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To play Geometry Dash on your Android device is very simple and easy. But you must know that it is available in premium version. But, if you download Geometry Dash Apk then easily you will get this paid app for free. In actual, Geometry Dash is a joyful game first released in 2013 by Sweden-based developer Robert Topala. This game was initially introduced by Robert's own company RobTop Games. Each game level has unique music as well as an extraordinary background. To control the game, simply you need to tap and click.
Currently, Geometry Dash Apk has 21 different levels and over 30 million online levels. This sounds quite interesting right with astounding rhythmic as well as a unique background. We guess the users are enjoying grinning cheerfully when playing this app. The main motive of this game is by winning the level until the end. You can jump and fly through dangerous ways while playing Geometry Dash game. Flip jump and prepare for the rhythmic based game and just win over the entire level. More details are mentioned in the below section with some downloading and installing step.
Information about Geometry Dash App: V2.121
Geometry Dash is a single-player square game and its main objective is to complete the level. But, if you as a player gets killed then automatically you need to start from the beginning itself. And from the starting itself, all the official levels are open to the gamers so that you can play them efficiently. However, in each official level, the main player can accommodate and collect three coins. But they are not available easily as some are scattered and some are hidden. So, you yourself have to find them out by playing. However, if you complete any level then you will be awarded icons or colors. As this app is available for iOS as well as Android, Microsoft Windows and Mac we have ways to download the Apk of Geometry Dash App.
Geometry Dash Apk – How to Download?
As per our concern to download Geometry Dash App is a very simple process. All you require is a proper internet connection.
- For downloading the Geometry Dash Apk, Click Here.
- If you want to go for a long process then first visit Google and type Download Geometry Dash Apk.
- Instantly, Google will provide you some results. You will see so many Apk file available, click on the genuine Apk file.
- Now, tap on the Download icon and wait for the downloading to get fully completed.
- Downloading is over.(Notification message is shown on the screen)
This is the simple process of downloading. At the most basic level, this game is also available in Google Play Store. Now, let us help you with installation step.
Note: (Do remember that Geometry Dash Apk is a third party application. And before installing the third party app, you must modify some changes on your Android device i.e, Allow Unknown Sources. For that very cause, visit Device Settings and then Security Settings and followed by Unknown Sources).
How to Install Geometry Dash Apk?
- Right after downloading, before installation, you need to allow unknown sources enabled.
- Now, locate the file on your device and hit the Install button.
- Tick the I Agree on the button and allow installation.
- Finally, installation is completed.
With this, we completed installing Geometry Dash Apk. As this Square boy always eager to win the level, let us see what he can do with some amazing features.
- It supports many levels with many unique rhythmic tracks. Know that you do not need to unlock those levels as they are already open so that you do not require going orderly.
- The app is available for free and you will also not find any in-app purchase while playing the game.
- Using the level editor, build as well as share your level via your friends.
- While playing when you meet success, it allows you to celebrate with lots of achievements and rewards.
- To bring a new look to your Square boy, unlock new icons and colors.
- It allows you to ride Square boy rocket from the dangerous passages.
With very easy and simple levels, Geometry Dash is a mind-blowing app for Android device. Even if the challenges are difficult you can still enjoy playing this addictive game. So, if you want to avail the game for free then download Geometry Dash Apk format. With so much fun and enjoyment, you can win over the level and earn rewards as well as achievement. Of course, if you fall down you need to start the level again. This will make your mind constant to win the challenge. We appreciate your struggle to download this game and with free services, one can never believe how cool this game is.


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Michael Pignone, MD, MPH; Russell Harris, MD, MPH; Linda Kinsinger, MD, MPH
Rates of colon cancer screening in the United States are low, in part because of poor communication between patients and providers about the availability of effective screening options.
To test whether a decision aid consisting of an educational video, targeted brochure, and chart marker increased performance of colon cancer screening in primary care practices.
Randomized, controlled trial.
Three community primary care practices in central North Carolina.
1657 consecutive adult patients 50 to 75 years of age were contacted. Of these, 651 (39%) agreed to participate; 249 of the 651 participants (38%) were eligible. Eligible patients had no personal or family history of colon cancer and had not had fecal occult blood testing in the past year or flexible sigmoidoscopy, colonoscopy, or barium enema in the past 5 years.
The 249 participants were randomly assigned to view an 11-minute video about colon cancer screening (intervention group) or a video about automobile safety (control group). After viewing the video, intervention group participants chose a color-coded educational brochure (based on stages of change) to indicate their degree of interest in screening. A chart marker of the same color was attached to their charts. Controls received a generic brochure on automobile safety, and no chart marker was attached.
Frequency of screening test ordering as reported by participants and frequency of completion of screening tests as verified by chart review.
Fecal occult blood testing or flexible sigmoidoscopy was ordered for 47.2% of intervention participants and 26.4% of controls (difference, 20.8 percentage points [95% CI, 8.6 to 32.9 percentage points]). Screening tests were completed by 36.8% of the intervention group and 22.6% of the control group (difference, 14.2 percentage points [CI, 3.0 to 25.4 percentage points]).
A decision aid consisting of an educational video, brochure, and chart marker increased ordering and performance of colon cancer screening tests.
Pignone M, Harris R, Kinsinger L. Videotape-Based Decision Aid for Colon Cancer Screening: A Randomized, Controlled Trial. Ann Intern Med. 2000;133:761–769. doi: https://doi.org/10.7326/0003-4819-133-10-200011210-00008
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Published: Ann Intern Med. 2000;133(10):761-769.
Cancer Screening/Prevention, Colorectal Cancer, Gastroenterology/Hepatology, Gastrointestinal Cancer, Hematology/Oncology.
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The average quality cosmetic products have made us confused about whether we should purchase these products or not. In fact, some people are now confused about purchasing products that are committed to providing extreme quality results for years. It's just because a few companies have ruined the names of other companies as well.
Well, there are consumers that are still purchasing the cosmetic products from top quality firms and they do not have any issue because they understand the process these companies use to maintain the quality of their products.
There are different kinds of tests that a cosmetic product needs to go through in order to get approved for the market. Most of the companies regularly run these tests in the factory because their product may get banned if they do not conduct these tests before sending them to the market. Today, we will talk about the tests that cosmetic products go through so that you may feel satisfied while purchasing a cosmetic product.
Performance testing, safety testing, stability testing, and micro-testing are the different types of tests a cosmetic product goes through. Let's take a look at the detailed information of these tests.
Microbial Testing
Contamination test and micro challenge testing are the two types of tests that come under this category. These tests are supposed to figure out that whether the product would stay safe from dangerous microbial growth or not. There are several preservative ingredients found in the cosmetic products that prevent the growth of dangerous microbes. Similarly, this test is supposed to find out that whether a product is contaminated or not.
Stability Testing
Cosmetic stability testing system is supposed to find out that whether the product will be able to survive in different circumstances or not. The weather may put an impact on the quality of the cosmetic product. This test helps you make sure that whether the product is perfect for different regions or not. It also helps you make sure that there won't be any kind of unsatisfactory factors when customers will purchase the product.
Safety testing
The safety testing is the most important part of testing as it helps you make sure that whether the product is safe for the customers or not. If the product doesn't pass this test, it won't get approved for the market. Therefore, the cosmetic companies pay a lot of attention to this test.
Performance testing
This test is supposed to find out that whether the product can produce the results according to the expectations or not. The cosmetic companies higher several professionals for this process. And ask them to provide their review of the performance of the product. Here is some other type of testing that cosmetic products go through.


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|TSO heading to Sells
The TSO will be performing for the Tohono O'odham Nation on May 1, 2010. The symphony's day-long residency in Sells will include a TSO String Quartet recital for the Nation's elders at the Archie Hendricks Senior Skilled Nursing Facility, a TSO Wind Quintet "Just for Kids" concert for children too young to attend the evening concert, and an evening performance featuring the entire TSO.
On the program for the evening concert will be TSO Concertmaster Aaron Boyd, performing Mozart's Violin Concerto No. 5, as well as Dvorák's Symphony No. 6 and the overture to Mozart's "Marriage of Figaro."
The TSO's appearance is made possible through a partnership between the orchestra and the Tohono O'odham Nation Cultural Center and Museum, along with support from the Tohono O'odham Senior Services Department, the Sells Recreation Center (Tohono O'odham Nation Education Department), the Archie Hendricks Senior Skilled Nursing Facility and the Indian Oasis-Baboquivari Unified School District. Please read the TSO press release for more information.
UPDATE: The orchestra had a wonderful time performing for the Tohono O'odham community. We were touched by their hospitality, and hope to have the honor of performing for them again in the near future. Please see the Arizona Daily Star article for more about the TSO's trip to Sells.


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Rebecca Hall made her New York stage début, in 2005, at the Brooklyn Academy of Music, playing Rosalind in "As You Like It," and if you were lucky enough to see her in the role it is unlikely that you have forgotten the experience. Hall, who was twenty-three at the time, exquisitely conveyed the sometimes tremulous combination of knowingness and naïveté that characterizes Rosalind, Shakespeare's most winning comic heroine. Hall's performance felt perfectly naturalistic—her Rosalind was absolutely real and present—and, at the same time, her delivery showed an adept grasp of Shakespearean verse: if you knew and loved Rosalind's lines, it was thrilling to hear the subtlety with which Hall delivered them. It also did not hurt that Hall looked perfect for the part: like Rosalind, Hall is "more than common tall," which meant that she was able to stand eye to eye and equal to equal with Orlando, her eventual beloved, played by a promising newcomer named Dan Stevens.
The production also showed the mastery of its director, Sir Peter Hall, the founder of the Royal Shakespeare Company, the former head of London's National Theatre, and Rebecca Hall's father. Given Shakespeare's dramatic fascination with the relations between fathers and their offspring, and with the complicated questions of lineage and inheritance, the casting choice looked less like nepotism and more like a fruitful artistic convergence. "My father was a real Shakespearean fascist, in that he had a view about how it should be done, in terms of how you speak the verse," Hall recalled recently. "But, at the same time, he taught me that, instead of being restrictive, understanding how to play the verse gives up the meaning. Like, if you have a breath at the end of a line and the sentence isn't complete, then you've got to find a reason why there's a pause for thought there. And your reason is what gives you interpretation. So within those parameters, he gave me complete freedom." Hall's key to unlocking the character of Rosalind was in identifying the character's trepidation—the fear experienced by someone who is cognizant of the demands entailed by the complexity of adult love, and finds herself on the brink of it for the first time. "Isn't that, on some level, the experience of first love, and isn't that what the whole play is about—how terrifying it all is?" Hall said.
More than a dozen years after that arrival in Brooklyn, Hall, who turned thirty-five this spring, is now a full-time resident of the borough: she lives in Brooklyn Heights, with the actor Morgan Spector, her husband of nearly two years, and the couple's two cats, whom Hall can sometimes be seen walking with along the neighborhood's leafy streets. One of them is leash-trained, and will pad down the sidewalk wearing a harness. The other prefers to be carried in a Japanese hoodie designed specifically for toting a pet, with a kangaroo pouch in front and pointy ears on the hood—a gift from Stevens, who is now a Brooklyn neighbor. "I'm very aware that it's sort of an eccentric thing to do, and I love the eccentricity of it," Hall told me. Hall and I spoke not in Brooklyn but sequestered in the aseptic luxury of a suite at the Four Seasons Hotel in downtown Manhattan—rented for the day by the producers of "The Dinner," a promising-on-paper, forgettable-in-actuality movie that was released last month. Hall was awaiting a "glam squad"—movie parlance for a hair-and-makeup team—to prepare her for television interviews later that afternoon.
She was not, it is worth pointing out, entirely lacking in glamour even before the squad arrived, as she poured the fussy cucumber-flavored bottled water with which the room had been supplied, made an ironical face, and sat cross-legged on the couch in jeans and a sleeveless T-shirt. Hall has become best known to American audiences not for her work on the stage but on the screen—the kind of work that gets you a glam squad and a Manhattan suite for the afternoon. (Though not, as Hall noted with some chagrin, for an overnight stay). Last year, she won acclaim for her performance in the title role in "Christine," a drama about Christine Chubbuck, the television reporter who took her own life on camera, in 1974. She was nominated for a Golden Globe, in 2008, for her winning turn in "Vicky Cristina Barcelona," Woody Allen's Catalan comedy. In between, she's appeared in a wide variety of roles, in movies ranging from excellent ("Frost/Nixon," in which she played Caroline Cushing, David Frost's girlfriend) to mediocre (like "Transcendence," in which she played the wife of an artificial-intelligence expert enacted by Johnny Depp). Writing in the Times of her performance, Manohla Dargis called Hall "one of those actresses who always seem smart even in dumb roles." Hall acknowledges the hazards of casting. "It's not easy to get roles that are satisfying," she said. "And, even when you get ones that you think are going to be satisfying, there is no guarantee that they are going to continue to be satisfying throughout the film, and indeed then when you see the film."
This month, she returns to the New York stage—a perhaps slightly more predictable environment—in a production of a new play, "Animal," by the British writer Clare Lizzimore. It would be spoiling the plot to say much more than that Hall plays a woman who fears she may be losing her mind. It's a demanding role: Hall is onstage for the entirety of its ninety-minute length, and the part requires her to course along a wide emotional range, from playfulness to supplication to anger. It's the first time that Hall has performed in New York since 2014, when she made her Broadway début, in a revival of Sophie Treadwell's "Machinal." (She met Spector in that production; he played her lover.) "Animal" is, she says, "a short, sharp shock of a play." When we spoke, she was about to go into rehearsals. "She's a very idiosyncratic character," Hall went on. "She is very mentally dexterous, and she is also full of rage, and it is also a real expression of female rage, which I find quite potent. I think it's going to be hard."
Hall grew up in the theatre, often quite literally. Her mother, Maria Ewing, is an internationally known opera singer. When Hall was born, her father had been the director of Britain's National Theatre for almost a decade, overseeing its controversial move from the Old Vic into its current home, on London's South Bank. "There's a very funny picture of my father trying to do what looks like change my nappy on the desk of the National Theatre, while being on the phone dealing with all that—the strikes, and all the criticism," Hall said. Sir Peter, who is eighty-six, is now ailing from dementia. To celebrate his eightieth birthday, the National invited him to direct "Twelfth Night," in which Rebecca took the role of Viola. While Hall had strenuously tried to be just another actor for her father in "As You Like It," performing in his "Twelfth Night" was a very different story. "That was totally about doing something that I knew he really wanted to do, and it was very emotional as a result," she said. The usual question that might be asked of the creative person—did you always know you wanted to do this?—does not even apply in Hall's case. "I know that's the privilege of the family I was born into," she said. "It's not a question of 'Oh, I would really love to do that,' it's more a question of 'I am one of those people. I am that, too, so I am going to do that, too.' The relationship to the dream is much more simple."
As a child, Hall lived in the shadow of her parents' lives on the stage. "I remember being taken to dinner parties when I was very small, and being allowed to stay up very late just to sit and listen to people," she said. "I remember sitting in rehearsal rooms and going to performances, and I remember noticing the way people looked at my father and mother, and noticing there was a sort of a level of importance or gravitas—that the energy changed when they walked into the room." She was frequently backstage when her mother was performing. "I often had free rein when she was onstage, and if I was in the theatre I would run around in the foyers and then run into the auditorium and peek to see where they were," she said.
Hall's parents divorced when she was seven or eight, but not before Sir Peter had directed Ewing in a daring production of "Salome," a role Ewing would continue to perform for a decade. "I couldn't not watch the last three minutes of that, where she gets smashed to death," Hall told me. "The way it was choreographed was that soldiers would all run together in a circle, and she would be in the middle, and she would jump up through the middle and contort her body, so it looked precisely like she was being crushed to death. Every night, I forced myself to watch. You know the way you have childlike superstitions: if I don't watch it, that would be the moment when she actually gets hurt." The production was also notable for the fact that Ewing's Dance of the Seven Veils ended in complete nudity: "She said it would be vulgar if you put on a bikini, and that what is not vulgar is the female form."
Hall's upbringing was bohemian and somewhat chaotic: "Like, how's she getting to school, has she been to the dentist, has she done her homework—that kind of stuff. I don't think either of my parents ever asked me that," she said. Her older siblings—there were four of them, from Peter Hall's two earlier marriages—had all gone to arty boarding schools, but, because Roedean was conveniently located close to her mother's home, Hall went at the age of fifteen to that institution, favored by aristocrats and the conservative élite. Ultimately, she became head girl. The school "was very sure of its place in raising young girls to go out and be great career women; and then there was this other side of it," she recalled. One Speech Day—an annual end-of-year ceremony, with distinguished guests and prizes for the best students—a teacher stopped Hall in the corridor. "She said, 'You've got to stop looking so sloppy, pull your socks up. This will be the most important day of your life, apart from your wedding day.' " Other teachers gave better advice that still resonates, particularly about the need to read ambitiously. "There was one who said, 'There is nothing wrong with being pretentious. Pretentious is often the place you have to start if you want to get somewhere else,' " Hall said.
Surrounded by titled young ladies, Hall was something of a class oddity. Though her father was knighted in the nineteen-seventies, for his services to the theatre, he came from more humble circumstances: his own father was a stationmaster. Her mother grew up in a working-class family in Detroit, discovering her gift for opera by singing along as her father played piano. Ewing's father, a doorman at a hotel, was African-American and possibly Sioux, and married to a woman of Dutch descent; it appears that he passed as white when Hall's mother was a girl, living in a working-class white neighborhood. (He died when Hall's mother was sixteen.) "She catapulted herself out of a biracial, impoverished, confusing situation, into this high-art world, as my father did on some level," Hall said. "And I sort of feel that in me. Neither of them fit into some sort of class mold. When I did hang out with these people who did operate in those worlds, I did feel slightly observational. I don't know where me and my family fit in."
In her teens, Hall flirted with not being an actor—she thought of following a career in the visual arts, and remains an adept painter, as is occasionally evidenced by her Instagram feed. "My husband laughs at me, because I have to be doing several things to incubate one thing," she said. "There's a sort of trail between my desk, where I think about things, and the piano, where there will be some open music, and another area, where I will have some drawing up, and I will dock between those three things." But there was never really any doubt that she would act. Hall did not go to drama school: she already knew how a rehearsal room worked, and needed no help finding an agent or making contacts in the world of the theatre. She'd already worked as a professional actor, at the age of ten, in a television drama, "The Camomile Lawn," which her father directed. "And I didn't want to be given a system of coping mechanisms to deal with how awful it all is," she said. "My father was a huge influence in that respect. He always said to me, 'If you want to be a good actor, acting holds everything.' It's the art form of interpreting human behavior. So one of the things that will strengthen that ability to do that is engaging with your mind. That means reading books, that means looking at art, that means interpreting the world analytically and having an analytic involvement with life."
She enrolled at Cambridge University to study English Literature, in which she had specialized in high school. As a wedding gift, she gave Spector a trousseau of canonical British books that he had never had occasion to read: "The End of the Affair," "Sons and Lovers," "The Rainbow," "Persuasion," and George Eliot's "Middlemarch"—the fact that he had failed to read the last, she said with a laugh, "nearly derailed my marriage." When I told Hall that she would have been the ideal actress to play Dorothea Brooke, the serious, ardent heroine of "Middlemarch," she told me I am not the only one with that notion: Sam Mendes, with whom she was in a relationship for several years before marrying Spector, had hoped to adapt the novel to the screen. There had even been a script that she'd read, but for one reason or another it never came together. "I went through my twenties praying that someone would make a 'Middlemarch' film," she said. "And now I am too old, probably. I would have loved it." (Mendes did direct her onstage, in "The Cherry Orchard" and "The Winter's Tale," which played in an ambitious double bill at the Old Vic in London, and at BAM, in 2009.)
At Cambridge, Hall spent much of her time in student theatrical productions—she first met Dan Stevens when she was cast opposite him in "Macbeth"—but left Cambridge two years into her three-year degree. "The trajectory of 'head girl from Roedean School, degree from Cambridge' suddenly felt really undesirable," she said. "I thought, If I can buck this and walk away from this, then, A), I will have no other option—that I will have to be an actor, in other words. And B), I won't have a sort of shorthand calling card that proves my intelligence. I thought that, if I have the strength to walk away from this thing that everybody wants, and is so wonderful, maybe I will have the strength to make those bold decisions for the rest of my life." Not having a Cambridge degree, she says, provides her with an impetus to keep learning. It leaves her with something still to prove.
These days, Hall is attempting to expand her artistic horizons: "I feel I am coming into my own in lots of ways, and that I can step beyond just doing the acting, and feeling more confident showing the world that I can write, and thinking about directing," she says. She is working on an original script, and has recently tried to write a play. She's also adapted as a screenplay the novella "Passing," by Nella Larsen, the Harlem Renaissance writer, and is shopping it around with the hope of directing it, in part as a way of exploring her maternal grandfather's life and her own racial heritage. "Spending any time in this country, and living here, you just think, This question of race is so integral to the very heart and soul of everything this country is built upon," she says. "It's huge. And so I find myself thinking about it increasingly and wanting to engage with that history, whatever it is." She expresses a perhaps surprising desire to be on the show "Who Do You Think You Are?," in which celebrities have their genes publicly analyzed. "It seems like a fascinating story that doesn't benefit from being hidden," she says.
Marriage has granted her a kind of peace of mind, she says, and an expansion of her creative capacities. As a "well-educated child of divorce," she thought that she would never marry; she certainly thought she would never marry another actor. "And then it came up, and it felt, like, absolutely that's what I want," she said. "If you are born of things that are disparate, and you are a bit nomadic and your life is a hodge-podge of beautiful, loving chaos, you can end up going through a large chunk of your life thinking that's what you need, or that is what makes you comfortable. And I feel really lucky that I had some sort of realization that, actually, I needed an anchor. And I got married, and I realized this is what I have been craving."
Spector plays Hall's husband in "Animal," and before the show started previews, at the Atlantic Theatre Company's stage on Sixteenth Street, the company rehearsed a few blocks away, on an upper floor of the Google building.* I stopped by one afternoon to watch them work. At first, Spector, who is bearded, with dark curly hair and saturnine features, was doing stretches on the floor in a corner, while Hall worked on a scene with another actor. Then they worked on a scene together: an intense confrontation, in which Hall was fey and fickle and furious by turns, while Spector stood on in helpless frustration. When a break was called, they leaned fondly against each other for a moment.
For the role, Hall had to switch between high heels and flat shoes. I had noticed when we'd talked in the hotel suite that on her ankle is a small tattoo: an inscription, she explained, in her own handwriting. It reads, "This above all:"—a fragment of a line from "Hamlet," spoken by Polonius, the pedantic adviser to the King, to his son, Laertes. (The rest of the line is more famous: "To thine own self be true.") "It's a useful reminder for me for a lot of reasons," Hall told me later, in an e-mail. The ink has blurred, and Hall said that she has thought of having it removed and redone. "Tattoos seem to be a good exercise in living with regret," she said. "But I love them, actually. I love the regret factor, too."
*This article has been updated to include the correct location of the Atlantic Theatre Company stage where "Animal" is in performance.


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In Steve's latest Guest Blog for the Q Source Resource, he recommends a process of PCB preparation for rework/repair.
Preparing PCBs (printed circuit boards) for rework or repair is a very important process. ACL Staticide has developed and manufactures an array of precision cleaners and surface preparation products, along with final finishing conformal coats to aid in this application. These products' primary focus is in the area of printed circuit board repair and OEM manufacture. Let's cover some key areas of PCB rework and repair using a two-step process for surface preparation and finishing.
In many instances of PCB repair, surface preparation with a pre-saturated wiper followed by treatment with conformal coating is the process of choice for reworking a board and getting it back into service.
With that in mind, ACL's 7600 IPA Wipers are perfect for surface preparation following repair. The 7600 is a pre-saturated wipe using a precise 70/30 blend of extremely pure, electronics-grade isopropyl alcohol blended with deionized water to prevent premature evaporation of the cleaning solvent. The solvent is added to the wiper in a cleanroom environment. These wipers use a non-woven Sontara® technology designed to be extremely low linting, even at the perforation. Available in a 100-wipes reclosable container (made of non-hazardous material), the 7600 product is perfect for final finishing work of any circuit board. It is great for removal of hand oils, conductive greases, carbonized soils, dust/dirt, light flux residues, and a variety of other soils.
A 2-wiper use process is recommended for general-purposed cleaning and hand wiping of larger components and various board surfaces. One wipe is used for initial cleaning of heavier residues, and a second wipe for final surface cleaning and finishing. All surfaces should be allowed to gently dry for one to two minutes, or dry using compressed air or a duster product like the ACL 8640 Turbo Blast Duster.
Following this process, the board is prepared and ready for application of surface protection like acrylic conformal coating. ACL's 8690 Acrylic Conformal Coating is the product of choice for protecting the PCB and all surface components from oils, moisture, and most soils. It is used following surface cleaning and preparation with the 7600 IPA wipers. ACL 8690 can be applied to the entire board surface. It is dry to the touch in less than 30 minutes and completely cures in 24 hours. It provides protection as well as heat resistance and contains a UV dye indicator so that the user can be sure the entire board and all components have been treated. ACL 8690 leaves behind a high-gloss cure (making it suitable for final presentation to the customer at contract manufacturers) and prepares the board for final installation.
This process of using both the 7600 wipes and 8690 conformal coating in conjunction with each other for final board preparation and final surface finishing prior to installation helps eliminate potential failures and damage to PCBS or devices. Please contact us with related questions or comments.
Thank you, Steve! That sounds like the way to go when preparing printed circuit boards. We look forward to your future articles.
For information about , or to order, any of the ACL products mentioned in this blog, please visit QSource.com. You may also contact us via email or phone at 800-966-6020 and we will be happy to assist you.
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text: 4 (4 oz.) Caramel Apple Tartlets The perfect choice for dessert or brunch! A delicious made-from-scratch pastry filled with freshly peeled apple slices and topped with real cream caramel. Have that homemade flavor like mom used to make. Individually wrapped. Simply heat in the oven or microwave and serve warm with ice cream for a delicious sweet treat. Nutritional and Ingredient Information Ingredients: Apples, Enriched Flour (Wheat Flour, Niacin, Reduced Iron, Thiamine, Mononitrate, Riboflavin, Folic Acid), Vegetable Oil Shortening (Palm and Modified Palm Oils), Sugar, Water, Corn Syrup, Glaze (Sugar, Agar Agar), Whipping Cream (Cream, Carrageenan), Modified Corn Starch, Eggs, Butter (Cream, Salt), Salt, Dextrose, White Vinegar, Concentrated Lemon Juice, Cinnamon, Modified Tapioca Starch, Natural Flavors (Milk), Blackstrap Molasses, Yeast, Enzymes, Caramel Color, Soy Lecithin Contains: Wheat, Egg, Milk, Soy


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Study Overview
The regional Bicycle and Pedestrian Study is intended to help establish a strategic vision for improving walking and bicycling opportunities in the greater Nashville region. That strategic vision fed into the Nashville Area Metropolitan Planning Organization's (MPO's) overall regional transportation plan and provide the basis by which future funding priorities of the MPO are established for bicycle and pedestrian accommodations within the Davidson, Rutherford, Sumner, Wilson, and Williamson counties, plus the cities of Spring Hill and Springfield. Study objectives included:
Major Findings
A complete set of design guidelines for bicycle and pedestrian infrastructure projects including cutting-edge design trends as well as traditional infrastructure and signage treatments.
1. Provide Facilities
Designate and implement a regional bicycle network of bicycle commuter corridors and community connections.
The Study received the 2010 Engineering Excellence Grand Award from the American Council of Engineering Companies Tennessee Chapter and the 2010 Best Project Award from the Institute of Transportation Engineers Planning Council.
Study Webpage
Executive Summary
Tech Memo #1 Regional Inventory
Tech Memo #2 Needs Assessment
Tech Memo #3A Objectives + Strategies
Tech Memo #3B Count Procedures Manual
Tech Memo #4 Project Evaluation Methodology
Tech Memo #5 Regional Priority List + Funding Options
Tech Memo #6 Policies + Programs
Tech Memo #7 Funding Toolbox
Tech Memo #8 Design Guidelines
Completion Date
Study Partners


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Tag Archives: Shorts
When I'm Itching My Bird
Family Game Night Review
I don't have the busiest schedule during a typical week, but there are certain days that I have less time than others it seems. I try my best to keep up with the films that I am constantly acquiring for my collection, but it is virtually impossible to do so. On nights where I really don't have time for a full-length feature, I count my lucky stars for short films! Tonight's viewing pleasure belongs to Nick Ferwerda's Family Game Night [...]
I Just Wanna Try it On
The Stylist Review
Hey guys… remember me? I know, I know. I've been m.i.a for quite a while now, but what better time to come back to all of you fine folks than… a random Thursday evening…? Anyway, time and day of the week aside, I am indeed back with another horror review and this time I am extremely excited. Why, you ask? Well, because I finally have, in my hot little hands, a copy of Jill "Sixx" Gevargizian's "The Stylist."
Claire (Najarra [...]
I Want What You Want
Call Girl Review
After a quick skim over some horror news and fan sites this morning, I ran across a podcast from not too long ago that featured an interview with Laurence R. Harvey who most fans now know from The Human Centipede II (Full Sequence). During this interview, of which I only listened to a fraction of, the show hosts and actor briefly discussed a horror short that Harvey had recently completed with director Jill Sixx Gevargizian. Not much was mentioned [...]
I Wish They Would Sleep Forever
Familiar Review
It always amazes me when filmmakers can make a short film that ends up being far more superior than most feature films that I watch. With the blending of multiple sub-genres and an overall fantastic production quality, so is the case with Richard Powell's amazingly entertaining short entitled Familiar.
John Dodd is a middle-aged man who is sick of performing the same routine, day in and day out. He is sick of his wife, his daughter, his entire existence. [...]
I Want These
Counter Parts Team Review
Patrick Rea's short film Counter Parts is already making noise winning "Best Short" at its very first screening. Counter Parts is reminiscent of a Twilight Zone episode and is executed flawlessly. The story revolves around two sisters with a bond, and an even deeper resentment.
Patrick Rea is no stranger to the genre either with many short films to his credit and the Lionsgate released Nailbiter. Counter Parts is well-crafted and does better in 10 minutes than most films [...]
That Nutjob's Hammer
Doll Boy Review
In August, when I went to Crypticon in Kansas City, I met a ton of people pushing independent projects. Among those people, I met a fella named Gary Cooper who helps run Slaughter Movie House. They screen and promote independent horror in a big way. He gave me some promotional material for a movie called "Doll Boy," which immediately peaked my interest. Unfortunately, they didn't have any copies of the DVD. It took me a few months to acquire the [...]


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Silos, Communication Breakdown and "I Don't Know What You Do"
It seems no matter what the size of the organization we work with, we typically hear these three complaints: "We work in silos." "We don't communicate well." "I don't know what you do." This seems equally true of an organization that has 30 employees relatively co-located or 30,000 employees spread across many sites across a large geography.
It can be a frustrating experience for leadership teams intent on breaking down those silos, improving communication across the organization and wondering why people just don't talk to each other to discover what they do to hear the same challenges emerge time and time again. Because these issues are not one off. They can't be solved with that being the end of the story. They need constant attentiveness.
There is no magic bullet. Ever. So, what is a leadership team to do? Keep these challenges in their sights and invest in the time and opportunities it takes to bring people together to talk to each other, to strategize together how to work across silos and be in conversations about what people do and how they contribute to the overall work of the organization.
We have been using Worldview Intelligence in a variety of settings with our clients. The program surfaces these age old complaints with a framework that provides a new lensof discovery, different language to enter into the conversations, a way to illuminate the hidden dynamics or patterns of behaviour within the silos and the organization overall and ways to think about a shared future that honours the individual workings of departments while making sure all are moving forward in alignment.
It is an iterative process. The same framework offers the opportunity for many different often interrelated explorations, including personal, professional, departmental or team, organizational and social systems.
The personal exploration is a leadership practice as individuals become aware of the lenses through which they see the world, work or community and learn how to invite other people to share their perspectives and influences on how they see the world. It is a heart centered exploration as people first turn curiosity and compassion inwards toward their own journey and then outward toward another. It invites genuine listeningand learning to really understand how life experiences, including day-to-day reality, are different. This is particularly true when people from different cultures are learning from and about each other and it is also true for what might be considered more minor differences like coming from a different community in the same city or region.
The professional exploration offers people the opportunity to understand how the views of their profession influence their own professional views. This includes everything from educational influences to the patterns and practices of the profession overall. It provides insights into communication challenges and points of tension with other professions or even within a profession. Within health care, for example, the different medical professions often experience points of conflict around scopes of practice and delivery of health care. Examining the worldviews of each of the professions offers insights and reminds people of the points of connection between them, offering new ideas, thoughts and strategies about how to communicate with the well being of the patient at the center.
The departmental and team explorations invite members of a team to reflect on the history of the department and team, even prior to the current composition of the team, how they think about and live into the future and the practices they use with each other and external to the team to get work done. It can illuminate how they treat each other and others outside the department, offering the opportunity to be intentional about their relationships.
When departments and teams share their worldviews with each other the resulting insights are often surprisingly dramatic and simple at the same time. The exploration surfaces things that can be blindingly obvious once illuminated but hidden until that time. Within an organization this could be the result of different leadership styles or perspectives on the future, it could be the lingering influence of conflictual relationships or any number of other scenarios. Across an organization, particularly one geographically dispersed, the location of a department or unit can have a significant impact on how they function and it is often unacknowledged until the system is mapped and explored.
Once departments or units across an organization share their worldviews with each other, the elements of a shared worldview can be elicited. The organization does not need a singular worldview, but worldviews across the organization should have elements that are common. An organization benefits from a diversity of views and learning how to draw out the greatest potential in addressing the issues and challenges the organization faces. The alignment across worldviews can be strategic and intentional as the organization moves forward on issues that are pertinent to its work and its future well-being.
Understanding what comprises the social systems of departments, units or the organization overall provides an opportunity to explore how to create consistent policies and practices across the organization that are also flexible enough to be responsive to local circumstances and influences.
When an organization takes the opportunity to collectively enter a worldview exploration, it also enters the conversation about how to work across silos, communicate more effectively because people are learning from and about each other and what they do. It is an iterative process. In one way it is simple. In another way it is difficult because it takes time, focus and strategic thinking to ensure ongoing attention to the age old issues. And it is important because these age old issues get in the way of getting work done.


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Avocado is rich in magnesium that reduces risk of excess belly fat, high blood pressure, high cholesterol and high blood sugar. Some of you might not know that you can also blend an avocado pit in your smoothie. It is packed with very good nutrients. It has the life force. It is very high Qi food! It's also the highest in soluble fiber. This soluble fiber binds to the fat and excess cholesterol. Then we can lower cholesterol and improve heart function naturally. We can improve the blood circulation by pulling out all the fatty deposits in our circulatory system with the soluble fiber of the avocado seed. Soluble fiber is very difficult to get in our diet. Oatmeal has some, but it cannot compare with the avocado seed. Any heart disease patient must eat the avocado including the seed. Avocados offer a generous supply of healthy fats, vitamin A, alpha-carotene, beta-carotene, and vitamin E. There are tremendous benefits to adding fresh avocado to your smoothie, it makes many of the nutrients in the other foods you eat much more easily absorbed. Vitamin A, vitamin D, vitamin E, vitamin K, alpha-carotene, beta-carotene, lutein, lycopene, astraxanthin, zeaxanthin, and calcium are all 50 to 1000 per cent better absorbed in the presence of fats from avocado. It is not necessary to use a lot of avocado to enhance absorption of fat-soluble nutrients. As little as 1 teaspoon of avocado is enough. Avocados are high in good fat, but they also deliver a day's supply of magnesium, and half a day's supply of fiber! The avocado smoothies that are very popular in Vietnam, the Philippines, Malaysia, and Indonesia are made with sweetened condensed milk. You can make a dairy-free version with almond, coconut, or rice milk. For a traditional Mexican avocado smoothie, sweeten with agave nectar. Use a half to one whole fresh avocado for every two cups of milk or milk substitute to make an avocado smoothie. For flavored smoothies, use half of the avocado for every two cups of milk or milk substitute with peaches, mangos, pineapple, or any kind of berries. Really the friut added is totally up to your taste and the consistency of the smoothie. As they say "Have it Your Way" season to taste so to speak. You will quickly develop your own recipe and hopefully learn to love avocado smoothies and avocados daily as they are one of the planets most delicious and nutritious foods.
Avocado Smoothie-Another Way to get Your Daily Avocado!


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This is a design project that I volunteered to create for the New Media dept. at the University of Maine. We were working on an updated curriculum revision / structure and I volunteered to create an infographic that would help our … Continue reading
Category Archives: Print
Design: Web (WordPress) Design, Print Design, Logo / Identity, Video Editing Website: www.rehappening.com
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The Bob Moog Foundation
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Toubab Krewe
Design: Flash Website, Poster & T-shirt Designs Video Production / Multi-Media Support for the Bob Moog Foundation Video Website: http://www.toubabkrewe.com
Downtown After 5
Design: Music Event Logo, Poster, Stage Banner and Newspaper Ad & T-Shirt
Holiday Groove Mix vol. 1-17
Design: Album Cover Designs An annual holiday holiday groove mix that I've been making for the past 16 years. Here are links to download the last 7 years worth of mixes: Download Links: Holiday Groove Mix vol. 17 Holiday Groove Mix vol. 16 Holiday … Continue reading
Synergy Alive
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The New Master Sounds Film
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P2 Cycles
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Chynnaa: contemporary body adornment
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Craig Klein Album & Card Design
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|Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly.
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MedLine Citation:
|PMID: 18001468 Owner: NLM Status: MEDLINE
|BACKGROUND: Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the NSD1 gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that NSD1 could be involved in other cases of autism and macrocephaly. METHODS: We screened the NSD1 gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of NSD1 was carried out using multiplex ligation-dependent probe amplification. RESULTS: We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed. CONCLUSION: Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for NSD1 mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.
|Joseph D Buxbaum; Guiqing Cai; Gudrun Nygren; Pauline Chaste; Richard Delorme; Juliet Goldsmith; Maria Råstam; Jeremy M Silverman; Eric Hollander; Christopher Gillberg; Marion Leboyer; Catalina Betancur
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Publication Detail:
|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-11-14
Journal Detail:
|Title: BMC medical genetics Volume: 8 ISSN: 1471-2350 ISO Abbreviation: BMC Med. Genet. Publication Date: 2007
Date Detail:
|Created Date: 2008-02-21 Completed Date: 2008-03-07 Revised Date: 2009-11-19
Medline Journal Info:
|Nlm Unique ID: 100968552 Medline TA: BMC Med Genet Country: England
Other Details:
|Languages: eng Pagination: 68 Citation Subset: IM
|Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, USA. firstname.lastname@example.com
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|APA/MLA Format Download EndNote Download BibTex
|MeSH Terms
Amino Acid Substitution / genetics*
Autistic Disorder / genetics*
Child, Preschool
Craniofacial Abnormalities / genetics*
DNA Mutational Analysis
Genetic Testing
Intracellular Signaling Peptides and Proteins / genetics*
Nuclear Proteins / genetics*
|Grant Support
Reg. No./Substance:
|0/Intracellular Signaling Peptides and Proteins; 0/NSD1 protein, human; 0/Nuclear Proteins
|Full Text
Journal Information
Journal ID (nlm-ta): BMC Med Genet
Publisher: BioMed Central
Article Information
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Copyright ? 2007 Buxbaum et al; licensee BioMed Central Ltd.
open-access: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received Day: 6 Month: 8 Year: 2007
Accepted Day: 14 Month: 11 Year: 2007
collection publication date: Year: 2007
Electronic publication date: Day: 14 Month: 11 Year: 2007
Volume: 8First Page: 68 Last Page: 68
Publisher Id: 1471-2350-8-68
PubMed Id: 18001468
|Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly
|Joseph D Buxbaum123
|Email: email@example.com
|Guiqing Cai123
|Email: email@example.com
|Gudrun Nygren4
|Email: email@example.com
|Pauline Chaste567
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|Richard Delorme567
|Email: email@example.com
|Juliet Goldsmith123
|Email: firstname.lastname@example.com
|Maria R?stam4
|Email: firstname.lastname@example.com
|Jeremy M Silverman23
|Email: firstname.lastname@example.com
|Eric Hollander23
|Email: firstname.lastname@example.com
|Christopher Gillberg48
|Email: firstname.lastname@example.com
|Marion Leboyer679
|Email: firstname.lastname@example.com
|Catalina Betancur107
|Email: email@example.com
1Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, USA.
2Department of Psychiatry, Mount Sinai School of Medicine, New York, USA.
3Seaver Autism Research Center, Mount Sinai School of Medicine, New York, USA.
4Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg, Sweden.
5AP-HP, H?pital Robert Debr?, Service de Psychopathologie de l'Enfant et de l'Adolescent, Paris, France.
6INSERM U841, Institut Mondor de Recherche Biomedicale, Psychiatric Genetics, Cr?teil, France.
7Universit? Paris 12, Facult? de M?decine, Cr?teil, France.
8Institute of Child Health, London, UK.
9AP-HP, Groupe Hospitalier Henri Mondor ? Albert Chenevier, Department of Psychiatry, Cr?teil, France.
10INSERM U513, Cr?teil, France.
Sotos syndrome (MIM 117550) is a childhood overgrowth syndrome characterized by distinctive facial features including prominent forehead, down-slanted palpebral fissures and pointed chin, macrocephaly and learning disabilities. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain protein 1) gene [1], which encodes a coregulator of nuclear receptors that can activate or repress transcription [2]. Point mutations are identified in the majority of non-Japanese patients with Sotos syndrome (~80%), whereas 5q35 microdeletions encompassing NSD1 are the major cause among Japanese patients (>50%) [3,4]. Most cases of Sotos syndrome are sporadic, but occasional familial cases have been reported, with dominant inheritance. Affected children usually exhibit developmental delay, and speech delay is common. In addition, autism spectrum disorders or autistic features have been described in a number of patients with Sotos syndrome [5-13].
Autism is a behaviorally defined neurodevelopmental syndrome characterized by social and communication deficits, and the presence of restricted and repetitive behaviors and interests, with onset in the first three years of life. Recent epidemiological studies indicate that autism is a common disorder, affecting as many as 2 in 1000 children [14]. The prevalence of all autism spectrum disorders, which include autism, pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger syndrome, is estimated at 6 per 1000 [14]. Autism is approximately four times more frequent in males than in females. Family and twin studies have shown that genetic factors play a major role in the susceptibility to autism [15] but genetic heterogeneity has made the identification of the genes involved difficult [16]. Monogenic disorders such as fragile X syndrome and other forms of X-linked mental retardation, tuberous sclerosis complex, neurofibromatosis, and various rare metabolic disorders are identified in a small percentage of patients [17]. Cytogenetically visible chromosomal aberrations are identified in approximately 5% of affected individuals [10], while recent higher-resolution whole-genome analyses using array-based technologies have revealed genomic imbalances in at least 10% of cases [18,19]. However, the underlying cause remains unknown in the majority of patients.
Autism is associated with macrocephaly in approximately 20% of cases [20,21]. Although macrocephaly is one of the most widely replicated neurobiological findings in autism, its pathogenesis remains unknown. The description of several cases of Sotos syndrome in patients with autism and macrocephaly [5-13] suggests that NSD1 could be involved in other cases of autism. Thus, the aim of this study was to assess the frequency of NSD1 mutations in cases of autism spectrum disorder associated with macrocephaly, defined as an occipitofrontal head circumference (HC) 2 SD or more above the mean. We screened NSD1 by direct sequencing in 88 subjects with autism spectrum disorder and macrocephaly. In addition, we searched for deletions of the NSD1 gene using multiplex ligation-dependent probe amplification (MLPA). Our results showed no point mutations or deletions of NSD1, indicating that Sotos syndrome is a rare cause of autism spectrum disorders with macrocephaly.
A total of 88 patients with an autism spectrum disorder and macrocephaly (HC ?+2 SD) were included in the study. Among these, 49 were recruited by the Paris Autism Research International Sibpair (PARIS) study at specialized clinical centers in France, Sweden, Norway, Italy, Belgium, Austria, and the United States, and 39 were collected at the Mount Sinai School of Medicine and/or the Autism Genetic Resource Exchange (AGRE) [22]. Patients were identified from a larger pool of 462 families for which head circumference measures were available. All patients with a HC ?+2 SD were included in the study; in families with two or more siblings with an autism spectrum disorder and macrocephaly, one individual was chosen at random for the mutation screening.
The patients from the PARIS study included 45 males and 4 females from 16 multiplex families (with two or more affected siblings) and 33 simplex families (sporadic cases), with a mean age at the last evaluation of 10.5 ? 5.8 years (range 3.5?26). All patients were evaluated by experienced psychiatrists or child neurologists; diagnoses were based on clinical evaluation and DSM-IV and ICD-10 criteria. In addition, patients with autistic disorder were assessed with the Autism Diagnostic Interview-Revised (ADI-R) [23] and those with Asperger syndrome were assessed with the Asperger Syndrome Diagnostic Interview (ASDI) [24]. Forty-five individuals met criteria for autistic disorder, 2 for PDD-NOS and 2 for Asperger syndrome. There were 35 patients with mental retardation and 22 with limited or no language. Laboratory tests to rule-out medical causes of autism included standard karyotyping, fragile X testing, and metabolic screening; brain imaging and EEG were performed when possible. Patients diagnosed with medical disorders such as fragile X syndrome or chromosomal abnormalities were excluded from the study. There were 41 individuals of Caucasian origin, 2 Black, 1 Asian and 5 of mixed ethnicity. The study was approved by the research ethics boards of the collaborating institutions. Informed consent was obtained from all families participating in the study.
Thirty-nine patients were recruited by the Seaver Autism Research Center (SARC) at Mount Sinai, New York, co-recruited by the SARC and AGRE, or obtained from AGRE. The patients included 31 males and 8 females from 35 multiplex families and 4 simplex families, with a mean age at the last evaluation of 10.5 ? 4.2 years (range 5?24). The ADI-R was used to assess affected subjects. There were 35 individuals with autism, 1 with borderline autism, 2 with Asperger syndrome and 1 with PDD-NOS. The term 'borderline autism' (or 'not quite autism') refers to individuals who are no more than one point away from meeting autism criteria according to the ADI-R on any or all of the 3 main domains of autistic impairment ? social, communication, and repetitive behavior ? and meet the age of onset criterion (before 36 months); or individuals who meet criteria on all 3 domains but do not meet the age of onset criterion. Seventeen patients had mental retardation and 16 had limited or no language. Subjects with co-morbid genetic disorders (fragile X syndrome, tuberous sclerosis, or chromosomal anomalies) were excluded. There were 32 individuals of Caucasian origin, 1 Black, 1 Asian, and 5 of mixed or unknown ethnicity. All parents provided written informed consent. The study was approved by the local institutional review board.
HC among the 88 subjects included in the study ranged from +2 to +9.6 SD for age and sex. There were 68 subjects with a HC between +2 and +2.9 SD, 18 with a HC between +3 and +4 SD, and only 2 subjects with a HC greater than +4 SD. The patient with the largest HC (+9.6 SD) among all the study subjects was later found to have a PTEN mutation [25].
The NSD1 gene consists of 23 exons, the first of which is non coding. All exons (including exon 1), intron-exon boundaries and flanking intronic sequences were analyzed for mutations by direct sequencing of forward and reverse strands. When variants not described previously were detected, the DNA of parents and unaffected siblings (when available) was analyzed by direct sequencing for the specific base change identified in the proband.
In order to identify microdeletions of the NSD1 gene we performed MLPA [26] using a commercially available kit, according to the manufacturer's protocol (SALSA P026B Sotos; MRC-Holland, Amsterdam, The Netherlands). The P026B probe set contains 24 NSD1 probes, including one probe in the promoter region (1 Kb 5' of exon 1) and one probe for each of the 23 exons. The kit also contains six probes for five neighboring genes on 5q31-35 (IL4, IL12B, FGFR4, FLT4 and TRIM52), as well as 12 control probes in other chromosomes. Electrophoresis of PCR products was performed on an ABI 3730 sequencing platform (Applied Biosystems, Foster City, CA, USA) and the resultant traces were analyzed using the software GeneMarker (SoftGenetics, State College, PA, USA).
Genomic DNA from 88 unrelated individuals with autism spectrum disorders and macrocephaly was screened for intragenic NSD1 mutations by sequencing analysis. No frameshift or nonsense mutations were identified in any sample. Three missense variants, R604L, S822C and E1499G, were each identified in one individual (Table 1). R604L, in exon 5, was described previously in one patient referred for genetic testing of Sotos syndrome, and was classified as a variant of unknown significance [27]. S822C, also in exon 5, and E1499G in exon 10, have not been described previously. None of these variants is in a known functional domain of the protein [28]. Segregation analysis showed that all three variants were inherited from reportedly healthy parents and in two cases were present also in unaffected siblings, indicating that they are likely nonpathogenic. Furthermore, we identified two synonymous variants and two intronic substitutions present in one patient each, which were also inherited from unaffected parents. Table 1 shows all the sequence changes identified in our patients, including several new polymorphisms identified in this study.
There was no evidence for partial or whole gene deletions or duplications of the NSD1 gene in any of the patients screened with MLPA.
Screening of the NSD1 gene in a cohort of 88 familial and sporadic cases of autism and macrocephaly did not reveal any intragenic mutations or deletions, indicating that Sotos syndrome is a rare cause of autism spectrum disorders. The three missense variants identified in one individual each (R604L, S822C and E1499G), were inherited from unaffected parents, suggesting that they are likely to be polymorphisms. In addition, none of these variants is located in a known functional domain [28], further suggesting that they are nonpathogenic. Previous studies have shown that missense mutations are pathogenic only if they occur within functional domains of the protein involved in chromatin regulation [4].
Our negative findings are in agreement with recent studies showing that virtually all patients with a NSD1 mutation or deletion have the characteristic facial features of Sotos syndrome (broad forehead, sparse frontotemporal hair, long narrow face, malar flushing, down-slanted palpebral fissures, prominent jaw, pointed chin) [4,29,30]. However, the facial features are subtle and are difficult to recognize by clinicians with limited experience with this condition. The patients in our study presumably did not have the facial gestalt of Sotos syndrome, although most had not been evaluated by a clinical geneticist and it is likely that the psychiatrists that evaluated the patients were not all familiar with Sotos syndrome because of the relative rarity of this condition.
The other key clinical features of Sotos syndrome are the macrocephaly and the developmental delay. HC and height are increased in the majority of children with Sotos syndrome. By adulthood, height may fall within normal limits, but macrocephaly usually persists. However, recent studies have shown that HC and height are normal in 10% of NSD1 mutation-positive patients, indicating that overgrowth, previously considered as a major criterion of the disorder, is not necessary for the diagnosis of Sotos syndrome [4].
Our series included a high proportion of familial cases of autism spectrum disorders, as compared to singletons (51 vs. 37). Because Sotos syndrome is mostly a sporadic disorder, this could have contributed to the negative results of this study. However, several familial cases of Sotos syndrome with NSD1 mutations have been described in the past years [4,27,30-35], suggesting that familial, usually milder, forms of the disorder might be underdiagnosed.
Besides Sotos syndrome, there are several other syndromes presenting with macrocephaly and developmental delay, which are sometimes associated with autism. Among the better known is the fragile X syndrome, which is the most frequent genetic disorder identified in patients with autism spectrum disorders, accounting for about 2% of cases [36]. Molecular analysis for fragile X is routinely performed in patients with autism and mental retardation, and was ruled out in the patients participating in our study. Another disorder associated with autism and macrocephaly is the PTEN hamartoma tumor syndrome, which includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. The PTEN gene has recently been found to be mutated in several children with autism spectrum disorders and macrocephaly [37-40]. We screened PTEN for mutations and deletions in the 88 individuals with autism spectrum disorders and macrocephaly reported in this study and identified one patient with extreme macrocephaly carrying a de novo missense mutation [25].
Other examples of disorders associated with macrocephaly which carry an increased risk for the development of autism include neurofibromatosis type I [41,42] and 22q13 deletions [43]. In addition, there are several reports in the literature of cases with progressive postnatal macrocephaly with autism, marked speech delay and mental retardation, referred to as the Cole-Hughes macrocephaly syndrome [44,45]. The Orstavik syndrome, described by Orstavik et al. [46], is characterized by macrocephaly, epilepsy, autism, mental retardation and dysmorphic features. Several other cases of the same syndrome were reported later by another group [47]. As Sotos syndrome, these disorders account for only a small number of patients with autism and macrocephaly.
The macrocephaly observed in about 20% of patients with autism appears to be an independent clinical trait, not related to sex, presence of morphological abnormalities, IQ, occurrence of seizures, or severity of autistic symptoms [20,21]. Converging evidence from HC measurements, MRI studies and postmortem brain weight indicates that an even greater proportion of children with autism have an abnormal regulation of brain growth, resulting in enlarged brains during early childhood [48]. At birth, HC is typically normal or slightly reduced, followed by accelerated growth during the first years of life. This early phase of excessive growth is followed by slowed growth after 2?4 years of age, so that in adolescents and adults HC measures are usually within normal range [48]. Other studies, however, have found increased brain volume in older populations of individuals with autism [49,50], so the timing of brain enlargement is not settled yet. Similarly, the pattern of enlargement across the brain lobes and cerebellum and the involvement of gray versus white matter remain unclear at present. Elucidation of the mechanisms involved in the pathological postnatal brain overgrowth may prove critical for understanding the emergence of autistic symptoms during the same time frame.
In conclusion, no NSD1 mutations, 5q35 microdeletions or partial NSD1 deletions were identified in this large sample of patients with autism spectrum disorders and macrocephaly. Our results suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for NSD1 mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.
The author(s) declare that they have no competing interests.
JDB and CB conceived the study, designed and coordinated it, performed part of the molecular genetic studies, and wrote the manuscript. GC and JG participated in the molecular genetic studies. GN, PC, RD, MR, JMS, EH, CG and ML participated in the recruitment of families. JMS, EH, CG and ML supervised the clinical evaluation of families. All authors read and approved the final manuscript.
The pre-publication history for this paper can be accessed here:
We are grateful to all the families that participated in this research. We thank the DNA and cell bank of the INSERM U679 (H?pital Piti?-Salp?tri?re) and the Centre d'Investigations Cliniques-H?pital Robert Debr? for processing the samples from the French families. We acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Cure Autism Now and is supported, in part, by the National Institute of Mental Health (grant MH64547 to Daniel H. Geschwind). This work was supported by the Beatrice & Samuel A. Seaver Foundation, the Milton & Miriam Handler Foundation, NIH (grants MH066673 and NS042165), INSERM, Assistance Publique-H?pitaux de Paris, Fondation pour la Recherche M?dicale, Fondation de France, Fondation France T?l?com, and the Swedish Science Council. Dr. Joseph Buxbaum is the G. Harold and Leila Y. Mathers Research Professor at Mount Sinai School of Medicine.
Paris Autism Research International Sibpair Study: France: Marion Leboyer, Department of Psychiatry, Groupe Hospitalier Albert Chenevier ? Henri Mondor, Cr?teil; Catalina Betancur, INSERM U513, Universit? Paris XII, Cr?teil; Pauline Chaste, Richard Delorme, Marie-Christine Mouren-Sim?oni, Service de Psychopathologie de l'Enfant et l'Adolescent, H?pital Robert Debr?, Paris. Sweden: Christopher Gillberg, Maria R?stam, Carina Gillberg, Gudrun Nygren, Henrik Anckars?ter, Department of Child and Adolescent Psychiatry, G?teborg University, G?teborg. Norway: Eili Sponheim, Centre for Child and Adolescent Psychiatry, University of Oslo, Oslo; Ola H. Skjeldal, Department of Pediatrics, Rikshospitalet, University of Oslo, Oslo. USA: Mary Coleman, Department of Pediatrics, Georgetown University School of Medicine, Washington D.C.; Philip L. Pearl, Children's National Medical Center, George Washington University School of Medicine, Washington, D.C.; Ira L. Cohen, John Tsiouris, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York. Italy: Michele Zappella, Divisione di Neuropsichiatria Infantile, Azienda Ospedaliera Senese, Siena. Austria: Harald Aschauer, Department of General Psychiatry, University Hospital, Vienna. Belgium: Lionel Van Maldergem, Centre de G?n?tique Humaine, Centre Hospitalier Universitaire du Sart Tilman, Universit? de Li?ge, Li?ge.
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Sequence variants identified in the NSD1 gene in 88 patients with autism spectrum disorders and macrocephaly
|Location and Nucleotide Change
|Protein Change
|Previously described1
|Intron 1
|Exon 2
|Paternal/maternal, present in 1 sib with autism and 1 unaffected sib
|[27, 33]
|Exon 5
|Paternal (no siblings)
|Maternal, present in 1 unaffected sib
|Maternal (absent in 1 sib with autism)
|Exon 10
|Paternal, present in 1 unaffected sib
|Intron 14
|Maternal, present in 1 unaffected sib
|Intron 17
|[51, 52]
|Exon 23
|[32, 52]
1 References are given only for variants without a RefSNP accession ID (rs number)
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