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The State of Java: Meeting the Multicore Challenge
"The multicore challenge" is the challenge to developers of software products to write code that effectively utilizes modern multi-core / multi-processor computers. Two years ago, I wondered if the multicore challenge was still relevant. In part, I was thinking about how applications were moving from the desktop into the cloud. So, if the apps people are running are running in a browser, does it matter if their desktop system (or pad or phone) is multicore?
Today many mobile phones can really be looked at as being computers. In an article about the contributions mobile phones are making in poor countries, the Economist noted that "Mobile phones are the world's most widely distributed computers." And many of the newer mobile phones are multicore.
So really, whether the target computer for your software is a traditional tower, a laptop, a pad, or a phone, the multicore challenge remains relevant today -- and its relevance will only increase in the coming years. Browsers, one would think, are going to have to evolve to utilize multiple cores and processors. The ones that do so will ultimately take away significant market share from the ones that don't. How they'll accomplish this is another question...
Java already has basic capabilities for utilizing multiple processors -- in the threads library, for example. But, clearly that's considered inadequate for meeting the needs of the future. Which is why we have JSR 335: Lambda Expressions for the Java(TM) Programming Language. The development of JSR 335 takes place in Project Lambda, a component of the OpenJDK project.
At JavaOne 2011, Alex Buckley presented a very well attended session titled "Project Lambda: To Multicore and Beyond" that outlined the vision and plan for bringing Lambda expressions into Java. This will happen in Java 8 -- so, we're still a ways away from having a formal release.
The key element, in my view, is that Lambda expressions (also called "closures") will be implemented largely via a rewrite of the underlying JDK libraries wherein they will "automatically" do the low-level work of divying up the task at hand and passing segments of it to the available processor cores. This will enormously reduce the effort for Java application developers to convert their existing programs such that they can utilize multiple processors/cores.
Writing multithreaded code is hard. I've been doing it for 18 years, starting out on 8-processor Sun machines where we took scientific C and Fortran code delivered by researchers and revised it to parcel out data segments to different threads. Tiny mistakes inevitably result in overwritten data, which produces non-repeatable erroneous results, crashes, hung threads, and other "fun" head-scratchers... Yeah, it's hard to write threadsafe code!
The approach taken by the Java 8 architects and developers is going to in essence hide all that complicated threading stuff from the higher level app developer, by implementing the multithreading and fork/join processing within the Java libraries themselves. This is an enormous effort in itself, but it's a much smaller effort than if every Java application development team had to multithread their apps, having to rewrite function after function to be threadsafe.
Of course, the efficiency of the apps on multicore computers will thus depend on how much of the processing actually occurs within the core Java libraries. It's not going to be a situation where, because of Project Lambda, all apps will suddenly utilize all available cores 100% of the time, and immediately speed up by nC times (where nC is the number of cores in the computer).
Still, Project Lambda is a major innovation, a key step into the future for Java.
If you find all this interesting, you may want to take a look at Mike Duigou's JavaOne 2011 presentation "Bulk Hauling: Parallel Data and Lambdas in Java 8." The PDF for that is available in the JavaOne Content Catalog.
java.net Weblogs
Since my last blog post, quite a few people have posted interesting new java.net blogs:
- Kirk Pepperdine, Is setting -Xmx==-Xms still considered harmful?;
- David Herron, The DLJ project is dead - long live the OpenJDK;
- Brian O'Neill, Programmatically submitting jobs to a remote Hadoop cluster;
- Manfred Riem, Using HtmlUnit, Glassfish and Maven in a multi-project setup for integration testing;
- Bongjae Chang, Introduction to Grizzly-Thrift and sharing the benchmarking results; and
- Carol McDonald, Finding bugs that matter with Findbugs .
Our current java.net poll asks you to respond to The most important Java/JVM related happening in 2011 was. Voting will be open until Friday, December 23.
Our latest java.net article is SWELL - An English-Like DSL for Swing Testing by Sanjay Dasgupta and Chirantan Kundu.
Java News
Here are the stories we've recently featured in our Java news section:
- Maurizio Cimadamore outlines the Lambda Integration Plan;
- Jasper Potts demonstrates Styling FX Buttons with CSS;
- Geertjan Wielenga celebrates an Industry Award for Microchip's NetBeans Platform Application;
- Michael Kopp presents How to manage the performance of 1000+ JVMs;
- Geertjan Wielenga shares NetBeans API Video Tip 1: Decoupling via Lookup.Provider;
- Adam Bien reports Java FX 2
Related Topics >>Blog Links >>
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Overall score
would recommend to a friend.
Reviewer score
Would recommend
Great staff, clean, comfortable
Great location to downtown. Staff was extremely helpful. Loved the pool. Very clean. Large beds. Great Value
Would not recommend
One night getaway
When I checked in I asked about how long it takes to get a taxi, knowing Dallas and that area it could be up to 20 minutes. I just wanted to be able to schedule my departure for downtown in time. I was told by the desk agent that I was more than
welcome to use the shuttle that it ran until 11 PM. I went down at 7:30 PM and was told that the shuttle had headed for the airport and I was basically out of luck. I would like to say this....there was another shuttle sitting right outside the front door. After acknowledging my irritation at this I asked for a taxi to be called for me. As I waited for the taxi to arrive the shuttle driver came out and left. Please explain to me how it was not available to me to go a few miles into downtown but yet ready to go wherever he was going? Highly irritated I let it go. Went out had a good time, took a cab back late in the evening. Get into my room to find that there is no "privacy" door hanger. The cleaning crew woke me up twice before 11:30. Checkout was noon by the way. The pillows were ridicoulsy uncomfortable with no extras available in the room. I complained the next morning as I was checking out only to get an "I'm sorry" with complete disregard for my irritation. This hotel is located between a railroad and the DART which is the Dallas Area Rapid Transit system, an above ground train! 2:30 AM the train blows it's horn. I will never stay here again. I hope that many people read this review and please listen to it. This is not a nice hotel, this is not a good place to stay, even for one night. I do not recommend this particular Holiday Inn Express to anyone, not even my worst enemy!!
Iron Cactus - Mexican Food in Downtown Dallas, it's my favorite in Dallas and I try to go every time I am in town.
For business is perfect
Near my work area ... the staff very attentive.
Super good. I loved to have internet in the roons.
Great Experience
Hotel was clean and ready upon arrival. Check in was quick as well as check out. Was a great experience will highly recommend Holiday Inn to family and friends.
great hotel
freindly staff, good food, clean facility. close to everything.
Wonderful Stay
Everything was great except the a/c not working very well.
Business Trip
Solid location close to downtown. Great rate for a spacious king room. Very clean and comfortable. Fitness center is above average. A few too many smokers hanging out by the front entrance.
I was highly impressed, this Hilton was a very nice hotel.
I booked a room at this hotel for the 2012 Guitar Show hosted at Market Hall. The hotel is located within walking distance directly behind Market Hall. The location was ideally located for the show, we only had to walk across the street (Harry
Hines Blvd.) to get to Market Hall. Check-In time is listed as 3:00PM but we arrived early and were able to check-in at 12 noon without any issues whatsoever. Check-out time is at 12-noon - which is much better than most hotels that have a check-out time of 11AM. That extra hour makes all the difference. Breakfast was served till 10AM and we were able to eat breakfast without feeling rushed to get checked out early. Like I said, 12-noon check-out time is ideal. The room itself was extremely nice for the price, a king-size bed, AC that kept the room very cold as we desired. Bathroom was extremely clean and with plenty of thick bath towels. The bath towels were of very nice quality and not the cheap, thin bath towels you might find in some other hotels. Overall I was so impressed that I said if I'm coming to Dallas and need to stay close to downtown, then this is the hotel I will choose. The price is about right if you book online in advance.
Business Stay
Staff helpful and polite, train annoying. Location good for our business trip, but not the nicest area.
Good and warm staff
Very Good and according to ads. however pictures look a little different
Great family getaway
We had a great time our trip was fabulous the hotel was nice and very accommodating ! We would deffinetly book here again
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subset: commoncrawl


text:
People would describe me as smart, funny, loyal, compassionate and giving. I put people I care about ahead of myself, and I'm looking for someone who will do the same. I love to laugh, and I love to make other people laugh. I'm stable, self-sufficient, pretty handy around the house, and I'm a decent cook. I know who I am, and what I want. I'm also very comfortable in my own skin. I'm Italian with a little Irish thrown in for good measure. I have my geeky side, but I can hold intelligent conversations, and I get along with most everybody.
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41 • Tampa, FL • Man
I'm looking for
- Women
- Ages 29–43
- Near me
- Who are single
- For long-term dating, short-term dating
My details
- Last online
- Today – 5:30pm
- Orientation
- Straight
- Ethnicity
- White
- Status
- Single
- Height
- 5' 11" (1.80m)
- Body Type
- Average
- Smoking
- Sometimes
- Drinking
- Socially
- Drugs
- Never
- Religion
- Christianity but it's not important
- Sign
- Sagittarius
- Education
- University
- Offspring
- Has kids and wants more
- Speaks
- English
My self-summary
Write a little about yourself. Just a paragraph will do.
What I'm doing with my life
Don't overthink this one; tell us what you're doing day-to-day.
I have a 7 year old daughter who's a miniature version of me. So, father is at the top of the list. I'm also creative director for a software company in Tampa. Beyond that, I'm a friend, uncle, brother, a home improver, and the best person I can be.
I'm really good at
Go on, brag a little (or a lot). We won't judge.
Making people laugh. Getting along with most everyone. I'm a creative person, both personally and professionally. I grew up drawing and painting, I play guitar and the drums, and I'm a web and graphic designer by trade. I've been working out a lot, so I'm in pretty good shape.
The first things people usually notice about me
I'm an empty essay… fill me out!
I'm kind of a loud talker, especially when I'm excited about something (or when I've had a few drinks).
Favorite books, movies, shows, music, and food
Help your potential matches find common interests.
Movies - Goodfellas, The Shawshank Redemption, The Matrix, The Bourne Trilogy.
Shows - The Big Bang Theory, The Daily Show, Criminal Minds, Family Guy, The Colbert Report.
Food - Thai, Mexican, Good BBQ, Italian, Sushi.
Music - All over the road. Anything from Sinatra to Metallica, BB King to Carlos Santana, Lady Gaga to Van Halen, and lots in between.
Shows - The Big Bang Theory, The Daily Show, Criminal Minds, Family Guy, The Colbert Report.
Food - Thai, Mexican, Good BBQ, Italian, Sushi.
Music - All over the road. Anything from Sinatra to Metallica, BB King to Carlos Santana, Lady Gaga to Van Halen, and lots in between.
The six things I could never do without
Think outside the box. Sometimes the little things can say a lot.
In no particular order...My daughter, pizza, satellite radio, Long Island Iced Teas, my computer, friends and family.
I spend a lot of time thinking about
Global warming, lunch, or your next vacation… it's all fair game.
Why you have to wash a dish BEFORE putting it in the dishwasher... why hot dogs are sold in packs of 10, but buns are sold in packs of 8.
On a typical Friday night I am
Netflix and takeout, or getting your party on — how do you let loose?
I like to go out, but I'm perfectly content spending the night in as well. I enjoy stand-up comedy, movies, music, tv, video games, cooking.
You should message me if
Offer a few tips to help matches win you over.
you're seriously looking for a good guy who can make you laugh, hold an intelligent conversation, and knows how to treat a woman. If this sounds like you, message me...we should talk!
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text:
i do not know y this video only has 61 percent its amazing
Thanks for helping us associate the correct Pornstars to this video!
Pornstar Name:
Video Description:
Happy birthday Peter North
Todos los comentarios (17)
i do not know y this video only has 61 percent its amazing
Totaly Fake like all of OG's movies. Take note, he never takes his hand off the base of his cock, ever! Dosn't matter what position it is. Thats so he can hang on to this fake monster.
o my buda!!! D:
no cum shot!
not real
me meteria esa pinga grande completa
00:24 : ' Do you act like it's real?
omg thats so fake ,guy look at his dick tamn it ,and u cant see his balls too
o thats nothing..jk
damn :D
What a crock of crap. If he squirted a real load like that he would pass out.
look at that his dick gets bent to easily like he dun even have a boner i think it mite be fake but who knows
This is OG. trust me he has one of the biggest cocks in porn, I don't know about the cumshot?
Fake the Cock is more tanned then he self ^^
I bet she's blind now.


text:
Durant reacts to the passing of Abe PollinKevin Durant never knew Abe Pollin personally. But the Thunder's star forward and Washington, D.C., native was saddened by the passing of the Washington Wizards owner Tuesday and called the news "devastating." Pollin was 85 and had suffered from supranuclear palsy, a rare brain disorder. "He meant a lot," Durant said of Pollin's impact on basketball in the District. "He basically made the Wizards. "If you go downtown, he has his own avenue there right in front of the arena. And so he was Wizards basketball, and you can kind of say he was like the founder of basketball in Washington, D.C. I don't know about before I was born. But for me coming up, Abe Pollin and what he's done for the city of D.C. and how much he's given back. And so it's a devastating loss."
Tough crowdThe Jazz has established itself as one of the toughest teams to beat at home. Utah has a home record of 477-162 over the past 16 seasons and entered Tuesday's game against the Thunder with a home mark of 105-24 over the past three-plus seasons. "Great crowds," explained Brooks. "It's always been a great building. And the building, the way it's set up, basically the crowd is right on top of you. And it's kind of like our place where it's loud no matter what time of the year it is, opening game through January, February. And when the playoffs are here they even take it up another level."


text:
Boston girl's birthday wish to donate shoes to charity
She made it her business to collect new shoes to give to children in need instead of birthday gifts.
Right-to-die advocate's video out after death
The video was released by an advocacy group that worked with Maynard that prompted a national debate about allowing terminally ill people to…
A Texas Pit Bull is conquering his fear of certain doors in the cutest way possible
A very special dog is conquering his fear of going through doors in a very unusual way.
Arkansas father of 26 arrested for not paying child support
ST. FRANCIS COUNTY, AR (WREG/CNN) — An Arkansas man who may have fathered more than two dozen children is behind bars. He's accused of faili…
Watch: Giant panda enjoys snow at Toronto Zoo
The Toronto Zoo's male giant panda is celebrating this rush of winter weather.
Facebook releases new app just for Groups
One of Facebook's more popular, less attractive features is getting its very own app.
California dog chews off leg to escape chain
"Doesn't surprise me what people do anymore, it's so sad, it's so hard to believe and it's impossible to understand," said Melyssa Stayner.
Snapchat post leads to Colorado road rage arrest
It turns out the suspect may have has his daughter to blame for his arrest.
No on Keystone pipeline, but GOP vows replay
The Democratic-controlled Senate rejected legislation Tuesday night to force completion of the Keystone XL Pipeline.
NFL suspends Adrian Peterson for at least rest of season
Commissioner Roger Goodell told Peterson he will not be considered for reinstatement before April 15 for his violation of the NFL personal c…
Lawyer: Tracy Morgan battling severe brain injury
Tracy Morgan's lawyer didn't discuss specific aspects of the star's condition but said Morgan hasn't fully recovered.
Bruno Mars gets down retro-funk style in new music video
"Uptown Funk" is from Mars collaborator Mark Ronson's upcoming album.
Pearl Harbor park workers allege poor maintenance, mismanagement
Employees say that top park managers were complicit in the selling of free-admission tickets to tour companies.
Illinois fugitive wanted for child sex assault arrested in Honolulu
After being on the run for several months, 64-year-old James McKee was arrested outside the YMCA in Nuuanu Monday morning.
Helping plan your strategy for holiday shopping
When's a good time to buy it now, or buy it later?
3 Florida guys find a career playing video games
Playing video games for money? 3 guys make career out of gaming, blaze new path online.
'Facebook at Work' could be coming to your office
Facebook is working on an office version of its social network for employee-to-employee communication at work.


text:
Select Local Merchants
Robin's Tips N ToesRead MoreA manicurist with 14 years of nailcare experience pampers paws at her salon in Plymouth's Old Village. A salon state-certified for its sterilization standards, Robin's Tips N Toes Nail Salon's eponymous technician deploys new files and buffers on each mission to beautify her clients' nails in a bright studio kept peacefully quiet by the stern stares of a librarian minotaur. A vast lineup of pedicures, manicures, and soothing treatments awaits upper and lower appendages, and Robin welcomes appointment setters from 9 a.m. to 8 p.m. Tuesday–Saturday.120 E Liberty St.Plymouth, MI US
Hair Media SalonRead MoreThe stylists at Hair Media Salon in Westland can provide you with the must-have hair colors and cuts of the season. The professional nail care services at this salon will leave you with long-lasting, beautiful nails. This fashion-forward salon offers a wide array of hair care services. This season, try something new! Find your new style at Hair Media Salon.38407 Joy RdWestland, MI US
Legends Official Hair CutterRead MoreLet your personality shine with a trendy cut and color from one of the trained stylists at Legends Official Hair Cutter in Westland. After getting your hair done at this salon, the compliments will come pouring in. So what are you waiting for? If a hairstyle you love is what you want, book an appointment at Legends Official Hair Cutter today.6620 N Wayne RdWestland, MI US
Top Diamond NailsRead MoreKeep up with the latest nail craze at this trendy nail salon and leave with top-of-the-line nails. Say goodbye to blackheads and clogged pores with a facial! Top Diamond Nails offers a wide range of painless and effective hair removal remedies, including waxing, threading, laser hair removal, electrolysis, and epilation. Keep your nails looking on fleek with a nail care treatment from this salon, such as no-chip gel manicures, pedicures, manicures, nail art, and mani-pedis. For beauty services that are sure to impress, such as eyelash extensions, head to Top Diamond Nails. You're in luck! This salon always accepts walk-ins for all beauty services and treatments. With relaxing spa treatments at an affordable price point, Top Diamond Nails is just the spa you're looking for. Top Diamond Nails happily accepts all major credit cards as a form of payment. The parking lot near Top Diamond Nails will have you in and out in a jiffy. Top Diamond Nails is ready to scrub, trim and design those beautiful nails of yours so give the salon a call today and book a mani-pedi.8363 N Wayne RdWestland, MI US
Saranda His and Hers Hair SalonRead MoreWhat services does your business offer and what makes your business stand out from the competition? We have been in the business for 40 years. We are top of the line. We regularly attend classes to further our education and bring the best in new products and styles to our clients! What was the inspiration to start or run this business? Being a hairdresser in the salon for 20 years and watching how the business was run by the previous owner inspired the current owner to want to buy the business and help it grow to be one of the top salons in the city. What do you love most about your job? Nothing makes us happier than making somebody else feel good and look beautiful! What is the best reaction you've ever gotten from a customer? Clients who have moved away but regularly fly back to Michigan because they love how I (the owner) do their hair and they do not want anybody else to do it!35135 Warren RdWestland, MI US
Elle Nail N SpaRead MoreIf spa services are your guilty pleasure, you will love the luxury treatment selection at Elle Nail N Spa in Westland. Spice up your toenails and fingernails with a specialized nail treatment. This establishment provides hair removal services for all hair and skin types, even those with sensitive skin. This spa exercises an open-door policy. All you have to do is walk in for a fabulous appointment. At Elle Nail N Spa, you can escape reality and indulge in an affordable spa treatment. You'll love that payment is as easy as any major credit card at Elle Nail N Spa. With a parking lot adjacent to Elle Nail N Spa, you won't get stuck circling the block. Regardless of how your natural nails look, the professionals at Elle Nail N Spa can make them look great with a little buffing and paint of polish.37612 Ford RdWestland, MI US


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Heath Court Hotel enjoys a very convenient location close to the town centre and overlooks the Newmarket gallops. Bedrooms are all well equipped and spacious, and free WiFi is available throughout the...More about BEST WESTERN Heath Court Hotel
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text:
Most people, if they were set to turn 88 next month, would be content to have good physical health and their mental faculties intact.
However, Stan Lee has proven yet again that he is not most people. He remarkably, continues to produce exceptional work in the comic field.
He also continues to break industry records.
It was recently announced by BOOM! Studios that the latest creation with his fingerprints, "Stan Lee's Soldier Zero," has sold over 24,000 copies so far, BOOM!'s best-selling comic ever.


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These two authors contributed equally to this article.
The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings
Article first published online: 27 JUN 2013
DOI: 10.1111/cge.12173
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clinical Genetics
Volume 84, Issue 4, pages 303–314, October 2013
Additional Information
How to Cite
The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings., , , , , , , .
All authors declare no conflict of interest.
Publication History
- Issue published online: 11 SEP 2013
- Article first published online: 27 JUN 2013
- Accepted manuscript online: 26 APR 2013 09:59AM EST
- Manuscript Revised: 19 APR 2013
- Manuscript Accepted: 19 APR 2013
- Manuscript Received: 17 FEB 2013
- Abstract
- Article
- References
- Cited By
- lymphoedema;
- generalized lymphatic dysplasia;
- phenotyping;
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010, we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This article reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge.
Lymphoedema is chronic swelling due to impaired lymphatic drainage typically affecting the extremities, but may involve any body site. It causes considerable lifelong physical and psychological morbidity; it is disfiguring and results in increased susceptibility to recurrent infection and increased risk of local malignancy [1, 2].
The lymphatic system is made up of a network of capillaries, collecting vessels and lymphoid organs that serve to maintain fluid homeostasis, immune surveillance and fat absorption from the gut [3]. Extravasated interstitial water and proteins are absorbed by lymphatic capillaries and propelled along the lymphatic network by lymph vessel peristalsis or by compression from surrounding skeletal muscles. Lymphoedema is the clinical consequence of swelling within tissue caused by the accumulation of lymphatic fluid due to damage, malfunction, absence or malformation of the lymphatic system.
The lymphatic system may fail for several reasons. The most common scenario is as a result of damage; known as secondary lymphoedema. For example, tumours, cancer treatment (lymphadenectomy and radiotherapy), trauma, venous hypertension and severe infection including filariasis may all damage a previously healthy lymphatic system [4-7]. Alternatively, an individual may develop primary lymphoedema as a result of a genetic predisposition; the lymphatic system fails to develop normally causing impaired drainage of lymph.
Limited data exist on the prevalence of lymphoedema. In 1985, Dale estimated the prevalence of primary lymphoedema as 1/6000 population based upon one UK clinic [8]. More recently chronic lymphoedema (of primary and secondary causes) was estimated to affect as many as 1.33/1000 population in the UK [9]. A similar survey in Derby estimates 4/1000 (VK, pers. comm.). Further epidemiological studies are needed to establish the true prevalence of primary and secondary lymphoedema.
A review of the literature on primary lymphoedema reveals the term 'primary lymphatic dysplasia' used interchangeably with 'primary lymphoedema' in several papers (e.g. 2009 Consensus Document of the International Society of Lymphology) [10]. We consider lymphatic dysplasia as an inherent developmental abnormality of the lymphatic system resulting in primary lymphoedema. Both terms are used within this review article.
Although the underlying abnormality of the lymphatics is often congenital, with the swelling manifesting as early as the prenatal period, at times it may not develop until puberty or adulthood. The lymphoedema can range from mild swelling to that of grotesque enlargement in chronic cases that have not received adequate treatment. Skin changes may be present, including brawny fibrotic skin and the presence of the Kaposi–Stemmer sign (the failure to pinch/pick up a fold of skin at the base of the second toe as a result of its thickness) that is pathognomonic of lymphoedema [11]. Papillomatosis (small flesh-coloured papules) occurs as a result of dilatation within the upper dermal lymphatics and subsequent fibrosis of the dermis. Lymphangiectasia appear as small blisters on the skin surface as a result of engorgement of lymphatic vessels. Lymph fluid frequently leaks as a result of minimal trauma and is termed lymphorrhoea.
The mainstay of treatment for lymphoedema is limited to physical therapy in the form of manual lymphatic drainage and compression hosiery/garments in combination with exercise [12, 13]. Early intervention with skin hygiene advice, appropriate footwear and compression hosiery has beneficial effects on swelling and reducing the risk of complications (e.g. cellulitis) in our paediatric cohort (KG and PSM, pers. comm.). There are no effective drug therapies available for the management of primary lymphoedema. Surgical management is largely unsuccessful and is often reserved for use in palliative situations where debulking of tissue is necessary. The use of tumescent liposuction may significantly reduce limb volume in patients who develop increased adipose deposition within their lymphoedematous limb [14]. Patient selection prior to liposuction treatment is key to its success; patients must comply with lifelong (all day, every day for life) post-operative compression garments in order to avoid deterioration in lymphoedema.
Mutations in several genes are now recognized to cause lymphatic dysplasia. Some, but not all, of these factors have been demonstrated to play a role in the pathway regulating lymphangiogenesis. Lymphangiogenesis refers to the development of the lymphatic system and begins during embryonic week 6–7 in humans. Recent research has demonstrated that it is regulated by several key factors/proteins [15-17]. The first two genes to be identified as causative for human lymphoedema were FLT4 in Milroy disease (MD; MIM 153100) [18-21] and FOXC2 in lymphoedema distichiasis syndrome (LDS; MIM 153400) [22-24]. As then several new genes for human lymphatic disease have been discovered and these will be discussed below.
Classification of primary lymphatic dysplasia
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
Allen introduced the first known classification of primary lymphoedemas in 1934 [25]. He divided primary lymphoedema into two broad groups: 'lymphoedema congenita', i.e. present at birth or shortly thereafter and 'lymphoedema praecox' which described cases where swelling occurred after birth. In 1957, Kinmonth et al. added the term 'lymphoedema tarda' if the swelling developed after the age of 35 years [26].
It became apparent that this classification system based purely on age-of-onset was over-simplified and redundant in clinical practice as it failed to facilitate categorization based on more specific phenotypes of primary lymphoedema. In 2010, Connell et al. created a classification pathway founded on clinical phenotype [27]. This was based not simply on the age of onset of the lymphoedema but also the sites affected and the presence of associated features, e.g. dysmorphology, distichiasis (aberrant eyelashes), varicose veins, prominent large calibre veins, vascular malformations, and limb overgrowth. Systemic lymphatic involvement is taken into consideration, i.e. a history of hydrops fetalis in utero (the abnormal accumulation of fluid in two or more foetal compartments, including ascites, pleural effusion, pericardial effusion, and subcutaneous oedema [28]), pericardial or pleural effusions, chylous ascites, or gastrointestinal lymphangiectasia. A family history of lymphoedema with determination of the mode of inheritance is an important consideration in this classification.
Specific phenotyping facilitates the identification of subgroups of patients with the same type of primary lymphoedema. This leads to better understanding of the natural history and management of the specific conditions and more accurate recurrence risks for future offspring/generations. These cohorts can then be used for molecular studies to identify causal genes. This has been a fruitful exercise, leading to the identification of several genes, which will be discussed.
Use of the classification pathway
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
We have revised and updated the Connell et al.'s algorithm (see Fig. 1) and included the newly identified genes. In this review article, we will focus on the subgroups which now have genes assigned to them, and newly identified conditions based on the clinical presentation. Some of the subgroups in the algorithm will not be covered in this article as no genes have yet been identified and so the phenotype remains unchanged; the reader can refer to Connell et al. for descriptions [27]. Use of the pathway requires appreciation of certain terminology which is listed in Table 1 and should be read in conjunction with Fig. 1.
|Congenital onset
|Onset of lymphoedema before the age of one year.
|Cutaneous manifestations
|Naevi/pigmentation variations (e.g. epidermal naevi)/vascular malformations.
|Presence of aberrant eyelashes arising from the meibomian glands.
|Disturbed growth
|Hypertrophy (overgrowth) and hypotrophy of bone or soft tissue resulting in altered length of a limb or body part.
|Klippel—Trenaunay/ Klippel—Trenaunay-like syndrome.
|Late onset
|Swelling presenting after one year of age.
|Prenatal onset
|Detection of lymphatic abnormality in the prenatal period. Isolated pedal oedema is excluded from this definition as this may be a presentation of Milroy disease.
|A region of the body affected by lymphoedema (i.e. face, conjunctiva, genitalia, upper limbs, lower limbs—each constitute one body part). Multisegmental refers to more than one segment affected by lymphoedema. Bilateral lower limb swelling is not considered to be multisegmental lymphoedema.
|A constellation of abnormalities, one of which is lymphoedema.
|Systemic involvement
|Systemic lymphatic problems persisting beyond the newborn period or manifesting at any age thereafter. This includes hydrops fetalis, chylous ascites, intestinal lymphangiectasia, pleural and pericardial effusions, and pulmonary lymphangiectasia.
|Vascular anomalies
|Include congenital vascular abnormalities.
The lymphatic dysplasia classification pathway is presented in the form of a colour-coded algorithm to illustrate the five main categories of primary lymphoedema and the individual subtypes within these categories. We appreciate there will be exceptions and outliers to this classification system but for the vast majority of patients it has proved a useful clinical and research tool which is still evolving.
Syndromic (blue section)
Lymphoedema is a recognized feature of many syndromes. In some of these conditions the lymphoedema is not the primary problem but is an associated feature. The most common conditions in this category include Turner, Noonan (NS; MIM 163950) and Prader Willi (PWS; MIM 176270) syndromes. The genetic causes of many of these syndromes are known and testing is available. A molecular result means that the mode of inheritance can be established and where indicated, prenatal diagnosis can be offered. Table 2 provides a list of syndromes that include lymphoedema as a feature. A new addition to this list is Oculo-dento-digital syndrome (ODD; MIM 164200) which is caused by mutations in the GJA1 gene. Lymphoedema has recently been reported as an associated feature of ODD syndrome in a family, where a novel GJA1 mutation co-segregated with the affected status [29].
|Known syndrome
|Aagenaes syndrome
|Not known
|Carbohydrate deficient glycoprotein types 1a, 1b, and 1h
|Cardio-facio-cutaneous syndrome
|CHARGE syndrome
|Choanal atresia-lymphoedema
|Ectodermal dysplasia, anhidrotic, immunodeficiency, osteopetrosis and lymphoedema (OL-EDA-ID syndrome)
|Fabry disease
|Hennekam syndrome
|Irons-Bianchi syndrome
|Not known
|Lymphoedema-myelodysplasia (Emberger syndrome)
|Macrocephaly-capillary-malformation (MCM)
|Microcephaly-chorioretinopathy-lymphoedema-mental retardation (MCLMR)
|Mucke syndrome
|Not known
|Noonan syndrome
|PTPN11, KRAS, SOS1, and others
|Oculo-dento-digital syndrome (ODD)
|Progressive encephalopathy, hypsarrhythmia, optic atrophy (PEHO)
|Not known
|Phelan McDermid syndrome
|22q terminal deletion or ring chromosome 22
|Prader Willi
|15q11 microdeletion or maternal UPD 15
|Thrombocytopenia with absent radius
|1q21.1 microdeletion and RBM8A
|Turner syndrome
|Velocardiofacial syndrome
|22q11 microdeletion
|Yellow Nail syndrome
|Not known
The pathway works in such a way that in conditions in which lymphoedema/lymphatic dysplasia is a main feature, the condition may also be classified elsewhere in the algorithm so as to facilitate the identification of these phenotypes. So although Hennekam (MIM 235510) [30] and Microcephaly-chorioretinopathy-lymphoedema-mental retardation (MCLMR; MIM 152950) [31] are syndromes they are discussed in further detail in the 'Generalized lymphatic dysplasia' and 'Congenital lymphoedema' sections, respectively.
Systemic/visceral involvement (pink section)
Individuals with systemic/visceral involvement have a widespread developmental abnormality of the lymphatic system; the swelling is not confined to the peripheries. Onset of lymphatic dysfunction prenatally can present with hydrothoraces or hydrops fetalis. Prenatal hydrops may occur as a result of other conditions (e.g. Parvovirus infection, Rhesus incompatibility, non-immune hydrops due to a number of conditions) and these need to be excluded before considering primary lymphatic dysfunction as the diagnosis. In utero oedema can lead to dysmorphic facial features in an individual including epicanthic folds, a broad nasal bridge and neck webbing with low set ears [32].
Postnatal signs of systemic lymphatic abnormalities include pericardial and pleural effusions, chylous ascites, and pulmonary and intestinal lymphangiectasia. Patients with intestinal lymphangiectasia often complain of abdominal pain and diarrhoea following the ingestion of fatty foods, however, diagnosis is not always straightforward. Management of these patients is often complex and may include drainage of effusions and medium-chain-triglyceride (MCT) diets to manage intestinal lymphangiectasia and chylous disorders [33]. Prompt diagnosis of systemic lymphatic abnormalities aids early intervention that may prove lifesaving in some instances.
Individuals with systemic/visceral involvement can be further divided into two categories: 'multisegmental lymphatic dysplasia with systemic involvement' (MLDSI) and 'generalized lymphatic dysplasia' (GLD) [27].
Multisegmental lymphatic dysplasia with systemic involvement
MLDSI is characterized by a segmental pattern of lymphoedema affecting different body parts associated with systemic involvement (Fig. 2a–c). It may be associated with hemifacial swelling and conjunctival oedema on the affected side. More than one limb may be affected, but they may be contralateral. Intelligence is normal and there are no associated structural abnormalities. There is a low sibling and offspring recurrence risk and the underlying mechanism is thought to be explained by somatic mosaicism, but this requires further investigation (FC, pers. comm.).
GLD/Hennekam syndrome
Patients with GLD have a more uniform, widespread pattern of lymphoedema affecting all segments of the body (Fig. 2d,e) and often presenting in utero with hydrops fetalis. A number of affected individuals in this cohort have a positive family history of lymphoedema usually suggestive of autosomal recessive inheritance inferring a higher recurrence risk.
Hennekam syndrome [30] is an example of GLD (Fig. 2d). Other phenotypes exist for this subgroup of patients, but Hennekam syndrome remains the only one with an identified causal gene. Hennekam syndrome is also known as lymphoedema-lymphangiectasia-mental retardation syndrome. The phenotype comprises lymphoedema of all four limbs, lymphangiectasia (dysplasia of the lymphatic system of the intestines and/or lungs), variable degrees of learning difficulties and characteristic facies (flat face, flat and broad nasal bridge, hypertelorism) (Fig. 2e). Other associated problems include hypothyroidism, glaucoma, seizures, hearing loss and renal abnormalities. In severe cases it may present in the antenatal period with hydrops fetalis, and/or cardiac abnormalities [34, 35]. Lymphoscintigraphy has rarely been undertaken in this condition but Bellini demonstrated abnormal drainage in the upper and lower limbs and the thoracic duct in one patient [34].
Hennekam syndrome is inherited in an autosomal recessive manner. Mutations in CCBE1 (collagen and calcium binding EGF-domain 1) on chromosome 18q21 have been identified as causal [36, 37]. However, CCBE1 mutations were only present in 23% of cases [36], suggesting genetic heterogeneity.
CCBE1 function in humans has yet to be elucidated, but studies in mice and zebrafish confirm that ccbe1 enhances lymphangiogenesis induced by VEGFC and is also necessary for the budding and sprouting of lymphangioblasts [38, 39]. Nearly all identified CCBE1 mutations have been missense, but one frameshift has been reported [36, 37, 40].
Disturbed growth and/or cutaneous/vascular anomalies (yellow section)
Lymphoedema can be seen in conjunction with other vascular anomalies, disorders of growth and cutaneous abnormalities. Identifying the type of malformation and thereby the vessels involved is important for diagnosis and management. The International Society for the Study of Vascular Anomalies (ISSVA) Classification for vascular anomalies has been widely adopted to provide a common nosology [41].
This cohort of patients pose a phenotyping challenge as there is overlap in clinical findings and much confusion in the literature. The recent identification of de novo somatic mutations as the underlying mechanism for some of these conditions may promote further understanding.
AKT/PIK3/mTOR pathway
AKT acts within a molecular pathway that includes the genes, mTOR and PIK3CA. This pathway is critical as a pro-growth and anti-apoptosis facilitator in cancer but mutations in the genes also have other implications. AKT2 has been shown to have a role in lipomatous overgrowth in association with hypoglycaemia and AKT3 mutations cause hemimegalencephaly [42]. PIK3CA, PIK3R2 and mTOR have been implicated in a range of disorders associated with somatic overgrowth, vascular malformations, fibroadipose overgrowth, pigmented cutaneous lesions and megalencephaly [42-45]. Distinguishing specific phenotypes from within this cohort of patients is difficult, with much confusion surrounding this spectrum of disorders. CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal naevi and skeletal abnormalities) syndrome (MIM 612918) has been reported as a specific entity caused by somatic mosaicism of activating mutations in PIK3CA [43]. The same gene and same mechanism have also been implicated in a few patients with Klippel-Trenaunay syndrome (MIM 149000) and with fibroadipose hyperplasia [43, 46]. Lymphatic malformations can arise as part of these conditions. Further molecular studies, together with careful phenotyping, will facilitate the understanding of this spectrum of disease. Activated PIK3-AKT signalling underpinning the disease process gives rise to potential for therapeutic targets through inhibition of the PIK3/AKT/mTOR pathway [46]. It is likely that combined vascular malformations may also arise as a result of somatic mosaicism.
Proteus syndrome
Proteus syndrome (MIM 176920) is an overgrowth disorder characterized by progressive, segmental overgrowth of skin, connective tissue, skeleton and central nervous system. Lymphatic, along with capillary, malformations are the most common vascular changes seen in Proteus syndrome. Manifestations of Proteus syndrome may not be present at birth but develop and progress in infancy. The diagnosis can be established using diagnostic clinical criteria and/or molecular analysis [47]. The majority of individuals with clinically confirmed typical Proteus syndrome were identified to have a common activating mutation in AKT1, c.49G>A (p.Glu17Lys), arising as a result of somatic mosaicism. It is hypothesised that germline AKT1 c.49G>A mutations would be lethal early in embryonic development [48].
WILD syndrome
A phenotype with the acronym WILD (warts, immunodeficiency, lymphoedema, anogenital dysplasia) has been reported [49] which led us to identify patients in our register with similar clinical features. Therefore, they have been included in the updated pathway. They all have extensive, asymmetrical lymphoedema (multisegmental) (Fig. 3a,d) associated with facial and conjunctival oedema (Fig. 3e), swelling of the genitalia, capillary malformation over the chest (Fig. 3c), and epidermal naevi (Fig. 3b). Persistent wart infections with abnormalities in lymphocyte subset values (particularly CD4) are a consistent feature of this condition. These patients are all sporadic, suggesting probable somatic mosaicism. The underlying genetic cause has yet to be identified.
Congenital multisegmental lymphoedema
There is a cohort of patients with congenital multisegmental lymphoedema in whom the pattern of lymphatic failure is asymmetrical with limb sparing (i.e. some limbs are normal) but without overgrowth or cutaneous or vascular anomalies. We hypothesise that somatic mosaicism in gene(s) involved in lymphangiogenesis may explain the aetiology of this subtype of congenital primary lymphoedema, so this condition has been highlighted in yellow as it theoretically shares the same mechanism as the other cohorts in the disturbed growth and/or cutaneous/vascular anomalies section (yellow section).
Congenital onset primary lymphoedema (green section)
Historically, all cases of congenital onset primary lymphoedema were classified as MD but MD has a distinct clinical phenotype and there are several different types of congenital primary lymphoedema.
Milroy disease
MD was first described in 1892 by William Milroy in a family with congenital lower limb lymphoedema that was painless and non-progressive [50]. Brice et al. further refined the phenotype by analysis of 71 individuals with MD [51]. They summarized the clinical features of MD and as such the phenotype is easily recognizable. The features include symmetrical congenital lymphoedema of the feet (Fig. 4a). Occasionally, onset of swelling may occur in the first year of life. Lymphoedema is typically confined to the feet and ankles, but may reach the knees. Affected individuals have up-slanting 'ski-jump' toenails due to disturbance of the nail bed by oedema. Prominent large calibre veins may be present on the dorsum of the feet and lower legs. Varicose veins, most commonly the long saphenous vein, have been reported in adults with MD, but do not appear to affect the paediatric population [51]. A third of affected males have hydroceles [51]. Very rarely, MD may present in the antenatal period with hydrops fetalis [52]. The swelling may regress and remain confined to the feet, or the hydrops may progress and result in intrauterine death [53].
Lymphoscintigraphy in MD confirms the failure of initial lymphatic absorption and has been termed a 'functional aplasia' of lymphatic vessels (Fig. 5b). Unlike the mouse model (Chy-mouse) [54], in the human the initial lymphatic vessels are present (confirmed on histological examination) but unable to absorb interstitial fluid [55].
Abnormalities within FLT4; gene that encodes the VEGF receptor type 3 (VEGFR3) on chromosome 5q35 are causal of MD [18, 53]. Mutations in FLT4 are found in 70% of patients with congenital onset primary lymphoedema affecting bilateral lower limbs [56]. Inheritance is autosomal dominant with 85% penetrance [18, 19]. De novo mutations may occur so a family history is not mandatory [53]. Animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies have demonstrated that mutant VEGFR3 showed impaired kinase activity [20, 57]. All reported FLT4 mutations to date have occurred within the tyrosine kinase domain [53]. However, the exact mechanism of disease is not yet fully understood.
Milroy-like lymphoedema
Individuals with congenital lower limb lymphoedema who screen negative for FLT4 mutations are classified as having 'Milroy-like' lymphoedema. Recently a family with congenital lower limb lymphoedema, prominent large calibre veins and hydroceles inherited in an autosomal dominant pattern over three generations has been described. Affected individuals tested negative for FLT4 mutations but were found to have a frameshift mutation in VEGFC on chromosome 4q34 [58]. VEGFC is a ligand for VEGFR3 and controls lymphatic sprouting during embryonic development [38, 59]. Gordon et al. used in vivo overexpression assays in zebrafish to demonstrate that wild-type human VEGFC, but not mutant VEGFC, caused excessive sprouting of venous-lymphatic vessels, confirming that the VEGFC frameshift mutation was causative for the Milroy-like phenotype seen. It is therefore appropriate to consider VEGFC screening in patients with 'Milroy-like' lymphoedema.
MCLMR syndrome
A syndrome comprising microcephaly and congenital lymphoedema was reported by Leung in 1985 [31]. However, it was only recently that Ostergaard et al. identified that mutations in KIF11 on chromosome 10q24 were causative for autosomal dominant microcephaly variably associated with congenital lymphoedema and/or chorioretinopathy [microcephaly-lymphoedema-chorioretinal dysplasia (MLCRD) and chorioretinal dysplasia-microcephaly-mental retardation (CDMMR)] [60]. Now regrouped under the acronym MCLMR (MIM 152950).
Clinical features include microcephaly (−2 to −7 standard deviations from the mean) (Fig. 4b), congenital lower limb lymphoedema (mimicking MD) (Fig. 4c), eye abnormalities (chorioretinopathy and/or hypermetropic astigmatism), and mild to moderate learning difficulties [60]. Lymphoscintigraphy shows the same pattern that is seen in MD with a functional aplasia of lymphatic vessels. MCLMR should be considered in all microcephalic patients with congenital bilateral lower limb swelling.
The KIF11 protein product (EG5) is involved in spindle formation in mitosis but is not known to be directly involved in the lymphangiogenesis pathway [60]. The mechanism by which KIF11 exerts its influence on the development of lymphoedema remains a mystery.
Late onset primary lymphoedema (purple section)
Late onset lymphoedema refers to the development of lymphoedema occurring after the age of 1 year. This group contains a number of diverse disorders, some with life-threatening associated diseases (e.g. Emberger syndrome), but they all share the common finding of non-congenital limb swelling.
Lymphoedema distichiasis syndrome
Lymphoedema in association with distichiasis (aberrant eyelashes) was first recognized in 1899 [61]. The lymphoedema of the lower limbs (usually bilateral) (Fig. 5c, upper panel) develops in late childhood (usually during puberty) but onset may be congenital or as late as in the fifth decade. Distichiasis is frequently present at birth but rarely presents until childhood. Distichiasis, the presence of aberrant eyelashes arising from the meibomian glands (Fig. 6a, arrows), is sometimes only detectable on specialist examination and therefore frequently missed. These aberrant lashes can be highly symptomatic and cause ocular irritation, photophobia, recurrent infections (styes) and may require ablative treatment. Conversely, some individuals with distichiasis remain asymptomatic. Distichiasis was reported by Brice et al. to be 95% penetrant in this syndrome [62].
The LDS phenotype also includes ptosis (35%), cleft palate or Pierre-Robin sequence (3%) and congenital heart disease (8%) [62]. The vast majority of affected individuals have clinical and/or ultrasonographic evidence of incompetent or varicose veins [62]. LDS is inherited in an autosomal dominant manner. It occurs as a result of mutations in the FOXC2 gene on chromosome 16q24 [23]. Brice et al. demonstrated that mutations can be identified in more than 95% of cases with typical LDS [62]. Many cases are due to small deletions or insertions [63]. FOXC2 encodes a transcription factor necessary for the signal transduction pathway ensuring normal development of the lymphatic collecting vessels and valves [64].
Meige disease
Meige disease (MIM 153200) is probably the most prevalent subtype of primary lymphoedema and was originally described in 1898 by Henry Meige [67]. It typically presents with lower limb lymphoedema that rarely extends above the knee (Fig. 5d, upper panel). The lymphoedema does not appear in childhood, but in adolescence or adulthood. There are no other associated features of the condition [68]. Lymphoscintigraphy frequently demonstrates deep rerouting of lymph drainage as evidenced by increased uptake of tracer by popliteal lymph nodes and impaired main superficial lymphatic tract filling (Fig. 5d, lower panel) (PSM, pers. comm.).
Family history is often consistent with an autosomal dominant pattern of inheritance with variable penetrance. Whilst the causal gene of classical Meige disease has yet to be identified, a number of adolescents and adults with GJC2 gene mutations have presented with lymphoedema localized to the lower limbs (see section on 4-limb lymphoedema below). GJC2 should therefore be considered as a candidate gene for some patients historically labelled as having Meige disease.
Emberger syndrome
The association of primary lymphoedema with myelodysplastic syndrome and/or acute myeloid leukaemia was first described by Emberger in 1979 [69] (MIM 614038). Emberger syndrome is sometimes associated with a high frequency sensorineural deafness that may be congenital. Affected individuals develop bilateral or unilateral lower limb +/− genital lymphoedema in childhood, usually after the age of 6 years (Fig. 6c) [70]. Severe cutaneous warts are a common finding, presumably as a result of their immune dysfunction (Fig. 6b). Myelodysplasia develops at any stage and frequently progresses to acute myeloid leukaemia with a high mortality [70]. Lymphoscintigraphy has not been routinely performed in this condition, however, Mansour et al. demonstrated a functional hypoplasia of lymphatics within the affected lower limbs of their patients [70].
Mutations in the GATA2 gene on chromosome 3q21 are causal and inherited in an autosomal dominant manner [71]. GATA2 is expressed in lymphatic, vascular and endocardial endothelial cells [72]. Mouse studies suggest the programming of lymphatic valve development may be affected as a result of loss of function of GATA2 [73]. GATA2 is also involved in the regulation of haematopoiesis; GATA2 mutations have been reported in heritable forms of myelodysplastic syndrome and acute myeloid leukaemia [74] and two overlapping immunodeficiency syndromes, MonoMAC [75] and dendritic cell, monocyte, B and NK lymphoid deficiency [76].
Late onset 4-limb lymphoedema
In 2010, Ferrell et al. reported that mutations in GJC2 were implicated in the development of lymphoedema [77]. Ostergaard et al. provided further information on the phenotype with five pedigrees demonstrating an autosomal dominant pattern of inherited lymphoedema (MIM 613480) [78]. Although there was inter-familial variability of clinical signs the overall phenotype was one of late onset lymphoedema affecting the lower limbs or all four limbs (Fig. 6d,e). A significant number of these individuals also had varicose veins [78]. Lymphoscintigraphy demonstrates lymphatic tracts that appear normal but when quantification is done there is significantly reduced absorption from tissues by peripheral lymphatics in all four limbs [78].
We have seen a number of adolescents and adults with clinical evidence of lymphoedema localized to the lower limbs but with lymphoscintigraphic evidence of impaired lymphatic drainage within all four limbs. It remains to be seen whether these individuals progress to developed clinical signs of upper limb lymphoedema over time.
The functional role of GJC2 within the lymphatic system is unclear. GJC2 encodes the connexin 47 protein located on chromosome 1q42. Homozygous mutations in GJC2 have been reported in patients with Pelizaeus-Merzbacher-like disease (MIM 608804), a rare form of CNS demyelination, but none of these patients or their parents were reported to have lymphoedema [79].
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
A number of causal genes have now been identified in the pathogenesis of primary lymphoedema, the majority within the last few years. Gene identification helps delineate the phenotype more specifically. It is hoped that the identification of more pathogenic genes will further our knowledge of the aetiopathogenesis of lymphatic disease. In time this may allow for the development of therapeutic interventions.
The identification of the genetic causes of primary lymphoedema provides a molecular diagnostic test for some of the subtypes. However, there are other primary lymphoedema subtypes for which the underlying genetic cause remains elusive. We predict that rigorous phenotyping in combination with recent advances in genetic analysis, e.g. next generation sequencing, will enhance the identification rate of new genes that cause primary lymphoedema. Accurate phenotyping requires a consistent approach to assessing patients, and the clinical pathway detailed here has proved fit for purpose. As with many genetic conditions, as we learn more about the genotype/phenotype correlations our understanding of these lymphatic disorders will evolve.
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
We would like to acknowledge the members of the Lymphoedema Research Consortium, UK. We extend our thanks to the patients and their families and the British Heart Foundation for funding the work of K. G. (FS/11/40/28739) and P. O. (PG/10/58/28477).
- Top of page
- Abstract
- Classification of primary lymphatic dysplasia
- Use of the classification pathway
- Conclusion
- Acknowledgements
- References
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Gardening When It Counts: Growing Food in Hard timesby Steve Solomon
Synopses & Reviews
Publisher Comments:
The decline of cheap oil is inspiring increasing numbers of North Americans to achieve some measure of backyard food self-sufficiency. In hard times, the family can be greatly helped by growing a highly productive food garden, requiring little cash outlay or watering.
Currently popular intensive vegetable gardening methods are largely inappropriate to this new circumstance. Crowded raised beds require high inputs of water, fertility and organic matter, and demand large amounts of human time and effort. But, except for labor, these inputs depend on the price of oil. Prior to the 1970s, North American home food growing used more land with less labor, with wider plant spacing, with less or no irrigation, and all done with sharp hand tools. But these sustainable systems have been largely forgotten. Gardening When It Counts helps readers rediscover traditional low-input gardening methods to produce healthy food.
Designed for readers with no experience and applicable to most areas in the English-speaking world except the tropics and hot deserts, this book shows that any family with access to 3-5,000 sq. ft. of garden land can halve their food costs using a growing system requiring just the odd bucketful of household waste water, perhaps two hundred dollars worth of hand tools, and about the same amount spent on supplies andmdash; working an average of two hours a day during the growing season.
Steve Solomon is a well-known west coast gardener and author of five previous books, including Growing Vegetables West of the Cascades which has appeared in five editions.
Discover forgotten low-input food gardening methods for surviving uncertain times ahead.
Applicable to most areas in the English-speaking world except the tropics and hot deserts, this book shows that any family with access to 3-5,000 square feet of garden land can halve their food costs in most climates using just the odd bucketful of household waste water, a few hand tools, and a few hundred dollars per year spent on supplies and seeds - working just an average of two hours a day during the peak growing season. Helpfully illustrated, it covers a host of material including: vegetables ranked by how difficult they are to grow; root systems as the key to gardening mastery; seeds, spacing and irrigation; home made organic fertilizer that really works; how to choose, use and sharpen hand tools; compost making, root-cellaring and irrigation; and chemical-free handling of insects and diseases.
Designed for readers with no experience, yet an eye-opener for even the seasoned gardener, Gardening When It Counts returns the backyard food garden to center stage for uncertain times ahead.
The Decline of Cheap Oil and the threat of harder times to come is prompting people to grow more food themselves. But currently popular intensive vegetable gardening methods depend on cheap oil, requiring high inputs of water, fertility and organic matter. Prior to the 1970s, home food growing used more land because wider plant spacing reduces the need for irrigation and requires lower levels of soil fertility to be productive - and well-spaced plants can be weeded rapidly and conveniently with hand tools while standing upright. But these efficient systems have been largely forgotten. Gardening When It Counts helps readers rediscover these traditional low-input gardening methods in their quest to produce healthy and affordable food.
About the Author
Steve Solomon is a well-known west coast gardening guru, and author of five previous books. The founder of Territorial Seed Company, he has taught Master Gardener and Urban Farm classes at the University of Oregon in Eugene. His book, Growing Vegetables West of the Cascades has appeared in five editions.
Table of Contents
The coming hard times — Getting land — Becoming a vegetableatarian — What is a vegetable? — Helping plants grow — Increasing soil fertility — Tools and tasks — The basic three and a file — How to start a new garden — Raised beds and raised rows — The bow rake — Restoring a raised bed for planting again — The hoe — Miscellaneous tools — Care of tools — Garden centers — Transplants: Buyer beware — Growing your own seedlings the easy way — The garden center seedrack — Seeds — The mail-order seed business — Who to buy from — Making seeds come up — Saving on seed purchases — Growing your own — Watering ... and not — Four spacing systems — Not suffering drought — A gardener's textbook of sprinkler irrigation — Compost — Why compost? — Making low-grade compost — Medium-quality compost: The once-a-year heap — Humanure — Green manure and cover crops — Insects and diseases — Avoiding trouble — Insects and their remedies — Diseases and their remedies — What to grow ... and how to grow it — Some general tips — Crops that are easiest to grow — Crops that are harder to grow — Difficult vegetables.
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Encrypting Email with KMail, Mozilla Thunderbird, and Evolution
The leading email applications include new features for helping users secure and authenticate their mail messages, but each tool has a different approach to handling tasks such as signing and encryption. This article describes how to add encryption and digital signatures to the Thunderbird, Kmail, and Evolution mail clients.
Spoofers have an easier time on the Internet than anywhere else. There's no need to forge a signature to dispatch mail under someone else's name; all you need is a spoofed entry in the From header. The mail protocol does not provide any kind of protection against this kind of manipulation. If you want the people you write to to be able to rely on the authenticity of your messages, you should get into the habit of signing your email messages. The same thing applies to encryption: or would you really want a curious mail server admin reading your letters? Anyone with access to one of the computers that relays mail between your outbox and the destination could theoretically read your messages. GNU Privacy Guard (GnuPG) [1] is a program that protects your messages against monitoring and manipulation. GnuPG is a cryptographic system that uses asymmetric keys. For the user, this means having two keys, a private key and a public key, which are generated as a key pair. The passwordprotected private key is kept secret.
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Dyreza Malware is Back
Powerful man-in-the-middle attack is now targeting online shopping.
Kernel Developer Matthew Garrett Forks the Linux Kernel
Another high-profile coder says the kernel team needs a kinder, gentler culture.
Bugzilla Bug
Bug database has a bug of its own that could allow an intruder to create an unauthorized account.
US Launches New Strategy for Broadband Access
Report focuses federal resources on achieving universal Internet access.
RC4 Finally Gets the Fork
Leading browser makers say "no" to porous encryption algorithm
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Report from the X-Force group says attackers are using TOR to hide their crimes
Mozilla Announces new Firefox API
Future Firefox extensions will be compatible with Chrome.
Weird Security Flaw Affected Intel Chips for 16 Years
Better read this if you bought your computer before 2011
OpenSSH 7.0 Secure Shell Arrives
Users should upgrade to the new version as soon as possible
Qemu Flaw Lets the Guest Escape
Xen project announces a privilege escalation problem for Qemu host systems


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On April 14, Lowe's Companies Inc. reported that it has begun using hydrogen fuel cell forklifts at the company's new distribution center in Rome, GA. The retailer began using 157 lift trucks fueled by hydrogen after piloting the technology in warehouses in California and Connecticut.
The lift trucks are supplied by Plug Power, which has deployed thousands of units across the country in warehouses and distribution centers. The lift trucks take only three minutes to refuel and saves valuable warehouse storage space normally reserved for battery swapping and charging.
For a link to the full article, click here.
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The Patented blade system incorporates the stapler€™s driver blades into the cartridge. The most crucial wear parts for the stapler are than replaced every time you change cartridge.
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|Quantity: 5000 Per Box
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|Leg Length: 19/64 In
|Country of Manufacture: Sweden
About the ManufacturerFor more than sixty years, ELMER'S PRODUCTS, INC. has been providing creative adhesive solutions that support project success and turn ideas into reality. By continuing to develop innovative new products, Elmer's has become the trusted brand when it comes to fueling creativity and providing outstanding product performance in the classroom, at home, in the workshop and at the craft table. At Elmer's, they inspire people to create, build and learn for life.
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iHerb Customer Reviews
Very good D3 supliment
8 people found the following review helpful
Posted by Reviewer1838781 on Dec 07, 2009
Here in finland we need D-Vitamin supliment,and this HO's 360 5000IU softgels is about years consume for 1 person. They came packed very well and the softgels are good quality.
Excellent value
5 people found the following review helpful
Posted by Reviewer1234602 on Feb 22, 2010
These softgels represent excellent value and are much cheaper than the equivalent in the UK even with the delivery charges. This was my first order from iHerb and I was very impressed with the service - I placed my order on a Tuesday afternoon UK time and it was delivered to my door on Thursday morning! I used the DHL courier option, which was well worth paying the $10 for. The product is good, too - the softgels are easy to take and, after six weeks, my Vitamin D levels have gone from very low (18 ng/ml) to well within the normal range, although I have to admit that I switched to the 10,000IU version after a couple of weeks, as this was the amount I wanted to take on a daily basis, so it made sense to take only capsule instead of two. However, now that I have got my levels up to where they should be, I will be switching back to these softgels for the rest of the winter.
Works Very Well for Me
5 people found the following review helpful
Posted by Reviewer1204206 on Mar 23, 2010
I am deficient in Vit D3 and have had a holistic endocrinologist recommend that I take 10,000IU daily for osteopenia along with 1200mg of Calcium (not carbonate). I just had my D3 levels checked and was within the range. I believe the product is working as it should.
Positive feelings
5 people found the following review helpful
Posted by Reviewer2701481 on Dec 01, 2009
Just after three weeks I find it easier to get up in the mornings. Even if I haven't slept much because of my little kids (and their nightcries...). Maybe some first signs of growing energy levels are visible too, but it's too early to make final judgements yet.
Love this product.
7 people found the following review helpful
Posted by Reviewer1589454 on Feb 05, 2010
I love this product. I had never had my vitamin D level checked, and had not been to a "regular" doctor in a very long time since adopting a more healthy lifestyle, because I have been so well. So I decided to have a routine checkup, and the doctor said he almost never sees such a good Vitamin D level on anyone. So I guess this product works because it has been the only Vitamin D I have been using. Good price too.


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State Funeral Held For Hugo Chavez In Caracas
People watch a live broadcast of the funeral for Venezuelan President... News PhotoBroadcasting,Caracas,Diplomacy,Funeral,Government,Horizontal,Hugo Chávez,Human Interest,Military,People,Politics,VenezuelaPhotographer Mario TamaCollection: Getty Images News 2013 Getty ImagesCARACAS, VENEZUELA - MARCH 08: People watch a live broadcast of the funeral for Venezuelan President Hugo Chavez outside the Military Academy on March 8, 2013 in Caracas, Venezuela. Countless Venezuelans have paid their last respects to Chavez and more than 30 heads of state were expected to attend the funeral today. (Photo by Mario Tama/Getty Images)


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Dr. Jeffrey Wayne graduated from the Boston University School of Medicine in 1992. He works in Chicago, IL and 1 other location and specializes in Surgical Oncology. Dr. Wayne is affiliated with Ann & Robert H Lurie Childrens Hospital Of Chicago and Northwestern Memorial Hospital.
Surgical Oncology
Medical School: Boston University School of Medicine; Graduated 1992
*This physician has multiple office locations. See Office Information for details.
675 N Saint Clair St Ste 250
Chicago, IL 60611
675 N Saint Clair St Ste 21-100
Chicago, IL 60611
675 N Saint Clair St Ste 21-100
Chicago, IL 60611
900 W Nelson St
Chicago, IL 60657
2913 N Commonwealth Ave Fl 5
Chicago, IL 60657


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"Proud to be different" is the motto of Breed Watches, a Michigan-based company that designs a timepiece for every style and personality type. For aspiring aristocrats, the Gatsby chronograph watch features a polished surgical-steel body, Art Deco-style numerals and a crocodile strap; for the rebellious, the Swiss quartz Lacan and Alpha models emphasize the numbers 4, 8, 10 and 12 instead of the usual 3, 6, 9, and 12. Is German design your thing? Check out the Gunar, which features a square-shaped watch face and a practical date indicator. It's not just the little details that distinguish Breed watches from the pack: their durability, versatility and luxe quality ensure that they, and you, attract attention.
Shades with style, by Oliver Peoples, Ray-Ban, Super, and more top eyewear brands
These sturdy timepieces with artfully crafted cases will no doubt grab the attention of onlookers. The solid yet elegant Lucan, Arnold and Alpha models emphasize the numbers 12, 8, 10 and 4, instead of the usual 12, 3, 6 and 9. But it's not just the little details that separate these watches from the crowd—their durability, versatility and luxe quality ensure that they, and you, stand out.
Bold timepieces featuring precise movements and durable construction
Where precision movements, bold accents, and rubber straps meet your wrist.


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Tuesday, June 17, 2008 10:37 pm
MONROE - Mildred Jones Little, 95, died Friday, June 13, 2008 at Monroe Rehabilitation and Nursing Center. Funeral services were conducted Tuesday, June 17, in the chapel of Bright Funeral Home, Wake Forest. Burial followed in Wake Forest Cemetery.She was born in Franklin County, daughter of the late Henry L. and Nora Wheeler Little. She was a long-time resident of Wake County before moving to Monroe in 1999. She was retired from American Credit Company.Surviving: one sister, Evelyn Little Brinkley of Monroe; a host of nieces and nephews; and great-nieces and nephews.Memorials may be made to Flat Rock Baptist Church, 1529 Flat Rock Church Road, Louisburg, NC 27549.


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Packers Could Be Thin Up Front in the Opener with Suspensions
Packers defensive end Datone Jones only got a one game suspension for his violation of the league's substance abuse policy, but the Packers are likely going to be short more than one lineman for that game...
Andrew Quarless Arrested for Discharging Gun in Public: Latest Details, Reaction
Green Bay Packers tight end Andrew Quarless was arrested in South Beach early Saturday morning after firing a gun into the ground twice following an altercation...
Quarless Arrested in Miami for Discharging a Firearm in Public
It's not really a holiday weekend in Miami until a professional athlete gets arrested in South Beach. So get those Fourth of July firecrackers ready because early this morning, Green Bay Packers tight end Andrew Quarless got the weekend started...
Big Toe Woes Can't Stop Packers' Sitton
Letroy Guion's Agent: No Basis for New Civil Suit Against Packers' DT
Green Bay Packers defensive tackle Letroy Guion is facing a civil suit over a 2013 altercation in which no criminal charges were filed...
Green Bay Packers: Full Position Breakdown, Depth Chart Analysis at Nose Tackle
The nose tackle position went from being one of the Green Bay Packers ' most glaring weaknesses at the onset of free agency to one of their biggest strengths after the team re-signed B...
Green Bay Packers WR Jordy Nelson Voted No. 18 on NFL Network's Top 100
Time to Step Up: Green Bay Packers QB Scott Tolzien
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Packers' Datone Jones Suspended One Game
The Green Bay Packers will open their season without the services of Datone Jones. The NFL announced Thursday that the third-year pass rusher has been suspended without pay for...
Packers DL Datone Jones Suspended for 2015 Regular Season Opener
#Packers DL Datone Jones has been suspended for the first game of the 2015 regular season for violating the NFL 's substance abuse policy...
Packers Have Leapfrogged Seahawks as Super Bowl Favorites
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Training camp is less than a month away, and the Green Bay Packers still don't know whether Letroy Guion will be suspended for the start of this season...
NFC North Q Who Would You Rather Have, Brett Favre or Aaron Rodgers?
They each have one Super Bowl victory in their spectacular careers. But which quarterback would you rather have, Brett Favre or Aaron Rodgers ?.....
Time to Step Up: Green Bay Packers TE Andrew Quarless
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Making the Leap, No. 12: Davante Adams
Rajion Neal vs. John Crockett: Which Player Will Be Packers' No. 3 RB in 2015?
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Setting Realistic Expectations for Each Green Bay Packers Rookie
The Green Bay Packers are one of the best teams on which first-year players could land: Not only does general manager Ted Thompson usually keep all his draft selections past final ...
Why Davante Adams Will Have a Breakout Year in 2015
Datone Jones Wants to Show Packers Why He Was Worthy of 1st-Round NFL Pick
In a way, Datone Jones is happy that he's yet to become a full-time starter along the Green Bay Packers ' defensive line.....
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The Green Bay Packers started to tear down three homes near Lambeau Field Monday, continuing the team's efforts to clear property it owns near the stadium for future development....
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It seems to be the case every year: There are so many talented and high-upside players on the Green Bay Packers ' offseason roster, and so few spots for them on the 53-man roster...


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Burning too many calories a day from walking. Can'...
Hello, all! I'm a 28-year-old male, 5'6'' at 176 lbs trying to get down to the 115-155...
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Hello, all! I'm a 28-year-old male, 5'6'' at 176 lbs trying to get down to the 115-155 range. My weight has been static for a couple years now and I only recently learned through webmd that it's probably due to a calorie deficit. You see, I suffer from a severe anxiety disorder that has resulted in my only ever working part time and never having a driver's license (currently working on both, but it''s a very slow process). As such, I don't have a lot of money for food and have historically eaten about two decidedly unhealthy meals a day, usually value menu fast food stuff.
I'm now getting extra food money from my dad and can afford to eat much more healthy stuff and more of it, but the problem is, after years of eating so poorly I simply don't have the appetite to consume the 1,900 calories a day the webmd recommends (BEFORE fitness is factored in. The "sweet spot" is around 1650 after exercise). To top it off, I am an extremely hyper person who can barely tolerate sitting still for more than a half hour or so. This, coupled with my lack of transportation and a library job that has me on my feet most of the day means I burn anywhere from 700 to 1,000 calories a day just walking (according to the pedometer on my phone).
So what can I do? Walking less is simply not an option as I have too much energy and being sedentary for too long is mentally unbearable. And I worry that if I exercise more, either with more vigorous cardio or strength training (I can barely pull off 8 push-ups) that it'll only make my deficit worse. It seems like all I can do is eat more, but that becomes a chore and physically challenging given my low appetite. Any advice would be greatly appreciated.
Thank you!
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Burning too many calories a day from walking. Can't imagine consuming much more.
Hello, all! I'm a 28-year-old male, 5'6'' at 176 lbs trying to get down to the 115-155...
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Creamy Avocado Zucchini noodles
Friday, 23rd October 2015
Making courgette noodles is a fantastic replacement to pasta when your after something a little lighter, and as it's grain free it makes you feel amazing no matter how many allergies you may have!
Inside the Happy bread Company
Thursday, 22nd October 2015
We asked Karen from the Happy Bread Company to give us more details about her delicious fermented, gluten free and organic bread.
TEATOX: Coconut Balance Ice tea
Wednesday, 21st October 2015
Winter in the Raw with Tanya Maher
Tuesday, 20th October 2015
Join us on Tuesday 20th October at Planet Organic Westbourne Grove for an evening with Tanya Maher. She will be talking about raw food this winter and she will demo few recipes!