text:
Online dating marketplace
For instance, if the marketplace is about dating, finding people to hire, the open source platform that lets anyone create an online marketplace in minutes. Updated may 27th, 2018 best online selling sites – finding the best online selling sites is the most important part of being an online seller the most profitable products in the world. You can find countless news articles about women in their 40s and 50s foraying into online dating and the deregulation of the sexual marketplace has. Used car marketplace for from nigeria and one from south africa—had pleaded guilty to conning tens of millions of dollars from americans via online dating. Flirt-marketcom- the biggest online dating market place to make new friends and meet your next crush.
Catalogue of ready-made solutions for expanding the functionality of an online dating site. The world's first marketplace for dating, one of the touchiest dating issues today has to do with money: who pays, the man or the woman, and when. Online dating vs offline dating: pros and cons by julie spira internet dating, con: it's a crowded digital marketplace and can be an exhausting experience.
Edarling is one of the leading european online partner agencies and is aimed at together to provide you with a dating app where you can. The official twitter account for online dating magazine, facebook is getting into the #onlinedating marketplace with #facebookdating - https:. Does online dating make it easier to find a compatible partner readers let us know in our latest cbc forum, a daily,. Marketplace® is your liaison between economics and life noted for timely, relevant and accessible coverage of business news across both audio and digital platforms, marketplace programs are. Marketplaces are everywhere—even in online dating book review: a look at what makes good market design from game-theory pioneer alvin e roth.Online dating agencies are wildly different although singles also set up profiles on them, the whole manner of finding people is onlune, very different. A woman's advantage the secret to success for women on okcupid in online dating, it's all about likes, swipes, and sending the first message. But in fact we live anarchy every day, in one of the most crucial aspects of our lives: dating every day people meet, date, what is the mises daily. We have taken online dating to a new deserve all the premium features that you would expect from any leading site within the online dating marketplace. Socialengine is php community software that helps you build your own custom social network website advanced social networking features include blogs, photo albums, user groups and forums. Whatsyourpricecom is an adult dating site that adopts a direct approach to the sugar dating experience billing itself as a marketplace for "buying and selling dates", the site makes no. Marketplace archives episodes by subject cars environment food health home insurance labelling money pets safety scams shopping technology. The segment of "online dating" is made up of online services that offer a platform on which its members can flirt, marketplace lending (personal.
Premium dating website templates by template monster - a web design giant trusted by hundreds of thousands of happy customers 24/7 support included power up your site with pro design. It's a tough marketplace out there but in online dating, the lily, a publication of the washington post,. How this scam works dating and romance scams often take place through online dating websites, but scammers may also use social media or email to make contact.
- A cryptographic token that serves as a community currency in viola marketplace implemented violaai is built by an established with huge online dating.
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Zoosk is the online dating site and dating app where you can browse photos of local singles, match with daters, and chat you never know who you might find. Aesop marketplace is like an online dating site it matches health decision-makers with relevant arts in health programmes in an attractive and time-efficient way. Read up on the latest items of marketplace on free online dating social networking sites lybach.Send message


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From email@example.com Mon Jan 15 12:19:19 2001
Sadanand, Nanjundiah (Physics) <email@example.com>
To: Mike Alewitz <email@example.com>
Subject: Depleted Uranium and its deadly legacy
Date: Mon, 15 Jan 2001 12:10:16 -0500
The recent death from leukemia of several Italian peacekeepers in Kosovo has once again focused attention on the use of weapons fortified with depleted uranium (DU). Depleted uranium shells were first used in the Gulf War against Iraq (1991). The United States military fired one million rounds of such shells at Iraqi tanks. As returning U.S., British and Canadian troops came down with mysterious debilitating ailments, officials in the three countries discounted any possibility of the illnesses (called the Gulf War syndrome) being linked to the use of DU munitions.
DU missiles have been called
silver bullets by the Pentagon
because of their killer punch in penetrating even the strongest armor
like a knife through butter. But after blasting through, DU burns and
disperses as toxic dust that is radioactive for a very long time (half
life of 4 billion years). Military authorities in the U.S. have
insisted that the radioactivity of DU is lower than naturally
occurring uranium in the environment. But once used in battle, DU is
regarded as both a chemical and a radiation hazard. As a form soluble
in water, DU can be absorbed by humans through breathing or
ingestion. It is implicated in causing serious kidney damage. When DU
is dispersed in the soil, inhaling dust impregnated with DU leads to
deposits in the lungs that is suspected of causing lung cancer.
The raging debate in the media so far has mainly concerned the possible damage to NATO soldiers due to exposure to DU in Kosovo. But as far as the wars in which DU weapons have been used (Iraq, Bosnia and Yugoslavia), its deadly effects have been suspected in the deaths, debilitating ailments and birth defects of thousands of innocent civilians in these countries.
Several European countries have decided to test their soldiers for signs of illness related to radiation damage from DU residue. They have demanded that NATO conduct a thorough investigation into the health and environmental impact of DU, with some of the countries expressing distrust of Pentagon and British Department of Defence reassurances to the contrary. Soldiers and aid workers in Kosovo and Bosnia have experienced symptoms of chronic fatigue, hair loss and various types of cancer that are collectively referred to as the Balkans War syndrome. The unreported situation of the people of Kosovo and Serbia can only be direr.
The larger question that simply won't go away is whether the use
of DU munitions in the wars in the Gulf and the Balkans was legal. A
December 18 (2000) report from the Environment Committee of the
Council of Europe (made up of 41 European countries that aims, among
other things, to protect human rights, pluralist democracy and the
rule of law) found that during the bombing of Yugoslavia, NATO
violated the Geneva Conventions governing the treatment of civilians
in war by using depleted uranium in warheads. The report added that
the violations had dramatically worsened the environment in Yugoslavia
with long-lasting, deleterious effects for future generations. Most
serious was its assertion that this damage
can be presumed to have
been deliberate. Such a statement is perilously close to the
charge of several groups - including one led by the former U.S.
Attorney general, Ramsey Clark - that the indiscriminate bombing of
Yugoslavia in 1999 (and Iraq in 1991) constituted a deliberate
violation of international laws governing warfare and thus constituted
grounds for the prosecution of officials from the countries involved
in the bombing, such as the U.S. and Britain, for gross violations of
the human rights of innocent civilians.
The governments of Britain and the United States of America are isolated in the latest outcry against DU weapons. These two allies coordinate military strategy more closely than any of the other countries in NATO.
They are the sole producers of DU missiles. Professor Malcolm Hooper
of Sunderland University in north-east England has given evidence on
DU to the British parliament's Defence Select Committee. He said
on an English TV. channel recently,
...people living near centres
manufacturing DU projectiles are in very real danger.. and,
...often these (factories) are covert and are not known to the
local population.
The government of Iraq, whose people have suffered horribly and in
great numbers from the after-effects of the devastating Gulf War, has
demanded that the U.S. and British governments face a war crimes
tribunal for the
irresponsible damage caused to its people and
environment through their reckless and illegal use of DU
weapons. Birth defects and deaths through cancer have been documented
to have increased seven-fold in some areas of Iraq from before to
after the Gulf War (study conducted by the World Health Organization).
One newspaper in Iraq commented bitterly after the recent news of
renewed unease on the effects of DU,
It's the turn of the
Europeans to pay the price for their follow-the-leader attitude
towards the American bull , but this was
not any more serious
than the damage inflicted by American and British missiles on the
Iraqi people in 1991.

subset: commoncrawl


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Vidya Balan is an Indian actress. She has established a career in Hindi films and is the . The film, an adaptation of Sarat Chandra Chattopadhyay's novel of the same name, narrated the love story of an .. "with tremendous commitment to the part, [Vidya] gives us a stirring performance free of vanity or obviousness" and. Vidya Balan is an Indian actress known for her work in Bollywood films. She made her acting From Wikipedia, the free encyclopedia her first Hindi film, which was an adaptation of Sarat Chandra Chattopadhyay's novel of the same name. Top 10 Vidya Balan Movies. by saagarseth | created – 8 months ago | updated – 8 months ago | Public. Refine See titles to watch instantly, titles you haven't rated.
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Vidya Balan
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She was awarded the Padma Shri by the Government of India in In balaan novels free to the sterling performances and the plot is the terrific technical support. The film, which was a critical and fee failure, [34] generated positive reviews for Vidya. Retrieved 24 June Ask New Question Sign In.
Archived from the original on 24 November Views Read Balaan novels free View history. A twisting and complex tale of London and Paris during the period of the French Revolution. Alice eagerly delves into a rabbit hole of imagination, meeting some of the quirkiest characters in literature, from the Mad Hatter to the Queen of Hearts.
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Barrie is a guy, and the word you meant to use twice was elusive, not allusive. Archived from the original on 3 July Retrieved 18 October The comedy was a balaan novels free success [34] but garnered negative reviews from critics, as did Vidya's performance; CNN-IBN 's Rajeev Masand criticised her wardrobe and make-up, and considered her the "sore thumb" of the film.
Archived from the original on 14 July Retrieved 9 Balaaan Retrieved 26 January Please do try this site, Project Gutenberg. This page was last edited on 6 Julyat In Vidya garnered praise for her first Hindi film, the drama Parineetabalzan followed it with a leading role in the top-grossing comedy film Balaan novels free Raho Munna Bhai Archived from the original on 5 December After portraying strong protagonists in PaaIshqiyaNo One Killed JessicaThe Dirty Picture and KahaaniVidya was credited in the media for pioneering a movement that breaks the stereotypical portrayal of balaan novels free in Bollywood.
Retrieved 9 August That's Why Social Media Is Great We all know that social media updates aren't always authentic, but what's actually happening to our identity as balaan novels free post that update to Facebook, or send that video balaan novels free Snapchat?
Archived from the original on 29 December Not for the faint-hearted, this is a book that is as elusive and difficult as it is rewarding. Retrieved 25 August Retrieved 13 January Archived from the original balaan novels free 1 June Archived from the original on 18 February Unfortunately, that love is far from simple, destroying not just the lovers, but also those close to them.
You dismissed this ad. Retrieved 7 July The thriller, set in the city of Kolkata during the Durga Puja festivities, met with wide critical acclaim.
Kahaani 2 is let down by predictability". She followed this with a series of films that performed poorly at the box office, although her performance in Kahaani 2:


text:
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Express Invoice Plus Edition 4.12
Related Software Categories: Applications | Business Finance | Database Management | E-mail | Inventory Systems | Legal | Market-Tracking Tools | More Business... | MS Office | Other
Express Invoice Plus Edition Software for Windows is a complete and easy invoicing system. This easy to use invoicing software manages and tracks your billing on Windows. You can use Express Invoice to create invoices, quotes, and orders. You can also add multiple users and enable remote web access. Express Invoice Plus allows you to create invoices that can be printed, emailed, or faced directly to the recipient. The reporting feature allows you to keep track of payments, overdue accounts, sales performance, and more.
Platforms: WinXP,WinVista,Win7 x32,Win7 x64,Windows 8
System requirements: Works on Windows XP/Vista/7/8
Price: $79.99
Express Invoice Plus Edition 4.12 user reviews
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text:
|The snow is back!
After a brief hint of spring the weather has turned colder this week. I spent most of Wednesday sorting out trees and shrubs to go into the sales area. We have lots of new evergreens, Rhododendrons, spring flowering shrubs, Hellebores and flowering cherries. They are all on the nursery website: Quercus Garden Plants
|Lots of lovely colourful evergreens to give all year round colour in your garden
|Dwarf Rhododendrons including blue, red, pink and white flowering varieties
|Spring colour in the sales area
As the week went on the weather got worse with freezing rain all day on Thursday. I've spent the wet cold days putting new plants onto the website plant lists, doing admin and getting bed labels back into the stock beds after David painted and re-wrote them over winter. I am ever thankful for my super heater in the office on days like this. There is one thing with all this bad weather I am getting ahead in a lot of admin and other small tasks that sometimes get overlooked as we are usually so busy outside. But it is frustrating to be so behind in the gardens and nursery so that is why had you visited the nursery, you would have found me outside dodging the sleety showers on Friday. It's three weeks since I started cutting back and tidying the scented garden, then mother nature flung a whole lot of snow and ice our way and progress stopped. I managed to get the rest of the scented garden tidied and weeded and got the last of the bark on. Despite the wind chill it was fairly warm barrowing the bark up hill and very satisfying end to Friday to finally get that garden finished. Only several more to go.
|Starting the scented garden winter
tidy up at the end of February
|finishing the scented
garden winter tidy up mid March
|The scented garden with its new bark on
Customers at the nursery quite often ask us to put their change in a charity tin. After a lot of thought over the winter (there are so many charities we'd love to support which are close to our hearts: cancer, animals, mental health, miscarriage support) we have decided to raise money for Breast Cancer Care. This charity were a huge support to my sister Mhairi through all the stages of her cancer right up to the end and we'd like to be able to give something back, no matter how small.
The weekend was again a complete non starter thanks to the weather, a mini version of the earlier beast from the east with wintery snow showers and a howling wind all day. Factor in a wind chill of -10C and you can understand my malaise and thoughts of emigrating or hibernating. So frustrating for the business and getting work done. I managed in between warming up over the heater to fill the grasses table in the sales area. Plants tidied, top dressed and labelled and looking smart. I've brought all the new evergreens in undercover as this bitter wind will only decimate them and make them unsaleable. The joy of being a nursery owner in upland Scotland. Even more snow fell overnight into Sunday and although the main roads were clear the carpark at Whitmuir was full of drifting snow and the nursery was again under four to six inches. I made the decision to close for the day, put all the closed signs up and headed home. I never waste any extra time I get and spent the day in the warm cleaning the house, doing the ironing, admin and getting ahead for the coming week.
|Chionochloa rubra
|I always like when an delivery arrives in the post of new plants for my own personal plant collection. This time it was 10 new Pelargoniums, all species, for my collection, which now brings the number to 70. Still a few to go! Need another heated greenhouse....... David?
|Saturday at the nursery
|Sunday in the nursery
In order to catch up I decided to go in to the nursery on Monday and Tuesday. There was still snow lying for most of the day on Monday and everything is frozen but it is melting just not where I need it to melt. The sun was out most of the day which helped so I spent the morning doing jobs that don't require being outside. Sowing seeds, great to get started on this task at last, there's a lot to get through! Writing a newsletter, bringing up the new pots that were delivered, terracotta and glazed in a variety of sizes, more on them later once I've taken photos. I also got the rest of the stock bed labels out in place and a list made of ones still missing.
|Great to see some blue sky at last and the snow melting
Tuesday saw me starting to tidy up the herb garden at last. The sun was out and there was even a hint of warmth. Although a big area, the borders in the herb garden are small and fairly quick to cut back and weed. I also top all the borders with our home made compost to help boost the very poor soil there. I didn't get the two L shaped beds done, they will have to wait for another day. But I was very pleased with progress made. I'm really pleased to see how many herbs have survived and in fact look really good after such a cold and snowy winter. I always recognised planting a herb garden on cold clay soil in a north facing garden would be / could be somewhat challenging, but we gardeners love a challenge, or trying something out and chancing our luck that it might just work. So far so good! One or two plants look a bit poor but hopefully they will pull through. I was proved correct about one of the L shaped borders that was very wet last year. The Santolinas and Helichrysum italica have all died, not liking their feet in waterlogged soil all winter. I will have to reconsider what to plant in this border.
So that's another winter week, it does feel that spring has abandoned us completely and I can't remember the last time I felt warm. Surely the weather must improve soon and we can enjoy having all our lovely customers visiting again. Have a good week, hopefully some gardening too.
If you want to find out what's been happening in our garden at home like our Facebook page
If you to see whats new and looking good at the nursery like our Facebook page
Find out more about the nursery here - our web site: www.quercusgardenplants.co.uk
Follow us on Instagram @quirkybirdgardener
Follow us on Instagram @quirkybirdgardener
You can now sign up for our monthly newsletter on the facebook page or by emailing us to be added to our mailing list
All contents and photographs © Rona, unauthorised reproduction & use of these images is strictly forbidden, thank you


text:
Bentley breaks SUV record with the Bentayga at Pikes Peak
The big SUV defied physics to climb the mountain in a brilliant 10:49.9 minutes
Please Tell Us Your City
Knowing your city will help us provide relevant content to you.
| 3.78 Crores onwards
| 24.8 kmpl
| 3996 cc
| Automatic
Bentley Bentayga price starts at ₹ 3.78 Crores and goes upto ₹ 4.4 Crores. Petrol Bentayga price starts at ₹ 3.78 Crores.
|Variant name
|3996 cc, Petrol, Automatic, 24.8 kmpl
|₹ 3.78 Crores
|5950 cc, Petrol, Automatic,
|₹ 4.4 Crores
Sorry, no matching variants found.
After building cars for almost a century, most of the car marques are now looking to build SUVs or as they call it – the crossovers. Bentley Bentayga is a true blue modern SUV from the British luxury car maker. Based on the new generation Audi Q7 platform, the car was first showcased at Frankfurt in 2015.
While it has been developed on the Volkswagen group's MLB platform, the Bentayga shares almost nothing other than the underpinnings. The front fascia is signature Bentley with the twin round headlamps and a large rectangular mesh grille in the centre. The Bentayga gets a unique mix of creases and curves that effectively mask the bulk of this massive SUV at first glance. The tail is rather simple looking with the horizontal LED tail lamps and twin rectangular exhausts.
The interior is as stately as it should be in a Bentley. The cabin gets wooden veneer with metal inlays along with the leather upholstery. You can choose from 15 colours for your upholstery and get the cabin done in single or dual tone as per choice. The seats are 22-way adjustable in the front and the car can be ordered with four or five-seat configuration. The front seats get six massage types and also are ventilated. Of course, the massagers can be opted for in the back. The 8-inch touch-screen infotainment system gets navigation, 60GB storage and can be used in 30 languages.
The new twin-turbocharged massive 6.0-litre W12 TSI petrol mill develops 600bhp at 6000rpm and 900Nm of torque from as low as 1250rpm. The over two-tonne SUV goes past the 100kmph mark in just 4.1 seconds to attain a top speed of 301kmph. The power is delivered to all four wheels (40:60 front-rear torque split) through the eight-speed automatic gearbox. To improve efficiency, the Bentley gets active cylinder management where only six cylinders work under part load, start-stop technology and coasting. A hybrid powertrain is expected to make it to the SUV by 2017 and a diesel mill will be offered by 2018.
The Bentley Bentayga competes with the Range Rover Sport SVR in the Indian market. At a price tag of Rs 3.85 crore (ex-showroom, Delhi), the Bentayga is more expensive than the Mercedes Maybach S600 by almost Rs 1 crore.
Bentayga is available/sold in the following colours in India.
|Fuel Type
|Engine Capacity
|3996 cc
|24.8 kmpl
Seating Capacity
The big SUV defied physics to climb the mountain in a brilliant 10:49.9 minutes
Since it is the age of sporty SUV's, Bentley is all-set to jump on the bandwagon as well
With testing complete, Rhys Millen will make the record attempt over the weekend
Discount on Volvo S90
|On-Road Prices
|New Delhi
|₹ 4.35 Crores onwards
|₹ 4.17 Crores onwards
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Imagine these illustrations each paired with a journaling page with prompts inspired by each Wild Strength.
This project will eventually become a full printed coloring book. For now, let's add some color as pages are published.
Support this project by becoming a patron.
I use Patreon, where you can choose how much you would like to donate on a monthly basis.
Learn more here.
Follow this journey...
#wildstrengthpages Facebook Subscribe to my mailing list. Instagram: @wildstrengthpages
"Don't ask what the world needs.
Ask what makes you come alive, and go do it.
Because what the world needs is people who have come alive."
― Howard Thurman
"There is a creative spirit within you desiring to be free,
and you may as well get out of its way for it will give you no peace until you do."
― Mary Caroline Richards
"Tell me, what is it you plan to do with your one wild and precious life?"
― Mary Oliver


text:
Vitamin D and juvenile idiopathic arthritis
Vitamin D has been implicated in the pathogenesis of autoimmune diseases. While the roles of vitamin D in other autoimmune diseases have been investigated, less is known about the role of vitamin D in chronic childhood arthritis.
Main body
This review summarizes and evaluates evidence relating to 25-hydroxyvitamin D (25(OH)D) and chronic childhood arthritis. A scoping literature review was conducted using Ovid Medline, Ovid Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Scopus. Further, we geo-mapped the results of the studies to identify the patterns of the association between vitamin D and chronic childhood arthritis across the globe. Of 38 studies reporting 25(OH)D concentrations in childhood chronic arthritis, 32 (84.2%) reported that a significant number of children had suboptimal (< 75 nmol/L) status.
The data indicate suboptimal vitamin D status in children with chronic arthritis. Further, the association between low vitamin D and increased arthritis activity follow a north-south geographical gradient.
KeywordsVitamin D Childhood arthritis Juvenile idiopathic arthritis
1,25-dihydroxyvitamin D
25-dihydroxyvitamin D
Cumulative Index to Nursing and Allied Health Literature
Childhood Arthritis Risk factor Identification sTudY
Cytochrome p450 27B1
Geographic Information Systems
Institute of Medicine
Juvenile Chronic Arthritis
Juvenile Idiopathic Arthritis
Juvenile Rheumatoid Arthritis
- MeSH
Medical Subject Heading
Vitamin D receptor
Arthritis is among the most common chronic diseases in children. Juvenile Idiopathic Arthritis (JIA) is the current nomenclature applied to denote a group of clinically distinguishable subsets that share chronic, childhood-onset arthritis of unknown cause as a unifying feature. The etiologies of JIA are unknown and the pathogeneses unclear but are likely multifactorial. Among epidemiologic studies there is substantial variability in the frequencies with which JIA and its respective subtypes are reported to occur; chronic arthritis prevalence rates range from 0.07 to 4.01/1000 children and annual incidences from 0.008 to 0.226/1000 children [1]. Putative explanations for the disparities in reported juvenile arthritis prevalence rates include, as examples, differences in diagnostic criteria applied (specifically, JIA or the earlier Juvenile Rheumatoid Arthritis (JRA) [2] or Juvenile Chronic Arthritis (JCA) [3] classification systems) and in case ascertainment methods.
While methodologic inconsistencies among JIA epidemiologic studies might account for perceived prevalence differences, actual differences might occur as a consequence of genetic, ethnic, environmental, and lifestyle influences. Vitamin D status is potentially governed by these same factors; vitamin D receptor genotype, ethnically related skin tone and clothing, environmental variations in exposure to ultraviolet B radiation relating to the latitude of residence and season, and vitamin D nutritional intake are factors that modulate vitamin D concentrations.
As an immune and inflammatory mediator, vitamin D is implicated in the pathogenesis of autoimmune diseases including, as examples, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, Crohn's disease, and chronic childhood arthritis [4, 5, 6]. Cells involved in innate and adaptive immune responses such as macrophages, dendritic cells, T cells, and B cells express enzymes required to activate and respond to vitamin D [7, 8, 9]. Cytochrome p450 27B1 (CYP27B1) is the enzyme required to synthesize 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D, from circulating 25-hydroxyvitamin D (25(OH)D). The actions of 1,25(OH)2D are mediated by its binding to the vitamin D receptor (VDR), a nuclear transcription factor. VDR then binds to the Vitamin D Response Element (VDRE), a genetic sequence located in the promotor region of genes regulated by vitamin D [7, 8, 9]. Vitamin D tends to suppress the immune response [6]. Consequently, low vitamin D concentrations are associated with an increase in pro-inflammatory mediators and more active disease [6, 10] consistent, for example, with the observation that low serum 25(OH)D is associated with increased disease activity in rheumatoid arthritis [11].
Reports of relationships between vitamin D and chronic childhood arthritis are derived from studies having different methodologic approaches, originating from multiple geographic regions, and comprising demographically disparate populations. Since the last analysis of these reports in 2013 [12] the number of studies reporting 25(OH)D concentrations in children with chronic arthritis have increased from 14 to 38. An updated, systematic analysis of pertinent literature should help to further refine understanding of the relationships between vitamin D and juvenile arthritis, contribute to optimizing management of vitamin D status in children with arthritis, and clarify vitamin D's potential role in mediating disease pathogenesis.
Scoping reviews are methodologic approaches for thoroughly distilling and synthesizing information derived from different studies having varied designs. The purposes of scoping reviews are to not only capture key concepts that can guide care but also to recognize knowledge gaps that can inspire future research priorities [13].
Although nomenclature applied to chronic childhood arthritis classification systems has changed over the years, JIA is the current terminology. For clarity, this review will hereafter use the term JIA to encompass the forms of chronic childhood arthritis also included in the JCA and JRA classification systems. However, in this review, when quoting the literature, we use the terminology for chronic childhood arthritis (JCA, JRA, or JIA) that was applicable at the time the cited reference was published [14].
Here we report the results of a vitamin D- JIA scoping review that summarizes, synthesizes, evaluates, and interprets pertinent evidence from the literature to address the following research questions: 1) What is the relationship between vitamin D status and the occurrence of JIA? 2) What is the relationship between vitamin D status and childhood arthritis activity? 3) What is the relationship between vitamin D status in JIA and medication use? 4) What is the relationship between vitamin D status and geographic and demographic characteristics in children with JIA?
Comparison of classification systems of chronic childhood arthritisa
American College of Rheumatology 1977 [2]
European League Against Rheumatism 1978 [3]
International League Against Rheumatism 1994 and 2001 [17]
Classification Title
Juvenile Rheumatoid Arthritis
Juvenile Chronic Arthritis
Juvenile Idiopathic Arthritis
Symptom duration
Minimum 6 weeks
Minimum 3 month
Minimum 6 weeks
Polyarthritis RF negative
JRA (RF positive Polyarticular)
Polyarthritis RF positive
Juvenile psoriatic
Psoriatic arthritis
Juvenile ankylosing spondylitis
Enthesitis-related arthritis
Arthritis associated with inflammatory bowel disease
Undifferentiated arthritis
Geographic Information Systems (GIS) mapping was performed using ArcGIS version 10.4 to visualize studies by juvenile arthritis classification, 25(OH)D status, location, and latitude. For all reported studies, an additional map comparing the difference in 25(OH)D concentration between those reporting active versus inactive disease was made.
Defining vitamin D status
Vitamin D deficiency is defined as a serum 25(OH)D concentration less than 30 nmol/L, a 25(OH)D concentration between 30 and 50 nmol/L is considered insufficient, greater than 50 nmol/L is considered sufficient and a 25(OH)D status greater than 125 nmol/L is considered at risk of adverse effects [19]. These values are based on the Institute of Medicine (IOM) review of published research focused on determining the optimal vitamin D concentration for maximal calcium absorption, prevention of rickets, reduction of fracture risk and prevention of osteomalacia in healthy populations [19]. In the most recent review of vitamin D requirements, the IOM concluded that there was inadequate information to make intake recommendations in relation to other biologic roles of vitamin D [19]. The current recommended dietary allowances (RAD) of vitamin D are 400 IU from 0 to 12 months of age and 600 IU per day from 1 to 18 years of age [19].
The Endocrine Society has published clinical practice guidelines for patients at risk of vitamin D deficiency [20]. The Society recommends that at-risk populations, including "obese children and adults and children and adults on anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for acquired immune deficiency syndrome be given at least two to three times more vitamin D for their age group to satisfy their body's vitamin D requirement" [20]. The optimal 25(OH)D concentration suggested by the Endocrine Society is 75 nmol/L. To meet this concentration it is recommended that 400–1000 IU be given between 0 to 12 months of age, 600–1000 IU per day from 1 to 8 years of age, and 1500–2000 IU for children between ages 9–18 years [20]. These recommendations, however, are not specific for children with chronic arthritis.
Results of scoping review and discussion
Summary of current literature of 25(OH)D status and chronic childhood arthritis
Study Location and Reference
Sample size (number female)
Age (years) Mean ± SD or range
25(OH)D (nmol/L) Mean ± SD or range
Results relating to vitamin D
Control Group Results
Vitamin D Intake
Study Design: Meta-Analysis
Meta-Analysis Nisar et al. 2013 [12]
n = 529
Mean of 14 studies 61.4 nmol/L (Range 28.7–139.8) prevalence reported from 3 studies 82% insufficient.
Study Design: Randomized Controlled Trial
Cincinnati, Ohio USA Stark et al. 2006 40°N [45]
n = 49
4–10 y
79.9 ± 25.0 (39.9–142.3)
Behaviour intervention to increase calcium intake successful.
Ioannina, Greece Siampoulou et al. 2001 39°N [40]
n = 10 (6F)
13.1 ± 2.5
53.9 ± 8.5
All patients were vitamin D replete 25(OH)D > 17.5 nmol/L, most were measured between February to May.
Missouri, USA Hillman et al. 2008 37°N [54]
Children with arthritis
n = 18
82.1 ± 38.7
Supplemental vitamin D improved status, but supplemental vitamin D or calcium did not improve bone mass.
Kansas, USA Warady et al. 1994 39°N [55]
Rheumatic disease (6 with JRA)
n = 10 (7F) 6 JRA
70.1 ± 21.2
Children with rheumatic disease would benefit from receiving calcium and vitamin D supplements.
Illinois, USA Reed et al. 1991 40°N [46]
n = 13 (12F)
70.0 ± 40
Vitamin D may help prevent bone loss in children with active disease.
Study Design: Case-Control
Istanbul, Turkey Dagdeviren- Cakir et al. 2016 41°N [21]
Active disease: n = 64 (41) Remission: 53(35)
Active disease: 9.7 ± 4.3 Remission: 9.8 ± 4.3
Active disease: 46.5 ± 23.0 Remission: 47.3 ± 27.5
Vitamin D concentrations in children with JIA were significantly lower than healthy children. Of those who were measured while in remission there was no difference in 25(OH)D concentrations.
Healthy control n = 100 66.8 ± 26.6 nmol/L.
Mexico city, Mexico Hernandez Rosiles et al. 2015 19°N [39]
n = 37 (27)
12.5 ± 3.1
55.0 ± 13.9
No difference between children with JIA and controls.
Healthy controls n = 79 59.0 ± 7.7 nmol/L.
Fortaleza, Brazil De Sousa- Studart et al. 2015 3°S [22]
n = 51 (31 F)
13.4 ± 4
55.4 ± 25.0
25(OH)D similar for disease activity status, JIA category, and arthritis severity measure.
Age sex-matched controls 25(OH)D, 75.9 ± 14.0 nmol/L.
Hangzhou, China (article in Chinese, English Abstract) Wang et al. 2015 30°N [60]
n = 53
Not reported
Median 42.6
A significant difference between JIA and control 25(OH)D p < 0.01. No correlation between 25(OH)D and JIA subtypes, ACR pediatric 30, CRP or ESR.
Control n = 106 25(OH)D 49.9 nmol/L.
Florence, Italy Stagi et al. (2014) 43°N [23]
n = 152 (115F)
16. ± 7.4
54.4 ± 20.5
JIA had reduced 25(OH)D and higher PTH compared to controls. Active disease or frequent flare-ups resulted in lower vitamin D than non-active and no frequent flare-ups.
Control group 25(OH)D 74.4 ± 28.0 nmol/L p < 0.005.
Intake JIA 164 ± 84 IU/day control 160 ± 72 IU/day.
New Delhi, India Dey et al. 2014 28°N [31]
n = 35
22.0 ± 18.0
Decreased dietary intake of vitamin D and calcium, decreased weight bearing physical activity and sunlight exposure were the major factors for low BMD. Duration of disease 2.30 ± 1.91 yrs.
Age sex-matched controls 25(OH)D 37.9 ± 10.0 nmol/L significant difference.
Intake JIA 123 ± 53.6 (50–207) control 309 ± 62.38 (213–387) IU/day.
Lodz, Poland Szyamanska-Kaluza et al. 2013 51°N [24]
n = 50 (40)
9.4 ± 5.52
43.4 ± 21.1
Vitamin D deficiency is common in this population. No correlation between disease activity, type of JIA or metabolites of vitamin D.
Control n = 28 Age, gender matched, hospitalized children 43.4 ± 40.7 nmol/L.
Sao Paulo, Brazil Munekata et al. 2013 23°S [25]
JIA- polyarticular
n = 30 (23F)
14 (4–20)
64.1 ± 21.6
High frequency of 25(OH)D deficiency in both control and JIA groups; no difference between the two. No association of 25(OH)D with disease activity.
Control group age-sex matched (n = 30). 16 non-Caucasian; mean disease duration 5y (1–12) control 2 5(OH)D 67.2 ± 19.0 nmol/L.
Oslo, Norway Lien et al. 2005 59°N [26]
n = 108
6 to 18
49.7 ± 16.5
No difference in 25(OH)D between control and JIA groups.
Control n = 108 25(OH)D 50.4 ± 8.1 nmol/L D
Intake JIA 164 ± 84 IU control 160 ± 72 IU
London, UK Rooney et al. 2000 51°N [49]
n = 34 (23F)
9.2 (4.6–13.6)
Estimated from graph 45 (14.5–62.5)
Vitamin D status was significantly lower in JCA patients than age-matched controls before treatment, Steroid-treated children have low vitamin D. All but three children received corticosteroids.
Control group 25(OH)D estimate 75 nmol/L.
Florence, Italy Falcini et al. 1998 43°N [48]
n = 47 (34)
15 months-12 years(7.13 ± 4.1)
61.4 ± 20.5
The lower serum concentrations of osteocalcin in active disease support the hypothesis that both bone formation and resorption are reduced in JRA
Controls n = 47 25(OH)D 56.7 ± 21.5 nmol/L.
Missouri, USA Pepmueller et al. 1996 37°N [43]
n = 41
45.7 ± 23.5
Suggest an association between decreased bone mineralization in JRA and low bone formation that is related to disease severity.
Control n = 62 65.5 ± 23.5 nmol/L significant difference.
Vitamin D intake in JRA 464 ± 262 IU
Intake of controls not reported.
Ioannina, Greece Tzoufi et al. 1994 39°N [50]
n = 35 (14)
8.8 ± 4.1
39.8 ± 20.5
Disease activity of JCA appears to be associated with lower vitamin D.
Mean disease duration 3.4 years Control n = 15 25(OH)D 68.1 ± 15.5 nmol/L control group taking corticosteroids n = 4 25(OH)D 51.4 ± 24.5 nmol/L.
Missouri, USA Hillman et al. (1994) 37°N [47]
n = 44 (28)
11.8 ± 3.8
66.6 ± 26.7
Lower bone mineral content and bone biomarkers in JRA patients that controls but higher vitamin D in JRA.
N = 37 controls 25(OH)D 53.2 ± 18.7 nmol/L.
Milano, Italy Bianchi et al. 1990 45°N [41]
n = 36 (64%)
9.96 (5–17)
45.9 nmol/L Reported from Nissar et al. Review
Suggests severe JRA has an influence on bone mass possibly mediated by a decrease in active vitamin D metabolites.
Study duration one year, controls only measured at baseline 25(OH)D 92 ± 17.5 nmol/L
Huddinge, Sweden Johansson et al. 1986 59°N [52]
26 (all female)
63.2 ± 36.4
Statistically lower than controls, however no evidence of deficiency.
Healthy controls n = 28 76.2 ± 28.0 nmol/L
Study Design: Cross Sectional
Chongqing, China Tang & Mingyue Conference Abstract 2016 29°N [27]
n = 76 (36)
8.49 ± 3.09
52.8 ± 15.3 nmol/L
JIA patients have reduced serum 25(OH)D3, particularly those with active disease or/and using glucocorticoid.
Riyahad, Saudi Arabia Alhomaidah et al. 2016 24°N [28]
n = 22 (13)
14 > 75 nmol/L 8 < 75 nmol/L
Vitamin D insufficiency is frequent in children with JIA.
Bialystok, Poland (abstract only) Goralczyk et al. 2015 53°N [29]
n = 189 (113)
40.6 ± 23.5
67% 25(OH)D < 50 nmol/L. Obese children had significantly reduced 25(OH)D compared to normal weight peers. Negative relationship between MTX use and 25(OH)D.
Oporto, Portugal Peixoto et al. 2013 Conference Abstract 41°N [30]
n = 40 (31)
22.3 (4–63)
10 > 75 nmol/L, 19 between 50 and 75 nmol/L, 11 < 20 nmol/L
Prevalence of vitamin D deficiency/insufficiency among JIA patients is very high.
Antalya, Turkey Comak et al. 2014 36°N [32]
n = 47 (29)
9.3 ± 3.9
44.2 ± 29.0
Only 27.7% patients had 25(OH)D > 50 nmol/L. There was a significant negative correlation between vitamin D concentration and disease activity (p = 0.01, r = − 0,37).
Salé, Morocco Bouaddi et al. (2014) 34°N [33]
n = 40 (18)
11 ± 4.23
55.4 ± 27.2
25(OH)D < 75 nmol/L in 75% of sample. Poly arthritis and oligoarthritis 25(OH)D status negatively associated with disease activity in univariate but not multivariate analysis.
Median disease duration two years.
Helinski, Finland Miettinen et al. 2013 Letter to the Editor 60°N [34]
n = 136
Suggest that JIA subtype may be associated with 25(OH)D concentration in female patients. Seasonal difference with female patients.
CambridgeUK Nisar et al. 2013 Conference Abstract 52°N [35]
n = 37 (31)
0–10 (n = 13), 11–20 (n = 12) and > 21 years (n = 12)
49.6 nmol/L (range 13.2–112.0 nmol/L).
Half of patients with JIA have low Vitamin D levels which are inversely related to disease activity and disease duration.
Boston, USA Pelajo et al. 2012 42°N [36]
n = 154 (61%)
72.9 ± 23.0
13% deficient, 42% insufficient. Age, ethnicity, season, BMI associated with 25(OH)D but not vitamin D deficiency.No association with whole sample; small negative association for new onset JIA; mean time since onset 28 months.
Helinski, Finland Markula-Patjas et al. 2012 60°N [37]
n = 50 (41)
14.8 (7.0–18.7)
53 nmol/L (20–95 nmol/L)
62% sufficient, 24% insufficient and 14% deficient.
52% taking vitamin D supplement % of DRI median and IQR 187 (57,331).
Saskatchewan, Canada McNally et al. 2009 52°N [59]
Pediatric arthralgia
n = 730 25(OH)D n = 73
< 18
Significantly more reported fall and winter as season of onset – more referrals from northern SK 40% < 50 nmol/L 42% 50–75 nmol/L Association between psychological stress, school absenteeism vitamin D insufficiency and arthralgia.
Helinski, Finland Valta et al. 2007 60°N
JIA Glucocorticoid treated
n = 62 (43)
Median 11.8 (4.6–17.9
Median 49 nmol/L 16 (23%) ≤ 37.5 nmol/L
Osteoporosis is a concern in glucocorticoid treated children with JIA.
32% prescribed 400–800 IU vitamin D daily
Mean intake 316 IU (range 44–1204 IU).
Ohio, USA Henderson et al. 1997 40°N [44]
n = 48 (37)
8.1 ± 1.9
89.4 ± 28.7
Serum 1,25-dihydroxyvitamin D concentrations were able to accurately segregate 79.6% of the JRA subjects into either the low or normal BMD groups.
Illinois, USA Reed et al. 1993 40°N [42]
n = 27 (23)
84.9 ± 11.0
No difference in vitamin D status between active and inactive groups. Children with JRA who have improvement in their disease activity have an improvement in BMD heralded by an increase in serum osteocalcin values 4–87 months from disease onset.
Harrow, UK Reeve et al. 1993 51°N [53]
JCA- treated with glucocorticoids
Prednisone n = 17 Deflazacort n = 17
Prednisone 10.6 ± 3.7 Deflazacort 10.3 ± 3.9
Prednisone 140.8Deflazacort 115.6
25(OH)D was surprisingly high, there was no difference between the two groups p = 0.8.
Chicago, Illinois Reed et al. 1990 40°N [57]
Chronic Rheumatic Disease
n = 113 (82) JRA n = 83
1.5 to 21
Range of groups 44.9 ± 15.0 to 54.9 ± 22.5
No difference between those with active and inactive disease.
London, UK Elsasser et al. 1982 51°N [51]
n = 63 serum 25(OH)D n = 29
Not reported
24.5 nmol/L (9 > 25 nmol/L, 20 < 25 nmol/L)
There was a marginally significant correlation between TBD and 25(OH)D concentrations (r = 0.37. P < 0.05). Only nine children had acceptable vitamin D status.
Vitamin D status in relation to chronic childhood arthritis classification
Twenty-one of the 38 studies (55.3%) reported 25(OH)D status for patients with JIA [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40], eight (21.1%) for patients with JRA [41, 42, 43, 44, 45, 46, 47, 48] and five (13.2%) for JCA patients [49, 50, 51, 52, 53]. Additionally, there were four studies that included patients with juvenile arthritis and other rheumatic diseases [54, 55, 56, 57]. As the JRA classification system tended to be applied in North America and the JCA classification in Europe, there was a corresponding hemispheric-specific division in the geographic region from which JRA and JCA articles originated. Studies originated from 17 countries at latitudes ranging from 3°S to 61°N (Table 2). There were no eligible studies found that reported data below a latitude of 39°N prior to the introduction of the ILAR JIA disease classification systemic and no eligible JRA studies above 42°N.
The 2013, systematic literature review of 19 childhood arthritis studies reported vitamin D status (14 reporting 25(OH)D and 11 reporting 1,25(OH)D) suggested that at that time there was no clear link between vitamin D status and children with chronic arthritis [12]. The review also contained a meta-analysis comprising three studies that reported the prevalence of vitamin D insufficiency to be 82% in JIA [12]. Only three studies reported in the meta-analysis were conducted using ILAR JIA criteria [12].
Comparison of study design
Seventeen studies used a cross-sectional design (n = 17; 44.7%) [27, 28, 29, 30, 32, 33, 34, 35, 37, 42, 44, 51, 53, 57, 58, 59], 16 (42.1%) a case-control design [21, 22, 23, 24, 25, 26, 31, 39, 41, 43, 47, 48, 49, 50, 60] and the remainder (5; 13.2%) were randomized controlled trials [40, 45, 46, 54, 55]. The primary objective of the majority of studies was to investigate the relationship between juvenile arthritis and bone health (n = 20; 52.6%). In all studies where sex distribution was reported, there were significantly more female participants than males, an observation consistent with the overall preponderance of females in JIA [61]. With the exception of one study [35], the age range of the participants was 0–21 years.
25(OH)D status
Of the 38 studies reviewed, six (15.8%) had mean 25(OH)D concentrations above 75 nmol/L [28, 42, 44, 45, 53, 54]. Seventeen studies (44.7%) had mean 25(OH)D concentrations between 50 and 75 nmol/L [22, 23, 25, 27, 30, 33, 34, 36, 37, 39, 40, 46, 47, 48, 55, 59] and 15 (39.5%) had values below 50 nmol/L [21, 24, 26, 29, 31, 32, 35, 38, 41, 43, 49, 50, 51, 57, 60]. Of those 15 studies, 10 reported the mean 25(OH)D value, the median value reported for one study and a range or cutoff was provided for four studies). Of the 14 studies (36.8%) that published mean 25(OH)D status of healthy control groups, nine (64.3%) had mean control values significantly greater than the population with childhood arthritis [21, 22, 23, 31, 41, 43, 49, 50], three (21.4%) had concentrations that were statistically similar [25, 39, 60], and two studies (14.3%) had mean 25(OH)D values significantly below the juvenile arthritis comparison groups [47, 48]. One study compared 25(OH)D concentrations in children with JIA to hospitalized children and found no statistically significant difference between the two groups [24]. Mean 25(OH)D status of most studies (32 of the 38; 84.2%) was below the optimal concentration of 75 nmol/L in children with arthritis [20].
Geography in relation to 25(OH)D status in chronic childhood arthritis
The major source of vitamin D for most people is endogenous vitamin D synthesis induced by sunlight exposure [62]. Above 33° latitude UVB radiation is not intense enough for the cutaneous synthesis of vitamin D all year long [63, 64]. At latitudes 42° and 53o North, between October to April, UVB radiation is not intense enough to elicit endogenous vitamin D synthesis [65] thus potentiating the risk of vitamin D deficiency, [63].
The prevalence of JIA, as well as the dominating subtype, varies with latitude [1]. As illustrated in Fig. 2, seven reviewed studies (18.4%) were conducted in populations residing at latitudes at or below 33° [22, 25, 27, 28, 31, 39, 60], 19 studies (50.0%) were conducted between 33 and 50° [21, 23, 30, 32, 36, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 54, 55, 57, 66], and 12 at a latitude above 50° [24, 26, 29, 34, 35, 37, 38, 49, 51, 53, 59]. For those below 33°, 1 study (14.3%) reported a mean 25(OH)D concentration > 75 nmol/L, 4 (57%) reported a concentration between 50 and 75 nmol/L, and two (29%) reported values less than 50 nmol/L. For the studies that took place between 33 and 45° latitude, four studies (21.1%) reported a 25(OH)D concentration > 75 nmol/L (21%), nine (47.4%) reported a concentration between 50 and 75 nmol/L(47%) and six (31.6%) reported values less than 50 nmol/L. From the studies that took place above 45° latitude, one study (8.3%) reported a 25(OH)D concentration > 75 nmol/L, four (21.1%) reported a concentration between 50 and 75 nmol/L (33%) and seven (36.8%) reported values less than 50 nmol/L (39%).
Current chronic childhood arthritis diagnostic criteria
Of the 21 studies that applied the current chronic childhood arthritis criteria used by ILAR to diagnose children with JIA, only one study reported mean 25(OH)D concentrations above 75 nmol/L (15%) [28]. The majority of the studies (n = 11; 52.4%) reported mean concentrations between 50 and 75 (52%) nmol/L [22, 23, 25, 27, 30, 33, 34, 36, 37, 40, 67], and the remaining studies (n = 9; 42.9%) reported a mean concentration below 50 nmol/L (43%) [21, 24, 26, 29, 31, 32, 35, 38, 60]. As latitude increased, the percentage of studies that reported mean 25(OH)D in the 50–75 nmol/L range decreased.
Vitamin D and disease activity
No single measure has been established as an accurate indicator of childhood arthritis disease activity. While C-reactive protein and Erythrocyte Sedimentation Rate are indicators of inflammation, they alone do not fully reflect overall disease activity. In the studies reviewed, a variety of validated composite scores were used to measure function or disease activity, including the Childhood Health Assessment Questionnaire (CHAQ), the Juvenile Arthritis Disease Activity Score − 27 (JADAS-27) and American College of Rheumatology Pediatric 30 Criteria (ARC Peds 30) [68, 69, 70].
Fifteen of the 38 studies comprising this present review (39.5%) evaluated the relationship between vitamin D and disease activity (Fig. 3). Seven studies (18.4%) reported that patients with active disease or those with elevated inflammatory biomarkers had lower 25(OH)D concentrations than those patients who were in remission or who had less disease activity [23, 27, 30, 32, 35, 41, 50]. One study (26.3%) showed the opposite relationship; those with active disease had higher vitamin D concentrations than those with inactive disease [34]. Of the seven studies (18.5%) that reported no relationship between 25(OH)D and disease activity [21, 22, 25, 33, 36, 42, 57] one found a relationship between 25(OH)D concentrations and disease activity in the univariate but not the multivariate analysis [33]. Except for one study conducted in Turkey [21], all other studies conducted in Europe that explored disease activity reported an inverse association between vitamin D and disease activity.
Long-term cohort studies can further clarify the relationship between vitamin D concentration and disease duration or frequency of relapse. Such an association was explored in a cross-sectional study which found significantly reduced 25(OH)D status in JIA patients (n = 152) compared with 188 age-and-sex-matched controls [23]. Active disease or frequent relapse was associated with reduced vitamin D status compared to patients with no active disease or frequent flare-ups. The authors questioned whether JIA patients with more severe disease require higher supplementation of vitamin D to maintain normal 25(OH) D concentrations. As latitude increases more studies report a difference in vitamin D status between patients with active versus inactive disease in comparison to lower latitudes as illustrated in Fig. 3.
To date, the evidence to support a relationship between vitamin D and disease activity with autoimmune diseases in humans is correlative and not causative [71]. Long-term, adequately powered randomized studies which control for confounding variables (sun exposure, season, and vitamin D intake) are required to confirm a causative relationship between vitamin D and disease activity.
Potential requirements of vitamin D intake
Vitamin D intake was only measured in seven studies [23, 26, 31, 37, 38, 43, 44]. All of these studies reported a mean or median vitamin D intake that was less than the Estimated Average Requirement (EAR) of 400 IU per day set by the IOM [19]. This is the amount of vitamin D that is expected to be sufficient for 50% of the population [19]. This indicator is used to evaluate the prevalence of inadequacy at the population level. The recommendation at the individual level is the Recommended Dietary Allowance (RDA) which ranges from 400 to 600 IU based on age groups. Two studies reported intake of vitamin D supplements by study participants but neither had a mean 25(OH)D that reached the optimal concentration [38, 44]. Three studies reported intake of both children with JIA and healthy controls [23, 26, 31]. Vitamin D intake and status was similar for two JIA patient groups [23, 26], and lower intake resulted in lower vitamin D status in the third group [31]. In comparison to the control groups, Lien et al. found similar intake and 25(OH)D status between those with JIA and controls [26]. Stagi et al. reported similar intake of vitamin D and higher 25(OH)D in controls, and in the study reported by Dey et al. the intake of control participants was two times higher than the participants with JIA and the control group had higher 25(OH)D concentrations [23, 31].
It has been theorized that there may be an increased utilization of vitamin D during active inflammation, possibly caused by \the presence of vitamin D receptor polymorphisms in patients with autoimmune diseases [6, 72]. Additional studies investigating vitamin D intake from all sources (both food and supplements) are required to determine if children with chronic arthritis require additional vitamin D to maintain serum concentrations in comparison to healthy children. Understanding this relationship will be important in the use of vitamin D as a potential adjunct therapy. Additionally, improved understanding of vitamin D needs in children with chronic arthritis will help to clarify the role of vitamin D in the underlying disease processes so that therapies that target specific vitamin D responsive immune pathways can be developed. By exploring the factors that influence vitamin D status (genetics, environment, and nutrition), we will be better able to discern an association between vitamin D and JIA.
Two articles have discussed vitamin D requirements for children with rheumatic conditions not in the context of corticosteroids. In 2011, von Scheven and Burnham suggested that in the absence of specific guidelines for children with rheumatic conditions that the American Academy of Pediatrics guidelines of 400 IU per day be used as a suggested minimum dosing regimen [4]. The authors cautioned that providing large doses of vitamin D can result in providing "too much of a good thing" and that studies comparing children with rheumatic diseases to healthy children are required. The second article was published by Vojinovic and Cimaz in 2015 and recommends that the guidelines set out by the Endocrinology Society for patients receiving corticosteroids be followed for all children with rheumatic diseases [73]. This would result in a dose of 2–3 times the current recommendation and would be approximately 2000 IU/day. This dose is still below the IOM's tolerable upper limit for all children over the age of one (2500 IU) [19].
Vitamin D and medication interactions in JIA patients
All but one study [24], have been conducted with children already being treated for arthritis, many receiving corticosteroids, which could impact 25(OH)D concentration and inflammatory status. Corticosteroids promote the breakdown of both 25(OH)D and 1,25(OH)D and also counteract effects of vitamin D on bone formation [74, 75]. These patients also had varying disease duration. A study of newly diagnosed individuals, however, did not compare patients with JIA to healthy controls but to hospitalized children [24] . Comparing children with JIA to healthy controls allows for discerning biologic differences that could inform treatment targets.
The lowest mean 25(OH)D concentration, 22 nmol/L (n = 35) was reported from India. These patients were found to be consuming significantly less vitamin D and had less sun exposure compared to healthy controls [31]. The highest 25(OH)D, 140.8 nmol/L (n = 17), concentrations were reported in Finland, in a population receiving Prednisone [53]. The authors hypothesized that the reason their patients' 25(OH)D concentrations were so high was that their previous research had found low concentrations of 25(OH)D and they were encouraging their patients to consume vitamin D fortified foods and to spend time in the sun [53]. A survey of steroid-related osteoporosis, prevention and treatment practices of pediatric rheumatologists in North America was conducted by Soybilgic et al. in 2014 [76]. They found that the majority of pediatric rheumatologists are recommending vitamin D for patients who were on long-term corticosteroids [76]. The role of vitamin D in mediating bone health, especially in relation to corticosteroids, has been established [75]. Both short and long-term corticosteroid intake even at small doses impact bone health in patients with autoimmune diseases [74]. The role and an appropriate amount of vitamin D intake or 25(OH)D target for inflammation or disease activity have yet to be established.
Additional research directions
Considering ethnicity when comparing incidence and prevalence amongst populations would be useful in understanding if the regional differences observed are due to environmental or genetic factors or a combination of the two. Evidence from a multiethnic cohort study of 1082 children at The Hospital for Sick Children, Toronto, Canada investigated the influence of ethnicity on the risk of developing JIA [77]. When the diversity of the study population was compared to that of the general Toronto region population, there was an overrepresentation of patients of European and Indigenous descent and an underrepresentation of patients of Black, Asian, or Indian subcontinent ethnicity in their cohort. European descent was significantly associated with an increased risk of developing JIA, including all subtypes except RF-positive polyarticular JIA. Exploring the environmental and genetic factors that may contribute to JIA risk in the same individual will help to clarify these findings.
While this review focused on vitamin D status in children with JIA, vitamin D may be involved in both disease development and subsequent disease activity status. Exploring elements of vitamin D status that may have a role in disease development such as early life and gestational vitamin D status as well as genes in the vitamin D pathway will help to clarify the role of vitamin D.
Season of birth has been suggested to have an impact on the risk of developing a number of autoimmune diseases such as multiple sclerosis, type 1 diabetes and celiac disease [78]. A recent study investigating month of birth and risk of JIA found a difference in the pattern of the birth month for children with JIA compared to that of the general population [78]. Children with JIA were more likely to be born between November to March, with the birth month for the general population peaking in the summer months. The study by Carlens et al. also investigated the relationship between season of birth and the risk of developing JIA and found no increased risk [79]. Season of birth may be a marker for vitamin D status in utero with children born in the non-vitamin D synthesizing periods being exposed to less vitamin D during their time in utero than those who are born during the vitamin D synthesizing seasons.
The Childhood Arthritis Risk factor Identification sTudY (CLARITY) explored the use of nutritional supplements during pregnancy and the risk of developing JIA [80]. The use of vitamin D and fish oil during pregnancy in case mothers was not significantly different from controls following covariate adjustments [80]. A case-cohort investigation from Denmark, comparing 25(OH)D status in children diagnosed with either oligoarticular or polyarticular JIA using dried blood spot samples that were collected at birth did not find any association between 25(OH)D status at birth and risk of developing JIA [81]. Concentrations of 25(OH)D fluctuated significantly by season of birth and year of birth (calendar year). There was no follow up to determine if 25(OH)D status or season during the first few months of life impacted risk of JIA or whether other subtypes of JIA were impacted by season of birth of 25(OH)D status at birth.
Certain VDR gene polymorphisms may be associated with different biologic response to vitamin D. The Cdx2 polymorphism of the VDR gene specifically the GG genotype, have been suggested to be more represented in patients with JIA compared to healthy controls who more often have the GA genotype [82]. Recently the idea of investigating epistasis (gene-gene interactions) amongst genes in the inflammatory and vitamin D pathway and how their interactions contribute to JIA risk was explored by Ellis et al. [86]. This is the first study to explore this interaction, and the authors suspect that through exploring these interactions there is the opportunity to account for the missing heritability that has been observed with complex diseases with genetic components [86]. Their work found evidence of epistasis amongst tyrosine-protein phosphatase non-receptor type 2 (PTPN2) gene and the vitamin D binding protein gene in contributing to the risk of JIA [86]. The role of genes in the vitamin D pathway on both disease development and disease activity are still in the early stages of investigation. Also how they impact the biological response involving vitamin D and inflammation remains unclear. Investigating genetic, nutritional and environmental factors that influence vitamin D in JIA could help inform ways in which vitamin D status influences the occurrence and activity of JIA. Understanding if genetic variants increase the risk of disease development will help tailor vitamin D management in individual patients and contribute to improving control of disease activity and improve outcomes.
A north-south gradient of incidence and a mechanism for the suppression of inflammation in relation to 25(OH)D status has been suggested. However, no study has summarized the current evidence of chronic childhood arthritis diagnosis by 25(OH)D status in relation to latitude and disease activity. This first step is important for the development of future studies leading to the exploration of potential optimal target concentrations of vitamin D for the reduction of inflammation in children with chronic arthritis.
This scoping review has limitations due to the limited amount of comparative data. Season of measurement and JIA subtype could not be considered due to a lack of reporting in most reviewed articles. With the exception of one study, all studies reviewed used various unreported types of medication in patients who had had JIA for varying durations. These variables can make it difficult to interpret the relationship between vitamin D and disease activity in relation to both inflammation status and risk of relapse. Of the studies that investigated the relationship between vitamin D and function or disease activity, various measures were used. The most common included the CHAQ, JADAS-27 and ARC Peds 30. The JADAS-27 and ACRS Peds 30 both include active joint counts in their scoring which confounds comparisons of disease activity between patients with different JIA that are defined by numbers of joints involved. Subtypes [17, 83, 84]. Many studies included multiple subtypes of JIA measured by the same disease activity score that included an active joint count. This review was unable to explore the relationship between vitamin D status and ethnicity, vitamin D receptor genes or other genes that influence vitamin D metabolism.
This is the first scoping review to summarize research relating to vitamin D and JIA in the context of vitamin D status, latitude, disease activity. It is also the first to map the results according to geography. Thirty-two studies (84.2%) reported a mean 25(OH)D concentration below 75 nmol/L or the optimal value. This suggests that whether due to inadequate intake or increased utilization the majority of children with juvenile arthritis do not have optimal 25(OH)D status as defined by the Endocrine Society [20]. The optimal concentration of 25(OH)D and the corresponding dietary requirements for patients with chronic childhood arthritis has yet to be determined. Further, the relationship between vitamin D status and disease activity in children with JIA is still unclear. Studying newly diagnosed patients who are treatment naive for longer periods of time would help characterize this relationship as there would be fewer confounders associated with patients who have had the disease for varying durations (medication, lifestyle modifications, and disease duration). Thus far, we know that there is a role for vitamin D in the inflammatory pathways, a high prevalence of 25(OH)D insufficiency among children with JIA, and an established link of vitamin D with other autoimmune diseases. We do not, however, know the optimal vitamin D status for children with JIA, whether reduced vitamin D is caused by increased utilization or reduced vitamin D status in children with JIA, the impact of vitamin D in disease activity or the role of VDR polymorphisms with JIA. Larger, long-term studies of new-onset JIA are required to explore the association. The relationship between vitamin D status and JIA over time in newly diagnosed individuals has yet to be investigated. Investigating the genetic and environmental role that vitamin D plays in the prevention and control of JIA in the same children will help to tease out the multifaceted role played by vitamin D in this disease. Being able to suggest specific targets for vitamin D status as a potential adjunct therapy in the treatment of JIA and understanding how genetic variants increase the risk of disease development will enhance the quality of life of patients and their families.
We acknowledge the help of Vicky Duncan, Librarian, University of Saskatchewan, in designing the outline of the search procedure, and Dr. Weiping Zeng of the Spatial Analysis Initiative/Social Science Research Laboratory at the University of Saskatchewan for creating maps. This research was supported, in part, by the Jim Pattison Children's Hospital Foundation of Saskatchewan.
The University of Saskatchewan Scholarship for Sarah Finch.
The Jim Pattison Children's Hospital Foundation.
Authors' contributions
The co-authors designed the review. SF drafted the manuscript under the direct supervision of HV and AR. HV and AR provided critical review and feedback throughout different stages of the manuscript preparation. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This paper is a review article, does not need ethic approval.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Cabbage soup
Main dish
Variety of deep fried mini schnitzels with potato salad (chicken and pork)
Deep fried carp fillet in breadcrumbs, potato salad
Fried white sausage, mashed potatoes
Baked apples with vanilla cream
Unlimited acces to wellness , Wi-Fi
Room size: 45 m2
Room facilities: bathroom with bathtub and WC, hairdryer, direct dial phone, satellite TV, safety deposit box, desk.
* Price depends on your arrival date and length of stay. Price per night.


text:
Upton powers Tigers to 6-5 victory over Royals
KANSAS CITY, Mo. (AP) Justin Upton hit a two-run homer with two out in the eighth inning, sending the Detroit Tigers to a 6-5 victory over the Kansas City Royals on Sunday.
Upton also doubled in J.D. Martinez in the second. He has seven homers and 18 RBIs in his past 14 games.
Miguel Cabrera was on first after a leadoff single when Upton drove a fastball from Joakim Soria over the wall in center for his 20th homer, giving Detroit a 6-5 lead. Soria (4-7) blew his fourth save in five opportunities.
Shane Greene (3-3) pitched 1 1/3 innings for the win. Francisco Rodriguez worked the ninth for his 38th save in 42 opportunities.


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The Copier Service Co was established in 1991 to meet a requirement of corporations wanting old school good high quality service. Our technicians are extremely skilled, all with a few years' experience working in New Zealand environments. We service all makes and fashions of photocopiers, printers and multifunction's together with Fuji Xerox, Konica Minolta, Canon, Ricoh, Toshiba, Panasonic, Sharp, Kyocera Mita e.t.c. Many corporations use us to service a wide range of brands they might have within their organizations. We will service them all.
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We would like to thank you for taking the opportunity to allow us to assist you to with your copier buy. We try to make the buying and support of your copier so simple as potential. First, regarding service - we now have nationwide USA protection which implies we'll only use a hundred% manufacturing facility approved Xerox reps.
Areas We Sell & Service Copiers In Minnesota
Albert Lea, Albertville, Andover, Annandale, Anoka, Apple Valley, Arden Hills, Becker, Big Lake, Bloomington, Brooklyn Center, Brooklyn Park, Buffalo, Burnsville, Cambridge, Cannon Falls, Center City, Centerville, Champlin, Chanhassen, Chaska, Chisago City, Circle Pines, Columbia Heights, Coon Rapids, Corcoran, Cottage Grove, Crystal, Dakota, Dayton, Deephaven, Delano, Eagan, Eden Prairie, Edina, Elk River, Excelsior, Falcon Heights, Faribault, Farmington, Fergus Falls, Forest Lake, Fridley, Golden Valley, Independence, International Falls, Inver Grove Heights, Isanti, Lakeville, Lindstrom, Lino Lakes, Litchfield, Little Canada, Long Lake, Long Prairie, Loretto, Maple Grove, Maple Plain, Maplewood, Marine on St. Croix, Marshall, Medicine Lake, Medina, Mendota, Mendota Heights, Minneapolis, Minnetonka, Minnetonka Beach, Minnetrista, Monticello, Mora, Mound, Mounds View, New Brighton, New Hope, Newport, New Prague, Nicollet, North Oaks, North St. Paul, Norwood Young America, Oakdale, Oak Grove, Oak Park Heights, Orono, Osseo, Otsego, Pine City, Plymouth, Princeton, Prior Lake, Richfield, Robbinsdale, Rockford, Rogers, Sacred Heart, St. Bonifacius, St. Louis Park, St. Michael, St. Paul, St. Paul Park, Copier Leasing Sauk Rapids, Savage, Scandia, Shafer, Shakopee, Sherburn, Shoreview,Shorewood, Spring Lake Park, Spring Park, Stacy, Stillwater, South Saint Paul, Taylors Falls, Tonka Bay, Vadnais Heights, Victoria, Waite Park, Waseca, Watertown, Watkins, Watson, Wayzata, West Concord, West St. Paul, White Bear Lake, Willmar, Woodbury, Wood Lake, Woodland, Woodstock, Wright, Wyoming, Zimmerman.
Find Us At:
99 5th Avenue N.E
Suite 1000
New Brighton, MN 55112