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Cheap Landscaping Ideas Pool Area
Pocket-friendly Poolscaping: Splashy Ideas!
Dive into these pocket-friendly poolscaping ideas!
With the weather getting hotter, there’s no better way to cool down than to take a dip in your very own swimming pool. However, pools can be expensive to install and maintain, especially when it comes to landscaping. But don’t worry! There are plenty of pocket-friendly ways to give your pool area a fresh new look without breaking the bank.
One easy and affordable way to add some flair to your pool area is by incorporating potted plants. You can mix and match different types of plants for added texture and color. Some popular options include ferns, succulents, and tropical foliage. Not only will they add some life to your pool area, but they can also provide some much-needed shade on a hot summer day. Bonus points if you opt for plants that are low maintenance and drought-resistant.
Another cost-effective way to revamp your pool area is by using gravel or stones instead of traditional flooring. Not only is this option cheaper than tiles or concrete, it can also add some texture and dimension to your pool area. Plus, it’s a great way to prevent slipping and falling when things get wet. You can also use stones to create a border around your pool, which can help define the space and prevent grass and dirt from getting in.
Finally, consider adding some outdoor lighting to your pool area. Not only will it help extend the use of your pool area into the evening, but it can also add some ambiance and mood lighting. There are plenty of affordable options, from string lights to solar-powered lanterns. You can also play around with different colors and styles to find something that fits your personal taste.
Make a splash without breaking the bank!
When it comes to poolscaping on a budget, there are plenty of ways to make a big impact without spending a fortune. One great option is to repurpose old materials. For example, you can use old pallets to create a DIY poolside bar or lounge chairs. You can also use free materials like rocks and driftwood to create a rustic and natural look.
Another low-cost option is to opt for DIY pool furniture. You can make your own poolside table or bench using cheap materials like cinder blocks and wood planks. Not only is this a great way to save money, but it also allows you to customize your furniture to fit the exact dimensions of your pool area.
Finally, consider using affordable pool accessories to add some personality and fun to your pool area. From inflatable pool toys to colorful pool floats, there are plenty of options that won’t break the bank. You can also use fun pool accessories like waterproof speakers or floating drink holders to add some practicality and convenience to your pool area.
With a little creativity and ingenuity, you can transform your pool area into a stunning oasis without spending a fortune. From repurposing old materials to incorporating affordable pool accessories, there are plenty of pocket-friendly ways to give your pool area a fresh new look. So go ahead, dive into these splashy ideas and enjoy your revamped pool area all summer long!
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28 Anglesea Street
17th April 2018
Euronext Dublin approves the admission of the undermentioned securities to listing on the Official List and trading on the Global Exchange Market.
GRUPO BIMBO, S.A.B. DE C.V.
USD 500,000,000 Subordinated Perpetual Notes US40052VAF13
This announcement has been issued through the Companies Announcement Service of
This information is provided by RNS

domain: economics


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I’m sad to announce that En Masse Entertainment will be closing down our AVA service, effective June 29, You, our players, mean everything to us and we’re sorry to see the end of AVA after nearly two years of operation. Effective immediately, new AVA accounts and. Alliance of Valiant Arms is a free-to-play online first-person shooter video game, developed by A point man enjoys a quicker reload time and faster move speed, while a rifleman gains more ammo and the ability to hold more, along with. Here you will find some Alliance of Valiant Arms reviews, download, guides, gameplay and fast paced first-person shooter (FPS) action, ensuing visceral.
Fast-paced FPS Action Online. Alliance of Valiant Arms carries on u-press.info's signature triple-A gaming style, offering players a robust, quick-fragging Unreal. Alliance of Valiant Arms is a free game app for the Windows which is a Download the Alliance of Valiant Arms now and enjoy a fast paced. Alliance of Valiant Arm (AVA). likes. This is a high-quality fps game in modern settings.I recommend you all to play this game.
I've been playing AVA for a long time and I LOVED it. need sprint as you move really fast as it is and with a knife you are even faster, just like.

domain: hobby


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Metabolism and the Immune System
- Life: Eating and Being
- Swallowing Cells: The Basic Unit
- Evolution of Metabolism
- Metabolism, Sugar and Diabetes
Life: Eating and Being
Life forms can be found that are made up of only one cell or millions of cells. Millions of years ago, life consisted mostly of one-celled organisms, but over time a myriad of bigger and more complex organisms emerged.
Single-cell organisms like bacteria are very efficient at surviving in very specific environments and sometimes even very harsh environments! More complex organisms need more energy but are also more able to move and interact with their environment and seek food and comfort, with more specialized ways of protecting themselves or muscles and legs that allow them to move greater distances with greater control.
Life has evolved over millions of years, taking a myriad of shapes and forms, from one-cell organisms like bacteria to organisms with millions and millions of cells, like human beings! But in every size, shape and form, Life is always in a constant balancing act of getting food for energy and protecting ourselves from things that might disrupt and infect our bodies. These basic needs give rise to the most fundamental processes in our bodies: metabolism and the immune system!
All organisms, no matter how big or small, and all the cells that compose them, need energy to survive. Metabolism is the process through which a life form gets energy from its environment and uses it to live. Metabolism includes eating food, breaking it down into nutrients, getting the nutrients to each cell of the body and each cell’s processes that utilizes this food energy.
The immune system is not a simple organ or a simple function. It is a constellation of cells and tissues that work together in the challenging task of identifying what belongs to the body (the self) from those that may be harmful- like old, dead cells or outsider particles like some kinds of bacteria, viruses. Our immune systems have to be very intelligent to deal with the magnificent variety of unknowns in the world.
Metabolism and the immune system share a common purpose, somehow they must swallow other particles, one for energy, one to stop a harmful invader. Discover the role of the swallowing cells in both…
Swallowing Cells: The Basic Unit
All cells, even today, are able to absorb small particles from their environment and digest them for energy. Early on, all organisms were single-celled. These cells could get all their energy from the ocean and the Sun. They absorbed and digested what they could, individually.
Then, some cells appeared that had the ability to swallow other smaller cells, the swallowing cells. These cells were able to get energy a lot faster! These swallowing cells became central to the development of more complex digestion and immune systems.
Cell Cooperation & Specialization
Millions of years ago, cells started to be able to work together. This cooperation allowed the cells that make up these tiny animals to start specializing, and carry out different roles. Some cells, on the outside of the animal become tougher to protect the animal like a sort of skin. Some swallowing cells became really good at absorbing food and took over eating. In very small animals, this works very well, as all cells were very close to eating cells, so they can easily share energy with their neighboring cells.
Cell cooperating involves cells being able to communicate with each other. This communication is at the basis of almost all processes in your body! For example, your immune cells use tiny chemicals to work together, and your neurons and muscle cells send electrical signals from one to another.
Some swallowing cells became really good at moving around and sniffing out harmful cells or particles, like in the sponge to the right. This is the beginning of a simple immune system!
Even in modern animals, the ancient ability to swallow up certain cells and small debris has been retained by some special cells. So, in addition to digesting food, swallowing cells can destroy things that may be harmful to an animal, like some kinds of bacteria, viruses, or old dead cells. So what was once a form of nutrition became a form of protection too!
These swallowing cells are found in the immune system of human beings too! They are called macrophages and B cells.
As animals got larger, these mechanisms were not enough, find out what came about>>
Evolution of Metabolism
In the obelia above, digestion of food starts in the digestive cavity, outside of each individual cell!
Over time more complex organisms, with more and more cells, and a greater need for energy, appeared.
Extra Cellular Digestion
Some cells formed stomach-like pockets, which became special areas devoted to eating, like a kind of stomach.
In the obelia, to the right, we can see a special pocket or cavity. This pockets is lined with special cells including swallowing cells that release tiny chemicals to the pocket. These chemicals breakdown food as itcomes in.
These different cells cooperate to breakdown and absorb the food, and then share the food energy with their neighboring cells. So, digestion started to occur more outside each cell, in the digestive pocket - or, extra-cellular digestion.
As animals got larger, some cells became further and further away from the eating cells—and wouldn’t be able to get food in the simple way. So in larger animals, cells are found to have formed passageways, like human blood vessels, that spanned their whole bodies, to distribute energy and oxygen to all their cells.
In the polychaete above, passageways like blood vessels transport food and oxygen.
The circulatory system of blood vessels is not the only distribution system in the human body! Our immune cells also travel in the lymphatic system, a super immune system of vessels and nodes that span the body.
The more an animal can eat, the faster and the more efficiently he can digest its food, the more energy an animal has to move around, and seek food and a comfortable environment.
In order to eat faster and get even more energy, some animals’ stomach pocket elongated to become a passageway going through the center of their entire bodies—the gut or digestive tube! This digestive tube allows the outside environment—the ocean and all its nutrients—to pass through the animal without being in contact with most of its cells
Other special pockets evolved around the digestive tube in humans, forming organs like the liver and the pancreas. The pancreas helps by making chemicals that help break down food in the intestine. Also, it makes insulin that helps cells absorb sugars really well.
The digestive tube, being very good at absorbing broken down food, is also a big point of entry for outsiders! So, lots of immune cells are found very close to digestive tubes.
As organisms became more complex and specialized, with many different types of cells, the harder the immune system's job became. Think of the human body, how many different cells and particles can you think of that belong to you body? Skin cells, hair cells, eye cells, calcium in your teeth, bone cells!.. So, the immune system needed to become more complex! New types of cells, like B cells and T cells, and tissues, like the lymphatic system, evolved to work together and be more efficient and specific. Once the immune system has discovered a particle or dead cell in your body, it calls a team of special swallowing cells that set to work breaking it down, like food!
Metabolism, Sugar and Diabetes
Your body needs a great deal of energy to complete your day-to-day activities, such as doing homework, playing soccer, or even reading a book! For any of these activities, even when you’re just sleeping, all of your cells need energy to continue being healthy.
Therefore, your body is constantly busy getting energy, storing storing the food energy, and then spending it, maintaining itself and doing fun things! All of the processes in your body that involve getting or spending energy are known as your metabolism. A high metabolism occurs when your body is both getting a lot of energy and using a lot of energy, whereas a low metabolism occurs when the body neither has nor is able to use a lot of energy.
We get energy through digestion, and insulin is very necessary!
So where does your body get all of this energy from? Well, eating a healthy diet helps to provide your body with a great deal of its energy. The food you eat is broken-down into smaller parts like sugars, fats and proteins and other nutrients in a process called digestion. The broken-down nutrients are absorbed by the body, mostly in your intestine, and are then transported to every cell and tissue in your body with the help of your blood vessels. A special chemical helps cells absorb sugar from the blood stream – it is called insulin. Sugar is one of the main sources of energy for the body so without insulin, most of the cells in your body would starve!
Our body has a very careful regulating mechanism to deal with the amount of sugar in our body. Too much and too little can be harmful! Our body constantly decides how much sugar each cell needs, how much sugar to have on our blood stream for quick use and how much sugar to store for later.
The trouble with Diabetes: not enough insulin
Learn more about Diabetes here >>
In some cases, like in the case of Diabetes, the body does not have enough insulin. In this case, the cells can’t absorb sugars as well and the sugar level in the blood start to rise. The body gets tired, dehydrated and blood pressure lowers, and lots of other health problems can occur.
So what does all this information about sugar, metabolism, and its effects on health mean? Maybe you think that you should then just eat tons of sugar! But, if you gave a human being that much sugar their metabolism level would not be sustained and would quickly drop! But why? The human body has a very delicate mechanism that controls the use and storage of its sugars. Too much sugar can over-whelm the body’s ability to store and use sugar appropriately!
Getting too much or too little sugar both cause problems. But getting too much sugar is a more common problem, especially because sugars pack a lot of calories into a small bite so it is easy to over-eat them!
Some sugars are better than others
Contrary to what you may think, there are “good sugars” out there! Natural sugars are kinds of “good sugars” your body can easily store and use. They even have other health benefits like boosting your immune system, strengthening the power of your pancreas, and ridding your body of toxins that may make you feel sluggish and not healthy. These kinds of “healthy sugars” can be found in some fruits like apples, pears, and blueberries, vegetables and legumes like yams and beans, nuts, and foods containing whole grains.
So, Sugar and Sugar aren't the same thing?
While there are many “good sugars” out there, you have to watch out for the sugars that aren't so good for you! The main sugar to watch out for is called “refined sugar”. It is also known as “white sugar” and most people use it everyday! It is present not only in obvious foods like candy and soda, but also in other foods like breads, lunch meats, ketchup, canned vegetables and fruits!
So what does this bad sugar do?!
When a bar of candy is digested, white sugar is broken down by the body into very simple sugars unusually quickly. This causes a person’s sugar levels in their blood to rise drastically (hyperglycemia), and causes an equally quick response of big insulin-production from the pancreas. This uncontrolled production of insulin can lead to removing too much sugar from the blood! In this situation, the body gives order to release sugar that is in storage in the liver to replenish the sugar in the bloodstream. If these unbalances happen a lot, they can really wear out our sugar control mechanism! This can lead to health problems like diabetes and hypoglycemia, as well as a lot of trauma to the pancreas!
People with diabetes are prone to experience the sharp highs and lows described above, since the lack of insulin leaves the body in a state of stress usually with too much sugar in their blood stream. So, when a diabetic eats, their body will immediately have a harder time dealing with the added sugars.
The balance of sugar in your body is directly related to the kinds of foods you eat. A healthy, balanced diet lets your body have an easy time digesting and using its energy.
As you read above, eating too much sugar (especially refined sugar) can have serious effects on your health and general well-being.

domain: medical


The Environment Agency has defended the way it approved changes to the rules governing an oil site in East Yorkshire.
The local government secretary needs more time to decide whether expansion plans at an oil site in East Yorkshire need a detailed environmental study.
New rules at an East Yorkshire oil and gas site should be suspended because of alleged inconsistencies by the environmental regulator, a resident has argued.
Development of new oil and gas fields must stop this year if the world is to meet its goal of net zero carbon emissions by 2050, the leading energy organisation has said.
Union Jack Oil announced this morning that the proppant squeeze planned for the Wressle oil well in North Lincolnshire had been approved.
Final consent had not yet been granted for the stimulation of the Wressle oil well in North Lincolnshire, Union Jack Oil confirmed today. But the company announced that tests on wells at two West Newton sites in East Yorkshire were expected soon.
Funding for work at the Saltfleetby gas field in Lincolnshire has been agreed, it was announced this morning.
Support for fracking fell to its lowest level in the latest phase of a government survey of public attitudes, published today.
BP’s emission targets are “too little too late” for the climate, said anti-fracking campaigners protesting against the company in London this morning.
Rathlin Energy has confirmed it is seeking to extend road closures around its West Newton-B oil and gas site in East Yorkshire until autumn 2022.


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"This is My Beloved, I care for My own!"
Some time back the Lord led me to listen to some prophecies entitled "Prophecies by Henry Grover." It contains several of his visions plus others by other people. The one that really caught my attention was one given to AC Valdees in 1929. Here is an overview of His vision:
The vision opens and comes to a ICBM missile flying over (what he thinks was) Berkley CA. It finally explodes and an angel with AC Valdees takes him down into the city. (There was much more here-) Valdees asks God, "Oh God, would You destroy the righteous with the wicked?" God instructs the angel, "Take him to My abode." They go up and fly across the land towards the east. They pass over the Sierra Navadas - across high dessert country - across rugged country - and come to rolling hills and a multitude of people (without number) dressed in white. He heard them before He saw them. They were singing and worshiping the Lord, and the Lord spoke from above and said, "This is My Beloved, I care for My own!" The Hill called "the Place" is generally in but at the start of the rolling hills, when you come from the West. Years ago there was a man who stood on the Hill called "the Place" and he saw houses covering the land - all the quarters of land surrounding the Hill. Interestingly, when God began leading this corporate body in preparation for the first "Marriage Feast of the Lamb," as described in Revelation 19,
Let us be glad and rejoice, and give honour to him: for the marriage of the Lamb is come, and his wife hath made herself ready. 8 And to her was granted that she should be arrayed in fine linen, clean and white: for the fine linen is the righteousness of saints.
a seer felt a ring being put on her hand that had Hebrew lettering on it. It was like it was more than one person wearing it. Then on 10-31-04 it was revealed that the Hebrew lettering said, "My beloved." As you can see the "My Beloved" on the ring fits into what God said in the AC Valdees vision, as well as the terrain description.
Full AC Valdees Vision Voice

domain: literature


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The 19-year-old enjoyed a breakthrough campaign last year but has been forced to be patient this season with a series of issues relating to his growth.
He has featured twice this campaign, but his current absence extends to 38 games, an entire Premier League season, but there is a clear plan in place for his return.
Klopp explained: “He is now in partial training with the U21s, and he will be in full training with the U21s next week because we pretty much don’t train because we play all the time.
“Then after that, he will join our training. That’s the plan, and then we will see.”
During the youngster’s absence, he has bulked up significantly and Klopp has noticed, adding: “The boy grew, put a few muscles on. Looks good.”
While Bajcetic will make the transition to first-team training shortly, his likely avenue to games is at academy level before focusing on hitting the ground running in pre-season under a new manager.
However, Klopp did use Conor Bradley‘s return from a long-term back injury as an example of what is possible, saying: “Football brain-wise, he is a natural. I don’t think he lost anything [there], but rhythm is something else.
“Conor Bradley did not need long after he was out for a long, long time as well, a smart kid so I think he will be fine.
“He definitely watched a lot of football, but it’s not that he played for us regularly.”
Liverpool have been cautious with the Spaniard’s return as his body was “not 100 percent ready for the intensity professional football is asking for,” in the words of Klopp.
He is rebuilding his foundations, and it will be intriguing to see how the club’s new manager chooses to use him going forward considering his versatility in midfield and defence.
To date, Bajcetic has 21 appearances for Liverpool, 12 of which have been as part of the starting XI.

domain: news


BEACHWOOD-If you’re a Toms River resident and haven’t attended a school board meeting or wrote letters to your state representatives, according to one Toms River Regional School Board member, you’re part of the problem.
The Toms River School Board representative of this tiny outer lying borough once again lashed at the community at-large in Toms River for what he claims is an apathetic reaction to pending legislation that could cut $3.3 million from the district school budget next year.
This time, Leonard took to his Facebook page, which is usually filled with raucous insults about fellow board members, the media and those who don’t agree with him.
Today, he mocked those who don’t attend school board meetings.
“Apparently, if you go by the ‘Apathy’ Park Press comments section, the entire tax paying district ‘works’ every 3rd Wednesday at 7:30 PM!” Leonard quipped about low attendance at school board meetings. “And they are soooo[sp] ‘over worked’ that they can’t find 2 minutes to call Trenton or email a Legislator, but can find unlimited time to comment on Social Media (without all the facts) about the budget crisis.”
Leonard doubled down on his attack against the community, calling them “willfully ignorant” and “bystanders”.
He was also upset over the public’s non-attendance at a daytime press conference last week, held at 1:30 pm in the afternoon, when most are working. Leonard, a Republican, is a public employee, employed by Ocean County, was able to attend the conference.
It wasn’t Leonard’s first confrontational situation since taking his seat on the nine member board. This year, Leonard has been confrontational with non-Republican school board members after the board voted against hiring a Leonard election campaign donor for a lucrative auditing contract earlier this spring. Leonard said on many occasions he will work to elect more of his fellow Republicans to seats on the board this year in an effort to remove the “Clean Slate Team” which seized power from the Ritacco era board, returning power back to the Republican political power base in town.
Leonard’s view of the public was not shared by fellow Republican Freeholder Joseph Vicari who instead placed blame where it was deserved, with New Jersey Democratic controlled legislature and senate.
Vicari took a swing at the funding proposal’s backer, Steven Sweeney.
“It is hard to believe that Mr. Sweeney and Mr. Prieto have already forgotten about the devastation caused by Superstorm Sandy in October 2012 and that Ocean County is still reeling financially from its blow,” Vicari said.
Leonard, continued his rant.
“I’ll be damned if I’m not going to call these folks [the public] out,” he posted on Facebook.


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Ancient myths have been a source of inspiration for millennia. The Maidens by Alex Michaelides blends Greek mythology, murder, and obsession in a taut psychological thriller that draws the reader in from the very first page.
The author’s sophomore effort is a worthy follow-up to his debut novel, The Silent Patient, published in 2019, which spent over a year on the New York Times bestseller list and is currently being developed for a film adaptation by Brad Pitt’s Plan B production company, according to an author interview in The Bookseller magazine.
The Maidens, published in June 2021, includes key elements that captivated readers of The Silent Patient- Greek mythology, therapy, and a psychologist at the center of a murder mystery. Michaelides, born in Cyprus to a Greek father and English mother, studied English literature at Trinity College, Cambridge University, and earned his MA in Screenwriting from the American Film Institute in Los Angeles. He also studied psychotherapy for three years and worked for two years at a secure psychiatric unit for young adults, both of which provided inspiration for his first book and for The Maidens as well.
The book follows Mariana Andros, a brilliant but troubled group therapist who becomes fixated on The Maidens, a secret society of female students at Cambridge, when one member, a friend of Mariana’s niece Zoe, is found murdered.
Mariana, who was once herself a student at the university, quickly suspects that a handsome and charismatic Greek tragedy professor, Edward Fosca, is the murderer regardless of his alibi.
The myth of Persephone, also called the maiden, and her journey to the underworld figures into the mystery and when another body is found, Mariana’s obsession with proving Fosca’s guilt spirals out of control, threatening to destroy her credibility as well as her closest relationships. Mariana is determined to stop the killer, even if it costs her everything, including her own life.
London-based Michaelides spoke about his writing process for The Maidens in an interview posted on his U.S. publisher Celadon Books’ website: “The actual writing of the book during lockdown gave me a way to escape from my apartment — in my mind, at least. Every day, I was able to journey to Cambridge in my head, and try to live there. And in a way, lockdown was good for me creatively; it enabled me to focus. There’s nothing like being locked up in your apartment to concentrate your mind.”
Of the influence of Greek mythology on his work and especially on the plot of The Maidens, Michaelides said: “I think growing up in Cyprus, immersed in Greek mythology and Greek tragedies, inevitably provided me with a world in which to dwell creatively as a writer. I’m extremely grateful for my upbringing and my education, my heritage, I suppose — it’s definitely enriched me as a writer. I’m always thinking about the myths — they are timeless and violent, magical and powerful; stories about passion and heartbreak and love and loss. I feel closest to Euripides; he’d have to be on my list of writers who have majorly influenced me. And in The Maidens I’m looking at the myth of Iphigenia, who was sacrificed by her infanticidal father, Agamemnon, at the start the Trojan War. Except in Euripides’ version of the myth, she sacrifices herself to please her father — which is a much more complicated and perverse relationship. And something about that — about why we sacrifice ourselves for others, in order to win their ‘love’ — captured my imagination. I looked for a way of writing about that story in a fresh way, and the plot grew from there.”
The Maidens by Alex Michaelides is available online and in bookstores.

domain: artistic


Evacuation from Kabul has been terminated (external website). Norwegian authorities can no longer assist with departure from Kabul. We know that it may be challenging to leave Afghanistan now. Unfortunately, UDI cannot answer questions regarding leaving Afghanistan or the situation in Kabul.
The Ministry of Foreign Affairs advises all Norwegian citizens against travelling to Afghanistan. When the Norwegian embassy in Kabul is closed, Norwegian authorities will not be able to provide consular assistance to Norwegian citizens who experience challenges when travelling to Afghanistan.
The situation in Afghanistan is unclarified, and UDI follows the situation closely. Several people who contact us ask if UDI can prioritize their application because of the situation in the country.
Family immigration applications from Afghanistan will be processed consecutively. For applications where the investigations are conducted, such as DNA-test or interviews, the waiting time may be shorter than usual.
However, the waiting time will probably be the same as before for most applicants because the investigations are not conducted yet. Even if we process applications from Afghanistan consecutively now, the process may take time because:
Because of the processes described above, this means that it will usually take as much time as usual before UDI have processed an application.
If you have further questions regarding the prioritization of your application, you can use our guide to check if your case can be moved to the front of the queue.
Due to the current security situation in Afghanistan and difficulties crossing national borders, it will temporarily be possible for a family member in Norway (the reference person) to apply for family immigration on behalf of a family member who is in Afghanistan.
You can read how to apply here.
It is a requirement that the person in Norway has been granted a residence permit in Norway. There are also income requirements in family immigration cases. There are exemptions to this income requirement if the reference person has recently received protection (asylum) and the application has been registered within 6 months after the date stated in the first decision letter the reference person received.
Several requirements apply to obtain family immigration. Amongst other things, the marriage must be valid and entered into voluntarily. You will find an overview of additional requirements by answering our web page's questions, «Want to apply for family immigration».
There are no changes in which family members can obtain a family immigration permit from Afghanistan.
Those who usually apply for family immigration are spouses or children of a person who already lives in Norway. Other examples are parents who have minor children in Norway or minor full siblings of persons residing in Norway.
Adult siblings, aunts/uncles, grandparents, nephews/nieces, cousins, or other distant relatives cannot get family immigration to Norway.
There are neither no changes in the requirements to obtain a family immigration permit. For information regarding the requirements for your case type, please follow this link and answer the questions to find the relevant information.
Suppose you already have a family immigration permit and cannot travel to Norway within the entry deadline stated in your permit. In that case, UDI can help you extend the entry deadline. You can call us or send us an email by choosing the relevant case type and filling in the contact form.
There is no change in the application process for a residence permit in Norway, and the rules for family immigration are the same.
To apply for protection in Norway, you must be in Norway or at the Norwegian border to apply. It is not possible to apply for asylum in Norway from a different country. Afghans who may get residence through the quota refugee scheme must have a direct or indirect connection to Norway. There is no quota for receiving refugees from Afghanistan except those who have a connection to Norway. This is the case for the following persons:
An application scheme will be established for former employees of the Norwegian armed forces and the Norwegian embassy. UDI does not currently have more information about this scheme and cannot answer questions about it.
If you are in Afghanistan and you previously have received a final rejection on an application for protection or another residence permit, the case in which you have received a decision will not be reconsidered.
Please be aware that the Norwegian authorities have stopped the evacuation in Kabul.
We know that many experience challenges in leaving Afghanistan now. Unfortunately, UDI cannot help people to get out of Afghanistan.
UDI follows the situation closely. The situation is uncertain, and many applications will not be processed until we know more about how the situation evolves. If your application is set on hold until we clarify the processing of these cases, you will receive a letter from us.
Some of those evacuated to Norway will have their case processed as resettlement refugees (quota refugees).
Afghan citizens who were evacuated and allowed to enter Norway as a family member of a Norwegian citizen will have their case processed as an application for protection (asylum). If this applies to you, it means that you should not apply for family immigration. The same applies to other evacuees who will not be processed as transfer refugees.
The application for protection (asylum) starts with a conversation with the police and others affiliated with the Norwegian authorities. We need your explanation to start an application for protection (asylum) and further process your application. We will contact you, and you will then receive additional information. Please note that without your explanation, the Norwegian authorities cannot process your case. If your case is not processed, your rights in Norway will be limited.
We recommend you stay where you are until the Norwegian authorities have spoken to you. You will get information on where and when to attend the interview.
If you move, you must inform the police about your new address so that the Norwegian authorities can contact you. This is also important for your case to be processed.
Have you already applied for family immigration?
The UDI processes the application for protection first. If you have already applied for family immigration, the UDI will wait to process this application. We process the application for protection (asylum) first.
Before you leave the quarantine hotel or reception centre, the police and other Norwegian authorities must talk with you. Without your explanation, the Norwegian authorities cannot process your case. If your case is not processed, you will have limited rights in Norway.
We recommend that you stay at the hotel or reception centre until the Norwegian authorities have spoken to you. You will be told where and when to attend the interview.
If you must leave the quarantine hotel or reception centre, it is important that you give your contact address to the police, so that the Norwegian authorities can contact you. It is also important for your case to be processed.
If you have questions about the housing situation or quarantine for evacuated persons in Norway, please call +47 400 18 788. Opening hours: 10 a.m. – 6 p.m., every day (Monday to Sunday). If you are a volunteer or wishes to contribute, you may also call this phoneline.
No, family and friends cannot visit you while you are staying at the OCC.
The entire facility at the OCC is a quarantine hotel for persons who travel to Norway and are required to be in an entry quarantine (quarantine hotel). Due to the risk of spreading the coronavirus, people from outside, friends and family cannot visit you while you are staying here.
The Norwegian authorities recommend that we keep at least one meter distance and are not with anyone other than those we live with. If anyone comes to visit you, they will be stopped at the entrance and expelled from the place.
If you break the visiting rules, UDI may decide that you must move to another location.
No, you cannot go on overnight visits outside the OCC.
Due to the risk of spreading the coronavirus, we ask you not to go on overnight visits outside the OCC.
We ask you to stay at the OCC until UDI informs you that you are moving. In the days ahead, a lot will happen. Some persons will be interviewed, some will move, and some will go for a health check which is mandatory when you come to Norway. You will get information on what will happen next. It is important that UDI can find you to give you information and tell you when it is your turn.


We are open through the COVID-19 Outbreak. God Bless the USA!!!
Lion Steel Knives is well known for its manufacturing quality and have even won the “Manufacturing Quality Award” in 2014. The company was established in the year 1969 by an Italian couple Lion Gino Pauletta and Cesarina. They strive for producing the sharpest knives at an affordable price point.
Framelock Pocket Knives
The framelock pocket knife was invented as an update to the liner lock knives by Chris Reeves. Also known as the monolock or the integral lock knife, the framelock knife uses a partial cutout in its handle to lock the blade into position, unlike the linerlock knife that employs a separate liner for the task. When you hold the knife in your hand the locking bar is squeezed against the blade, reinforcing the locking mechanism and making it more stable and secure. The small size of these knives allows you to carry them in your pant or shirt pockets.
Browse Through the Huge Selection of Knives at Knife Country USA
Knife Country USA is one of the most reliable dealers in the knife and outdoor tool industry. Having a flourished inventory, which includes more than 30,000 models of pocket knives, fixed blade knives, hunting knives, butterfly knives, machetes, flashlights and knife sharpeners; Knife Country USA gives you a huge variety of options to choose from. The online store has a huge selection of premium outdoor accessories and survival gear, manufactured and supplied by some of the elite brands across the globe. You can find an array of tactical gear from over 700 name brands including Buck Knives, Case Knives, Cold Steel Knives, CRKT Knives, Gerber Knives, Kershaw Knives, SOG Knives, TOPS Knives, Victorinox Swiss Army and many more. A superb megastore with an expanding product line, you can always trust Knife Country for quality and variety! Call us today if you need further assistance as we are here Monday through Friday for help.


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I was in Cabo, staying on the beach on the tip of the Pacific Ocean side. My friends had heard about this place from a chef friend and asked me to join them. We ordered a taxi and took a one hour drive back towards the airport to San Jose del Cabo. After passing large hotel after large hotel, we turned down a dirt road and drove another 10 minutes and arrived at Flora Farms. Flora Farms in an organic compound owned by Gloria and Patrick Greene. As the car parked, we came across a few shops, including one where over-priced locally-made soaps were for sale as well as a James Perse clothing store. There was also a wine and coffee bar. We followed the path to the left and at the end is Flora’s Field Kitchen and Flora’s Farm Bar. An open-air restaurant, Flora’s Field Kitchen has an rustically modern and natural feel to it. We took a seat at our table as the water misters cooled us down.
07 December, 2017

domain: geography


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SAN FRANCISCO (CBS SF) -- In San Francisco, there's a growing dispute over tree maintenance.
If a tree falls in San Francisco, who's responsible? Not the city.
For years, the city's been shifting the responsibility of caring for trees onto homeowners. But some residents are now trying to shift it back.
San Francisco resident B.W. Lee was outraged to see signs on trees outside her home stating that she would be responsible for the tree adjacent to her home.
"Basically, its a transfer of money from the city's responsibility to the people," Lee said.
A tree outside her house is among the latest batch of trees officially being handed over to residents through San Francisco's tree transfer program.
"Let's not do something so basic as not take care of the plant life in this city,"Lee said.
Under the program, if a tree falls in the city the people living next to it are responsible. They're also on the hook for watering, raking, and pruning. Functions that used to be done by city workers.
Rachel Gordon, a spokeswoman for the city's Public Works Department said, "It really is less than ideal, but we knew we did not have the funds necessary to take care of the tress and we thought this would give the trees a fighting chance."
The city couldn't afford to maintain its trees and the trees are supposed to be pruned every three to five years, but due to funding, most are on a 10 to 12-year cycle.
So in 2011, the city began transferring ownership to homeowners on adjacent properties.
So far, 8,000 trees have been handed over, with 24,000 left to go.
"This has been a very slow process, we don't want to turn over a tree that's unhealthy so that takes time to fix those things," Gordon said.
But several proposals are now aiming to put the trees, and their upkeep, back in the hands of the city.
Supervisor Scott Wiener has proposed legislation that would create an $18 million tree maintenance budget and property owners would pay a small parcel tax of around $30 to $40.
Much cheaper, he points out, than bringing in an arborist or paying the insurance deductible damage from a downed tree.
The San Francisco Board of Supervisors is set to consider the measure on Tuesday. If passed, it will be on the November ballot.
for more features.


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The National Research Council and Federal Judicial center last week released the new edition of the Reference Manual on Scientific Evidence. Readers of MassTortDefense know about this manual as a guide for judges searching for effective and fair ways to handle science-based issues, including assessing expert testimony. The Supreme Court has made clear that the law imposes on trial judges the duty, with respect to scientific evidence, to become evidentiary gatekeepers. The judge, without interfering with the jury’s role as trier of fact, must determine
whether purported scientific evidence is “reliable” and will “assist the trier of fact,” thereby keeping from juries testimony that lacks the same level of intellectual rigor that characterizes the practice of an expert in the relevant field.
The manual is intended to assist judges in managing cases involving complex scientific and technical evidence by describing the basic tenets of key scientific fields from which legal evidence is typically derived and providing examples of cases in which that evidence has been used. As the introduction to the new edition notes, the search is not a search for scientific precision. Courts cannot hope to investigate all the subtleties that characterize good scientific work. A judge is not a scientist, and a courtroom is not a scientific laboratory. But the objective is to seek legal decisions that fall within the boundaries of scientifically sound knowledge.
The Manual includes general chapters such as on “The Admissibility of Expert Testimony” and “How Science Works,” and specific chapters on (of interest to our readers) Exposure Science, Epidemiology, and Toxicology, and new chapters on Neuroscience, and Mental Health Evidence. The authors note the new edition has a focus on two critical topics that judges frequently confront, causation and expert bias.
The new edition was produced by a committee of judges, scientific experts, attorneys and academics. Bu it will be interesting to see if readers, after getting a chance to review it, will find that this version inappropriately undermines the Daubert guidelines enunciated by the Supreme Court and overemphasizes the “discretion” of trial judges to “manage” their dockets despite the meaning of the Federal Rules of Evidence.

domain: library


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Drew Barrymore is getting more candid about her search for love as a single parent.
The TV host and mom of two, 47, became emotional when speaking about her dating history on Jay Shetty’s podcast, On Purpose, during which she admitted she is still “scared” and “nervous” about “receiving love” after her split from ex-husband Will Kopelman, with whom she shares daughters Olive, 10, and Frankie, 8.
“I’m really good at giving [love] to my daughters and to my friends, but I’ve noticed how much of my history with the romantic space, I am so stuck, and I’m the person who doesn’t want to be stuck,” she explained.
“I want to know what work I can do to take my walls down, believe and trust,” she added, crediting the benefits of therapy for helping her move toward those goals. “I’m still scared, or nervous,” she says, explaining that when it comes to dating, she has trouble creating a “safe space” for romance to flourish.
“If you’re not feeling safe, how can you make yourself feel safe? If you’re not getting that from others, how do you make it OK for you?” she asks rhetorically.
Barrymore says she’s learning important lessons about love through trial and error. For example, after she was recently “ghosted” by a man (referring to when someone abruptly cuts off all contact with another person after they’ve had long bouts of communication), she says she’s been able to find a silver lining.
“I went on a date with this guy. I thought it was the best date. I mean it really was,” she remembered. “We made a plan for that weekend and we were texting back and forth and it was so cute, and I was like, I really like him. What a nice guy. I was attracted to him. I loved his job because he was in the news business and I love news, and I’m like, oh my god this is so cool.”
“I never heard from him again,” she continued. “I guess that’s what you call getting ghosted. I was like, whoah, that is so, that is so weird. OK.”
Barrymore likened her situation to a famous scene in Sex and The City where the character Carrie Bradshaw (Sarah Jessica Parker) is broken up with by her boyfriend, Jack Berger, via a Post-it note that read: “I’m sorry. I can’t. Don’t hate me.“
When that episode aired so many years ago, Barrymore says she remembers siding with Carrie, but upon closer inspection in therapy, she’s found a healthier perspective around being ghosted.
“We can’t be mad at people because they’re not what we want them to be,” she told Shetty, admitting that had she gotten a “Jack Berger Post-it note” from the guy who ghosted her, she may have felt a bit of closure.
That’s when, she says, her therapist gave her sound advice: Why not write it yourself?
“I was literally like, you just took out all the frustration, anxiety, uncertainty, unfinished business, lack of control, helplessness I feel,” she said of her therapist’s advice. “I feel good. I feel empowered. I feel like I wanna get on a bullhorn and share this wisdom.”
Barrymore has spoken in the past about dating anxiety as a single mom.
In a December 2022 profile with People, the host said, “I love being with my friends and I love being alone, where does dating fit in?”
“Every once in a while, I’ll go on a date because it’s a very human, natural thing to do,” she told the outlet. “I’ve gone on dates where I’m like, ‘Oh my God, why did I say yes to dinner? Because we haven’t ordered yet, and I don’t want to be here.’”
Wellness, parenting, body image and more: Get to know the who behind the hoo with Yahoo Life’s newsletter. Sign up here.

domain: celebrity


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More good news on the medical front. I just got back from my first doctor’s appointment where I had a full physical, blood taken for lab tests, and had my doctor sign off on a few forms. The big news is that my over-cautiousness last fall before my Peru/Ecuador trip really paid off. I already had all of the shots required by the Peace Corps – including Yellow Fever and Tetanus. Assuming everything is normal, all I need to do is wait until Tuesday for my blood work to come back. My doctor had filled out Peace Corps forms before and he seemed comfortable with all of the required information needed. Total cost of the copay and blood work was $350, of which Peace Corps will reimburse $125, so the total damage wasn’t too bad.
Next up is my eye doctor appointment tomorrow and then picking up my dental x-rays that were taken yesterday. Assuming everything is normal on my blood work, I’ll have finished all of the medical requirements less than a week from my first appointment! Could this be the fastest Peace Corps medical process of all time?


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A place for Meteorologist, enthusiast/hobbyist to come together and discuss various weather events, including pattern changes, storm threats, and observations.
A forum for the responsible pickup enthusiast.
Free forum : The place for the listening enthusiast.
audio, forum, michael, green, audiophile, tuning, roomtune, speaker, wire, cone, tuneland, tuned, mga/roomtune, room, acoustical, treatment, home, racks, interconnects, audiopoints, sound, consultant, stereophile
ENTHUSIAST HARDWARE & OVERCLOCKING SOCIAL FORUMS
A Forum for RWD and AWD Sports Car Enthusiasts. NoFF A Forum for RWD and AWD Sports Car Enthusiast
This is a club put together for Car Enthusiast who love to put there own touch to there cars Your Creation hence the name! We dont care what you drive and what it looks like its all abou
Forum gratis : Legend Enthusiast and OT Forum. Legend OT. legend acura fun 3000gt 3si stealth offtopic sweet civic accord honda RL,
An Australian forum for toy hobbyists, collectors, and designers. Hosted by Wednesday Toys and Uncle Tony's Toys.
This is a site for Subaru enthusiast that live in WV or nearby. . .
Car Forum for the Auto Enthusiast in Ireland
A meeting place for modified car enthusiasts in the South West of England! We're also on Facebook!
The Forum for all Longdrive Enthusiast's from around Australia
The Ford Focus enthusiast community for Florida.
Free forum : Forum for fishing enthusiasts. If you are into high end tackle and chasing prized sport fish then this is the place for you.
A forum to communicate with other all wheel drive vehicle owners and car enthusiasts in the city and surrounding cities of El Paso. Centered around All Wheel Drive vehicles but not limited to just all wheel drive vehicles, we invite anybody with a tr
Non profit poker hangout for the poker enthusiast.
A forum for any Z enthusiast! Young or old. This is a place for those who have questions and need help or Z enthusiasts that just wanna hang out and share stories of their Z's
Welcome to Gaming Enthusiast of Ohio (GEO) a dedicated place for people in and/or around Ohio to meet and talk about all things gaming.
Watsons Scoobies is a family of subaru enthusiast's who love the impreza since it came out and appered in the rally scene!!
An automobile club for the enthusiast who enjoys the last of the big GM cars. The rear wheel drive B and D bodys.
Welcome to the 1970 Mustang Mach1 World Registry this forum is open to all 1970 Mach1 owners & enthusiast around the world.
A community for urban and skyscraper enthusiast


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Beyond the bustling centre of Venice lie sleepy islands that brim with culinary culture and a gentle Italian lifestyle, writes Skye McAlpine who travels from Burano to Pallestrina and many islands dotting the famous city.
Venice is a magical city: dreamy with its winding canals, and majestic with its opulent, crumbling palazzi – quite unlike anywhere else in the world. But the city centre is small and can become crowded, especially in peak tourist season, which is when I like to travel off the beaten track and explore the islands in the surrounding lagoon area. Here, life moves with a distinctly slower, lazier pace – there is a peace about life on the islands, and a rich culinary tradition to discover. If you have the time on your next visit to Venice, I highly recommend taking a boat out on a sunny summer’s day and heading for lunch on one of these beautiful little islands.
Burano is a small island in the north of the lagoon, some 20-30 minutes in a water taxi from the centre of Venice, perhaps a little longer if you take the slow but rather charming local ferry (known as a vaporetto). If Venice is all grandeur and opulence, Burano is fairytale-like in its charm: a crescendo of quaint cottage houses, painted in a rainbow of vibrant colours and poised upon sleepy canals. The pinks, yellows and sky blues of the houses shimmer and reflect in the water – you couldn’t dream up something more enchanting if you tried. Burano is mostly famous for its lace: for generations women from the island have worked on weaving and embroidering ornate creations – a tradition which, with every generation, fades a little more.
But what I love most about Burano is the food. As well as shops selling lace and linens, you will also find some gems of restaurants there. My particular favourites: Trattoria al Gatto Nero is a family-run restaurant that has become a cult favourite among those chefs and foodies-in-the-know worldwide. The menu is simple, traditional Venetian fare with an emphasis on locally caught seafood, think buttery risotto with prawns, tiny shrimps with creamy polenta, and whole, large baked fish. Its tiramisu is legendary. Another favourite is Trattoria da Romano – lunch here is like stepping into a Fellini movie. Copper pots and pans and colourful, hand-painted ceramic plates hang from the walls, waiters dash here and there in dapper white jackets, and the whole restaurant bustles in the most welcoming way. The food is unpretentious, exquisite and unchanged in the 50-plus years since the restaurant first opened its doors. There are big plates of spaghetti alle vongole with warm, crusty bread to mop up its delectable juices and plates of buranelli biscuits (buttery polenta biscuits local to the island) with sweet wine.
Mazzorbo is a tiny island (not much more to it than a handful of houses) which neighbours Burano. You can get there either by taking a short boat ride, or by walking across the bridge from Burano. Pretty and quaint with an ancient bell tower and little else by way of grand architecture, there is no real reason to visit this island other than the fact that no-one else does, which makes it one of Venice’s best hidden secrets. Here you will stumble upon the kind of soothing peace and quiet which is nigh on impossible to find anywhere else. The restaurants are pretty good, too. For a fancy lunch, try Venissa Osteria Contemporanea, where the food is elegant and simple. Venissa is a local wine producer that cultivates an ancient Venetian grape to produce a unique wine which comes in magnificent bottles, each one hand-blown by glassmakers in Burano. Beyond the restaurant, Venissa also offers wine tastings, and overnight stays in its charming bed and breakfast.
For something more relaxed, but equally delicious, try lunch under the pergola at family-run Trattoria Alla Maddalena, a short walk away along the waterway. Not to be missed is its fritto misto (a plate of mixed fried seafood), risotto con go (a local specialty of buttery white risotto made with goby fish, one of the most delicate and creamy rice dishes you’ll ever taste), and the fig tart, which is made with thick, velvety mascarpone custard filling and sweet fruit picked from the trees in family’s garden.
Perhaps one of the most special places in the world, Torcello is a rural island that carries about it a seductive aura of old- world glamour. Another very small island (with a population of some 11 people), this is where Ernest Hemingway stayed while writing Across the River and Into the Trees (absolutely a must-read for anyone visiting Venice). Time has stopped in Torcello, and it feels deliciously peaceful for it.
The island boasts a magnificent Byzantine church which is most certainly worth a visit, and an ancient bell tower where you can climb to the very top and then indulge in majestic views of the surrounding lagoon. The highlight for me, however, is lunch at Locanda Cipriani. Run and owned by the same family as the iconic Harry’s Bar in Venice, the Locanda is every bit as glamorous, and the food every bit as indulgent – though the atmosphere feels rather more relaxed (think celebratory family lunch). The waiters are always charm personified, and you sit in the garden amongst bushes of lavender and sweet- scented roses to dine. I always want to eat everything on the menu, but the bellini before lunch and the plate of crepes suzette which come to the table drenched in Cointreau and flaming extravagantly for dessert are perhaps the highlights. Also a hit is the plate of creamy baked linguine drenched in an unbelievably moreish parmesan and pancetta sauce.
Pellestrina is a long, skinny island to the far south of the Venetian lagoon, blessed with a special magic all its own. The local community is small and vibrant, and fishing is their trade, making this the place to go for the very best seafood. My favourite restaurant there is da Celeste, a family-run trattoria poised on the edge of the island. You sit out on a pontoon with expansive sky-blue waters stretching out for as far as the eye can see. The menu here changes constantly depending on what’s in season and what the fisherman have caught that day, but their specialty is whole roasted turbot on a bed of baby potatoes, artichokes and wonderfully succulent roasted tomatoes. I would happily choose it as my last supper, I can’t recommend it enough. Also not to be missed is its sgroppino, a lemon sorbet blended with iced vodka, for dessert. The journey back to Venice, speeding through the lagoon by water taxi, is almost every bit as spoiling as the meal itself.
Head here, for more hidden treasures in some of Italy’s best spots.


When it comes to decreasing energy use in privately owned buildings, is it more effective to use a carrot or a stick?
That was one of the questions explored during a panel discussion sponsored by the National Building Museum and the Urban Land Institute (ULI) in Washington, D.C. Other issues tackled by panelists included how to standardize and utilize building energy use data.
It’s well known that buildings account for about a third of the energy used in the United States. Thus, reducing building energy use is a critical component in the effort to reduce climate-changing carbon dioxide emissions. The federal government aims to slash greenhouse gas emissions nationwide by 80 percent by 2050; ULI is looking toward a 50 percent cut in building sector emissions by 2030.
But what’s the best way to achieve these goals? Some well-known voluntary programs have been criticized for complexity, cost, focus on new construction, and limited reach. For these reasons, nearly a dozen U.S. municipalities have gone beyond voluntary measures and passed new laws requiring property owners to measure and publicly release their buildings’ energy use.
Cities that have launched mandatory building energy use reporting programs are facing a number of challenges, panelists noted, but they agreed that they are doing the right thing. While some 80 percent of New York City building owners reported their energy use as required, Seattle and San Francisco have achieved only 30 percent compliance to date. None of the three cities has gone so far as to issue violation notices to noncompliant landlords, but that idea is not off the table.
“We feel we need more mandatory standards,” said Laurie Kerr, senior policy adviser, New York City Mayor’s Office of Long-Term Planning and Sustainability. “California has led the nation for 35 years, yet even with all their effort, they have only kept energy use flat. New York City could add a million new residents and is outgrowing its buildings, so we need to do more.”
Landlords may be subject to the “Lake Wobegon syndrome,” Kerr said. “Transparent published energy use data would reveal which buildings are below and above average, and no one wants to be seen as below average,” she noted. “We are seeing a four-to-one difference between the top and bottom performers, so it’s clear that those buildings with below-average scores are using a lot of energy and have a great deal of room to improve.”
Jayson Antonoff, energy and climate change policy adviser for the city of Seattle, said that sending violation notices to the 70 percent of building owners who have not reported their energy use would not be politically viable. “That’s why our focus is outreach, education, technical support, and helping building owners understand the benefits of participating,” he pointed out.
In San Francisco, the situation is similar, said Barry Hooper, private sector green building specialist for the San Francisco Department of Environment. “We have a 30 percent compliance rate in part because we adopted and implemented the new policies quickly, and have not followed up with communication. We do not intend to use public shaming to drive compliance. Our agency is structured to provide analysis and positive services such as free energy audits, dramatic rebates, and follow-up services to make sure the measures we recommend are installed.”
One major impediment to reducing building energy use is “inertia,” which can be attributed in part to the landlord/tenant “split incentive” issue, according to Charles “Chuck” Leitner, chair of the ULI Greenprint Center for Building Performance. “Landlords say they don’t control energy consumption in tenant space, while tenants say they care but often have no real incentive to save energy,” he explained. “To unlock this debate, we have to standardize building energy performance measurement and get away from the notion that all energy-efficiency investments must have quick paybacks.”
Kerr suggested that building owners’ increasing use of the Environmental Protection Agency’s Portfolio Manager tool is a good first step toward standardization. “In a few years, there will start to be a consensus as to what works best,” she predicted.
Leitner also concluded on a hopeful note: “We have learned that once landlords become comfortable with benchmarking, there is a lot of enthusiasm for making investments to reduce the carbon footprint. Markets are transforming, with large users driving change, and the definition of a quality building now includes energy efficiency.”


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Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation.
ABSTRACT The functional capacity of the human monocyte receptor for the Fc portion of IgA (Fc alpha R) in mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-Fc alpha R monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse antibody [F(ab')2 fragments] induced a significant release of TNF-alpha and IL-6 by human blood mononuclear cells, indicating requirements for Fc alpha R aggregation on the cell surface to transmit signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the responding cells within the mononuclear cell population. This cytokine release could not be due to contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide (LPS) inhibitor. Moreover, purified recombinant soluble Fc alpha R inhibited the anti-Fc alpha R mAb-mediated cytokine release from blood monocytes, demonstrating that TNF-alpha and IL-6 were released in a receptor-specific manner. Our data suggest that Fc alpha R, through its capacity to mediate secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin production. On the other hand, release of TNF-alpha following stimulation of Fc alpha R molecules directly implicates these receptors in amplification and regulation of the inflammatory process occurring during IgA-mediated host defence.
Article: Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor.[show abstract] [hide abstract]
ABSTRACT: The objective of these studies was to examine the ability of phorbol myristic acetate (PMA), Fc fragments, and various forms of immune complexes to induce the production by human monocytes of factors stimulatory to chondrocytes or thymocytes. All of these materials were prepared free of detectable contamination with bacterial lipopolysaccharides (LPS) at the level of less than 0.1 ng/ml. Supernatants and lysates from stimulated human monocytes were assayed for their ability to induce collagenase production in cultured rabbit articular chondrocytes or to augment mitogen-induced proliferation of murine thymocytes. The activity detected by these assays exhibited an m.w. of approximately 15,000, and electrophoretic heterogeneity in the pH ranges of 5 to 5.5 and 6.5 to 7.0, characteristics of human interleukin 1 (IL 1) or IL 1-like factors. Monocytes cultured with 2 ng/ml LPS produced chondrocyte and thymocyte stimulatory factors. PMA, Fc fragments, and soluble, precipitated, particulate, or adherent immune complexes were inactive in stimulating the monocytes. However, complement fixation by precipitated immune complexes did generate activity capable of inducing monocytes to synthesize and secrete chondrocyte and thymocyte stimulatory factors. Adherent immune complexes and PMA were biologically active, as evidenced by induction of superoxide generation in the human monocytes. Supernatants from monocytes cultured on adherent immune complexes contained a factor inhibitory to chondrocyte and thymocyte responsiveness. This factor had a m.w. approximately 22,000 and appeared to inhibit specifically IL 1 stimulation, not interleukin 2 stimulation or cell proliferation. It was concluded that PMA, Fc fragments, and various forms of immune complexes in the absence of complement do not induce IL 1 production in human monocytes. However, complement fixation by immune complexes does lead to activation of monocytes to produce IL 1. Monocytes cultured on adherent immune complexes produce an IL 1 inhibitor.The Journal of Immunology 07/1985; 134(6):3868-75. · 5.79 Impact Factor
Article: Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals.[show abstract] [hide abstract]
ABSTRACT: Fc alpha receptors (Fc alpha R), detected by the binding of IgA and by anti-Fc alpha R antibodies, were found to be differentially expressed on eosinophils and neutrophils. Neutrophils were the major granulocyte population expressing Fc alpha R, and they expressed much higher levels of Fc alpha R than eosinophils. The expression of Fc alpha R by eosinophils could be upregulated approximately threefold by Ca2+ ionophore treatment in a dose- and time-dependent manner. This effect, which was blocked by a chelating agent, was not duplicated by other cellular stimuli. Eosinophils in allergic individuals displayed enhanced Fc alpha R expression, whereas neutrophils did not. The Fc alpha R on eosinophils had a higher molecular mass (70-100 kD) than those identified on neutrophils (55-75 kD). However, removal of N-linked carbohydrates from Fc alpha R of eosinophils and neutrophils revealed a major protein core of 32 kD for both cell types. The data indicate that expression of Fc alpha R molecules with a characteristic glycosylation pattern is upregulated on eosinophils in allergic individuals.Journal of Clinical Investigation 11/1993; 92(4):1681-5. · 15.39 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: In mice with targeted disruption of the gene that encodes interleukin-6 (IL-6), greatly reduced numbers of immunoglobulin A (IgA)-producing cells were observed at mucosae and grossly deficient local antibody responses were recorded after mucosal challenge with either ovalbumin or vaccinia virus. The IgA response in the lungs was completely restored after intranasal infection with recombinant vaccinia viruses engineered to express IL-6. These findings demonstrate a critical role for IL-6 in vivo in the development of local IgA antibody responses and illustrate the effectiveness of vector-directed cytokine gene therapy.Science 05/1994; 264(5158):561-3. · 31.20 Impact Factor
Immunology 1995 86 1-5
Fca receptors mediate release of tumour necrosis factor-a and interleukin-6 by
human monocytes following receptor aggregation
C. PATRY, A. HERBELIN, A. LEHUEN, J.-F. BACH & R. C. MONTEIRO Institut National de la Santeet de la
Recherche Medicale, Unite 25, H6pital Necker, Paris, France
The functional capacity of the human monocyte receptor for the Fc portion of IgA (FcaR) in
mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-FcoaR
monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis
factor-a (TNF-at) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse
antibody [F(ab')2 fragments] induced a significant release of TNF-ax and IL-6 by human blood
mononuclear cells, indicating requirements for FcaR aggregation on the cell surface to transmit
signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the
responding cells within the mononuclear cell population. This cytokine release could not be due to
contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide
(LPS) inhibitor. Moreover, purified recombinant soluble FcaR inhibited the anti-FcaR mAb-
mediated cytokine release from blood monocytes, demonstrating that TNF-at and IL-6 were
released in a receptor-specific manner. Our data suggest that FcaR, through its capacity to mediate
secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin
production. On the other hand, release ofTNF-ax following stimulation ofFcaR molecules directly
implicates these receptors in amplification and regulation of the inflammatory process occurring
during IgA-mediated host defence.
Large numbers of cytokines are released during host injury
through triggering of monocytes by several soluble factors,
including products of the humoral immune responses. For
example, activation signals can be transmitted to cells through
a well-defined interaction between antigen-antibody com-
plexes and Fc receptors (FcR).1 It has been shown that cross-
linking of FcyR molecules by IgG2-4 or receptor-specific
monoclonal antibodies (mAb)5 results in release of several
cytokines, including interleukin-1
necrosis factor-a (TNF-x), which either directly mediate the
inflammatory process or amplify immune responses.
IgA Fc receptors (FcaR) have been described on mono-
cytes, neutrophils and eosinophils as heterogeneously glyco-
sylated proteins varying from 55 000 to 100 000 MW.6-8 These
receptors can bind monomeric and polymeric IgAl and IgA2
antibodies via their Fc regions.7 The sequence from a cDNA
encoding for FcaR identified
transmembrane protein belonging to the immunoglobulin and
(IL-1), IL-6 and tumour
this receptor as a type
Received 14 March 1995; revised 18 May 1995; accepted 23 May
Abbreviations: FcaR, receptor for Fc portion of IgA; sol-FcaR,
recombinant soluble FcaR.
Correspondence: Dr. R. C. Monteiro, INSERM U25, Necker
Hospital, 161, rue deSevres, 75743Paris, France.
1995 Blackwell Science Ltd
FcR families.9 Five mAb have been used to characterize the
designated as CD89.
The identification of FccxR has elucidated the link between
phagocytic cells and IgA antibodies, which can result in a
variety ofresponses, including superoxide generation, release of
inflammatory mediators, phagocytosis and killing of micro-
organisms.'2 Elevated levels of IL-1, IL-6 and TNF-cx were
detected in sera from patients with diseases associated with
increased polyclonal IgA, including IgA nephropathy, alco-
holic liver cirrhosis and acquired immunodeficiency syndrome
(AIDS),'3-16 suggesting that FcaR may be involved in this
The present study addressed the functional properties of
FcoeR molecules by studying cytokine production after specific
receptor triggering on human monocytes, using F(ab')2 frag-
ments of anti-FcaR mAb' 1 and an inhibitor, the recombinant
soluble FcoxR (sol-FccxR),17 that specifically blocks the binding
site of anti-FcaR mAb.
structure of FcocR proteinsl0"',
MATERIALS AND METHODS
The mouse mAb used were A59, A62 and A77 (y1K), all specific
for FcaR." Control antibodies were irrelevant mouse IgG 1K
produced in our laboratory. F(ab')2 fragments of A59 and
C. Patry et al.
A77 mAb and the IgGlK control were made by pepsin (Sigma
Chemical Co., St Louis, MO) digestion [enzyme to substrate
ratio (w/w) 1/50 in 0 1 M acetate buffer, pH 4 0, for 8 hr at 370],
and were affinity purified over rat anti-mouse K chain mAb
coupled to Sepharose 4B beads. Complete digestion and
F(ab')2 purity were established by sodium dodecyl sulphate-
polyacrylamide gel electrophoresis (SDS-PAGE). Goat anti-
mouse immunoglobulin antibodies were purchased from Southern
Biotechnology Associates (Birmingham, AL), extensively adsor-
bed against human paraproteins, pepsin digested to prepare
F(ab')2 fragments as described elsewhere,'8 and coupled to
CNBr-activated Sepharose 4B beads.
Preparation of Sol-FcoxR
Sol-FcaR had been produced previously by removing the
transmembrane and cytoplasmic coding regions from full-
length FcaR cDNA and ligating it into a mammalian expression
vector.17 Supernatants of COS-7 cells transfected with the sol-
FcaR plasmid(kindly provided by Dr C.
Immunex, Seattle, WA) were purified by using an anti-FcocR
(A59) mAb immunoaffinity column, as described elsewhere.'7
Purified sol-FcocR was stored at
50,g/ml. The irrelevant control preparation (sol-FcaR-) was
obtained by passing supernatants from COS-7 cells transfected
with plasmids containing cDNA in reverse orientation over the
A59 affinity column. The functional capacity of purified sol-
FcoaR was verified by dose-dependent inhibition of A59 anti-
FcaR mAb reactivity to phorbol myristate acetate (PMA)-
activated U937 cells, by flow cytometry using a FACScan (Becton
Dickinson, Mountain View, CA), as described previously.17
at a concentration of
Isolation ofhuman mononuclear cells and monocytes
Peripheral blood mononuclear cells (PBMC) were isolated
from heparinized blood ofhealthy donors by centrifugation over
Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) density gradi-
ents. The number ofmonocytes was evaluated by morphological
characteristics after May-Gruinwald-Giemsa staining, and the
PBMC were plated at a concentration of 105 monocytes/well in
flat-bottomed 96-well microtitre plates. In some experiments,
adherent cells were obtained by incubation of PBMC (106/ml)
for 2 hr at 37° in 96-well plates using RPMI-1640 supplemented
with 5% autologous serum. Non-adherent cells were obtained
after three cycles of plastic adherence in Petri dishes.
F(ab')2 fragments of A59 and A77 mAb and IgG 1k control
mAb were used either in soluble form or co-incubated with
F(ab')2 fragments of goat anti-mouse immunoglobulin anti-
bodies coupled to Sepharose 4B beads. In some experiments,
mAb were directly coupled to beads. Beads were first washed in
RPMI-1640 medium (Gibco, Grand Island, NY) containing
inactivated fetal calf serum (FCS). The stimulating material
was then preincubated with polymyxin B (20,g/ml) for
37°, except in experiments where cells were stimulated with
lipopolysaccharide (LPS; 5ng/ml, Escherichia coli 055:B5, L-
2880; Sigma). This concentration ofpolymyxin B fully inhibited
TNF-oc and IL-6 release induced by 1-5 ng/ml LPS. Cells (105
monocytes/well) were cultured for 18 h in 0-2ml RPMI- 1640
culture medium at 37° in a humidified atmosphere with 7% CO2
in the presence of the various stimuli. After incubation, culture
1 hr at
supernatants were separated by centrifugation (Omin at 600g)
and then stored at - 70° until assay. For inhibition experiments,
the stimulating material was preincubated for 1 hr with sol-FcacR
or sol-FcaR- before addition to the cell cultures.
Enzyme-linked immunosorbent assays (ELISA; kindly pro-
vided by Dr D. De Groote, Medgenix Corp. Research and
according to the manufacturer's instructions for determining
TNF-oa and IL-6 in culture supernatants. The detection limits
for TNF-oc and IL-6 were 10 pg/ml, and samples below the
detection limit were assumed to have values below 5 pg/ml.
Biological activities for TNF-a and IL-6 were determined with
the L929 tumour cell line cytotoxic assay and IL-6-dependent
cell line B9, respectively.'9' 20
Belgium) were used,
Each representative experiment is a typical result obtained with
cells from a single donor; it was verified that at least three
donors gave a similar pattern of results. Results are expressed
as mean + SEM and were compared using Student's paired t-
Induction of TNF-cx and IL-6 release through triggering of FcacR
To examine the functional capacity of FcaR molecules in
transducing signals for secretion of IL-6 and TNF-a, crude
mononuclear cell populations from normal individuals were
eliminate unrelated FcyR triggering via the mAb Fcy portion.
Preliminary dose-response experiments performed on PBMC
from two donors indicated that an optimal response was
obtained with between 2 and 10 jug/ml of F(ab')2 fragments of
anti-FcaR mAb coupled to beads (data not shown). Results
obtained from three different donors (Table 1) demonstrated
of anti-FcaR mAb
Table 1. FcaR-mediated release of cytokines by human mononuclear
PBMC from three different donors were cultured for 20 hr in the
presence of Sepharose 4B beads coupled to either control F(ab')2
fragments of irrelevant IgGI or F(ab')2 fragments of A59 anti-FcaR
mAb. Culture supernatants were assayed by immunoassays specificfor
TNF-oc and IL-6. Significance was evaluated using Student's t-test: A59
F(ab')2 beads versus control IgGl F(ab')2 beads; P = 0 004 and
P = 0-033 for TNF-a and IL-6, respectively. Differences obtained for
control IgGI F(ab')2 beads and medium (110 + 35 and 22 ± 7pg/ml
for TNF-a and IL-6, respectively) were not significant.
*5pgof mAb/ml of packed beads.
© 1995 Blackwell Science Ltd, Immunology, 86, 1-5
Fcax receptor-mediated cytokine production
that incubation of PBMC for 18 hr with 5yg/ml F(ab')2
fragments of A59 anti-FcaR mAb coupled to beads, in the
presence of 20 ,ug/ml polymyxin B, induced secretion of
both TNF-a (mean + SEM; 2027 ± 241 pg/ml) and
(743 ± 229 pg/ml) in all donors. The same donors exhibited
approximately 20-30-fold lower constitutive production of
TNF-a and IL-6 with control medium, and no significant
induction was observed with F(ab')2 fragments of irrelevant
IgG1-coupled to beads. Similar results were also obtained with
papain-digested Fab fragments coupled to beads of another
anti-FcaR mAb, A62 (data not shown). These results were
confirmed by biological assays for TNF-a and IL-6 (data not
FcaLR-mediated release of cytokines requires multivalent
To determine whether cytokine release mediated by FcaxR was
dependent on receptor aggregation, the respective effects of
anti-FcaxR F(ab')2 fragments, either in soluble form alone or co-
incubated with F(ab')2 fragments of goat anti-mouse antibody-
coupled beads, were compared. As illustrated in Fig.
F(ab')2 fragments ofboth A59 and A77 mAb were ineffective in
inducing TNF-a release by PBMC, compared to those cross-
linked by the secondary anti-mouse antibody coupled to beads.
Cross-linking with A77 mAb induced a TNF-ax release threefold
higher than that obtained with A59 mAb (7402 versus 2468 pg/ml,
Specificity of FccaR-induced cytokine release performed by
inhibitory assays using recombinant soluble FcoaR molecules
To demonstrate the specificity of activation through FcaxR
molecules, we studied the inhibition of cytokine release by
Figure 1. TNF-a release after multivalent cross-linking of FcaR. PBMC
(adjusted to 105 monocytes/well) were incubated for 18 hr with soluble
F(ab')2 fragments of tested mAb (5 pg/ml) alone or cross-linked by
F(ab')2 fragments of goat anti-mouse immunoglobulin coupled to
Sepharose 4B beads (IOg/ml). Culture supernatants were assayed by
immunoassays specific for TNF-a. Open columns represent control
IgG1 F(ab')2 fragments, whereas hatched and black columns represent
the two anti-FcaR mAb F(ab')2 fragments, A59 and A77, respectively.
This is representative of three experiments performed with different
t 1995 Blackwell Science Ltd, Immunology, 86, 1-5
Figure 2. Specificity ofanti-FcacR mAb-induced TNF-a and IL-6 release
determined by inhibitory assays using sol-FcaR. PBMC (105 mono-
cytes/well) were stimulated for 18 hr with A77 F(ab')2 fragments (5Pg/
ml), or control IgG
F(ab')2 fragments plus F(ab')2 fragments of goat
anti-mouse antibodies coupled to beads (10 ,ug/ml), in the presence or
absence of sol-FcaR (25
pg/ml), and with a control preparation
(sol-FcaR-) obtained from COS-7 transfected with plasmids contain-
ing reverse-orientation sol-FcaR cDNA. Culture supernatants were
tested for TNF-a and IL-6 by specific immunoassays. Similar results
were also obtained in three additional experiments.
co-incubation of the anti-FcaxR mAb with either sol-FcaR or
sol-FcaxR-, the control preparation. The latter was obtained
from supernatants of COS-7 cells transfected with plasmid
containing sol-FcaxR cDNA in the reverse orientation. Figure 2
shows that production of TNF-ac and IL-6 induced by anti-
FcaR mAb was completely abolished by addition of sol-FcaR
(25,g/ml; giving 83% and 87% inhibition ofTNF-a and IL-6,
respectively), whereas the control sol-FcaR- had no significant
FcaR-mediated cytokines are released by monocytes
As the FcaR recognized by these anti-FcaR mAb
exclusively expressed on cells of the myeloid lineage,'1 we
verified that monocytes were the only responding cells to FcaXR
cross-linking within the total mononuclear cell population.
PBMC were separated into two populations based on the
adherence properties of monocytes. As illustrated in Fig. 3,
monocytes appeared to be the main source of TNF-a and IL-6
in response to stimulation with F(ab')2 fragments of A77 anti-
FcaR mAb plus anti-mouse antibody coupled to beads. In
accordance with this, a significant TNF-a and IL-6 release was
observed after stimulation of adherent cells (3154 pg/ml and
1459 pg/ml, respectively), whereas non-adherent cells failed to
release significant amounts of these cytokines (191 pg/ml and
respectively). Addition of non-adherent
adherent cells increased the release of both TNF-xt and IL-6
(5028 pg/ml and 3243 pg/ml, respectively),
lymphocytes may play an indirect role amplifying cytokine
release by monocytes. Cytokine levels were similar to those
obtained with the whole unseparated PBMC population
(5018 pg/ml and 2290 pg/ml, respectively). In an additional
mediated TNF-a release by adherent cells was also inhibited
by addition of sol-FcaR, indicating further the specificity ofthe
FcaR response to the A77 antibody (610 pg/ml with sol-FcaR
a different donor, A77 anti-FcaR mAb-
C. Patry et al.
Figure 3. Anti-FcoR mAb-mediated TNF-a and IL-6 production is
restricted to monocytes. Adherent(0)and non-adherent cells (E) were
stimulated for 18 hr with A77 or IgGI control F(ab')2 fragments (5 jg/ml)
plus goat anti-mouse beads (10pg/ml).As controls, unseparated PBMC
(O-1) and mixed populations (M) were stimulated in the same conditions.
Culture supernatants were tested by immunoassays specific for TNF-a
and IL-6. Similar results were obtained in two additional experiments.
versus 1787 and 2192 pg/ml with
or without sol-FcaR-,
In the present study, the functional capacity ofFcaR molecules
to mediate cytokine release was addressed by using F(ab')2
fragments of anti-FcaR mAb, and recombinant sol-FcaxR as
specific probes. Multivalent cross-linking of FcaR by three
anti-FcaR mAb induced a significant release of both TNF-a
and IL-6 by monocytes. A77 mAb triggered more FcaR
release of cytokines than the other two mAb, A59 and A62.
This suggests that different functional properties of FcoaR
epitopes are recognized by these anti-FcaxR mAb, as described
for other molecules such as Thy-1.21 This study demonstrates
a direct role of FcaR molecules in the mediation of cyto-
kine production. Stimulation of the FcacR resulted in TNF-ac
and IL-6 release by monocytes but not lymphocytes, as would
be expected, as FcaR are expressed selectively on myeloid
Endotoxins, well-known monocyte activators, often con-
taminate biological materials and may contribute to triggering
the secretion ofcytokines such as TNF-a and IL-6.22 However,
several findings rule out the possibility of cytokine production
due to LPS contamination in our assays: (1) soluble anti-FcaR
mAb alone did not have a direct effect on monocytes, whereas
LPS at concentrations as low as 10-20 pg/ml (which were
undectectable in the Limulus assay) significantly stimulated IL-
6 release under the same culture conditions; (2) polymyxin B,
an LPS inhibitor, was added to all culture stimulations; and (3)
addition of recombinant sol-FcaR product, which specifically
blocks the binding site of anti-FcaR mAb, led to complete
inhibition of cytokine release.
Our findings expand and validate the observations of
other investigators, who have shown significant effects of
purified IgA on the release of inflammatory cytokines by
monocytes. In these studies, TNF-a release was observed after
stimulation with polymeric IgA'5 or IgA-immune complexes,23
but not with monomeric IgA. These observations
agreement with our results, indicating that FccxR-mediated
release ofcytokines requires receptor aggregation to deliver cell
Aggregation of FcBR and FcyR molecules on different cell
types delivers transducting signals that result in production of
several cytokines.24 Our data on production of cytokines via
FcaR molecules indicate that these receptors may transduce
signals following aggregation, despite the absence of tyrosine
residues in the predicted cytoplasmic tail of the FcoeR.9 In
recent elegant studies, Pferfferkorn & Yeaman25 have shown
that FcaR molecules from a monocytic cell line (U937) are
associated with the FceRI-y2 subunits, indicating that the
FcaR-mediated signals described here may be transmitted via
the y chain tyrosine motifYXXL/I,26 as described for other Fc
receptors including FcERI, FcyRI and FcyRIII."'24 Interest-
ingly, in the latter study,25 only multivalent cross-linking of
FcoeR by anti-FcaR mAb plus anti-mouse antibodies resulted in
phosphorylation of the FcaR-y2 subunits. This is in agree-
ment with our data, that only multivalent cross-linking ofFcaR
induced by F(ab')2 fragments of anti-FccxR mAb plus F(ab')2
fragments of anti-mouse antibodies, but not F(ab')2 fragments
alone, mediated the release of cytokines.
The fact that all three anti-FcaR mAb, including A62,
induced cytokine release indicates that all previously described
heterogeneously glycosylated FcaR" may transduce signals
required for cytokine production. This is in agreement with the
observation that A62-reacted FcoaR molecules are also non-
covalently associated with FcERI-y2 subunits.25
The multifunctional cytokines TNF-c and IL-6 have been
described as central mediators of multiple inflammatory and
immune reactions.27'28 Release of TNF-a and IL-6 by trigger-
ing the FcaR reveals an additional effector function for
in IgA-mediated inflammatory
TNF-a promotes an up-regulation of FccxR expression on
monocytes,29 it is likely that TNF-a release following FcaR
cross-linking may form a positive feedback loop where IgA-
immune complexes could stimulate TNF-ac production via
FcaR, and TNF-cx promote FcaR expression.
FcaR-mediated release of IL-6 may also indirectly enhance
IgA synthesis by B cells. This was first suggested by clinical
studies in patients with alcoholic liver cirrhosis, in which cross-
linking ofFccxR by IgA induced IL-6 release by monocytes, and
conversely anti-IL-6 mAb abrogated IgA production.'5 The
role of IL-6 in IgA production has been demonstrated recently
in mice with targeted disruption of the gene encoding IL-6.
These mice have a profound reduction in the number of IgA-
producing cells and have grossly deficient local antibody
responses on mucosal challenge.30 Interestingly, this defect
was corrected by IL-6 gene therapy, demonstrating a critica
role for IL-6 in vivo in the development of a mucosal IgA
endogenous IgA in blood phagocytic cells from patients with
diseases associated with increased polyclonal IgA, including
IgA nephropathy, AIDS and alcoholiccirrhosis,31-33it islikely
that the continuous cross-linking of FcaR by IgA could be
responsible for the elevated levels of IL-1, IL-6 and TNF-a
observed in the serum of these patients.13-16Finally, the high
levels of TNF-a and IL-6 could play an important role in the
pathogenesis of such diseases by amplifying and regulating
inflammatory responses occurring during IgA-mediated host
© 1995 Blackwell Science Ltd, Immunology, 86, 1-5
to be saturated by
Fc.a receptor-mediated cytokine production
We thank Dr C. Maliszewski for the generous gifts of sol-FcaR
plasmid, Dr D. De Groote for TNF-a and IL-6 ELISA kits, L.
Beaudoin for excellent technical assistance, and Dr M. Webb and Mrs
D. Broneer for critical reading ofthis manuscript. R.C. Monteiro was a
recipient of a grant from the Association pour la Recherche sur le
Cancer (no. 6490).
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