflammatory index in AOSD patients. Correlation between CMV DNA copy number and leukocytes (A), ESR (B), and CRP (C), and TNF-α levels (D). The correlations were evaluated with Spearman's non-parametric test. p < 0.05 represents a significant difference.
DNA-Sensing PRRs Were Upregulated in AOSD
To demonstrate the pathogenetic role of viral infections in AOSD, we first detected the nucleic acid receptors that initiate virus sensing pathway. We found a significant upregulation of IFI16 (Figure 6A, P < 0.05) in PBMC of AOSD compared with HC PBMC. The level of AIM2 expression had an increasing tendency in AOSD patients with statistical significance (Figure 6A, P < 0.001). The level of DNA-dependent activator of IFN-regulatory factors (DAI) and DDX46 has an increasing tendency without any significant difference (Figure 6A). In contrast, other DNA-sensing receptors, DDX41 and GAS were significantly downregulated in AOSD patients compared with HCs (Figure 6A, P < 0.01 and P < 0.001, receptively). Additionally, polyglutamine binding protein 1 (PQBP1) and meiotic recombination 11 (MRE11) tended to be lower in AOSD patients compared with HCs (Figure 6A). In conclusion, our data suggest that DNA-sensing receptors IFI16 and AIM2 were higher in AOSD patients.
Figure 6. Detection of DNA sensors in AOSD patients. (A) Comparison of diverse DNA-sensing receptors in AOSD patients and HCs. (B,C) Skin lesion tissue from an AOSD patient and a HC were stained with antibodies specific for IFI16 (B) and AIM2 (C). Representative examples of immunohistochemical data (AOSD, N = 4; HCs, N = 4) are shown. Scar bar: 50 μm. Original magnification: 200×.
To further assess protein expression of IFI16 and AIM2 in AOSD patients, we assessed the expression of IFI16 and AIM2 in AOSD skin biopsies (N = 4) and healthy controls (N = 4). Figures 6B,C showed a representative staining for AOSD skin. The staining pattern for IFI16 and AIM2 was most prominent in patients with AOSD. Based on these results, we hypothesize that DNA viral infection may play a role in AOSD patients.
A number of studies have addressed the possible role of viral infections in the pathogenesis of AOSD, while to date, the evidence and the pathogenic role of viral infections in AOSD is still to be determined. A potential role for viral infection in the pathogenesis of autoimmune disease has long been an attractive hypothesis, in part based on clinical manifestations that mimic acute or chronic viral infection (20). The concept that environmental factors including infections trigger disease in individuals with certain genetic backgrounds is broadly recognized (21). The presence of elevated plasma anti-viral antibody and virus DNA in blood and tissue of patients with lupus and other systemic autoimmune diseases, including primary Sjogren's syndrome (SS) (22), rheumatoid arthritis (RA) (23), and dermatomyositis (24) are consistent with a viral trigger, indicating that autoimmune disease can be influenced by viral infections. We hypothesized that viruses, which represent an endogenous source of ligands for nucleic acid sensors, promote a host microenvironment supportive of immune dysfunction, autoimmunity, and inflammation, similar to the immunopathological characteristic of some chronic viral infections (25, 26).
To pursue this possibility, we studied the expression pattern of nucleic acid sensors in AOSD patients. We found that the expression of DNA-sensing receptors significantly increased in PBMC and skin biopsies from AOSD patients, indicating that non-self nucleic acids may present in AOSD. We then used ELISA analysis to detect anti-viral antibodies in plasma samples from 100 AOSD patients and 70 healthy controls. We demonstrated that anti-CMV IgM and IgG antibodies were significantly higher in AOSD patients compared to HCs. Moreover, elevated levels of anti-CMV IgM antibodies were found in patients with fever, sore throat, arthralgia and rash, which are typical clinical manifestations of AOSD. After identifying CMV DNA in plasma of AOSD patients with disease new-onset and relapse, we further demonstrated that CMV infections play a role in the initiation or amplification of the inflammatory responses in AOSD.
Much attention has been drawn potential pathogenetic role of diverse bacterial and viral pathogens in AOSD, particularly virus, including CMV, EBV, rubella virus and human herpesvirus 6 (4). The results of these studies, taken in aggregate, are suggestive of a viral contribution to AOSD, though findings offer little insight into potential mechanisms, and a consistent association with a specific exogenous virus as an etiologic agent has not emerged in AOSD. Human CMV, a ubiquitous beta-herpes virus, has been reported to be associated with several autoimmune diseases (27–29). While, there are insufficient data to directly implicate CMV infection in the onset and relapse of AOSD. Several characteristics of CMV raised our interest in investigating this DNA virus as a candidate trigger of an innate immune response and autoimmunity. First CMV DNA was positively correlated with the count of leukocytes in AOSD patients. Neutrophils, the first line of innate immune defense against infection, are the primary effector cells in the pathogenesis of AOSD (30). Recent data demonstrate a profound survival response and delayed apoptosis in neutrophils exposed to CMV by secreting pro-survival secretome (31), further supporting the hypothesis that CMV infection may trigger inflammatory response of neutrophils. Second CMV-exposed neutrophils release factors that enhance monocyte recruitment, facilitating the inflammatory response (31). The correlation between CMV DNA and acute phase protein (ESR and CRP) in our study suggests CMV infections as underlying contributors to the cytokine storm in AOSD. Third it has been established that inflammatory monocyte/macrophages egress from the bone marrow and into the peripheral blood during CMV infection in a C-C motif chemokine receptor (CCR)2-depedent manner (32), further supporting investigation of the mechanism for CMV in the immunopathology of AOSD by activating neutrophils and macrophages. However, a clear association between CMV seroprevalence and disease has thus far been difficult to establish, because CMV is widespread, and then there is indeed a need for further follow-up study of AOSD patients enrolled in our study. Besides, the relatively low correlation coefficients between CMV DNA load and inflammatory index indicated that other endogenous or exogenous trigger factors may be involved in the pathogenesis of AOSD, which should be explored in a large cohort of AOSD patients in the future. Moreover, the direct relationship of CMV in inducing AOSD needs further investigation in vivo.
Since CMV belongs to DNA virus, we hypothesized that it might be recognized by cytoplasmic DNA sensors and potentiate an innate immune response. Elevated expressions of IFI16 and AIM2 in PBMC and skin biopsy from AOSD patients lead to a hypothesis that DNA virus might represent an endogenous source of ligands. Studies labeled IFI16 and AIM2 as a new family of innate DNA sensors "AIM2-like receptors (ALRs)" (33). The ability of IFI16 and AIM2 to induce the inflammasome (34, 35) also draws attention to a potential role of IFI16 and AIM2 in AOSD. Infected with herpesvirus, IFI16 interacts with the adaptor molecule ASC and procaspase-1 to assemble a functional inflammasome (36). And AIM2 has been demonstrated to trigger caspase-1 dependent signaling and innate immunity to DNA viruses, particularly mouse CMV (37). Thus, our findings suggest a potential role of CMV infections in AOSD by activating two DNA sensors, IFI16, and AIM2.
In conclusion, levels of anti-CMV IgM and IgG antibodies were higher in AOSD patients, and increased copy number of CMV DNA was found in patients with new-onset and reactive AOSD. Moreover, we found an upregulation of cytoplasmic DNA-sensing receptor IFI16 and AIM2 in PBMC and skin from AOSD patients, further supporting the hypothesis that CMV infections exist in AOSD. In addition, anti-CMV IgM antibody level and CMV DNA copy number were significantly increased in patients with fever, sore throat, arthralgia and rash. And the significant association of the CMV DNA level with the levels of leukocytes, ESR, CRP and TNF-α was observed, suggesting that CMV infections may play a role in the inflammatory response in AOSD. Taken together, these data provide some evidence that CMV infections might contribute to the onset and exacerbations of AOSD.
The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. Biological samples were obtained under a protocol approved by the Institutional Research Ethics Committee of Ruijin Hospital (ID: 2016-62), Shanghai, China. All subjects signed written informed consent.
JJ and HS participated in RNA extraction, qRT-PCR, and wrote the manuscript. ML analyzed the results of skin biopsy. TL helped to revise the manuscript. JG and LW collected the clinical samples and data. JT and HL prepared the figures. XC and JY prepared the tales. YutS and YueS performed statistical analysis. WG prepared the supplementary figures. CY designed the experiments and revised the manuscript. QH designed experiments, performed statistical analysis, and revised the manuscript. All authors read and approved the final manuscript.
This work was supported by the National Natural Science Foundation of China (81671589, 81871272, 81801602, 81602747, 81502016).
We thank all the patients who were involved in the study.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2019.00898/full#supplementary-material
Supplementary Figure 1. Comparison of the anti-CMV IgM antibody levels in AOSD patients with different clinical manifestations. The levels of anti-CMV IgM antibody in AOSD patients with or without pneumonia (A), pleuritis (B), pericarditis (C), hepatomegaly (D), splenomegaly (E), lymphadenopathy (F), and myalgia (G). The data represent the mean ± SD by Student's t-test.
Supplementary Figure 2. Comparison of the anti-CMV IgG antibody levels in AOSD patients with different clinical manifestations. The levels of anti-CMV IgG antibody in AOSD patients with or without pneumonia (A), pleuritis (B), pericarditis (C), hepatomegaly (D), splenomegaly (E), lymphadenopathy (F), and myalgia (G). The data represent the mean ± SD by Student's t-test.
AOSD, Adult-onset Still's disease; HC, Healthy control; SS, Sjogren's syndrome; RA, Rheumatoid arthritis; CMV, Cytomegalovirus; HSV, Herpes simplex virus; EBV, Epstein-Barr virus; IFI16, Interferon gamma-inducible protein 16; AIM2, absent in melanoma 2; ELISA, Enzyme-linked immunosorbent assay; qPCR, Quantitative polymerase chain reaction; PBMC, peripheral blood mononuclear cell; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; ESR, Erythrocyte sedimentation rate; CRP, C-reactive protein; TNF-α, Tumor necrosis factor-α; IL, Interleukin; RIG- I, Retinoic acid inducible gene I; IFIH1, Interferon induced with helicase C domain 1; DDX, DExD/H-box helicases; cGAS, cyclic GMP-AMP synthetase; NLRP3, NOD-like receptor protein 3; DAI, DNA-dependent activator of IFN-regulatory factors; HRP, Horseradish peroxidase; TMB, Tetramethybenzidine substrate solution; OD, Optical density; CCR, C-C motif chemokine receptor; ALR, AIM2-like receptors; PQBP1, Polyglutamine binding protein 1; MRE11, meiotic recombination 11.
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Keywords: adult-onset Still's disease, virus, CMV, IFI16, AIM2
Citation: Jia J, Shi H, Liu M, Liu T, Gu J, Wan L, Teng J, Liu H, Cheng X, Ye J, Su Y, Sun Y, Gong W, Yang C and Hu Q (2019) Cytomegalovirus Infection May Trigger Adult-Onset Still's Disease Onset or Relapses. Front. Immunol. 10:898. doi: 10.3389/fimmu.2019.00898
Received: 01 February 2019; Accepted: 08 April 2019;
Published: 24 April 2019.
Linda F. Van Dyk, University of Colorado Denver, United States
Pilar Perez-Romero, Instituto de Salud Carlos III, Spain
Sarah Rowland-Jones, University of Oxford, United Kingdom
Copyright © 2019 Jia, Shi, Liu, Liu, Gu, Wan, Teng, Liu, Cheng, Ye, Su, Sun, Gong, Yang and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chengde Yang, yangchengde@hotmail.com
Qiongyi Hu, huqiongyi131@163.com
†These authors have contributed equally to this work


The last decade has seen an explosion in our understanding of the solar system with the discovery of the largest Kuiper belt objects (KBOs) of comparable size to Pluto. Each one of these objects; including Makemake, Pluto, Eris, Haumea, Sedna, Quaoar, and Orcus, has provided a wealth of information. Each of these large bodies tells a unique story, from Haumea's mantle-shattering collision to Sedna's lonely, strange orbit. These objects are the lighthouses of their population, bright enough for astronomers to discover them and study their physical properties and orbits using medium and large telescopes.
Comparison of the eight largest TNOs. Five of these TNOs are known to have moon(s). 2007 OR10, Orcus, and Quaoar are all estimated as about the same volume. Since Quaoar and Orcus have moons, it is known that Quaoar is much more massive than Orcus. The top 4 are official dwarf planets while the bottom 4 are dwarf planet candidates.
But the inventory of dwarf planets in the Kuiper belt is incomplete. All of the surveys that astronomers have ever conducted -- including Clyde Tombaugh's search, which led to his discovery of Pluto -- have been performed from telescopes in the northern hemisphere. We have covered the northern skies thoroughly and found the brightest bodies, including Eris, Pluto, Haumea, Quaoar, Makemake, Orcus, 2007 OR10 and Sedna. Although telescopes from the northern hemisphere can reach part of the southern sky, the southern hemisphere has remained virtually unexplored. The southern sky is the last unexplored frontier of the solar system. Perhaps one or two (or possibly zero) new dwarf planet-sized bodies await discovery. But we won't know if they're out there until we've looked, and that's why I've headed south. I'm not the only one; two other groups have also headed that direction too.
This equipment gave us the opportunity to conduct a survey to search for KBOs in the southern hemisphere. So after finishing graduate school and winning a National Science Foundation postdoctoral fellowship at Yale, I headed back to the east coast to be part of the La Silla-QUEST KBO survey, led by David Rabinowitz. The goal of our survey: to search the entire sky south of the ecliptic for large and bright KBOs out to distances of 100 astronomical units, more than three times farther out than the orbital distance of Neptune.
We look for KBOs each night that the Moon is not too bright. In order to find these icy planetoids, we take three images spaced several hours apart. We observe target fields near opposition. We choose to look near opposition because that exploits the relatively fast orbital motion of Earth to make the slow-moving KBOs appear to have retrograde (backwards) motion.
In a single image a KBO will appear to be a like a stationary star or galaxy in each one of our images, but when you look at the three images together, the KBOs will be the objects that appear to move from one image to the next. KBOs are extremely distant (30-100 AU) and so move very slowly (around one to three arcseconds per hour); this amounts to only a few pixels' worth of motion across our digital images.
Our survey observations are taken automatically by the telescope at night, and the images are sent to Yale each morning. Each morning, the first thing I do after I wake up is to check and see how the night went. Did our images go deep enough, or was it cloudy? Then I pick the fields we'll schedule for observation on the next night.
During the day, the "moving object pipeline" will remove the stationary background stars, search for moving objects, and link together what it thinks are moving KBOs. To confirm the presence of a moving solar system body, we crop snapshots from the discovery images centered around where the software thinks there is a moving object. Then we align and blink these snapshots by eye, more or less as Tombaugh did. If we can see a possibly real object moving across the three frames, we schedule further observations to confirm the discovery and help determine the KBO's orbit.
When the first surveys started looking for the brightest KBOs in the northern skies a little more than a decade ago, no one could predict what these discoveries would reveal. Studying the large dwarf planets has changed our perspective of the Kuiper belt and outer solar system. Perhaps there is something big or an object on a strange orbit lurking in the southern skies waiting to be found. Maybe it will yield exciting new results; I can't even attempt to speculate or imagine what they will be. That's why I'm looking. With a little luck and some clear skies perhaps we'll discover something new and interesting with La Silla-QUEST.
The newly robotized 1.0-m Schmidt telescope at the European Southern Observatory (ESO) at La Silla, Chile.


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by Vanessa M (follow)
Sydney (13) New South Wales (56) Festivals (4) Annual Events (2)
If you visit Sydney during May or June, you've chosen the right time. Not only will the harbour be its spectacular self during the day, but for a few weeks during these months it will also be a pretty impressive sight at night, as locations around the harbour are transformed with colourful productions of light and sound.
It's all part of Vivid Sydney, the festival of light, music and ideas, which also involves musical performances held around the city (with a particular highlight being the Sydney LIVE series at the Opera House, featuring both and international artists) and the Vivid Ideas Exchange, a series of public talks and debates.
For most people, however, Vivid is all about the light shows and while Darling Harbour (and to a lesser extent Lunar Park) do play host to some attractions, Circular Quay and its giant projections and sculptural installations are the true heart of the event. Everywhere you look in this area there is something to see.
On my visit in 2013, First Fleet Park, located next to the Museum of Contemporary Art, was full of light sculptures, including glowing stalks of flowers sprouting among trees, a tunnel and a garden of glowsticks.
The installations extended under the railway line and up into The Rocks too.
Further off the main track there were glowing buildings and green-lit trees.
All these sights are pretty spectacular, but it's the projections on major buildings around the area that really draw the crowds and have come to be synonymous with Vivid. Each year, the facades of the MCA, Customs House, the Sydney Opera House are all lit up.
Projections on Customs House
Smaller buildings in the area are also transformed.
There were figures in the window at Cadmans Cottage
A visit to Circular Quay during Vivid Sydney definitely can't be missed in my opinion, but a lot of people share this view, so the place can get packed. I visited on the Sunday of the Queen's Birthday long weekend, which also happened to be the last weekend of the festival, and couldn't get anywhere near the Sydney Opera House due to the massive crowds.
However, apparently the numbers attending the festival on this particular night 'blindsided' organisers, who have promised to put better measures in place next time. But you'll still want to be prepared for lots of people and long queues for the toilets and food trucks (but you can also wait till you're in one of the more out-of-the-way locations, like Walsh Bay, where there are far fewer people).
You don't need to get close to appreciate the fun, evocative light show projected onto the Sydney Opera House - you can see it from the other side of Circular Quay anyway
To help you see everything in this area (the amount is a little daunting), there is a walk you can do that incorporates it all. A map app can be downloaded to keep you on track and all the works are accompanied by glowing, numbered towers, which also make them easy to spot (particularly those that don't involve light, like performances and photography). This walk begins at the Sydney Opera House, passes through Circular Quay and The Rocks, goes round Dawes Point Park and finishes in Walsh Bay.
You can get close to the works without the crowds over in Walsh Bay
We sat back and watched this projection
The lights on the Sydney Harbour Bridge can be viewed from Walsh Bay, and were able to be manipulated by visitors to Luna Park in the year I visited
From Circular Quay and Walsh Bay, you can get to the other locations like Darling Harbour and Luna Park by walking or catching the train, but there are also free shuttle buses and ferries available to help you make your way around (but again, expect long lines).
Be prepared that you won't fit everything into one night; it may be best to chose one area you want to focus on, and consider it a bonus if you get to any others. The lights are only on between 6.00pm and 12.00pm each night, and while it seems like a long time, there's a lot of ground to cover and you're slowed down by the amount of people around.
If you have the time (and the patience) it may be best to dedicate a few nights to the event. After all, there's still the all music and debates to see.
Where: Locations around Sydney Harbour, including Circular Quay, Darling Harbour, Walsh Bay and Milsons Point
When: For a few weeks between May and June each year, when the lights are turned on between 6.00pm and run till 12.00pm
Phone: www.vividsydney.com
#New South Wales
#Sydney
#Festivals
#Annual Events
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