tomekkorbak/gifted_hugle
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"Jorge Porcel\n\nJorge Raúl Porcel de Peralta (; September 7, 1936 – May 16, 2006), known as Jorge Porcel, was an Argentine comedy actor and television host. ",
"He was nicknamed El Gordo de América (America's Fat Guy). ",
"Porcel is considered, along with Alberto Olmedo, one of Argentina's greatest comic actors of the twentieth century.",
"\n\nMovie career\nPorcel worked in 49 movies, starting with 1962's Disloque en Mar del Plata, and ending with Carlito's Way (1993). ",
"Many of these 49 movies were collaborations with Olmedo. ",
"Among the movies they did together was 1986's Rambito y Rambón: Primera Misión. (",
"Little Rambo and Big Rambo: First Mission)\n\nMany of Porcel and Olmedo's movies in the 1970s and 1980s were adult-oriented comedies. ",
"Conservative Argentine authorities rated these movies as PM-18 (age 18 and above), except for some movies planned for family audiences, which had \"tamer\" content. ",
"These movies are considered to be the pinnacle of Argentina's sexy comedy movie genre. ",
"Most of these movies were directed by Gerardo Sofovich or his brother Hugo. ",
"Porcel virtually stopped appearing in these movies after the accidental death of Olmedo, which left him clinically depressed.",
"\n\nFilms\n\nTelevision career\n\nPorcel had many TV hit shows as well, including Operación Ja Ja (both the 1960s original and the 1980s remake) and Polémica en el bar (Debate at the Café), where he had celebrated moments of comedy with fellow comedian Juan Carlos Altavista. ",
"Most of these TV efforts were linked to the Sofovich brothers. ",
"He also did Las Gatitas Y Ratones de Porcel (Little Cats & Mice of Porcel).",
"\n\nAfter he retired from filming movies in Argentina, he moved to Miami, where he starred in a risqué late-night variety show named A la cama con Porcel (To Bed with Porcel) on the Telemundo network, and was given a cameo in Hollywood production Carlito's Way. ",
"A La Pasta con Porcel is a restaurant in Miami Beach opened by Porcel and named after his popular television show.",
"\n\nPorcel's health deteriorated with time, due to his struggles with obesity and diabetes, to the point of ending up using a wheelchair in his later years. ",
"He toured during 1999 through Latin America to promote his autobiography Laughs, Applause and Tears. ",
"By this time, he had also become a born again Christian.",
"\n\nPorcel died in a hospital in Miami after a gallbladder surgery at the age of 69. ",
"His body was flown to Argentina and buried at the Chacarita Cemetery.",
"\n\nMusic \nIn 1980 he recorded a bolero record called Pure heart (Spanish: Puro Corazón (1980)) . ",
"Jorge Porcel loved music and in his shows he used to sing boleros, as in Las gatitas y ratones de Porcel (Porcel's kittens and mice) (where he was frequently accompanied by piano player Mike Rivas) and at ¿Lo viste a Porcel? (",
"Have you seen Porcel). ",
"With his character Don Mateo he took part in a record from the show Operacióm Ja-Já (Operation Ha ha) singing along with Rolo Puente, Leo Dan's hit «Libre, solterito y sin nadie» (Free, single and with nobody).",
"\n\nComics \nIn 1970's decade, for several years, Cielosur Editora published several magazines dedicated to TV characters, as Piluso, Minguito and El Gordo Porcel. ",
"Las aventuras del Gordo Porcel (The adventures of Porcel the Fat Man) was the title of the one dedicated to Jorge. ",
"The usual play -with drawings by Francisco Mazza- consisted of el Gordo getting in trouble and several confusions, during the time in between the feasts of food prepared by his mother, who he lived with. ",
"Other frequent characters are his girlfriend and his dog Banana, who had his own comic.",
"\n\nSee also\n\nArgentine humour\nList of television presenters/Argentina\n\nExternal links\n \n \n \n \n\nCategory:1936 births\nCategory:Male actors from Buenos Aires\nCategory:Argentine male film actors\nCategory:Argentine male television actors\nCategory:Argentine comedians\nCategory:Argentine evangelicals\nCategory:2006 deaths\nCategory:Burials at La Chacarita Cemetery\nCategory:20th-century comedians"
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"Lower Your Risk Of Postpartum Depression With These Six Steps\n\nThe experience of motherhood is both joyous and overwhelming at the same time. ",
"It sets a new phase in your life. ",
"Mothers look forward anxiously to the new phase. ",
"You may have amazing plans and well cut out schedules in place just waiting for the baby to check in. ",
"However, reality hits you once the baby is finally here. ",
"All the things you read in your postnatal and antenatal blogs are all but a sad fantasy.",
"\n\nYou even watched celebs pose for photos looking all dressed up with their little ones; you are just waiting to do the same and post the photos on your Instagram page. ",
"The truth, however, dawns on you that even taking a simple bath is a luxury. ",
"Watching TV is next to impossible, and you are also unaware of what’s happening in your world.",
"\n\nYou feel completely lost, helpless and frustrated. ",
"You think that your little girl or boy has turned into a terrorist. ",
"This kind of feeling can lead to postpartum depression. ",
"So, what are some of the things you can do to lower the risk? ",
"Here’s your guide:\n\nUnderstand the triggersFor you to prevent a disease, you must understand the causes. ",
"What are some of the factors that are likely to leave you exposed to extreme baby blues? ",
"If for instance, you were not ready for the pregnancy, you may have mixed feelings about your baby. ",
"Your motherly love for the baby may turn to hatred and even have ideas of harming the baby. ",
"However, since the pregnancy is already there, you can consider going for counselling before the baby’s birth so that you can accept the situation. ",
"Other triggers include;\n\nBaby’s poor health\n\nCongenital disabilities\n\nToo much trauma during childbirth\n\nPreterm baby\n\nDo not wait for the situation to get worse before seeking professional help.",
"\n\nGet adequate restDuring the fourth trimester, your baby will find it difficult to understand the world. ",
"She was used to an entirely different environment in the womb. ",
"She was cushioned from harm by the amniotic fluid. ",
"Once born, she is exposed to all manners of pollution. ",
"She will find the world around her too overwhelming. ",
"Therefore, her fussy moments will be too frequent and her sleep pattern will differ from yours. ",
"She may find it comfortable to sleep during the day and stay awake at night. ",
"For the baby, day and night are all the same. ",
"Therefore, to beat the risk of postpartum depression, adapt the baby’s schedule. ",
"Once she sleeps, do the same. ",
"This will ensure you are not too exhausted hence reducing baby blues.",
"\n\nLearn to seek helpAll mothers want to feel in charge. ",
"Your wish is to be entirely in control of your schedule, family and the baby. ",
"However, this may not be possible. ",
"The sudden lifestyle change could expose you to depression especially if you are not able to manage the transition.",
"\n\nMake it easy by seeking an extra pair of hands to help you. ",
"Talk to your spouse and hire the best confinement nanny Singapore to give you the necessary support in the daily running of your home. ",
"The nanny can prepare meals, take care of the baby and even give you a body massage occasionally.",
"\n\nTalk about your feelingsMembers of your family may not have an idea of what you are going through. ",
"To them, you are just another member of the family who brought forth a child. ",
"All they see is the brighter side. ",
"They have no idea you are going through a turmoil, and cannot handle the changes. ",
"Talk to them about your situation; about your feeling of despair, solitude and even frustration.",
"\n\nTheir assurance that you are on the right track will give you the necessary strength to carry on your duties. ",
"Talking also helps in resolving any bolted feelings that may be building up within your system. ",
"You can even cry, it’s positive and quite healthy. ",
"All you need is a listening ear.",
"\n\nConfront your fearsThere are moments when you may not want to think about your problems. ",
"You feel helpless and consider pushing the problems to the back of your mind. ",
"Unfortunately, they will not disappear. ",
"They will always cause you more worry and fear.",
"\n\nWhat are some of the things that you are afraid of about your status? ",
"Are you worried that you do not have adequate resources to care for your child? ",
"Are you fearful that your spouse will not always be there when you need him? ",
"Some of your fears could be assumptions. ",
"Face each of your problems with possible solutions. ",
"There are those that may seem too complicated for you. ",
"Let them be. ",
"You can only do so much.",
"\n\nForget perfectionNo one is perfect. ",
"Not even your parents or spouse. ",
"So how do you expect to be perfect? ",
"You will make mistakes during your motherhood journey. ",
"Your baby may even get a reaction from the food you gave her. ",
"Don’t judge yourself too harshly. ",
"The most important thing is to understand you are doing the best for the baby. ",
"If your baby gets the flu, don’t feel too sad that you could do something about it.",
"\n\nBringing forth life is divine and beautiful. ",
"It is the ultimate prize of womanhood. ",
"If you have the opportunity to enjoy such a gift, embrace it with love and happiness. ",
"Let each milestone of your baby be full of joy, laughter, and endless gratitude. ",
"In case the journey gets tough, remember you are not alone. ",
"Make use of your support system and fight any signs of PPD."
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"Van Wieren\n\nvan Wieren is a surname. ",
"Notable people with the surname include:\n\nLarry van Wieren (born 1951), Dutch ice hockey player\nPete Van Wieren (1944-2014), American sportscaster\n\nCategory:Surnames of Dutch origin"
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"\"На \"поребрике\" россиян будет судить Майдана\": судейская бригада матча Россия - Южная Корея - аргентинцы\n\nФИФА обнародовала состав судейских бригад на ближайшие матчи чемпионата мира-2014.",
"\n\nМеждународная федерация футбольных ассоциаций обнародовала состав судейских бригад на ближайшие матчи чемпионата мира-2014. ",
"Об этом сообщается на официальном сайте ФИФА.",
"\n\nПоединок группы Н, в котором встретятся сборные России и Южной Кореи, обслужит аргентинская бригада арбитров во главе с Нестором Питаной.",
"\n\nПомогать 38-летнему рефери будут Эрнан Майдана и Хуан Пабло Белатти.",
"\n\nМатч сборной России против Южной Кореи состоится в бразильском городе Куяба. ",
"Игра начнется 18 июня в 1:00 по киевскому времени.",
"\n\nМатч сборной России против Южной Кореи состоится в бразильском городе Куяба 18 июня в 1:00 по киевскому времени.",
"\n\nНапомним, 12 июня в Бразилии начался 20-й чемпионат мира по футболу. ",
"Соревнование состоится в Бразилии с 12 июня по 13 июля.",
"\n\nДобавьте ukranews.com в избранные источники Google Новости"
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"According to Mountain Girl, Garcia originally purchased the hat in a costume shop in San Francisco in 1966: Stars and stripes, and red white and blue were popular themes in new art during the rebellious 1960's as American youth sought to expand their civil liberties by wearing flag-themed clothing and to attract attention and to identify changing behaviors in America as freedoms [were] protected by the U.S. Constitution... [He] wore it to public appearances, concerts with the band, and in photos by well-known San Francisco photographer Gene Anthony, who documented the ‘Summer of Love’ in Haight-Ashbury.",
"\n\n\n\nGarcia chose to wear the hat for the now famous shoots with Gene Anthony on the steps of the Grateful Dead communal house at 710 Asbury and with Herb Greene at the home of Gene Estribou, who recorded one of the first demos for the band. ",
"Photographs from both shoots were used for the cover and liner of the Grateful Dead’s 1967 debut album The Grateful Dead, where the corresponding liner notes named Garcia as Jerry (\"Captain Trips\") Garcia. ",
"The hat became synonymous with Garcia’s ‘Captain Trips’ persona. ",
"Herb Greene remembers …Garcia became Captain Trips when he put it on.",
"\n\n\n\nAccording to Denise Kaufman of The Ace of Cups, the nickname originally came from an episode at Ken Kesey's Acid Test at the Big Beat Club, Mountain View in Palo Alto on 18th December, 1965: At one point, I was standing out in the parking lot talking to Jerry Garcia, and this police car drove up… It was the usual: \"What's going on here?\" ",
"Whatever Jerry said satisfied him because he turned to leave. ",
"As he turned to walk away, Jerry kind of tipped his hat and said, \"The tips, captain.\" ",
"The way he said it just knocked me out. ",
"I told Kesey about this interaction and out of that Jerry got his name Captain Trips. ",
"Of course, the nickname also reflected Garcia’s fondness for psychedelic drugs and his prototypical psychedelic persona, although he came to dislike the moniker himself.",
"\n\n\n\nAccording to Mountain Girl, The hat was part of Jerry Garcia's personal wardrobe for several years and when he stopped wearing it, he gave it to his friend Harry Tsvi Strauch who ran a gallery on Haight Street. ",
"Strauch explains …In the Summer of 1966, The Grateful Dead became our neighbors, moving into 710 Ashbury, the house two doors up from ours. ",
"September 1967, an anti-War/Peace march was to come through Haight Street for a rally at Kezar Stadium. ",
"My wife - Hyla Strauch - was designing a Red, White & Blue American Flag themed window display for our shop in support of the march. ",
"She thought that Jerry Garcia's Capt'n Trips hat would be the ideal, iconic centerpiece for the display. ",
"We brought this up to Jerry, and he gave us the hat to use in the shop window! ",
"When it was time to take the display down, we offered to return the hat - Jerry Told us \"I don't want the hat...You keep it, take care of it.\"",
"\n\n"
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"As the world struggles to find out more information about the San Francisco crash landing, Twitter user Steve Baker used flight tracking website FlightAware to compare yesterday's Asiana Airlines Flight 214 (AAR 214) to today's ill-fated flight.",
"\n\nHere's his Tweet:\n\nLook at an enlargement of the two descent paths (the part of the graphic that looks like a solid black wall):\n\nCompare the two flight paths, and you'll notice Friday's glide slope was much smoother than today's. ",
"Saturday's flight path suddenly veered downward just before the tail section of the plane hit the rocks on the shore at the end of the runway.",
"\n\nThe reason for this deviation is still unknown.",
"\n\nSEE ALSO: Plane Crashes While Landing at San Francisco Airport\n\nMeanwhile, an audio recording of air traffic control during the crash has surfaced:\n\nHere's the transcription, courtesy Time:\n\nFlight 214 cleared into land 28L at 18:21:12 Zulu 18:22:27: Flight 214 calls ATC 18:22:30: Tower says, “214 Heavy, Emergency Vehicles are responding” 18:22:37: Flight 214 calls again. ",
"Can’t make out what is said. ",
"18:23:10: Flight 214 calls again. ",
"Can’t make out what is said. ",
"18:23:25: ATC says, “Emergency vehicles are responding. ",
"We have everyone on their way.” ",
"18:27:02: Another plane calls ATC, “We see people (at our vicinity) that need immediate attention. ",
"They are alive and they are walking around.”",
"\n\nPics courtesy FlightAware, Steve Baker; audio file via YouTube, Anon Nymous"
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"[[install-and-run]]\n== Install and run\n\nThe easiest way to get started with Elastic APM is by using our\nhttps://www.elastic.co/cloud/elasticsearch-service[hosted {es} Service] on\nElastic Cloud. ",
"The {es} Service is available on AWS, GCP, and Azure,\nand automatically configures APM Server to work with {es} and {kib}.",
"\n\n[float]\n=== Hosted Elasticsearch Service\n\nimage::images/apm-architecture-cloud.png[Install Elastic APM on cloud]\n\nSkip managing your own {es}, {kib}, and APM Server by using our\nhttps://www.elastic.co/cloud/elasticsearch-service[hosted {es} Service] on\nElastic Cloud.",
"\n\n{ess-trial}[Try out the {es} Service for free],\nthen jump straight to <<agents>>.",
"\n\n[float]\n[[before-installation]]\n=== Install and manage the stack yourself\n\nimage::images/apm-architecture-diy.png[Install Elastic APM yourself]\n\nTo install the stack yourself, first see the https://www.elastic.co/support/matrix[Elastic Support Matrix] for information about supported operating systems and product compatibility.",
"\nWe recommend you use the same version of Elasticsearch, Kibana, and APM Server.",
"\n\n* <<install-elasticsearch>>\n* <<install-kibana>>\n* <<apm-server>>\n* <<agents>>\n\n[float]\n[[quick-start]]\n=== Quick start with Docker\n\nIf you're interested in Elastic APM and want a quick and easy development environment to try things out,\nsee <<quick-start-overview>>.",
"\n\n[[install-elasticsearch]]\n=== Step 1: Install Elasticsearch\n\n// This will move to tagged regions so we can pull the installation instructions\n// here (instead of linking out)\n\nInstall an Elasticsearch cluster, start it up, and make sure it's running.",
"\n\n. ",
"Verify that your system meets the\nhttps://www.elastic.co/support/matrix#matrix_jvm[minimum JVM requirements] for {es}.",
"\n. {",
"stack-gs}/get-started-elastic-stack.html#install-elasticsearch[Install Elasticsearch].",
"\n. {",
"stack-gs}/get-started-elastic-stack.html#_make_sure_elasticsearch_is_up_and_running[Make sure elasticsearch is up and running].",
"\n\n[[install-kibana]]\n=== Step 2: Install Kibana\n\n// This will move to tagged regions so we can pull the installation instructions\n// here (instead of linking out)\n\nInstall Kibana, start it up, and open up the web interface:\n\n. {",
"stack-gs}/get-started-elastic-stack.html#install-kibana[Install Kibana].",
"\n. {",
"stack-gs}/get-started-elastic-stack.html#_launch_the_kibana_web_interface[Launch the Kibana Web Interface].",
"\n\n[[apm-server]]\n=== Step 3: Install APM Server\n\nInstall, set up, and run APM Server.",
"\n\n. {",
"apm-server-ref-v}/installing.html[Install APM Server].",
"\n. {",
"apm-server-ref-v}/apm-server-configuration.html[Set up APM Server]\n. {",
"apm-server-ref-v}/setting-up-and-running.html[Start APM Server].",
"\n\nNext, use the config file if you need to change the default configuration that APM Server uses to connect to Elasticsearch,\nor if you need to specify credentials:\n\n* {apm-server-ref-v}/configuring-howto-apm-server.html[Configuring APM Server]\n** {apm-server-ref-v}/configuration-process.html[General configuration options]\n** {apm-server-ref-v}/elasticsearch-output.html[Configure the Elasticsearch output]\n\n[[secure-api-access]]\nIf you do change the listen address from `localhost` to something that is accessible from outside of the machine,\nwe recommend setting up firewall rules to ensure that only your own systems can access the API.",
"\nAlternatively,\nyou can use a {apm-server-ref-v}/securing-apm-server.html[secret token and TLS].",
"\n\nIf you have APM Server running on the same host as your service,\nyou can configure it to listen on a Unix domain socket.",
"\n\n[[more-information]]\nTIP: For detailed instructions on how to install and secure APM Server in your server environment,\nincluding details on how to run APM Server in a highly available environment,\nplease see the full {apm-server-ref-v}/index.html[APM Server documentation].",
"\n\n[[agents]]\n=== Step 4: Install APM agents\n\n// This tagged region is reused in the Observability docs.",
"\n// tag::apm-agent[]\nAgents are written in the same language as your service.",
"\nMonitoring a new service requires installing the agent\nand configuring it with the address of your APM Server, a secret token (if necessary), and a service name.",
"\n\n[cols=\"h,,\"]\n|=======================================================================\n|Agent\n2+|\n\n.2+|Go\n2+|The Go agent automatically instruments Gorilla and Gin, and has support for Go’s built-in net/http and database/sql drivers.",
"\n|{apm-go-ref-v}/supported-tech.html[Supported technologies]\n|{apm-go-ref-v}/getting-started.html[Set up the Go Agent]\n\n.2+|Java\n2+|The Java agent automatically instruments Servlet API, Spring MVC, and Spring Boot out of the box.",
"\n|{apm-java-ref-v}/supported-technologies-details.html[Supported technologies]\n|{apm-java-ref-v}/setup.html[Set up the Java Agent]\n\n.2+|.NET\n2+|The .NET agent automatically instruments ASP.NET Core applications, and .NET Framework applications.",
"\n|{apm-dotnet-ref-v}/supported-technologies.html[Supported technologies]\n|{apm-dotnet-ref-v}/setup.html[Set up the .NET Agent]\n\n.2+|Node.js\n2+|The Node.js agent automatically instruments Express, hapi, Koa, and Restify out of the box.",
"\n|{apm-node-ref-v}/supported-technologies.html[Supported technologies]\n|{apm-node-ref-v}/set-up.html[Set up the Node.js Agent]\n\n.2+|Python\n2+|The Python agent automatically instruments Django and Flask out of the box.",
"\n|{apm-py-ref-v}/supported-technologies.html[Supported technologies]\n|{apm-py-ref-v}/set-up.html[Set up the Python Agent]\n\n.2+|Ruby\n2+|The Ruby agent automatically instruments Rails out of the box.",
"\n|{apm-ruby-ref-v}/supported-technologies.html[Supported technologies]\n|{apm-ruby-ref-v}/set-up.html[Set up the Ruby Agent]\n\n.2+|RUM\n2+|Real User Monitoring (RUM) captures user interactions with clients such as web browsers.",
"\n|{apm-rum-ref-v}/supported-technologies.html[Supported technologies]\n|{apm-rum-ref-v}/getting-started.html[Set up the RUM Agent]\n\n|=======================================================================\n\nTIP: Check the {apm-overview-ref-v}/agent-server-compatibility.html[Agent/Server compatibility matrix] to ensure you're using agents that are compatible with your version of Elasticsearch.",
"\n\n[[choose-service-name]]\n[float]\n==== Choose a service name\n\nThe service name is used by Elastic APM to differentiate between data coming from different services.",
"\n\nElastic APM includes the service name field on every document that it saves in Elasticsearch.",
"\nIf you change the service name after using Elastic APM,\nyou will see the old service name and the new service name as two separate services.",
"\nMake sure you choose a good service name before you get started.",
"\n\nThe service name can only contain alphanumeric characters,\nspaces, underscores, and dashes (must match `^[a-zA-Z0-9 _-]+$`).",
"\n\n// end::apm-agent[]\n\n[[configure-apm]]\n=== Step 5: Configure APM\n\nNow that you're up and running with Elastic APM, you may want to adjust some configuration settings.",
"\nLuckily, there are many different ways to tweak and tune the Elastic ecosystem to adapt it to your needs.",
"\n\n[float]\n==== Configure APM agents\n\n// This tagged region is reused in the Observability docs.",
"\n// tag::configure-agents[]\nAPM agents have a number of configuration options that allow you to fine tune things like\nenvironment names, sampling rates, instrumentations, metrics, and more.",
"\n\n|===\n|*Agent configuration documentation*\na|\n\n* {apm-go-ref-v}/configuration.html[Go Agent configuration]\n* {apm-java-ref-v}/configuration.html[Java Agent configuration]\n* {apm-dotnet-ref-v}/configuration.html[.NET Agent configuration]\n* {apm-node-ref}/configuring-the-agent.html[Node.js Agent configuration]\n* {apm-py-ref-v}/configuration.html[Python Agent configuration]\n* {apm-ruby-ref-v}/configuration.html[Ruby Agent configuration]\n* {apm-rum-ref-v}/configuration.html[RUM Agent configuration]\n|===\n\nA select number of configuration options can be changed directly in Kibana, without needing to redeploy the Agent.",
"\nSee {apm-app-ref}/agent-configuration.html[Agent configuration in Kibana] for more information.",
"\n\n[float]\n==== Configure Elastic Cloud\n\nIf you're running APM Server in Elastic cloud, you can configure your own user settings right in the Elasticsearch Service Console.",
"\nAny changes are automatically appended to the `apm-server.yml` configuration file for your instance.",
"\n\nFull details are available in the {cloud}/ec-manage-apm-settings.html[APM user settings] documentation.",
"\n\n[float]\n==== Configure a self installation\n\nIf you've installed APM Server yourself, you can edit the `apm-server.yml` configuration file to make changes.",
"\nMore information is available in {apm-server-ref-v}/configuring-howto-apm-server.html[configuring APM Server].",
"\n\nDon't forget to also read about\n{apm-server-ref-v}/securing-apm-server.html[securing APM Server], and\n{apm-server-ref-v}/monitoring.html[monitoring APM Server].",
"\n// end::configure-agents[]\n\n[[quick-start-overview]]\n=== Quick start development environment\n\n// This tagged region is reused in the Observability docs.",
"\n// tag::dev-environment[]\nifeval::[\"{release-state}\"==\"unreleased\"]\n\nVersion {version} of APM Server has not yet been released.",
"\n\nendif::[]\n\nifeval::[\"{release-state}\"!=\"unreleased\"]\n\nIf you're just looking for a quick way to try out Elastic APM, you can easily get started with Docker.",
"\nJust follow the steps below.",
"\n\n**Create a docker-compose.yml file**\n\nThe https://www.docker.elastic.co/[Elastic Docker registry] contains Docker images for all of the products\nin the {stack}.",
"\nYou can use Docker compose to easily get the default distributions of {es}, {kib},\nand APM Server up and running in Docker.",
"\n\nCreate a `docker-compose.yml` file and copy and paste in the following:\n\n[\"source\",\"yaml\",subs=\"attributes\"]\n--------------------------------------------\ninclude::./docker-compose.yml[]\n--------------------------------------------\n\n**Compose**\n\nRun `docker-compose up`.",
"\nCompose will download the official docker containers and start {es}, {kib}, and APM Server.",
"\n\n**Install Agents**\n\nWhen Compose finishes, navigate to http://localhost:5601/app/kibana#/home/tutorial/apm.",
"\nComplete steps 4-6 to configure your application to collect and report APM data.",
"\n\n**Visualize**\n\nUse the APM app at http://localhost:5601/app/apm to visualize your application performance data!",
"\n\nWhen you're done, `ctrl+c` will stop all of the containers.",
"\n\n**Advanced Docker usage**\n\nIf you're interested in learning more about all of the APM features available,\nor running the Elastic stack on Docker in a production environment, see the following documentation:\n\n* {apm-server-ref-v}/running-on-docker.html[Running APM Server on Docker]\n* {stack-gs}/get-started-docker.html[Running the Elastic Stack on Docker]\n\nendif::[]\n// end::dev-environment[]\n"
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[
"PROJECT SUMMARY Ischemic heart disease accounts for approximately 42.5% of all cardiovascular-related deaths and afflicts 720,000 individuals/year. ",
"While current medical treatments have significantly decreased heart attack- associated mortality, post-ischemic myocardial tissue undergoes pathologic remodeling and scarring, subjecting patients to cardiac dysfunction and heart failure. ",
"As endogenous cardiac regeneration is limited, stem cell and regenerative medicine-based approaches to cardiac repair represent promising solutions towards regaining normal heart function. ",
"Bolstering interest in cardiovascular tissue engineering has given rise to the development of novel biomaterials capable of maintaining cardiac cell function within a 3D tissue-like environment, while detailed protocols have been developed to derive mature cardiomyocytes from a myriad of stem cell sources; however, the essential ability to generate a construct that recapitulates the cellular density and composition, thickness, and helicoid structure of the native heart has limited the therapeutic applicability of tissue engineered constructs thus far. ",
"Utilizing photodegradable polymer-based hydrogels that enable a spatially-defined co-culture of hES-derived cardiomyocytes and endothelial cells, we propose to generate a densely-vascularized 3D cardiac construct exhibiting biomimetic helical tissue architecture. ",
"To support the culture of a thick myocardial tissue and enhance mass transport of oxygen and nutrients, vessels will be photopatterned into cell-laden hydrogels containing mature cardiomyocytes to generate perfusable vasculature with similar size, shape, and structure to that of the native heart. ",
"Channels will be endothelialized and perfused with fresh media using biomimetic pulsatile flow to encourage endothelial-cardiomyocyte cell interaction. ",
"We aim to demonstrate that by controlling micron-scale channel architecture in a biomimetic helical arrangement with near-native heart capillary density, paracrine signaling, ECM deposition, and direct contact of endothelial cells and cardiomyocytes, we can direct cardiomyocyte orientation, enhance construct contractility, and recapitulate the native torsional tissue contraction. ",
"As the proposed research will represent the first successful strategy to generate perfusable vasculature networks with 3D features on the single-micron scale, we expect that the developed methodologies will find wide applicability in the engineering of vascularized constructs beyond cardiac tissue."
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[
"Introduction {#Sec1}\n============\n\nSince the early 1980s, scientists have relied on nonhuman primate (NHP) models to assess whether cell-based therapies (CBTs) can be beneficial for Parkinson's disease (PD). ",
"CBT strategies and NHP models of PD emerged into the scientific arena simultaneously. ",
"In a way, the availability of the new NHP models fueled CBT progression towards clinical application.",
"\n\nAs the main aim of CBTs for PD was and still is the replacement of neurons lost in the disease, PD animal models with neurotoxin-induced neuronal loss became an ideal platform to assess the approach. ",
"CBT studies in rodent models provided invaluable information on neuronal survival, migration and integration after grafting (Kim et al. [",
"@CR73]). ",
"Clinical translation of CBTs requires progressive evaluation in different species and as a first-in-class and invasive brain therapy, NHP experiments are a logical next step (Capitanio and Emborg [@CR20]). ",
"Compared to rodents that are inbred, NHPs are outbred. ",
"Behavioral outcome measures such as fine motor skills, which are affected in PD, can be easily tested in NHPs but not in other large species, like pigs. ",
"Clinically relevant behavioral outcome measures are critical to determine the efficacy of the strategy, including the selection of intracerebral grafting targets. ",
"In that regard, NHPs and humans share a similar organization of the striatum, with the caudate nucleus and the putamen clearly delineated by the white matter tracts of the internal capsule. ",
"In rodents, transecting white matter tracts perforate throughout the striata, without presenting a physical barrier for cell distribution (Fig.",
" [1](#Fig1){ref-type=\"fig\"}).Fig.",
" 1Coronal brain sections of **A** rhesus and *a* mouse brain immunostained against tyrosine hydroxylase (TH) highlighting the comparison of brain size and complexity. *",
"Scale bar* 1 cm. *",
"Cd* caudate, *ic* internal capsule, *Put* putamen, *ac* anterior commissure, *CPu* caudate and putamen\n\nIn this article, we aim to discuss the role of NHP models of PD in CBT development, keeping in perspective how the field of PD is evolving, analyze ongoing advances in CBTs and the issues that need to be considered to maximize the value of NHP studies for the successful clinical translation of CBTs for PD.",
"\n\nParkinson's disease: then and now {#Sec2}\n=================================\n\nParkinson's disease (PD) is the 2nd most common neurodegenerative disorder affecting around 1% of the population over the age of 60 (Driver et al. [",
"@CR35]). ",
"When CBTs were first envisioned for actual clinical application, the conceptualization of PD suggested that it was an ideal candidate disease for brain repair. ",
"Patients were diagnosed by typical motor symptoms (resting tremor, rigidity, bradykinesia, and postural instability), which were associated with the loss of dopaminergic (DAergic) nigral neurons. ",
"As the symptoms responded to oral dopamine (DA) replacement therapy, it was expected that dopamine replacement with a cell source should be an efficient way to securely and locally deliver DA and, basically, cure PD. ",
"In addition, the brain was viewed as an immunoprivileged, postmitotic organ.",
"\n\nThe understanding of PD and the brain has evolved over time, which affects the application of CBT strategies. ",
"Today, PD diagnoses still depend on the presence of typical motor symptoms, and postmortem confirmation of nigral DAergic neuron loss and the presence of intracytoplasmic neuronal inclusions termed Lewy bodies \\[LBs; (Vermilyea and Emborg [@CR153])\\]. ",
"Yet, PD is now recognized as a complex neurodegenerative disorder that includes non-motor symptoms (NMS). ",
"Depression, anxiety, loss of sense of smell, gastrointestinal dysfunction and cardiac dysautonomia are common PD NMS, which are associated with neurodegeneration in other areas of the central and peripheral nervous system (Chaudhuri and Odin [@CR21]; Chaudhuri et al. [",
"@CR22]). ",
"Interestingly, NMS precede the onset of the movement disorder by decades and are now proposed as prodromal signs of the disease (Postuma et al. [",
"@CR109]). ",
"Earlier PD diagnoses would increase the chances of success of neuroprotective strategies. ",
"In that regard, brain immunoreactivity has been documented (Kordower et al. [",
"@CR77]; Roitberg et al. [",
"@CR123]; Tambur [@CR145]) and neuro-inflammation has been linked to PD neurodegeneration, suggesting that immunomodulation can be neuroprotective (Kannarkat et al. [",
"@CR68]). ",
"Neurogenesis has been documented in the adult brain of rodents (Altman and Das [@CR1]; Kaplan and Hinds [@CR69]; Kempermann et al. [",
"@CR71]), NHPs (Gould et al. [",
"@CR60]) and humans (Eriksson et al. [",
"@CR46]), and directed neurogenesis has been discussed for self-brain repair (Rakic [@CR111]).",
"\n\nAnother chain of events that led to findings with great implications for PD and CBTs started in 1996, when mutations in the alpha-synuclein (α-syn) gene were found in familial forms of PD (Polymeropoulos et al. [",
"@CR108]). ",
"Subsequent studies identified α-syn as the main component of LBs (Spillantini et al. [",
"@CR137], [@CR138]). ",
"Then, in 2008 LBs were reported in dopaminergic fetal grafts of PD patients that were transplanted a decade earlier, suggesting that the grafts \"caught PD\" from the host (Li et al. [",
"@CR87]; Kordower et al. [",
"@CR78]). ",
"Since then, α-syn research has taken a center stage in PD research (Bendor et al. [",
"@CR10]; Vermilyea and Emborg [@CR153]). ",
"Investigations on whether α-syn has prion-like activity revitalized the Braak and Braak hypothesis that PD may start in the brainstem and propagate through the neural axis (Braak et al. [",
"@CR17]; Chu and Kordower [@CR25]; Hilker et al. [",
"@CR65]). ",
"Studies on protein aggregation followed (Luk et al. [",
"@CR89]), as well as the search for neuroprotective approaches aiming to prevent aggregation (Kalia et al. [",
"@CR67]). ",
"It should be noted that the cause of PD is still unclear and that the question of whether the early peripheral symptoms reflect where PD starts or less neuroplasticity is being debated (Engelender and Isacson [@CR45]).",
"\n\nNHP models of PD used for CBT evaluation {#Sec3}\n========================================\n\nCommon marmoset, vervet and macaque monkeys are the most used NHP species for CBT studies. ",
"To the best of our knowledge, only neurotoxin-induced NHP models of PD have been used as testing platforms for CBTs, mainly by the administration of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), although new models are emerging (Table [1](#Tab1){ref-type=\"table\"}).Table 1Comparison between NHP models of PD highlighting key features for evaluation of CBTs for DA cell replacementNHP PD modelPD motor symptomsNigrostriatal DA depletionTypical LIDsSynucleinopathyComments6-OHDAYesYesNoNot reportedUnilateral model. ",
"Requires multiple intracerebral stereotaxic injections to induce a stable lesionMPTP systemicYesYesYesUpregulation of a-synBilateral model. ",
"Needs to be individually titrated, and depending on dosing paradigm may require from one week to over a year to induce syndrome. ",
"PD symptoms may spontaneously recoverMPTP systemic+agingYesYesYesUpregulation of α-syn, possible aggregatesSame as MPTP systemic plus animals may require more intensive care post intoxicationMPTP ICAYesYesNoNot reportedUnilateral model. ",
"Requires surgical set up; Induces a stable and reproducible lesionMPTP ICA+agingYesYesNoNot reportedSame as MPTP ICA except MPTP dose needs to be 2/3 of younger animals. ",
"Monkeys may require more intensive care post intoxicationAged NHPsYesYesNoTranslocation of α-synNot enough dopamine deficit to be responsive to [l]{.smallcaps}-DOPA treatmentViral vector delivery of α-synYes (Common marmosets)YesUnknownOverexpression of α-syn, aggregatesUnilateral model. ",
"Requires intracerebral stereotaxic injectionsLewy body extractsNoYesUnknownOverexpression of α-syn, aggregatesUnilateral model. ",
"Requires intracerebral stereotaxic injectionsα-syn TransgenicMild (Cynomolgus 1.5--2 years old)UnknownUnknownUnknownBilateral model*6-OHDA* 6 hydroxydopamine, *α-syn* alpha-synuclein, *MPTP* 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, *ICA* intracarotid artery, *[l]{.smallcaps}* *-DOPA* L-3,4-dihydroxyphenylalanine, *LIDs* [l]{.smallcaps}-DOPA induced dyskinesias\n\n6-OHDA (Senoh and Witkop [@CR129]) is preferentially used in common marmoset monkeys (Ungerstedt [@CR152]; Blandini et al. [",
"@CR15]; Eslamboli et al. [",
"@CR47]). ",
"As 6-OHDA does not cross the blood--brain barrier (BBB), it is stereotaxically injected directly into the right or left striatum, medial forebrain bundle or substantia nigra, inducing unilateral motor impairments. ",
"The neurotoxin is selectively taken up by catecholaminergic neurons through monoamine transporters, and induces sympathetic neuronal loss by increasing the production of reactive oxygen species (ROS), and disrupting energy metabolism and neuronal activity (Blum et al. [",
"@CR16]).",
"\n\nMPTP (Davis et al. [",
"@CR33]; Langston et al. [",
"@CR83]) is most commonly administered to macaque monkeys, although it is also used in other old and new world NHP species (Fox and Brotchie [@CR52]; Emborg [@CR39]). ",
"Unlike 6-OHDA, MPTP crosses the BBB and is administered to NHPs via s.c., ",
"i.m., ",
"i.v. ",
"or intracarotid artery (ICA) injection. ",
"Severity of PD symptoms depends on route, dose and frequency of administration; dosing regimen varies between species (Emborg [@CR39]). ",
"In the brain, MPTP is transformed into its toxic metabolite MPP^+^ by monoamine oxidase-B (MAO-B). ",
"MPP^+^ is then selectively taken up by the DA transporter into dopaminergic neurons where it disrupts normal mitochondrial respiration by acting as a mitochondrial complex I inhibitor, leading to oxidative stress and apoptosis (Przedborski and Vila [@CR110]).",
"\n\nAlthough it can be argued that neurotoxic models are missing critical components of PD, such as \"true\" LB formation (Dauer and Przedborski [@CR32]), several reasons justify their use to test CBTs as DA replacement/network restoration strategies: (1) neurotoxin-induced models present PD-like motor symptoms and dopaminergic nigrostriatal loss, (2) they are well characterized, and (3) they can be induced in a protracted period of time, which facilitates their use as testing platforms.",
"\n\nWe agree with the concept that an ideal NHP model of PD should mimic the disease by replicating its etiology, which should induce the pathological mechanisms that give rise to the typical symptoms. ",
"Yet, although great progress has been made towards understanding the complexity of PD and possible pathways of neurodegeneration, its cause is still unknown. ",
"Neurotoxin-based models attempt to capitalize on the knowledge that exposure to environmental toxins is a PD risk factor. ",
"In that regard, both neurotoxins trigger mechanisms associated with neurodegeneration in PD. ",
"In addition to disrupting energy metabolism and increasing oxidative stress, dosing with 6-OHDA and MPTP induces inflammatory responses (Rodriguez-Pallares et al. [",
"@CR122]; Joglar et al. [",
"@CR66]; McGeer et al. [",
"@CR97]). ",
"MPTP dosing has also been shown to trigger an increase in α-syn expression and, in some cases, its accumulation (Halliday et al. [",
"@CR64]; Kowall et al. [",
"@CR81]; McCormack et al. [",
"@CR95]).",
"\n\nOther identified PD risk factors include aging and genetic mutations which are exploited for modeling purposes (Emborg [@CR39]). ",
"Studies in aged NHPs with or without MPTP have been reported. ",
"Intact aged animals present subtle PD-like symptoms (e.g.: slowness and overall decreased amount of movement) and nigrostriatal dopaminergic loss, with individual variations. ",
"As the symptoms in aged monkeys do not respond to DA replacement therapies, the animals are not useful models to assess cell replacement strategies. ",
"In contrast, aged animals intoxicated with MPTP present the typical motor and pathological syndrome observed after neurotoxin, plus the background aged condition associated with PD, and could be useful testing platforms, yet CBT studies in models combining aging and neurotoxins have not been reported.",
"\n\nGenetic-like NHP PD models have been induced by intracerebral injection of viral vectors encoding for mutated α-syn or administration of LB extracts \\[see review (Vermilyea and Emborg [@CR153])\\]. ",
"Adeno-associated viral (AAV) vector-induced nigral overexpression of human α-syn wild type and A53T has been shown to induce PD-like motor symptoms, significant nigral dopaminergic cell loss, and α-syn aggregates in common marmoset monkeys (Eslamboli et al. [",
"@CR48]; Kirik et al. [",
"@CR74]). ",
"AAV and lentiviral vectors encoding for A53T α-syn have also been used in cynomolgus (Koprich et al. [",
"@CR76]) and rhesus (Yang et al. [",
"@CR163]) monkeys. ",
"In both studies, A53T α-syn induced nigral cell loss and α-syn accumulation and aggregation; behavioral changes were not reported. ",
"A combination of AAV-induced overexpression of Parkin and A53T α-syn was reported in cynomolgus; although the animals had decreased striatal dopaminergic markers and α-syn accumulation and phosphorylation, no motor symptoms were observed. ",
"It should be noted that in vervet monkeys nigral injection of AAV expressing a short hairpin RNA (shRNA) to knock down α-syn induced a region-specific decrease in TH-positive nigral cell number and striatal innervation compared to animals that received scrambled shRNA; no behavioral changes were reported (Collier et al. [",
"@CR29]). ",
"Intracerebral inoculation of α-syn fibrils has been extensively used in rodents, but not yet in monkeys (e.g.: (Luk et al. [",
"@CR90]; Paumier et al. [",
"@CR106])). ",
"Instead cadaveric LB extracts have been injected into the striatum or nigra of cynomolgus monkeys with or without previous MPTP, (Recasens et al. [",
"@CR113]). ",
"The extracts induced some decreases in striatal and nigral dopaminergic markers and increases in α-syn expression, yet PD motor symptoms were not detected. ",
"It should be noted that with exception of the AAV α-syn studies in marmosets, all the other reports in genetic-like models were performed in a few subjects; further characterization and validation of the models are needed before they are used as testing platforms for CBTs. ",
"Transgenic NHP models induced by oocyte injection of lentiviral vectors encoding for mutations of interest are emerging; transgenic rhesus monkeys overexpressing mutant A53T α-syn have been reported (Niu et al. [",
"@CR104]). ",
"The authors also reported some behavioral deficits after 1.5--2.5 years of age. ",
"New technologies such as CRISPR/Cas9 genomic editing present an opportunity to create NHP models with PD associated mutations expressed at physiological levels that may help clarify the disease onset process, including motor and non-motor symptoms (Gaj et al. [",
"@CR56]). ",
"Timely evaluation of CBTs in these novel NHP models may provide clues to understand α-syn-related problems during clinical translation and define the role of CBTs in global therapies.",
"\n\nCBTs for DA cell replacement: from rodents and monkeys to PD patients {#Sec4}\n=====================================================================\n\nFetal mesencephalon and autologous adrenal medullary tissues were the first sources used to demonstrate the feasibility for DA cell replacement. ",
"In 1979, Bjorklund and Stenevi (Bjorklund and Stenevi [@CR12]) reported positive effects of fetal grafts in circling behavior of 6-OHDA-treated rats, and in 1981, Freed et al. (",
"Freed et al. [",
"@CR53]) showed adrenal graft survival in a similar model. ",
"In 1984, Morihisa and colleagues (Morihisa et al. [",
"@CR101]) transplanted adrenal medullary tissue and fetal mesencephalic cells into MPTP-treated parkinsonian rhesus monkeys and showed some survival of adrenal, but not fetal, cells. ",
"In follow-up experiments, poor survival of transplanted adrenal tissue was reported (Morihisa et al. [",
"@CR102]) yet as the PD signs ameliorated, researchers hypothesized that the intense host-derived dopaminergic sprouting in the transplanted area was responsible for the behavioral improvements. ",
"Improved graft survival was observed when methods were applied to minimize the endothelial components (Schueler et al. [",
"@CR128]). ",
"With regard to fetal mesencephalic grafts, between 1986 and 1994, 15 NHP reports were published (Bakay et al. [",
"@CR5]; Collier et al. [",
"@CR26]; Redmond et al. [",
"@CR115], [@CR116]; Sladek et al. [",
"@CR132]; Annett et al. [",
"@CR2], [@CR3]; Bankiewicz et al. [",
"@CR6]; Collier et al. [",
"@CR27]; Dubach et al. [",
"@CR36]; Elsworth et al. [",
"@CR37]; Fine et al. [",
"@CR50]; Sladek et al. [",
"@CR133]; Taylor et al. [",
"@CR146], [@CR147]) demonstrating the feasibility of the approach, as well as different degrees of antiparkinsonian effects. ",
"It should be noted that these studies were performed in a limited number of NHPs per treatment group, in most cases the area of the brain targeted was the caudate nucleus, the animals did not receive immunosuppression and the effect of antiparkinsonian medication was not evaluated (Fitzpatrick et al. [",
"@CR51]).",
"\n\nBoth CBT approaches were rapidly translated to humans. ",
"In [@CR4], Backlund et al. ",
"reported two cases of patients receiving adrenal medulla grafts resulting in mild effects, and in 1987, Madrazo and colleagues showed the first dramatic improvement of PD symptoms in two patients (Madrazo et al. [",
"@CR92]). ",
"Following these promising results, several similar case studies were undertaken, with different, less favorable outcomes \\[see review: (Redmond [@CR114])\\]. ",
"Goetz et al. ",
"reported the results of a multi-center study of 19 patients in 1989 (Goetz et al. [",
"@CR57]). ",
"The grafted patients showed minimal temporary antiparkinsonian effects, described as decreased mean severity of \"off\" time (time when the positive effects of pharmacological treatment wear off) as assessed by both the Activities of Daily Living subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab and England scale. ",
"Yet, the patients' antiparkinsonian medications could not be decreased and postoperative morbidity was considerable, due to the double surgery (abdominal and brain) required to harvest the adrenal medulla and then transplant the cells. ",
"Postmortem results revealed poor cell survival and localized host regional neuronal sprouting, similar to the results in the NHP experiments.",
"\n\nWith regard to fetal mesencephalon grafting, after multiple case reports in PD patients \\[see (Freed et al. [",
"@CR54]; Redmond et al. [",
"@CR117])\\] the National Institute of Health (NIH) funded two prospective, double blind, randomized control trials aiming to assess the efficacy and safety of transplanting fetal mesencephalic tissue to treat PD. ",
"The Freed et al. (",
"Freed et al. [",
"@CR55]) trial consisted of 40 PD patients: 20 received bilateral post-commissural putaminal grafts of ventral mesencephalic fetal neurons, and 20 had a burr hole drilled into their skull as a sham procedure. ",
"Immunosuppression was not administered. ",
"The fetal cells were cultured for 1 week prior to transplantation. ",
"The primary endpoint was patient self-reports on activities of daily living (recorded at home for 12 months). ",
"The Olanow et al. ",
"trial ([@CR105]) consisted of 34 PD patients: 11 received bilateral post-commissural putaminal grafts of ventral mesencephalic fetal neurons from one donor fetus, 12 from four donor fetuses, and 11 received bilateral sham procedures. ",
"Oral cyclosporine (CsA) immunosuppression was administered to all patients starting 2 weeks prior to surgery and continued for 6 months after grafting. ",
"The primary endpoint was the UPDRS motor subscore. ",
"Both trials did not show significant differences between treatment groups, although further analysis revealed that patients younger than 60 years old or with less severe PD at baseline had improvements in their parkinsonian signs. ",
"Positron Emission Tomography (PET) imaging demonstrated increased \\[^18^F\\]fluorodopa uptake in the grafted areas suggesting graft survival that was later confirmed by postmortem examinations.",
"\n\nAn unexpected outcome for both trials was the occurrence of what was then named \"runaway\" dyskinesias, also known as graft-induced dyskinesias (GIDs). ",
"Unlike typical PD dyskinesias that are induced by chronic long-term [l]{.smallcaps}-DOPA administration \\[see (Bezard et al. [",
"@CR11])\\], these uncontrolled abnormal movements were not associated with antiparkinsonian medication and did not ameliorate with reduction or cessation of [l]{.smallcaps}-DOPA treatment. ",
"GIDs were observed in a quarter of the grafted patients in the Freed et al. ",
"and half the Olanow et al. ",
"trials.",
"\n\nSeveral issues may have contributed to the onset of GIDs. ",
"As patients that received the fetal mesencephalic grafts presented focal points of increased PET signal (Ma et al. [",
"@CR91]), it was proposed that the grafts produced \"hot spot\" regions in which DA was being excessively released. ",
"To answer the question of whether there was an association between GIDs and focal versus widespread distribution of cell grafts in the striatum (Maries et al. [",
"@CR94]), 6-OHDA-treated rats received either a focal striatal transplant of 200,000 cells, or the same number of cells across six different striatal locations. ",
"The experiment showed that GIDs were only present in the focal graft recipients. ",
"It also brought to light that the number of functional cells within a focal site might be of equal concern. ",
"Another proposed contributing factor for GIDs was that the chronic [l]{.smallcaps}-DOPA treatment preceding the transplantation may have \"primed\" the patients to have dyskinesias. ",
"In 6-OHDA-intoxicated rats, [l]{.smallcaps}-DOPA pre-treatment affected graft integration and functionality, although GIDs were present with or without [l]{.smallcaps}-DOPA pre-treatment (Steece-Collier et al. [",
"@CR139]). ",
"A study in 24 systemic MPTP-treated vervet monkeys (*Chlorocebus sabaeus*) assessed whether priming the animals to develop [l]{.smallcaps}-DOPA-induced dyskinesias (LIDs), and then injecting allogeneic fetal dopaminergic cells in a \"spread\" or \"hotspot\" pattern would affect the development of GIDs (Kordower et al. [",
"@CR80]). ",
"The investigators did not detect GIDs in any of the monkeys, regardless of cell distribution or condition. ",
"Possible species differences could be at play as well as methods of cell preparation. ",
"A critical limitation of this report is that the animals' MPTP-induced parkinsonism spontaneously improved overtime. ",
"All the monkeys presented similar mild PD scores with no differences between grafted and control subjects. ",
"Thus, the graft's antiparkinsonian efficacy or graft potential to produce true functional hotspots could not be evaluated.",
"\n\nInflammation has also been proposed to promote the onset of GIDs through aberrant synapse formation between grafted neurons and host striatal medium spiny neurons \\[MSNs; (Soderstrom et al. [",
"@CR135])\\]. ",
"This theory was derived from the observation of GIDs in patients who did not receive immunosuppression following fetal engraftment or those that had been recently taken off an immunosuppressive regimen. ",
"Interestingly, the evaluation of spine density maintenance in MSNs through administration of slow-release pellets of the calcium channel antagonist nimodipine has led to intriguing evidence about the importance of preserving MSNs for reducing LIDs and transiently reducing GIDs (Soderstrom et al. [",
"@CR136]). ",
"Patient and rodent studies have also highlighted that serotonergic and noradrenergic neurotransmission either by host innervation or by mixed-cell grafts may contribute to GIDs (Shin et al. [",
"@CR130]). ",
"As the cause of GIDs is being unraveled, new strategies aiming to prevent or decrease GIDs are being evaluated.",
"\n\nAnother potential complication for CBTs was uncovered in 2008, when follow-up postmortem analysis of PD patients treated a decade earlier with fetal grafts found LB-like pathology in the grafted cells (Kordower et al. [",
"@CR78]; Li et al. [",
"@CR87]). ",
"Although it is unclear how much the aggregates affected the functionality of the grafts, the implication that PD could be transferred to the grafted cells reverberated throughout the field (see \"[Parkinson's disease: then and now](#Sec2){ref-type=\"sec\"}\"). ",
"A preliminary confirmation of α-syn being transferred into grafted cells was obtained in rats injected with adeno-associated viral vector serotype 6 encoding for human α-syn into the striatum after fetal cell engraftment (Kordower et al. [",
"@CR79]).",
"\n\nNew clinical trials utilizing fetal mesencephalic tissue for DA cell replacement are currently ongoing in Canada, Europe (Transeuro), South Korea and Mexico (listed in: clinical trials.gov and isrctn.com). ",
"The investigators leading these trials aim to optimize the approach by taking advantage of the knowledge gained from the clinical and preclinical studies described above.",
"\n\nAdditional clinical trials using CBTs for DA cell replacement in PD {#Sec5}\n===================================================================\n\nA number of alternative sources for dopaminergic neurons, including mesencephalic fetal porcine cells, cadaveric human retinal-pigmented epithelium (hRPE) and autologous sympathetic and carotid ganglia, have been investigated to avoid the surgical complication of using autologous adrenal medullary tissue and to overcome the practical and ethical limitations of using human fetal cells for large-scale clinical applications. ",
"NHP preclinical studies were only performed for hRPE. ",
"The DA-producing cells were attached to gel microcarriers (Spheramine®) and placed into the striatum of parkinsonian monkeys. ",
"The grafts improved motor function and postmortem analysis showed cell survival and a mild inflammatory reaction (Watts et al. [",
"@CR159]). ",
"Controlled clinical trials for hRPE as well as all the sources listed above failed to show a significant antiparkinsonian effect (Fitzpatrick et al. [",
"@CR51]).",
"\n\n*Ex vivo* gene therapy for PD {#Sec6}\n=============================\n\n*Ex vivo* gene therapy originated as a method to engineer cells for delivery of therapeutic molecules (Raymon et al. [",
"@CR112]). ",
"The cells are typically genetically modified using viral vectors. ",
"The main advantage of this method compared to direct intracerebral viral vector delivery (in vivo gene therapy) is that the transfected cells can be monitored before transplantation for the effects of viral infection and the production of a foreign protein. ",
"Safety, genetically engineered, \"tricks\" have been developed to curtail unwanted side effects, such as regulatable promoters to stop gene expression and kill-switches to terminate the cells and completely stop product synthesis.",
"\n\n*Ex vivo* gene therapy strategies have been developed for DA replacement and trophic factor delivery with variable results. ",
"MPTP-intoxicated rhesus monkeys received autologous fibroblasts genetically engineered to produce tyrosine hydroxylase \\[the rate-limiting enzyme for DA production; e.g., (Bankiewicz et al. [",
"@CR7])\\] with minimal antiparkinsonian effects. ",
"Glial cell line-derived neurotrophic factor (GDNF) producing C2C12 cells were encapsulated and transplanted into MPTP-treated baboons (Kishima et al. [",
"@CR75]) inducing only temporary improvements of their parkinsonian symptoms, probably due to the low survival of encapsulated cells which led to a low and variable protein production. ",
"New cell sources for ex vivo gene therapy (see below) are emerging. ",
"For example, human neuroprogenitor cells (hNPCs) have been shown to survive and locally produce GDNF in the brain of parkinsonian immunosuppressed rats and monkeys (Behrstock et al. [",
"@CR9]; Emborg et al. [",
"@CR40]). ",
"Although the clinical translation for PD has not been pursued (probably due to the poor results of GDNF protein delivery trials; (Richardson et al. [",
"@CR121])), a clinical trial for amyotrophic lateral sclerosis is currently ongoing (<http://www.clinicaltrials.gov>).",
"\n\nStem cells as sources of cell lines {#Sec7}\n===================================\n\nBiological research breakthroughs and development of new technologies have paved the way for the identification of stem cells (SCs) as new cell sources for regenerative medicine approaches. ",
"SCs are defined by their self-renewal capacity and their potential for becoming a different cell type with a specialized function. ",
"These properties allow researchers to create cell lines to be repurposed for in vitro studies and transplantation.",
"\n\nhNPCs are typically obtained from the germinal layer of a fetal brain. ",
"Although they are not pluripotent SCs (they are already fated toward a brain cell phenotype), in vitro hNPCs can be expanded and differentiated to a DA phenotype (Sanchez-Pernaute et al. [",
"@CR124]). ",
"In MPTP-treated monkeys, hNPCs induced improvements of PD signs and postmortem analysis has shown their survival and migration. ",
"Their cell progeny seemed to differentiate in vivo into DA-like neurons and glial phenotypes and overall have a \"homeostatic\" impact (Bjugstad et al. [",
"@CR13], [@CR14]; Redmond et al. [",
"@CR118]). ",
"It should be noted that NPCs have been found in the adult human and NHP brains (Eriksson et al. [",
"@CR46]; Gould et al. [",
"@CR60]). ",
"These findings, plus earlier studies in rodents, refuted the idea that the adult brain is incapable of forming new neurons (Altman and Das [@CR1]; Buzanska et al. [",
"@CR19]; Kaplan and Hinds [@CR69]; Kempermann et al. [",
"@CR71]). ",
"The option of recruiting resident hNPCs for brain repair has tantalizing possibilities but its utility has not yet been proven (Rakic [@CR111]). ",
"Interestingly, one study grafted autologous adult cortical cells (cultured for a couple of weeks) into the caudate of MPTP-intoxicated vervet monkeys. ",
"Grafted cells were found 4 months post-surgery and their presence was associated with increased local levels of GDNF (Brunet et al. [",
"@CR18]).",
"\n\nBone marrow, umbilical cord blood and adult adipose-derived stromal tissue (Fallahi-Sichani et al. [",
"@CR49]; Levy et al. [",
"@CR86]; McCoy et al. [",
"@CR96]) have been proposed as SC sources as they can be obtained for autologous grafts. ",
"Although NHP studies with these cells have not been performed, evaluation in rodents suggests that they produce trophic factors that could be beneficial for PD. ",
"Several clinical trials are currently ongoing to test the safety and efficacy after administration of mesenchymal stem cells through intravenous, intracarotid or intranasal routes (clinicaltrials.gov). ",
"Intravenous infusion of adipose-derived stromal vascular fraction cells is also being investigated for safety and efficacy, as well as for benefits to the quality of daily living in PD patients.",
"\n\nEmbryonic stem cells (ESCs) obtained from blastocysts are pluripotent SCs, thus they have the potential to become any cell of the body. ",
"In 1995, Thomson et al. (",
"Thomson et al. [",
"@CR148]) reported the isolation of ESCs from rhesus monkeys. ",
"Common marmoset ESCs were isolated in 1996 (Thomson et al. [",
"@CR149]), followed in 1998 by human ESCs \\[hESC; (Thomson et al. [",
"@CR150])\\]. ",
"Differentiation of ESCs into a DA phenotype was first accomplished in mice (Lee et al. [",
"@CR84]), followed a few years later in human (Perrier et al. [",
"@CR107]; Yan et al. [",
"@CR162]) and rhesus (Takagi et al. [",
"@CR142]). ",
"Since then, investigators have been looking for more efficient ways to produce mesencephalic DA neurons, as well as to solve the problems of intracerebral graft survival and other challenges identified by the fetal tissue trials. ",
"The ethical dilemma of the cells' origin triggered the 2001 restriction of USA federal funding for hESC research to studies performed on authorized cell lines, limiting the chances for creating new ones. ",
"The 8-year ban on federal funding for ESC research was lifted on March 9, 2009.",
"\n\nParthenogenesis, somatic cell nuclear transfer and altered somatic cell nuclear transfer have been proposed as alternative sources of pluripotent SCs (Kastenberg and Odorico [@CR70]). ",
"In NHPs, parthenogenesis has been used to generate an SC line from cynomolgus monkeys (cyno-1). ",
"Parthenogenesis is an asexual form of reproduction; although mammalian eggs cannot fully develop, they can provide blastocysts to generate parthenogenesis-derived ESCs. ",
"Using the cyno-1 cell line, investigators differentiated the cells into dopaminergic neurons (Perrier et al. [",
"@CR107]). ",
"These cells were successfully transplanted into 6-OHDA-treated rats and one MPTP-treated cynomolgus monkey (Sanchez-Pernaute et al. [",
"@CR126]). ",
"hNPCs generated from parthenogenetic hSCs (hpNPCs) have been evaluated in rats and MPTP-lesioned vervet monkeys immunosuppressed with a combination of cyclosporine, prednisone and azathioprine (Gonzalez et al. [",
"@CR58], [@CR59]). ",
"The investigators first demonstrated graft survival and increased DA striatal levels 3 months post-surgery in two NHPs (Gonzalez et al. [",
"@CR58]). ",
"Antiparkinsonian efficacy of hpNPCs was then evaluated in 18 monkeys (Gonzalez et al. [",
"@CR59]). ",
"The animals were matched according to disability and assigned to one of 3 treatment groups: vehicle (*n* = 6), low (*n* = 6) and high (*n* = 6) cell dosing. ",
"Cells were inoculated in the caudate, putamen and substantia nigra. ",
"Twelve months post-grafting, the low dose animals showed significant behavioral improvements compared to their baseline condition; however, no significant differences between vehicle and dosing groups were detected. ",
"A clinical trial to assess the safety and tolerability of hpNPCs in PD is currently ongoing in Australia (clinical trials.gov). ",
"Three patient groups (each to receive different cell number doses) of four patients each who have moderate to severe PD will receive between 30 and 70 million cells injected into the striatum and substantia nigra.",
"\n\nThe development of induced pluripotent stem cells (iPSCs) from somatic cells (Takahashi et al. [",
"@CR143], [@CR144]; Yu et al. [",
"@CR164]) has further facilitated the production of additional cell lines for regenerative medicine and disease modeling purposes. ",
"iPSCs represent a major advancement towards personalized medicine as cells can be generated from the prospective recipient. ",
"iPSCs have been generated from macaque (Deleidi et al. [",
"@CR34]; Liu et al. [",
"@CR88]) and marmoset (Tomioka et al. [",
"@CR151]; Wiedemann et al. [",
"@CR160]; Wu et al. [",
"@CR161]; Vermilyea et al. [",
"@CR154]) monkeys. ",
"The derivation of iPSCs has been modified in recent years using expression plasmids that do not integrate into the host DNA, which increases their safety for clinical translation.",
"\n\nNHP studies assessing SC-derived DA cell replacement strategies {#Sec8}\n===============================================================\n\nOver the past decade, several NHP studies have analyzed the potential use of SCs from different sources and at different stages of differentiation for DA cell replacement (Table [2](#Tab2){ref-type=\"table\"}).Table 2Peer-reviewed publications in NHP models of PD evaluating SCs as sources for dopaminergic cell replacementReferencesHost speciesCell species; graft typeCell typeCell labelingTransplant locationModel*n*Immunosup.[l]{.smallcaps}-DOPABehavioral testPET imagingDurationTakagi et al. ([",
"@CR142])Cynomolgus (*M. fascicularis*)Cynomolgus; allograftESC-derived DAergic progenitorsBrdUBilateral putamen; 3 tracts per side, each with 4 depositsMPTP i.v. (",
"0.4 mg/kg; twice weekly for 7 weeks)6CsA 10 mg/kgNoneClinical rating\\[^18^F\\]DOPA14 weeksCynomolgus (*M. fascicularis*)N/ASham-operatedN/AN/AMPTP i.v. (",
"0.4 mg/kg; twice weekly for 7 weeks)4CsA 10 mg/kgNoneClinical rating\\[^18^F\\]DOPA14 weeksKikuchi et al. ([",
"@CR72])Cynomolgus (*M. fascicularis*)Human; xenograftiPSC-derived DAergic progenitorsNoneBilateral putamen (d28 to right, d42 to left); 6 tracts per side, each with 4 depositsMPTP i.v. (",
"0.4 mg/kg; twice weekly until symptoms persisted)1FK506 0.05 mg/kgNoneClinical rating, spontaneous movements, Gross Movements, Raisin pick-up test\\[^18^F\\]DOPA, \\[^11^C\\]DTBZ, \\[^11^C\\]PE2I, \\[^18^F\\]FLT6 monthsDaadi et al. ([",
"@CR31])Green monkey (*C. sabaeus*)Human; xenograftESC-derived DAergic progenitorsGFPCaudate and SNMPTP i.m. (",
"2.25 mg/kg cumulative dose; administered over 5-day period)4CsA 5 mg/kg/day Prednisone 2 mg/kg tapering to 0.6 mg/kg/day Azathioprine 5 mg/kg/day reduced to 1 mg/kg/dayNoneNoneNone2 monthsKriks et al. ([",
"@CR82])Rhesus (*M. mulatta*)Human; xenograftESC-derived DAergic progenitorsGFPBilateral posterior caudate, pre-commissural putamen and overlying white matter (GFP to one side, unmarked to other); 3 tracts per sideMPTP ICA (3 mg) followed by weekly i.v. ",
"administration (dose n.r.)2CsA 30 mg/kg tapered to 15 mg/kgNoneNoneNone1 monthEmborg et al. ([",
"@CR43])Rhesus (*M. mulatta*)Human; xenograftESC-derived DAergic progenitorsGFPUnilateral (ipsi-MPTP) rostral, medial and caudal caudate and putamen, and SN; 7 tracts totalMPTP ICA (3 mg)3CsA 40--50 mg/kgNoneNoneNone3 monthsEmborg et al. ([",
"@CR42])Rhesus (*M. mulatta*)Rhesus; autograftiPSC-derived DAergic progenitorsGFPUnilateral (ipsi-MPTP) precommisural and commissural caudate, pre-commisural, commissural and postcommisural putamen, and SN; 6 tracts totalMPTP ICA (3 mg)3NoneNoneNoneNone6 monthsWakeman et al. ([",
"@CR157])Green monkey (*C. sabaeus*)Human; xenograftESC-derived DAergic progenitorsGFPCaudate and SNMPTP i.m. (",
"2 mg/kg cumulative dose; administered over 5-day period)2Azathioprine, CsA and prednisoloneNoneNoneNone6 weeksHallett et al. ([",
"@CR63])Cynomolgus (*M. fascicul ris*)Cynomolgus; autograftiPSC-derived DAergic progenitors (Cooper et al. [",
"@CR30] protocol)NoneUnilateral postcommissural putamen; 4 tracts totalMPTP i.v. (",
"0.15--0.3 mg/kg) every 1--2 weeks1NoneNoneClinical rating, activity monitoring, FMS\\[^11^C\\]CFT2 yearsCynomolgus (*M. fascicularis*)Cynomolgus; autograftiPSC-derived DAergic progenitors (Sundberg et al. [",
"@CR141] protocol)NoneUnilateral postcommissural putamen; 4 tracts totalMPTP i.v. (",
"0.15--0.3 mg/kg) every 1--2 weeks2NoneNoneClinical rating, activity monitoring, FMS\\[^11^C\\]CFT2 yearsCynomolgus (*M. fascicularis*)Cynomolgus; allograftESC-derived DAergic progenitors (Sanchez-Pernaute et al. [",
"@CR125] protocol)NoneUnilateral putamenMPTP i.v. (",
"0.15--0.3 mg/kg) every 1--2 weeks3NoneNoneClinical rating, activity monitoring, FMS\\[^11^C\\]CFT1 yearCynomolgus (*M. fascicularis*)N/AN/AN/AN/AMPTP i.v. (",
"0.15--0.3 mg/kg) every 1--2 weeks4NoneNoneClinical rating, activity monitoring, FMS\\[^11^C\\]CFT2 yearsWang et al. ([",
"@CR158])Cynomolgus (*M. fascicularis*)Cynomolgus; autograftiPSC-derived DAergic progenitorsGFP and Feridex IVUnilateral (ipsi-MPTP) rostral, intermediate and caudal caudate and putamen, and SN; 7 tracts totalMPTP ICA (3 mg)1NoneNoneClinical ratingNone6 monthsCynomolgus (*M. fascicularis*)N/AVehicleN/AUnilateral (ipsi-MPTP) rostral, intermediate and caudal caudate and putamen, and SN; 7 tracts totalMPTP ICA (3 mg)3NoneNoneClinical ratingNone6 months*Immunosup* immunosuppression, *PET* positron emission tomography, *ESC* embryonic stem cell, *iPSC* induced pluripotent stem cell, *DAergic* dopaminergic, *BrdU* 5-Bromo-2′-deoxyuriding, *MPTP* 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, *L-DOPA* L-3,4-dihydroxyphenylalanine, *ipsi* ipsilateral, *i.v.* ",
"intravenous, *ICA* intracarotid artery, *mg* milligram, *kg* kilogram, *CsA* Cyclosporine A, *GFP* green fluorescent protein, *n.r.* ",
"not reported, *N/A* not applicable, *FMS* fine motor skills, *SN* substantia nigra, *\\[18 F\\]DOPA* 6-\\[18 F\\]fluoro-[l]{.smallcaps}-3,4-dihydroxyphenylalanineresentatio, *\\[11 C\\]DTBZ* \\[11 C\\]dihydrotetrabenazine, *\\[11 C\\]PE2I* (*E*)-*N*-(3-iodoprop-2-enyl)-2β-carbo\\[11 C\\]methoxy-3β-(4-methylphenyl)nortropane, *\\[18 F\\]FLT* 3′-deoxy-3′3\\[18 F\\]fluorothymidine\n\nTakagi et al. ",
"investigated monkey ESC-derived neural progenitors capable of producing dopaminergic neurons for transplantation into an NHP model of PD (Takagi et al. [",
"@CR142]). ",
"ESCs from a cynomolgus monkey (*Macaca fascicularis*) were differentiated on stromal cells with the addition of FGF2 and FGF20, and labeled in vitro with BrdU for postmortem identification. ",
"The ESC-derived dopaminergic progenitor cells were then transplanted into systemic MPTP-treated cynomolgus monkeys. ",
"Beginning at 10 weeks post-brain surgery, the neurological parkinsonian scores of animals receiving grafts (*n* = 6) decreased significantly (*p* \\< 0.05) compared with sham controls (*n* = 4) and were associated with a significant increase in striatal \\[^18^F\\]fluorodopa uptake observed by in vivo PET. ",
"Postmortem analysis at 14 weeks post-grafting verified survival of BrdU/TH colabeled neurons. ",
"Neither mitosis (identified by Ki67-immunoreactivity) nor tumor formation was observed in animals that received ESC-derived neuronal transplants.",
"\n\nAiming for human translation, Kriks et al. ",
"differentiated floorplate-derived dopaminergic neurons from human ESCs (hESCs), labeled half of the cells with GFP and then transplanted the labeled cells into one side of the striatum, and unlabeled cells to the other, of two systemic MPTP-treated rhesus monkeys immunosuppressed by CsA administration (Kriks et al. [",
"@CR82]). ",
"At one-month post-transplantation, grafted cells were observed in the posterior caudate and pre-commissural putamen as well as Iba1+cells, suggesting immunoreaction by the host. ",
"Daadi et al. [",
"@CR31] and Wakeman et al. ",
"2014 tested hESC-derived DAergic neurons expressing GFP in the caudate and nigra of MPTP-intoxicated vervet monkeys immunosuppressed with cyclosporine, prednisone and azathioprine (Daadi et al. [",
"@CR31]; Wakeman et al. [",
"@CR157]). ",
"The 4 monkeys treated by Daadi et al. ",
"showed a few TH-positive grafted cells, extending neurite outgrowth and expressing synaptic markers 2 months post-surgery; cell counts of grafts and immunological response were not reported. ",
"In the Wakeman et al. ",
"study, the two monkeys presented co-expression of GFP and βIII-tubulin positive cells but not TH, dopamine transporter (DAT) or other markers of midbrain floorplate differentiation 6 weeks after grafting, suggesting de-differentiation; evaluation of inflammatory markers was not reported. ",
"Emborg et al. ",
"also studied hESC-derived DAergic neurons; however, the brain evaluations were performed 3 months after grafting. ",
"The cells were genetically engineered to express GFP and grafted in the striatum and nigra of three rhesus monkeys that received MPTP by carotid artery injection. ",
"The three animals were immunosuppressed by daily oral dosing of cyclosporine that was started 48 h prior to grafting (Emborg et al. [",
"@CR43]). ",
"Postmortem analysis at 3 months revealed graft survival in only one of the three monkeys. ",
"The graft was infiltrated with GFAP, CD68 and CD45 immunoreactive cells, suggesting ongoing immune reaction despite immunosuppression. ",
"These results further demonstrated that immunological issues are a major concern for xenografts and that allogeneic or autologous transplants may render better graft survival and integration.",
"\n\nGrafts of human iPSC (hiPSC)-derived dopaminergic neurons have also been attempted. ",
"In 2011, Kikuchi et al. ",
"reported their evaluation of grafting into one FK506 immunosuppressed MPTP-treated monkey (Kikuchi et al. [",
"@CR72]). ",
"The hiPSCs were differentiated into DAergic neural progenitors in feeder-free conditions but were not labeled. ",
"Day 28 (d28) and d42 neurospheres were transplanted into the right and left putamen, respectively. ",
"Graft size and function was evaluated at 1, 3 and 6 months by MRI and at 6 months by PET using the radioligands 6-\\[^18^F\\]fluoro-[l]{.smallcaps}-3,4-dihydroxyphenylalanine (\\[^18^F\\]DOPA), \\[^11^C\\]dihydrotetrabenazine (\\[^11^C\\]DTBZ), (*E*)-*N*-(3-iodoprop-2-enyl)-2β-carbo\\[^11^C\\]methoxy-3β-(4-methylphenyl)nortropane (\\[^11^C\\]PE2I), to assess for DA synthesis, vesicle transport, and DA reuptake, and with 3′-deoxy-3′3\\[^18^F\\]fluorothymidine (\\[^18^F\\]FLT) to visualize cell proliferation. ",
"Interestingly, MRI showed increase in graft size on the side of grafted d28 neurospheres compared to d42. ",
"In general, PET did not identify any meaningful graft-related uptake, with exception of increased binding of (\\[^11^C\\]PE2I) in the d42-grafted putamen, suggesting cell differentiation. ",
"Neurological evaluation throughout the study showed no behavioral recovery. ",
"Postmortem analysis 6 months after transplantation revealed graft survival; d42 spheres produced higher amounts of TH+cells compared with the d28 spheres, while also maintaining some progenitor populations, which explains the observed intracerebral graft growth; immunological response was not reported.",
"\n\nA major advantage of iPSC technology is that patient-specific cells can be generated for grafting, which minimizes host immune reaction and avoids immunosuppression. ",
"In 2013, Emborg et al. ",
"reported their findings in three rhesus monkeys that received an intracarotid artery injection of MPTP, followed 6 months later with autologous iPSC-derived neuroprogenitors into the striatum and nigra, without immunosuppression \\[Fig.",
" [2](#Fig2){ref-type=\"fig\"}; (Emborg et al. [",
"@CR42])\\]. ",
"For identification, the cells were genetically modified to express GFP. ",
"Six months post-surgery, brain analysis showed abundant GFP-positive neuron-like cells, which integrated with the host brain and expressed TH. ",
"Most importantly, infiltration of host immune cells observed by CD3 and CD8 reactivity was minimal while HLA-DR and GFAP were mild, similar to MPTP-induced inflammation. ",
"Although neurological scores were not reported, it was mentioned that the animals' PD motor signs did not improve; the lack of recovery was probably due to low numbers of DAergic neurons grafted. ",
"Shortly after, Morizane et al. ",
"compared autologous and allogeneic transplantation of iPSC-derived neural cells in intact cynomolgus monkeys (Morizane et al. [",
"@CR103]). ",
"As expected, the allogeneic transplants elicited a marked immune response observed, with in vivo PET, as increased uptake of \\[^11^C\\]PK11195 compared to the autografts, further emphasizing the benefit of self-derived cells for translational applications.",
"Fig.",
" 2An example of a grafted autologous rhesus IPSC-derived dopaminergic neuron labeled with GFP (*green*) and immunostained against TH (*red*); DAPI (*blue*). *",
"Scale bar* 50 μm\n\nIn 2015, Hallett et al. ",
"reported that the differentiation protocols used to generate iPSC-derived DAergic neurons could be a factor for survival and functional integration of grafted cells (Hallett et al. [",
"@CR63]). ",
"After ten cynomolgus monkeys were rendered stably parkinsonian through systemic MPTP administration, the animals received iPSC- or ESC-derived DAergic grafts differentiated following three different protocols: (Cooper et al. [",
"@CR30]) (*n* = 1), (Sundberg et al. [",
"@CR141]) (*n* = 2), and a modified (Sanchez-Pernaute et al. [",
"@CR125]) (*n* = 3; for ESCs); no transplanted animals (*n* = 4) were used as controls. ",
"The grafts derived from the Sanchez--Pernaute differentiation protocol did not survive and were thus separately analyzed as the non-surviving transplant group, compared with the Cooper- and Sundberg-derived grafts. ",
"Only the animal that received cells using the Cooper differentiation protocol presented functional recovery of daytime activity and movement analysis. ",
"The animal recovered to pre-MPTP levels for global activity, and improved in fine motor skills after 2 years. ",
"\\[^11^C\\]CFT PET imaging corroborated graft function with increased uptake around the transplant site. ",
"The lack of functional recovery and survival of the Sundberg and Sanchez-Pernaute grafts provide evidence that DAergic differentiation patterning may be critical for functional integration.",
"\n\nWang et al. ",
"also assessed the feasibility of autologous iPSC-derived DAergic neuron grafts to one MPTP-treated cynomolgus monkey (Wang et al. [",
"@CR158]). ",
"Throughout the 6-month survival period, only between 6--8, and 22--24 weeks, the transplant monkey appeared to have an improved clinical rating compared with the control monkeys (*n* = 3). ",
"Postmortem analysis in the transplanted monkey showed graft survival and TH immunoreactivity.",
"\n\nAn examination of these SC-based studies highlights that, similar to the fetal tissue reports in NHPs, they were mainly feasibility/safety experiments, performed in a few animals (with exception of Takagi et al. [",
"@CR142]) and focusing on assessing cell survival, cell proliferation/tumor formation and whether the grafted cells integrated and showed a DA phenotype. ",
"Some antiparkinsonian effects were described. ",
"Considering the ongoing improvements on SC research, this approach shows responsible use of the NHP resource and also underscores that the results should be kept in perspective with the limitations of the experimental design and outcome measures utilized.",
"\n\nNigral vs. striatal targets {#Sec9}\n===========================\n\nFor DA cell replacement, the field strives to recreate and purify A9 DA nigral cells, yet in patients, the cells have been mainly transplanted in the postcommisural putamen \\[see review: (Redmond [@CR114])\\] with a few exceptions in which the fetal nigral cells were placed in the nigra and putamen \\[e.g.: (",
"Mendez et al. [",
"@CR99]); Fig.",
" [3](#Fig3){ref-type=\"fig\"}\\]. ",
"Putaminal targeting aims to provide DA in the area where needed, while nigral grafting is proposed to restore the nigrostriatal pathway, including the regulation of grafted cell activity and restoring the DA tone in the substantia nigra pars reticulata.",
"Fig.",
" 3Graphical depiction of a rhesus monkey brain hemisphere in intact and PD-like conditions and with striatal and nigral grafts. ",
"The main area of projection of nigral dopaminergic neurons is the striatum, which is composed by the caudate nucleus and putamen. ",
"In PD and PD-like conditions (e.g.: after MPTP intoxication), nigral dopaminergic neurons die; thus, striatal dopamine (DA) is decreased. ",
"Grafting of DA-producing cells into the striatum is envisioned as a way to ensure DA availability in the area of projection. ",
"Nigral grafts are proposed as a way to reconstruct the nigrostriatal pathway. *",
"Cd* caudate, *ic* internal capsule, *Put* Putamen, *ac* anterior commissure, *cc* corpus callosum, *Ctx* cortex\n\nTheoretically, the nigral location is a most optimal method for brain repair, yet an obstacle for its application is the long distance to be covered by the axons of cells inoculated in the nigra to reach their striatal targets. ",
"The successful reconstruction of the nigrostriatal pathway requires time for axonal extension, axonal guidance and ultimately recognition and synaptic connection with targets. ",
"In rodents, the feasibility and advantages of the approach have been reported using fetal cells (Mendez et al. [",
"@CR98]) and ESCs (Grealish et al. [",
"@CR61]), observing positive behavioral effects as soon as 6 weeks post-fetal grafting and 18 weeks with ESC-derived DA cells, with the latter requiring more time to mature and integrate in the host. ",
"In NHPs and humans, the nigrostriatal distance is greater, which means that the time needed after grafting to observe behavioral benefits may also increase; therefore, multisite grafting has been preferred.",
"\n\nThe feasibility of grafting fetal midbrain cells in the nigra (Collier et al. [",
"@CR28]) or in combination with fetal striatal grafts for axonal guidance (Sladek et al. [",
"@CR134]) has been demonstrated in MPTP-treated vervet monkeys; in both studies axonal extension through the nigrostriatal pathway and some modest caudal putamen reinnervation was observed at 6 months; although follow-up studies of co-grafting fetal nigra and striatum had limited effect (Redmond et al. [",
"@CR119]). ",
"Localized delivery of trophic factors has been proposed as a method to stimulate and guide axonal growth. ",
"Striatal GDNF overexpression via AAV2 vectors was reported to enhance the survival and outgrowth of fetal dopamine neurons implanted in the striatum (Elsworth et al. [",
"@CR38]). ",
"A follow-up comparison between MPTP-intoxicated monkeys treated with AAV5 GDNF in the caudate nucleus or solid fetal midbrain grafts in the caudate and putamen or a combination of AAV-GDNF and fetal grafts or buffered saline solution did not reveal greater functional improvement in the AAV-GDNF and fetal grafts monkeys during the 8 months of observation (Redmond et al. [",
"@CR120]). ",
"AAV2-induced overexpression of GDNF in the caudate supported outgrowth of fetal midbrain grafts maximally observed at 22 months post-grafting (Redmond et al. [",
"@CR119]), as well as stimulated neurite extension and dopaminergic differentiation of hNC grafts, both placed in the nigra of MPTP monkeys (Wakeman et al. [",
"@CR156]). ",
"The studies suggest that reconstruction of the nigrostriatal pathway can be achieved and that research on methods aiming to promote and guide axonal growth is needed.",
"\n\nThe future of CBTs and NHP studies {#Sec10}\n==================================\n\nNHP studies have paved the way for the first clinical trials using CBTs for PD. ",
"Although the number of monkey experiments and/or total number of animals was a fraction compared to rodent studies, they provided key evidence that CBTs could be used to treat PD. ",
"NHP experiments have facilitated the optimization of cell collection and preparation methods, cell viability, as well as identify potential brain targets. ",
"Today, old approaches are being re-evaluated and optimized and new ones are being developed; some are being translated into the clinic (Barker [@CR8]). ",
"NHP research can provide an even more crucial insight into CBTs, but as a limited resource, prioritization of issues to be evaluated will be critical. ",
"How cells are prepared and stored affect engraftment, the methods of delivery, the choice of targets and related timelines of recovery are basic questions that still need to be solved and tested in NHPs to improve CBT outcome. ",
"The response of the host to the candidate CBT encompasses a different set of topics related to efficacy, safety (e.g.: prevention of GIDs), immunomodulation and inflammatory response and propagation of α-syn. ",
"Each of these issues can also benefit from careful NHP research.",
"\n\nSeveral groups are invested in the development of the optimal cell for transplantation, working on generating cell lines of \"superdonors\" with immunological compatibility and improving the methods of cryoprotection to facilitate clinical application, as creating a cell line per individual to be treated would be a daunting task. ",
"While the idea of testing in NHPs the same cell lines to be grafted to humans is compelling, current data presented in this review highlight the limitations of the xenograft approach with current immunosuppression paradigms. ",
"Thus, a more parsimonious approach would be to produce equivalent cells derived from the same species, at least until the NHP equivalent of severe combined immune deficiency (SCID) mice becomes available (Sato et al. [",
"@CR127]).",
"\n\nDue to the brain volume and complexity of NHPs, questions regarding intracerebral targets and graft distribution will benefit from NHP studies and noninvasive imaging approaches. ",
"For example, great strides have been made towards the development and improvement of intraoperative MRI (iMRI) methods (Mislow et al. [",
"@CR100]). ",
"Silvestrini et al. (",
"Silvestrini et al. [",
"@CR131]) used real-time iMRI (RT-iMRI) for cell transplantation into a swine and cadaveric human head as a concept for application in the human brain. ",
"The platform technology utilizes a radially branched deployment strategy to access multi-directional deposit sites along a single cannula insertion tract. ",
"Our group modified an RT-iMRI delivery system that has a pivot point base, a clear silica cannula and inline pressure monitoring system (Emborg et al. [",
"@CR41], [@CR44]) for the in vivo delivery of DAergic progenitor cell spheres into the putamen of a rhesus monkey \\[Fig.",
" [4](#Fig4){ref-type=\"fig\"}; (Vermilyea et al. [",
"@CR155])\\]. ",
"Malloy et al. ([",
"@CR93]) used an MRI-compatible delivery system for MRI monitoring of the distribution of cells pre-labeled with a contrast agent into a baboon basal ganglia. ",
"These new MRI-based imaging methods can increase the safety and accuracy of the grafting procedures and facilitate the evaluation of different targeting sites. ",
"In that regard, imaging technologies, such as diffusion tensor imaging (Hall et al. [",
"@CR62]), can be applied to preclinical studies to evaluate circuit reconstruction, complementary to traditional PET imaging with DA-related radioligands. ",
"Application of imaging methods overtime to monitor graft integration and function would be critical to reduce the number of NHPs groups needed per experiment to understand recovery timelines.",
"Fig.",
" 4Real-time intraoperative MRI for intracerebral delivery of stem cells provides feedback of cannula placement and infusion site: **a** *oblique*, **b** *coronal*, **c** *sagittal* and **d** *horizontal planes*\n\nAt this time, GIDs cannot be prevented or cured; NHP safety studies on methods aiming to modulate grafted cell activity are needed. ",
"Optogenetics is a technique that uses light to control cells that have been genetically modified to express light-sensitive ion channels (Lerner et al. [",
"@CR85]). ",
"Optogenetic approaches have been applied to control electrophysiological and neurochemical properties of grafted SC-derived DA neurons in rodent models (Chen et al. [",
"@CR23]; Steinbeck et al. [",
"@CR140]), yet its clinical translation is not recommended as the patients would require the intracerebral placement of a probe to locally deliver the appropriate light wavelength. ",
"Compared to optogenetics, the designer receptors exclusively activated by designer drugs (DREADDs) technology use noninvasive methods to exert its effects, as it depends on designer drugs to modulate the activity of cells that are genetically modified to express the corresponding receptor. ",
"DREADDs have been used to modulate human PSC-derived DA neurons (Chen et al. [",
"@CR24]). ",
"There has been a lot of discussion regarding CBT safety centered on defining an adequate cell number and volume for intracerebral delivery. ",
"The use of DREADDs or an equivalent technology would allow more flexibility as, theoretically, cells can be further excited if behavioral recovery is not observed, or inhibited if serious GIDs occur. ",
"Basically, it would provide a strategy for patient-specific graft modulation that could be monitored by a combination of clinical and PET imaging tools.",
"\n\nHow can the value of the next generation of NHP studies be maximized for the successful clinical translation of CBTs for PD? ",
"We propose that first and foremost, the investigators should use NHP PD models that match the question at hand (Table [1](#Tab1){ref-type=\"table\"}). ",
"As we previously discussed, until now all monkey studies of CBTs for PD have been performed in neurotoxic models. ",
"Many basic questions regarding feasibility, efficacy, and safety can be answered in these models. ",
"Yet, the same way that only old animals can provide insight on grafting in the aging brain, studies in models of synucleinopathies are needed to assess the impact of protein aggregation in graft efficacy. ",
"In that regard, the field is anxiously waiting for the validation of current genetic models and the availability of transgenic and genomic edited PD monkeys. ",
"Second, a well-designed feasibility study in a few monkeys presents an opportunity to learn if an approach is worth pursuing, with the caution that improvement of PD symptoms could be due to individual variability or spontaneous recovery. ",
"Demonstration of efficacy requires properly powered NHP experiments with blind group assignment and evaluation. ",
"Third, the surgical method of cell delivery is critical to ensuring appropriate targets, optimized cell survival and distribution and should not be minimized. ",
"Fourth, the animals should be assessed with multiple outcome measures with clinical impact to maximize the knowledge to be extracted from the study. ",
"Behavioral evaluations complemented by in vivo imaging methods can facilitate postsurgical follow-up, especially for CBT studies taken several years to be completed. ",
"Postmortem analysis should include unbiased cell counts and evaluation of host immunological response in order to inform about the safety, efficacy and limitations of the approach. ",
"Fifth, grafted cells should be pre-labeled to facilitate identification from host cells. ",
"Images of grafts should be in low and high magnification to assess the extent of cell survival and interaction with host. ",
"Sixth, there are no bad results, but poorly designed experiments. ",
"Publication of positive as well as negative experimental results in NHPs should be encouraged for the overall evolution of the field.",
"\n\nTo conclude, NHP PD research plays a small but critical role in CBT clinical translation. ",
"Ultimately, investigators should remember that whether CBTs for PD work will depend on the benefits outweighing the patients' risk and that NHPs have unique characteristics to help identify and solve these problems.",
"\n\nThis research was supported by NIH grants R24 OD019803, R01NS076352, P51OD011106-53S2 (Wisconsin National Primate Research Center, University of Wisconsin-Madison), NINDS T32-Neuroscience Training Program (S.C.V.), Departments of Radiology and Medical Physics at UW-Madison, WARF Accelerator Program, and funding from the UW-Madison Vice Chancellor for Research and Graduate Education.",
"\n"
] | {
"pile_set_name": "PubMed Central"
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] | 0.029158 | 5 |
[
"ticket swap Manchester Apollo 2015\n\nHi, I bought 4 tickets for concert on the Thurs 5th Feb at Manchester Apollo. ",
"Two of the tickets were Xmas presents but they were unable to go on this date. ",
"Its a long shot but I am hoping to swap the 4 tickets for tickets on the Sunday 8th which is the only day we are all able to go. ",
"Thanks"
] | {
"pile_set_name": "Pile-CC"
} | [
0.017543859649122806,
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[
"Q:\n\nregular expression php to parse a file\n\nI want to parse a file, and store it into an Array in PHP. ",
"However, there are some rules which should the observed:\n\n(p=\"value\") should be ignored, but the \"value\" should be preserved.",
"\n- should be ignored.",
"\nwhitespaces should be ignored. ",
"\nsplit by \\t and \\n.",
"\n\nA sample string is :\nNPD4196-2a_5_0\nGeldanamycin - 0.166516 (p = 0.0068) Alamethicin - 0.158302 (p = 0.0206) 4-Hydroxytamoxifen - 0.1429 (p = 0.0183) Abietic acid - 0.133045 (p = 0.0203) Caspofungin - 0.130885 (p = 0.0432) Extract 00-303C - 0.12858 (p = 0.0356) U73122 - 0.113274 (p = 0.0482) Radicicol - 0.10213 (p = 0.0356) Calcium ionophore - 0.096183 (p = 0.0262)\n\nSo, the goal is to produce a data structure like:\nArray('NPD4196-2a_5_0' => Array(Array( 0 => 'Geldanamycin', 1 => '0.166516', 2 => '0.0068'), Array( ... ));\n\nI have this written so far ... \nwhile(($line = fgets($fp)) !",
"== false){\n $args = preg_split( '/[\\t\\n (=) ]+/', $line, -1, PREG_SPLIT_NO_EMPTY );\n if(count($args)){\n print_r($args);\n print \"\\n\";\n }\n}\n\nWhat am I missing in other to accomplish my goal?",
"\nThanks\n\nA:\n\nThis seems to work for one key-value pair (assuming NPD4196-2a_5_0 is the key in your example, and the second line is the value).",
"\n<?",
"php\n\n$fp = fopen('foo.txt', 'r');\n$regex = '/(\\w*)\\s*-\\s*([\\d\\.]+)\\s*\\(p\\s*=\\s*([\\d\\.]+)\\)/';\n$id = \"NO ID\";\n$result = Array();\n\nwhile(($line = fgets($fp)) !",
"== false){\n if (!",
"preg_match($regex, $line)) {\n $id = chop($line);\n } else {\n $all = Array();\n\n while (preg_match($regex, $line, $matches, PREG_OFFSET_CAPTURE)) {\n $last = end($matches);\n $line = substr($line, $last[1] + strlen($last[0]) + 1);\n\n $strings = Array();\n\n for ($i = 1; $i < 4; $i++) {\n array_push($strings, $matches[$i][0]);\n }\n\n array_push($all, $strings);\n }\n\n $result[$id] = $all;\n }\n}\n\nprint_r($result);\n?",
">\n\n(That is a slightly edited version of David B's regex.)",
"\nIf the line doesn't match that long RegEx pattern, it will store the line as the ID. ",
" Otherwise, it will match the RegEx, then chop off the matching part. ",
" Each iteration of the inner while loop will match one entry. ",
" Since I am grabbing the indices of the matches, the for loop is used to only add the strings to the result.",
"\nThis prints: \nArray\n(\n [NPD4196-2a_5_0] => Array\n (\n [0] => Array\n (\n [0] => Geldanamycin\n [1] => 0.166516\n [2] => 0.0068\n )\n\n [1] => Array\n (\n [0] => Alamethicin\n [1] => 0.158302\n [2] => 0.0206\n )\n\n [2] => Array\n (\n [0] => Hydroxytamoxifen\n [1] => 0.1429\n [2] => 0.0183\n )\n...\n\n"
] | {
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"Q:\n\nhow do I check if a particular Layout is included in android from JAVA?",
"\n\nI would like to do the following:\nsetContentView(R.layout.product_details_editpage);\n\nI want to check if product_details_editpage layout has another layout included in it?",
"\nIf so, for the included layout components, I would like to reuse the handlers from elsewhere in the App.",
"\nIf the included layout has a button such as Logout, then I dont want to re-implement that logout button handler again in th eactivity that sets calls setContentView() above.",
"\nWhat is the easiest way /best way to do this?",
"\n\nA:\n\nagreed with above comments.",
"\naccept te discussion is closed.",
"\n\n"
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"Ken Bradley: Scientists tell us that we have very little time in which to prevent the worst effects of global warming. ",
"Submitted photo\n\nKen Bradley is research and policy center director at Environment Minnesota, which describes itself as a \"statewide, citizen-based environmental advocacy organization.\"",
"\n\nGlobal warming is already beginning to affect life here in Minnesota, across America, and around the world. ",
"The first half of 2012 was the hottest January through July on record for the lower 48 states. ",
"Much of the country is suffering through prolonged drought. ",
"Species are on the move. ",
"Glaciers are melting while many political leaders are continuing to deny the indisputable science.",
"\n\nRoughly one month after the extreme downpour that hit Duluth and other communities in Minnesota, causing $100 million in damages, Environment Minnesota Research and Policy Center released a new report that documents one more way global warming is affecting our lives — an increase in the frequency and intensity of extreme rainstorms.",
"\n\nOur report, entitled \"When It Rains, It Pours,\" found that storms with heavy rain are happening 30 percent more frequently in Minnesota now than they were 65 years ago. ",
"In other words, an extreme rainstorm that used to hit Minnesota once every 12 months on average now occurs every 9.2 months on average.",
"\n\nScientists tell us that the trend toward heavier rainstorms is clearly linked to global warming, as warming increases evaporation and enables the air to hold more water, providing more fuel for these heavier rainstorms.",
"\n\nThe implications of more frequent extreme rainstorms are serious. ",
"In the 20th century, flooding caused more property damage and loss of life in the United States than any other type of natural disaster. ",
"More frequent downpours will leave Minnesota even more vulnerable to dangerous flooding in years to come.",
"\n\nWith more than half the United States suffering through one of the worst droughts in history, it's important to understand that bigger rainstorms happening more often does not mean more water will be available for us. ",
"Scientists actually predict that as global warming intensifies, longer periods of relative dryness will mark the periods between extreme rainstorms, increasing the risk of drought. ",
"This is because the same increased evaporation that leads to more water in the air also leads to drier soils.",
"\n\nIn our report, we examined trends in the frequency of large rain and snow events across Minnesota and the United States, using data from weather stations nationwide and a methodology originally developed by scientists at the National Climatic Data Center and the Illinois State Water Survey.",
"\n\nWe looked at daily rainfall and snowfall records from 1948 to 2011, identified the largest storms at each weather station, and analyzed when those storms occurred and how much precipitation fell with each.",
"\n\nAnother key finding of our report is that the biggest rainstorms are getting bigger. ",
"The amount of precipitation released by the largest annual storms in Minnesota increased by 12 percent from 1948 to 2011.",
"\n\nWhile scientists predict that the trend toward more storms with extreme precipitation will only intensify as a result of global warming, there are actions we can take to minimize the danger.",
"\n\nScientists tell us that we have very little time in which to prevent the worst effects of global warming — and a great deal of work to do. ",
"The good news is that the pollution reductions called for by scientists are achievable, and we already have started putting some of the most important pollution-reduction strategies to work.",
"\n\nAt the federal level, the Obama administration has proposed carbon-pollution and fuel-efficiency standards for new cars and trucks through 2025, as well as carbon-pollution standards for new power plants. ",
"Vehicles and power plants are the two largest sources of carbon pollution, so getting these proposed standards finalized and on the books this year is critical to tackling global warming.",
"\n\nWhile these are important steps, we need to do much more at the state, local and federal levels if we expect future generations not to judge us as neglectful, delinquent stewards of our nation.",
"\n\nNow is the time for us to come together to solve this challenging problem and embrace solutions that will leave our planet better for generations to come."
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"1993–94 Maltese Premier League\n\nStatistics of Maltese Premier League in season 1993/1994.",
"\n\nOverview\nIt was performed in 10 teams, and Hibernians F.C. won the championship.",
"\n\nLeague standings\n\nReferences\nMalta - List of final tables (RSSSF)\n\nCategory:Maltese Premier League seasons\nMalta\nCategory:1993–94 in Maltese football"
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"[Description and role of bacteriological techniques in the management of lung infections].",
"\nAcute pneumonias occur in a variety of clinical settings and accurate identification of bacterial causes is extremely important. ",
"No microbiological tool is either 100 % sensitive or 100 % specific, and despite investigations, aetiology remains unanswered in more than 30 % of pneumonia. ",
"No sample may be necessary for patients treated as outpatients, non invasive respiratory specimens are preferred in hospitalised individuals (community or healthcare associated), while invasive specimens are used as second line for community acquired pneumonia (CAP) in intensive care, and in the first line where pneumonia occurs in immunosuppressed patients. ",
"Bacterial cultures have an important place, if the sample is taken before the introduction of antibiotic therapy. ",
"Some contexts may justify the use of blood cultures, testing for urinary antigens or serology. ",
"PCR is already becoming available as a daily service but the short-term future probably belongs to molecular multiplex panels capable of detecting many microorganisms within hours, especially in severe CAP resuscitation and in pneumonia in the immunosuppressed. ",
"High-throughput sequencing nucleotide techniques will soon revolutionize microbiological diagnosis in respiratory medicine, as in other areas of infectious diseases."
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"The clinical, social and financial burden of Autism Spectrum Disorders (ASD) is staggering. ",
"They are the most prevalent of the developmental disorders and their incidence is rising. ",
"However, the ASD phenotype variability is large, and ASD symptoms can manifest over a range of ages and to different degrees. ",
"In part for these reasons, the ASD clinical diagnosis is challenging and often is not made until 3-5 years of age. ",
"Thus, there remains an unmet need for a valid and reliable endophenotype which would facilitate ASD diagnosis early in life, enable efficient study of ASD risk factors, and eventually serve as a useful biomarker to inform the development of effective therapies and assess treatment response in future clinical trials. ",
"The overarching goal of this proposal is to explore te utility of transcranial magnetic stimulation (TMS) measures of brain plasticity as a novel neurophysiologic endophenotype in high- and low-functioning adults and children with ASD. ",
"Our work to date demonstrates the potential utility of these measures in higher-functioning adults with ASD, and pilot data support the feasibility and safety of applying the same measures to children and lower functioning individuals in whom the value of such an endophenotype would be particularly high. ",
"We thus propose to apply single-pulse TMS to evaluate the modulation in corticospinal reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). ",
"The comparison of the motor responses induced by single-pulse TMS before and following TBS is a unique noninvasive measure of brain plasticity in humans, and we have found that it shows a reliable abnormality in high-functioning adult individuals with ASD. ",
"Our hypothesis is that the alteration of TBS-induced modulation of TMS responses is a common neuropathophysiologic trait that is reliably linked to the ASD phenotype, and that will not be limited to high functioning adults but be also valid in children and low-functioning individuals. ",
"W thus anticipate that data from the proposed studies will address an important need for a rapid, noninvasive, reliable and safe endophenotype available to patients with ASD across ages and level of function."
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"Monday, January 12, 2009\n\nThe human mind tends to default into duality. ",
"We tend to divide things into categories of good or bad, right or wrong, and ultimately, us or them. ",
"It’s easiest to see the faults of others, though our continued growth asks us to identify the faults within ourselves.",
"\n\nThere is plenty of judgment within the Yoga community. ",
"One teacher claims to be teaching the oldest and truest technique, while another lineage makes the same claim. ",
"Without waging all-out war, there’s a lingering judgment that festers just beneath the surface in the western yoga world.",
"\n\nInterestingly, there is little historical evidence to support these judgments. ",
"The primary yogic texts, the Bhagavad Gita and the Yoga Sutras of Patanjali, scarcely mention the physical practices of Asana and Pranayama. ",
"It wasn’t until much later that texts such as the Hatha Yoga Pradipika described the physical practices. ",
"Even within these relatively modern texts, there’s insufficient information to assert whether a technique is right or wrong. ",
"Surprisingly, the physical practices of yoga are scantily documented until recently.",
"\n\nBecause Yoga (as a spiritual path) has existed for so long, and most Westerners associate yogic postures as the essence of Yoga, the assumption that the asanas have existed since time immemorial is either directly promoted, or at least not actively discouraged. ",
"The teacher offering the most authentic, most ancient or truest approach to Yoga has a distinct marketplace advantage over the teacher offering the possibly-quite-old or fairly-recent interpretation of Yoga. ",
"Interestingly, many of today’s most popular approaches to Yoga occupy the latter category, despite their claims to the contrary.",
"\n\nWe all want to do the right thing, and to follow the path that’s most likely to work. ",
"It’s human nature, and not such a bad motivation. ",
"Unfortunately, these well-meaning motives can also cultivate less-than-yogic mindstates.",
"\n\nIn Hatha Yoga, the greatest growth occurs in sticking with a path for a long time. ",
"Whether you resonate with the flowing Ashtanga Vinyasa form, the BKS Iyengar precise alignment or the integration of breath and structure of Alignment Yoga, to mention just a few examples, find a form and stick with it. ",
"Along the yogic path, steer clear of dogmatic judgment of other forms you may not be following at the time. ",
"The concern over whether a form is right or wrong exercises an aspect of the mind that’s most distinctly contrary to the state of yoga. ",
"If none of the forms can be described as right, then by default, all of the forms are right.",
"\n\nIf you’re interested in learning more about Yoga, be sure to include the Bhagavad Gita and the Yoga Sutras of Patanjali in your studies. ",
"If you’re new to the roots of Yoga, a good start is the excellent book by Michael Stone, The Inner Tradition of Yoga. ",
"Within the pages of this book, the heart of Yoga unfolds. ",
"Yes, the physical practice is an elegant and time-tested path to health and vitality, though Yoga is so much more than perfecting a technique.",
"\n\nNo comments:\n\nWelcome to the Alignment Yoga blog, where you'll find yoga articles, videos and audio presentations by Scott Anderson, with an emphasis on how to avoid common mistakes we make doing this ancient practice with our Western bodies and minds."
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[
"use crate::relayer::block_proposal_process::BlockProposalProcess;\nuse crate::relayer::tests::helper::{build_chain, new_transaction};\nuse crate::Status;\nuse ckb_types::packed::{self, ProposalShortId};\nuse ckb_types::prelude::*;\n\n#[test]\nfn test_no_unknown() {\n let (relayer, always_success_out_point) = build_chain(5);\n let transaction = new_transaction(&relayer, 1, &always_success_out_point);\n\n let transactions = vec![transaction.clone()];\n\n // known tx\n {\n relayer.shared.state().mark_as_known_tx(transaction.hash());\n }\n let content = packed::BlockProposal::new_builder()\n .transactions(transactions.into_iter().map(|tx| tx.data()).pack())\n .build();\n\n let process = BlockProposalProcess::new(content.as_reader(), &relayer);\n assert_eq!(process.execute(), Status::ignored());\n}\n\n#[test]\nfn test_no_asked() {\n let (relayer, always_success_out_point) = build_chain(5);\n let transaction = new_transaction(&relayer, 1, &always_success_out_point);\n\n let transactions = vec![transaction.clone()];\n\n let content = packed::BlockProposal::new_builder()\n .transactions(transactions.into_iter().map(|tx| tx.data()).pack())\n .build();\n\n let process = BlockProposalProcess::new(content.as_reader(), &relayer);\n assert_eq!(process.execute(), Status::ignored());\n\n let known = relayer.shared.state().already_known_tx(&transaction.hash());\n assert_eq!(known, false);\n}\n\n#[test]\nfn test_ok() {\n let (relayer, always_success_out_point) = build_chain(5);\n let transaction = new_transaction(&relayer, 1, &always_success_out_point);\n let transactions = vec![transaction.clone()];\n let proposals: Vec<ProposalShortId> = transactions\n .iter()\n .map(|tx| tx.proposal_short_id())\n .collect();\n\n // Before asked proposals\n {\n relayer.shared.state().insert_inflight_proposals(proposals);\n }\n\n let content = packed::BlockProposal::new_builder()\n .transactions(transactions.into_iter().map(|tx| tx.data()).pack())\n .build();\n\n let process = BlockProposalProcess::new(content.as_reader(), &relayer);\n assert_eq!(process.execute(), Status::ok());\n\n let known = relayer.shared.state().already_known_tx(&transaction.hash());\n assert_eq!(known, true);\n}\n"
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"We currently Accept\n\nFirst Choice Health Network\n\nEBMS\n\nRegence/ Blue Cross Blue Shield\n\nIf you have inquiries about your insurance benefits or would like to schedule an appointment to be covered by your insurance company, please contact us with your information. ",
"We will happily find out your benefits for you.",
"\n\nPatients will be responsible for co-payments due at the time of service. ",
"Please note, a deductible may apply before Alternative Care benefits are effective."
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"Greg Biffle has had a darned good summer, now can he carry momentum through the rest of the chase?",
"\n\nGreg Biffle has been strong much of the season, particularly strong since mid-July. ",
"Can he make a strong bid for the Sprint Cup championship? (",
"Photo: Getty Images for NASCAR)\n\nBy Mike Mulhern mikemulhern.net\n\nFONTANA, Calif. Barely a week after sensing his title hopes doomed, Greg Biffle is suddenly looking pretty good in this championship chase. ",
"Putting Biffle's Kansas win in some perspective: Remember Greg Biffle's 'winning' move at Daytona, back in February? ",
"Yes, it was the right move....but foiled by NASCAR's newest green-white-checkered rules, which shook up the final miles of the season opener.",
"\n\nThen began the long drought for Biffle and the rest of the Ford teams, as the stock car tour began digesting the reemergence of the Richard Childress teams and the up-and-down performances by the Rick Hendrick teams. ",
"But now it's looking like this could well turn out to be quite a year for Biffle and crew chief Greg Erwin after all. ",
"Things looked dim for the Ford bunch much of the season, winless until Biffle's breakthrough at Pocono in August. ",
"But the way Jack Roush's guys ran at Kansas, well, something has certainly changed over on that side of the NASCAR garage. ",
"So just how much did the championship chase tighten up at Kansas last weekend, with Biffle's win and Denny Hamlin's off-day? ",
"Well, Biffle did put himself back in the hunt, rebounding from bad days at Loudon, N.H., and Dover, Del. \"But we've got a lot of work to do -- being 85 points out of the lead, and a four-time champion leading the points,\" Biffle concedes. ",
"That's Jimmie Johnson, of course. ",
"And Johnson won here in the spring, beating Kevin Harvick. ",
"But this has been a very good track to Biffle too over the years. ",
"And Biffle isn't the kind of guy to choke under championship pressure. ",
"Heck, he could well become the first driver in NASCAR history to win all three major series titles if he can win this season's Sprint Cup crown. \"",
"I certainly think being in any championship hunt gives you the mindset and discipline it takes to win a championship,\" Biffle says. \"",
"This is my fourth appearance in the chase, and we went right down to the wire in 2005, and we were close in 2008, finishing third. ",
"I feel I've got the experience.\" ",
"Yet Johnson atop the points three races into the 10-race chase should be concern, naturally. ",
"The year Johnson pulled that title-winning comeback with four straight chase wins is still hanging over this battlefield. ",
"Biffle, though, senses Johnson is 'vulnerable.' \"",
"They didn’t get off to a good start at Loudon...and everybody is vulnerable,\" Biffle says. \"",
"They've had more races this year that were hit-and-miss than the team normally has. \"",
"They're not clearly running away with this thing yet. ",
"We're not going to throw in the towel. \"",
"We're going to have to wait three or four more races before we get a clearer picture.\" ",
"Still, California, Charlotte and Martinsville are the tracks ahead, and Johnson is renown for his performances at these three. \"",
"Jimmie has won a lot at California...but maybe he doesn't come out of California with a win, or even a top five,\" Biffle says.",
"\n\nAnother point to ponder: the Kyle Busch David Reutimann tangle at Kansas. ",
"Busch brushed Reutimann early; Reutimann retaliated with a hard brush later, that damaged Busch's car. ",
"Busch is one of the 12 title contenders; Reutimann is not. \"",
"It doesn't matter if you're in the chase or out of the chase...or it's the end of the season, beginning of the season,\" Biffle says. \"",
"It doesn't really matter. \"",
"What you have to ask yourself is 'Is it worth it for me to wreck a guy to get him out of my way, to spin him out?'\" ",
"Biffle said Busch's first brush wasn't \"just a racing deal.\" \"",
"We saw Carl Edwards and Denny Hamlin get together and spin at Loudon -- that was a racing deal to me,\" Biffle said. \"",
"It looked like Kyle (at Kansas) ran straight back into the back bumper of David and spun him out and wrecked him. \"",
"It probably doesn't matter who you are – you're probably not going to get away with that in our sport today. \"",
"I don't think being in the chase or out of the chase makes a difference. \"",
"I have to ask myself 'Why did Kyle Busch spin out David Reutimann?' \"",
"That would be where I would start.\"",
"\n\nThe Roush men, across the board, were markedly impressive at Kansas. \"",
"We've been getting better and better and better,\" Biffle says. \"",
"I've talked a lot about the Chicago race (July) being the turning point.\" ",
"Biffle had the best car at Chicago but blew the engine. \"",
"It looked like we were on our way to winning that race, like we were at Kansas,\" Biffle said. \"",
"Carl (his teammate) ended up finishing second in that race. \"",
"Then we went to Indy and nearly won that race; we finished third. \"",
"And then we went to Pocono and won. \"",
"We went to Michigan (mid-August) and led the most laps. \"",
"So really, our 1-1/2-mile and two-mile program has been super-strong ever since Chicago, and I feel the Fords are back on track. \"",
"We still have a lot of work to do on our short-track program, and on our slower race tracks...Martinsville and Phoenix. ",
"Phoenix has been a great race track for us, but the last couple times there we've been off a little; and at Richmond and Martinsville and some slower-in-the-center (of the turns) tracks, we haven’t been as good as our competition. \"",
"But as far as the bigger tracks and the faster places, I think we're right in line with everybody else. \"",
"We're going to get our fair share of wins now.\"",
"\n\nStill, Biffle figures that untimely caution at Dover – while he was pitting under green – cost him 50 points. ",
"And that still aggravates him: \"We ran seventh, eighth, ninth...and even ran top-three...and ended up getting caught by a caution flag and getting two laps down,\" Biffle says. \"",
"If that wouldn't have happened to us, we would be 30 or 40 points out of the lead right now. \"",
"So there is tremendous pressure to make every position count, not to make mistakes driving the race car and in the pits. \"",
"I've lost one of these championships by 35 points (2005), and I hope I don't lose it again by 35 points, because I'll be thinking about that Dover race for a long time.\"",
"\n\nPost new comment\n\nYour name:\n*\n\nE-mail: *\n\nThe content of this field is kept private and will not be shown publicly."
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[
"About Flushing Town Hall\n\nFlushing Town Hall is a historic wedding venue in Flushing, New York. ",
"This building was built in 1862 and has provided the ideal event space for many years. ",
"Couples looking to have a vintage and romantic wedding day have come to the right place. ",
"You and your guests will have the opportunity to dance the night away in the venue's open-spaced ballrooms, making memories that will last a lifetime.",
"\n\nFacilities and CapacityWith a variety of event spaces to choose from, you will have the option of deciding the perfect spot for your wedding ceremony and reception. ",
"The Garden offers 2,000 square feet of outdoor space with tree-shaded lawns and perennial planters. ",
"It is ideal for those looking to utilize an outdoor ceremony space for their big day. ",
"The Theatre is the venue's biggest space, offering an open floor plan with room for many different seating arrangements, depending on the size and needs of your event. ",
"It can accommodate up to 190 people comfortably, with a minimum of 128 people. ",
"The Green Room is adjacent to the Flushing Town Hall Theatre and is a great space to hold your reception. ",
"If you’re looking to have a more intimate gathering with your closest family and friends, the Gallery is an open space of beautiful art and can accommodate 100 people for a ceremony and 70 people for a reception. ",
"There is also the option of renting all of the spaces for your event.",
"\n\nServices OfferedFlushing Town Hall's event coordinators will make sure all of your wedding details are taken care of so you can relax and enjoy your special day. ",
"The venue also has an exclusive list of vendors they can recommend to you if you are unsure which vendors you should go with, helping you finalize all of the details for your ceremony and reception. ",
"From wedding cakes to flowers and decor, they are more than happy to help connect you to potential vendors. ",
"The venue provides on-site staff to assist in the streamlining of your event, including front door security and facilities personnel to help you with anything you may need during the event. ",
"The venue offers the following services:\n\nBeautiful venue and helpful and accommodating staff. ",
"This venue was perfect for our big day!",
"\n\nSent on 06/01/2017\n\nT\n\nTing · Married on 10/29/2016\n\n5.0\n\nQuality of service:\n\n5.0\n\nResponsiveness:\n\n5.0\n\nValue:\n\n5.0\n\nFlexibility:\n\n5.0\n\nProfessionalism:\n\n5.0\n\nAMAZING, BEAUTIFUL VENUE! ",
"I can't say anything bad about FTH at all. ",
"Everyone was so nice and accomodating. ",
"Kevin and Mike were a pleasure to work with. ",
"They were super quick when responding to my many numerous inquiries and we're so patient and kind. ",
"Mike and his team did an amazing job with hanging up lanterns in the theater for us even when he got them pretty much almost at the last minute. ",
"All of our guests were amazed by how beautiful the space was and how unique it is. ",
"Definitely take advantage of all 3 areas- garden, gallery and theater. ",
"It definitely gives your wedding a wow factor because each space is so beautiful and unique. ",
"The gallery has different art displayed each month which made for beautiful decor. ",
"It's a dream for caterers because there's so much space and very accessible. ",
"HIGHLY RECOMMENDED!",
"\n\nSent on 11/02/2016\n\nL\n\nLindsey · Married on 07/10/2016\n\n5.0\n\nQuality of service:\n\n5.0\n\nResponsiveness:\n\n5.0\n\nValue:\n\n5.0\n\nFlexibility:\n\n5.0\n\nProfessionalism:\n\n5.0\n\nWe could not be happier that we chose to have our wedding at Flushing Town Hall! ",
"Not only is it really beautiful with tons of history, charm, and character, but everyone who works there could not have been more kind, helpful and accommodating! ",
"Kevin answered endless emails from us with thoughtfulness and good humor. ",
"He even stayed late one evening to talk us through everything. ",
"On top of that, Amin (who's there on the day of events), is incredibly sweet and so on top of things, that we didn't have to think about anything the day of the wedding, he just made it all happen. ",
"And the rest of the staff were always so thoughtful, going over and beyond the call over duty.",
"\n\nFlushing Town Hall is definitely a gem! ",
"We couldn't reccommend it more!"
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"County health officials are concerned a patient with tuberculosis at California State University San Marcos may have exposed others.",
"\n\nA person from the school is being treated for the disease, and others on campus may have been exposed between Aug. 25 and Oct. 29, the San Diego County Health and Human Services Agency (HHSA) says.",
"\n\nThe HHSA is working with the university to notify those they believe are at risk. ",
"The school is offering free testing the week of Nov. 17 at the CSUSM Student Health Counseling Services, located at 333 S. Twin Oaks Valley Road.",
"\n\nAccording to county public health officer Wilma Wooten, most people who come in contact with TB do not contract it. ",
"However, if symptoms develop, they include a persistent cough, fever, night sweats and unexplained weight loss.",
"\n\nThe disease can be treated and cured with medication once identified, Wooten says.",
"\n\nWhile not uncommon in San Diego, TB has been on the decline in the past few years. ",
"Local cases peaked in 1993 with 469 reported, but 2012 saw only 234, while 2013 had 206.",
"\n\nSo far in 2014, there have been 160 cases of TB reported in the county.",
"\n\nLast month, a person at Grossmont High School contracted the disease, and another case was reported at Lincoln High School in August.",
"\n\nCall the county TB Control Program at 619-692-8621 for more information about the CSUSM potential exposure."
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"Saint Agnes High School (Saint Paul, Minnesota)\n\nSaint Agnes High School is a private, Roman Catholic high school in Saint Paul, Minnesota, United States. ",
" It is located in the Roman Catholic Archdiocese of Saint Paul and Minneapolis, and is affiliated with the Church of St. Agnes in Saint Paul.",
"\n\nBackground\nSaint Agnes School was established in 1888, and currently educates students from pre-kindergarten until 12th grade.",
"\n\nAcademics\nSaint Agnes High School is fully accredited by the National Catholic Education Association.",
"\n\nArts\nSaint Agnes has a long-standing choral tradition that coincides with its Catholic identity. ",
" The Saint Agnes Concert Chorale performs several concerts a year and tours extensively. ",
" It also participates in state competitions regularly receiving superior ratings. ",
" On almost a yearly basis, singers from the school are selected to participate in the All-State Choirs.",
"\n\nAthletics\nSaint Agnes is a member of the Tri-Metro conference of the Minnesota State High School League and competes in Section 4 A. Boys athletics for the school include baseball, basketball, football, golf, hockey, soccer, track & field, and wrestling. ",
"Girls athletics include basketball, cheerleading, golf, hockey, soccer, softball, track and field, and volleyball. ",
"The St. Agnes football team has recently switched from the MCAA (Minnesota Christian Athletic Association) back to the Tri-Metro Conference.",
"\n\nMinnesota state titles\n\n Basketball 1994\n Baseball 2001, 2012\n\nSee also\n\nExternal links\n School Website\n\nCategory:Roman Catholic Archdiocese of Saint Paul and Minneapolis\nCategory:High schools in Saint Paul, Minnesota\nCategory:Catholic secondary schools in Minnesota\nCategory:Educational institutions established in 1888\nCategory:Private middle schools in Minnesota\nCategory:Private elementary schools in Minnesota"
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"Institutional Review of Mortality in 5434 Consecutive Neurosurgery Patients: Are We Improving?",
"\nDespite increasing emphasis on quality improvement in neurosurgery, few studies have evaluated the impact of quality initiatives on health-assessment metrics including risk of mortality (ROM), severity of illness (SOI), case mix index (CMI), and mortality index. ",
"To evaluate the impact of a multifactorial quality initiative on mortality and quality metrics on a neurosurgical service. ",
"Records of 5434 consecutive neurosurgery inpatients and consults including all inpatient mortalities were prospectively collected and reviewed from July 2014 to June 2016 at major academic institution. ",
"A multifactorial quality improvement intervention was implemented in July 2015. ",
"UHC risk models mortality index, CMI, ROM, SOI present on admission (POA), and at hospital discharge (DC) were compared in the prior 12 mo and the 12 m after implementation. ",
"For mortality cases, diagnosis-related group codes, procedure type, and etiology of mortality were collected. ",
"Compared to the pre-intervention cohort (n = 2793), the postintervention cohort (n = 2641) trended to have a decreased mean-observed monthly mortality (3.08 vs 4.17) and mean-monthly mortality index (0.73 vs 0.98). ",
"Additionally, the postintervention cohort had significantly higher CMI (3.14 vs 2.96, P = .02), POA-ROM (1.52 vs 1.46, P = .02), POA-SOI (1.97 vs 1.84, P = .0002), DC-ROM (1.69 vs 1.58, P = .003), and DC-SOI (2.1 vs 1.95, P < .0001). ",
"Of 131 mortalities (pre-intervention: n = 70, postintervention: n = 61), the postintervention cohort had a higher proportion of moralities due to emergent and trauma admissions than elective. ",
"Our study suggests that our quality initiative impacted observed mortality, improved documentation, and enhanced overall quality of care on a neurosurgical service."
] | {
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"The National Association for Environmental Management (NAEM) is the largest professional association for corporate environment, health and safety (EHS) and sustainability decision-makers. ",
"We are dedicated to empowering our members to advance environmental stewardship, create safe and healthy workplaces, and promote global sustainability.",
"\n\nThe Lake Michigan Chapter is NAEM’s local networking group for EHS and sustainability leaders in the Chicagoland area. ",
"To stay current with regulatory issues, share information with peers and learn valuable professional skills, register for an upcoming event today!",
"\n\nMergers & Acquisitions – Due Diligence & Integration\n\nThursday September 22, 2016\n8:00 a.m. - 1:00 p.m. (CDT)\n\nCost: Members $35, Non-Members $45, Optional Lunch $10\n\nThe NAEM Upper Midwest Chapter cordially invites you to the fall chapter meeting at General Mills. ",
"This meeting will have a panel discussion on due diligence including Phase I/II, data rooms, compliance reviews, asbestos surveys and working with attorneys. ",
"In addition, we will discuss best practices to address integration challenges such as culture, budgets, systems/tools, corporate standards, and sustainability.",
"\n\nIs a Phase 1 enough? ",
"How do you know when to stop the due diligence?",
"\n\nYou have 800 documents to review in the next two weeks, how do you get it done?",
"\n\nBalancing acquisition risk with desires of the business – is there a middle ground?",
"\n\nWhat is the goal of due diligence vs integration?",
"\n\nPost-acquisition: How do we integrate company cultures? ",
"What about EHS/sustainability metrics?",
"\n\nThe meeting will be followed by an optional networking lunch to allow continued discussion and networking with your peers. ",
"Come to learn and more importantly share what works well for your organization!",
"\n\nEach year NAEM’s annual conference convenes more than 550 attendees for a three-day showcase of the latest strategies corporate environment, health, safety and sustainability (EHS&S) leaders are using to keep employees safe, minimize their company’s environmental footprint and deliver business value through sustainability programs."
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"(Welcome to Let’s Get Animated!, ",
"a column that spotlights the best of film animation. ",
"In this edition: the best animated flying sequences.)",
"\nThe best kinds of animated films sweep you away — whether in their dazzling technical craft, their boundless imagination, or their awe-inspiring execution. ",
"And the best kinds of animated flying sequences achieve all three.",
"\nIn honor of the release of How to Train Your Dragon: The Hidden World, the third and final film in a franchise that has given us some of... Tags: Movies, China, Superman, Disney, Features, Egypt, Animation, Peter Pan, Brad Bird, Snyder, Tim Rice, Alan Menken, Jasmine, Aladdin, Rockwell, Zack Snyder\n\nIt’s been just about a year since the relaunch of WeWork Labs, an accelerator-type program operating under the WeWork umbrella. ",
"Since then, it’s grown to 37 locations in 22 cities. ",
"And it’s truly international, operating in 12 countries, including Brazil, China, Germany and India.",
"\nThese Labs offices are often — but not always — housed within a larger WeWork space, and, like an accelerator, they offer mentorship and programming. ",
"However, WeWork doesn’t take any equity; instead, it simply makes mo... Tags: Startups, Accelerator, New York, Microsoft, New York City, Israel, Tel Aviv, Tech, Shanghai, Manhattan, WeWork, Adler, Vazquez, Barak, Soluto, Dumbo\n\nJoseph Gatt is used to playing the bad guy. ",
"With his striking chrome dome, high cheekbones, and thin eyebrows, it’s no wonder that Gatt has been typecast as a villain. ",
"He’s tried to kill Thor as a Frost Giant, and he’s terrorized various heroes as countless Russian mercenaries. ",
"But in Dumbo, his villain Neils Skellig (the psychotic hunter and right-hand man of Michael Keaton’s ruthless circus entrepreneur V.A. Vandemere) hits a little closer to home.",
"\n“I’m very anti-hunting and I’m involved in a... Tags: Movies, Interviews, La, Fantasy, Disney, Features, Darth Vader, Thor, Michael Keaton, Tim, Keaton, Medici, Dumbo, Set Visit, Action/Adventure, Disney/Pixar\n\nBefore we get into the most obvious thing about the upcoming movies for 2019 – which is, Marvel is going to make a lot of money, again – can we first look forward to some great filmmakers who’ll be doing exactly what they want to do?",
"\nLike Martin Scorsese, whose Netflix-backed “The Irishman” reunites our greatest living filmmaker with old cronies Robert De Niro, Joe Pesci and Harvey Keitel, and tosses Al Pacino into the bargain. ",
"It’s a mob epic that spans decades, with a lot of digital de-aging, ... Tags: Hollywood, Movies, Tim Burton, Disney, Sport, Tom Hanks, Fox, Netflix, Things To Do, Soccer, Ferrari, Ford, Elton John, Leonardo Dicaprio, Hobbs, Seth Rogen\n\n“Dumbo” takes flight in the first official trailer for Tim Burton’s live-action remake of the Disney classic. ",
"This reimagining, which uses visual effects to portray the lovable elephant, sees Danny DeVito as the owner of a faltering circus. ",
"He enlists a former star (Colin Farrell) and his children (Nico Parker and Finley Hobbins) to look […] Tags: News, Tim Burton, Disney, Colin Farrell, Danny DeVito, Dumbo, Nico Parker, Finley Hobbins\n\nThanks to the latest trailer for Tim Burton’s live-action remake of Dumbo, you’ll still believe a horribly depressed elephant can fly! ",
"He will also be ripped away from his mother and be forced to wear clown make-up, among other cruelties.",
"Read more... Tags: Science, Tim Burton, Disney, Animation, Dumbo\n\n\"You can do it, Dumbo. ",
"Show them.\" ",
"Disney has revealed their first full-length, official trailer for the live-action Dumbo movie, about the little elephant who can fly. ",
"And you'll really believe he can fly after this! ",
"What a magnificent trailer, no thanks to that music. ",
"Dumbo is directed by iconic filmmaker Tim Burton, who has been working with Disney ever since Alice in Wonderland and most recently made Miss Peregrine's Home for Peculiar Children. ",
"This new Disney Dumbo adventure features an... Tags: Movies, Trailer, Tim Burton, Disney, Michael Keaton, Alice, Peregrine, Dumbo, To Watch, Disney Dumbo"
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[
"The Ghost Train\n\nLet’s start this story with the simple fact, that I am not a religious man, And I don’t truly follow any kind of religious belief. ",
"But this made me start to think that something else could be out there in this world.",
"\n\nThis happened when I was a young man, maybe at most 15, My one buddy who has passed away recently, Was walking with me along the coal train tracks with me, Let’s stick with his nickname, We called him Seamonkey. ",
"But it was late in the evening, had recently rained and a small bit of fog had rolled into the area, and we decided, to go for a walk along the train tracks, for a bit of fun and exploration. ",
"We were always the exploring type of young kids, the old mill, the trails across the bridge, and even some of the abandoned houses of the town. ",
"But today, was different.",
"\n\nWe both felt like something was wrong, the fog seemed thicker and almost gaseous, The smell that normal fog had the clean scent was gone, it smelled this time like rotten flesh, and blood. ",
"We thought at first that the smell was coming from a possible dead deer or other animal that might have gotten hit by one of the trains that still come through the area. ",
"But we couldn’t see anything near the tracks or even around them, We were starting to get a bit freaked out now cause the fog seemed to thicken a bit more. ",
"When we finally heard a noise. ",
"A low deep whistle, Howling through the fog and the area.",
"\n\nWe froze in place, but quickly got off the actual tracks moving to stand in the gravel that the tracks were surrounded by, And moved closer to the edge of the hill side which dropped down to the river, thinking it might have been one of the coal trains that came through. ",
"But soon we were proven wrong, As we watched and waited, we saw it, A single glowing red light coming towards us on the tracks. ",
"We both looked at each other at this time, and Seamonkey asked me. “",
"What the fuck?” ",
"I replied with “I have no idea, dude!” ",
"We both couldn’t even move as we watched it coming closer, only to hear that whistle blow again, This time though we both wanted to run, but we were half way through mill and the town, so we had no were to actually run.",
"\n\nBy this time though, we could make it out, it was a train, but was different, It seemed the fog was coming from the train itself, And we could see that it was not on the tracks, but floating above it. ",
"As we stood there horrified it slowed, and stopped near us, releasing a hiss of the fog, As we stared in fear, the door on the engine opened up, and a hand extended from it, beckoning us to come closer, We backed up now, finally finding our strength in our legs, when we heard a voice come from the conductors door. “",
"Are…you lost? ",
"Come in.” ",
"That was when Seamonkey shouted out in fear and spoke to me again. “",
"It’s not human!” ",
"That was when I noticed it myself, we could finally see the Conductor, It was a man, in olden clothes, almost like from the fifties, but his face, was angular he had a small pencil like mustache, but his eyes, was what finally shook me out of my stupor, They were red and slightly glowing, and the whites of his eyes were black. ",
"He spoke to us again at this time.",
"\n\n“Come boys, I will take you were you belong, don’t be afraid.” ",
"At this Seamonkey and I backed up, and I remembered something my Mother use to always tell me, That Train tracks were the home to the lost souls, and the Devil’s train would come for those it deemed lost. ",
"As I said when I started this story, I am not religious, but I did remember the Lord’s prayer. ",
"I started reciting it. ",
"At which this man visibly recoiled lightly, before he chuckled softly. ",
"and said one last thing. “",
"Ah…Your both still of this world, No matter, It is not your time for me it seems. ",
"Safe travels….My two lost souls.”",
"\n\nWith that he closed the door, and the train began to move again, we watched as it passed us, looking at the windows, seeing various types of people, but they all seemed sad, and lonely, as it passed fully the fog lifted, and Seamonkey looked at me as spoke “What in the fuck was that!” ",
"With a shaky breath I watched the train continue to travel away from us and I only could answer one thing. “",
"That…was the Grim Reaper’s train. ",
"It thought we were dead, and came for us. ",
"The Devil decided we were right…But we survived.” ",
"With that we both started to move faster, and soon reached the town again, and booked it to my house, where we told myMother what happened, she turned white and quickly stood up grabbing her cross and blessed us both, and told us. “",
"That train will come for you both….I hope you will resist it…” Now, til this day I still see that train once a year, and hear the whistle from time to time, I know that Train is waiting for me, and when my time comes, I know I have to board it, But I warn you all, If you see this train, DON’T TAKE THE RIDE!"
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[
"/*\n * Copyright 2009 Red Hat, Inc.\n *\n * Red Hat licenses this file to you under the Apache License, version 2.0\n * (the \"License\"); you may not use this file except in compliance with the\n * License. ",
" You may obtain a copy of the License at:\n *\n * http://www.apache.org/licenses/LICENSE-2.0\n *\n * Unless required by applicable law or agreed to in writing, software\n * distributed under the License is distributed on an \"AS IS\" BASIS, WITHOUT\n * WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. ",
" See the\n * License for the specific language governing permissions and limitations\n * under the License.",
"\n */\npackage com.codefollower.douyu.netty.handler.timeout;\n\n/**\n * A {@link TimeoutException} raised by {@link ReadTimeoutHandler} when no data\n * was read within a certain period of time.",
"\n *\n * @author <a href=\"http://www.jboss.org/netty/\">The Netty Project</a>\n * @author <a href=\"http://gleamynode.net/\">Trustin Lee</a>\n * @version $Rev$, $Date$\n */\npublic class ReadTimeoutException extends TimeoutException {\n\n private static final long serialVersionUID = -4596059237992273913L;\n\n /**\n * Creates a new instance.",
"\n */\n public ReadTimeoutException() {\n super();\n }\n\n /**\n * Creates a new instance.",
"\n */\n public ReadTimeoutException(String message, Throwable cause) {\n super(message, cause);\n }\n\n /**\n * Creates a new instance.",
"\n */\n public ReadTimeoutException(String message) {\n super(message);\n }\n\n /**\n * Creates a new instance.",
"\n */\n public ReadTimeoutException(Throwable cause) {\n super(cause);\n }\n}\n"
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Size of downloaded dataset files:
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Number of rows:
50,000