text:
Yassi Pressman
Heat vs Kings
JaDine break-up
Jazz vs Pacers
Grizzlies vs Pelicans
Cavaliers vs Knicks
Choi Woo Shik
Taal Volcano update January 20 2020
JaDine breakup
Senate asked to probe 'high price' of sugar
BACOLOD City – The Sugar Regulatory Administration (SRA) asked the Senate to investigate the alleged manipulation of sugar prices. The request was made through a letter addressed to Senator Juan Miguel Zubiri and signed by Atty. Emilio Bernadino Yulo, Sugar Board Farmers' Representative; and Atty. Roland Beltran, Sugar Board Millers Representative In the letter, Yulo […] The post Senate asked to probe 'high price' of sugar appeared first on The Daily Guardian......»»
Category: newsSource: thedailyguardianApr 28th, 2019
Is the problem in SRA?
So now there are moves to ask the Senate to investigate why prices of sugar in the shelves are high (P60/kilo) although the mill gate price is low and there is sufficient supply. If we go by economic theory then the end-user price should be low. This anomalous situation has only one explanation – there […] The post Is the problem in SRA? appeared first on The Daily Guardian......»»
Category: newsSource: thedailyguardianRelated NewsMay 2nd, 2019
Senate urged to probe high sugar prices
The local sugar industry is seeking the Senate's help to investigate the high prices of the commodity after the Department of Trade and Industry failed to look into the situation......»»
Category: financeSource: philstarRelated NewsApr 27th, 2019
Probe sought over concern China can shut down Philippine power
MANILA, Philippines – Opposition Senator Risa Hontiveros said on Tuesday, November 26, she has asked the Senate to conduct an inquiry into the potential threat of China shutting off the country's electricity supply. A Chinese state firm has a substantial stake in the National Grid Corporation of the Philippines (NGCP), which has ........»»
Category: newsSource: rapplerRelated NewsNov 26th, 2019
U.S. senators call for security probe of TikTok
WASHINGTON, USA – Two senior US senators called for the government to study national security risks possibly posed by Chinese-owned video app TikTok, saying it could leave American users vulnerable to Beijing's spying. Senate Democratic Leader Chuck Schumer and Republican Senator Tom Cotton asked the Directorate of National Intelligence to "conduct ........»»
Category: newsSource: rapplerRelated NewsOct 25th, 2019
'Probe DA officers for failure to contain ASF problems'
The chairman of Samahan ng Industriyang Agrikultura (SINAG) has asked the Senate committee on agriculture to probe the alleged failure of some officials to implement quarantine measures and preventive actions that could have contained the threat of the African swine fever (ASF) at its onset......»»
Category: newsSource: philstarRelated NewsSep 28th, 2019
FALSE: Sarah Elago's 'response' to parents of student activists
Claim: Kabataan party-list representative Sarah Elago "responded" to the parents of student activists who are still minors, following the Senate probe into the disappearance of senior high school students allegedly recruited by leftist group Anakbayan. On August 8, a photo started circulating on Facebook which stitched a ........»»
Category: newsSource: rapplerRelated NewsAug 13th, 2019
For US men, Gold Cup finally brings chance for revival
By Dave Campbell, Associated Press BLAINE, Minn. (AP) — The overarching goal for the fledgling U.S. men's soccer team, as frequently stated by new coach Gregg Berhalter, has been to improve the perception of this sputtering program within the cutthroat hierarchy of global soccer. Though a strong performance in the CONCACAF Gold Cup probably won't move the needle much, the Americans surely would benefit, simply, from winning. Their opening game against Guyana on Tuesday night at Allianz Field in St. Paul, the new home of Major League Soccer's Minnesota United, will mark the first competitive match for the U.S. since the infamous defeat at Trinidad and Tobago on Oct. 10, 2017, that kept the team for qualifying for the 2018 World Cup. It follows a stretch of 18 consecutive friendlies. "There will be some nerves, but for us it's just about continuing to make progress throughout this tournament," Berhalter said last week after a training session at the National Sports Center in Blaine, a suburb of Minneapolis. "I think part of our profession is playing under pressure, playing in big events, and this is a great opportunity for us to learn." The 20-month gap between competitive games is the longest for the Americans since a 38-month span following a loss to Costa Rica on May 31, 1985, their final qualifier for the 1986 World Cup. Their next match that counted was a draw at Jamaica on July 24, 1988, their first qualifier for the 1990 World Cup. The U.S. won the biennial Gold Cup in 2017, a sixth title in 14 editions of the championship of North and Central America and the Caribbean. Mexico, the clear favorite, has won seven such crowns. Before any mental energy can be spent on assessing the ability to compete with their border rival to the south, though, the Americans, who are ranked 30th in the world, must advance from the group stage. On the surface, Panama (75th), Trinidad and Tobago (92nd) and Guyana (177th) don't appear to be daunting competition, but the way the U.S. team played this month in exhibition losses to Jamaica (1-0) and Venezuela (3-0) there will be no guarantees of automatic wins. The Americans are missing injured players DeAndre Yedlin, John Brooks and Tyler Adams, all first-choice starters. "If it doesn't go well you can just feel that more pressure is going to build, more questions will be asked, more scrutiny will be on Berhalter and the federation, and the outside noise is only going to get louder," said former U.S. midfielder Stu Holden, now a Fox analyst. "That's why it's really important that this team has a really good showing in this tournament." With the U.S. women leading their side of the world rankings and off to a dominant start this month in France at the Women's World Cup , the men's team won't be able to avoid the comparison game. The Americans can't mute the fan angst that has followed them for nearly two years, either, but they can at least take a meaningful step forward in the Berhalter era by displaying some potential within the pressing, possession-prioritized style he has rolled out . "We want to progress. Of course that also means winning the games, but we want to develop our style," midfielder Weston McKennie said. "Our goal is to make people see U.S. Soccer as something different as what they see now, probably." McKennie is one of the 20-year-old up-and-comers the program has staked itself to in the quest to not only return to the World Cup in 2022 but do some damage on the sport's biggest stage. The other, of course, is Christian Pulisic , who is joining English Premier League power Chelsea from Germany's Borussia Dortmund for a $73 million transfer fee. That is a record price for an American player. Veterans of the national side like Jozy Altidore and Michael Bradley are still around, among just six holdovers from the roster that went to Trinidad. They are joined by Pulisic, defenders Omar Gonzalez and Tim Ream, and forward Paul Arriola on what has become a youngster's team. Getting this team in sync, socially and psychologically, might be just as important of a task for Berhalter as with the technical implementation of his system. "In warmups, they have to give each other high-fives," Berhalter said. "We do team events off the field, like going to movies together and going to restaurants together. I think that's really important to build that team chemistry." Now more than ever. "Everyone right now outside has their opinions about us, and the past couple of games, and that's perfectly fine," forward Paul Arriola said. "For us the message stays the game, and it's staying together as a team. That's how you're going to win an international tournament.".....»»
Category: sportsSource: abscbnRelated NewsJun 18th, 2019
Cartel behind high sugar prices?
BACOLOD City – Senator Cynthia Villar suspects that a cartel could be behind the spike in sugar prices recently. Villar told reporters here that the situation is bad for sugar farmers. Villar, chairperson of the Senate Committee on Agriculture, also wants the Department of Trade and Industry (DTI) to explain its failure to address what […] The post Cartel behind high sugar prices? appeared first on The Daily Guardian......»»
Category: newsSource: thedailyguardianRelated NewsApr 30th, 2019
Villar supports Senate probe on sugar prices
BACOLOD City – Senator Cynthia Villar on April 28, 2019 said she supports the request of the Sugar Regulatory Administration (SRA) for the Senate to investigate the alleged manipulation of sugar prices. Villar, however, noted that the call was made two weeks away from the May 13, 2019 elections The chair of the Senate Committee […] The post Villar supports Senate probe on sugar prices appeared first on The Daily Guardian......»»
SRA wants Senate to probe manipulation of sugar prices
The Sugar Regulatory Administration (SRA) is requesting the Senate to probe the allegedly unreasonable increase in the retail prices of sugar despite sufficient local supply. The post SRA wants Senate.....»»
Category: newsSource: philippinetimesRelated NewsApr 28th, 2019
Bangladesh seeks fresh Senate probe on heist
HIGH-LEVEL officials from Bangladesh met with Philippine counterparts this week to work for the return of the remaining chunk of the $81-million loot from February's cyber heist, demanding that the Rizal Commercial Banking Corp. (RCBC) pay the sum and ask.....»»
Category: newsSource: bworldonlineRelated NewsNov 30th, 2016
Probe on violent dispersal of anti-US rallyists called
Senate President Aquilino Pimentel III asked yesterday the police leadership to investigate the alleged violent dispersal of demonstrators in front of the US Embassy in Manila last Wednesday......»»
Category: newsSource: tempoRelated NewsOct 20th, 2016
Leave NBP riot probe to DoJ, PNP – Lacson
Senator Panfilo "Ping" Lacson is cool to the proposal for a Senate investigation into the alleged "riot" that recently occurred inside the New Bilibid Prison (NBP) that led to the death of one high-profile inmate allegedly involved.....»»
Category: newsSource: tempoRelated NewsOct 3rd, 2016
Senate asked to probe social media use in schools
MANILA, Philippines – The Senate was asked to conduct an inquiry on the proper education and development of responsible social media use in schools......»»
Category: newsSource: philstarRelated NewsOct 2nd, 2016
Nation: Senate probe into penitentiary riot urged
A RESOLUTION was filed on Wednesday by Senators Antonio F. Trillanes IV and Leila M. de Lima, seeking an inquiry into a reported riot that day at the New Bilibid Prison (NBP) which saw a Chinese drug lord killed and three other high-profile inmates wounde.....»»
Category: financeSource: bworldonlineRelated NewsSep 28th, 2016
Gov't told: Temper, trim tax proposals
By Mario B. Casayuran, Chino S. Leyco, and Charissa M. Luci Senate Minority Leader Ralph G. Recto asked Malacañang yesterday to study the impact of fuel tax on the price of rice and fish after it announced its plan to increase the excise tax on gasolin.....»»
Category: newsSource: mb.com.phRelated NewsAug 23rd, 2016
High sugar prices blamed on shipping cartels
Sugar producers on Negros Island are blaming shipping cartels for the high prices of sugar......»»
Category: newsSource: philstarRelated NewsJan 19th, 2020
Alphabet hits trillion-dollar mark
Alphabet, Google's parent company, just joined the trillionaire club. With its stock price closing at an all-time high of $1,450.16 on Thursday, the company's market value reached $1 trillion. The tech giant is the fourth U.S. company to hit the milestone after Apple, Microsoft and Amazon. Facebook could join the club next as its market value sits at roughly $630 billion. […] The post Alphabet hits trillion-dollar mark appeared first on Daily Tribune......»»
Category: newsSource: tribuneRelated NewsJan 18th, 2020
Sugar benchmark price could prove disastrous
The DTI and the SRA should realize the local sugar farmers have nothing to do with domestic retail prices. The post Sugar benchmark price could prove disastrous appeared first on Daily Tribune......»»
76ers center Joel Embiid to have surgery on finger
By Dan Gelston, Associated Press PHILADELPHIA (AP) — Joel Embiid needs more surgery, this time for a torn ligament in a finger in his left hand, the latest setback in the injury-riddled career of the Philadelphia 76ers' All-Star center. Embiid, averaging 23.4 points and 12.3 rebounds in 31 games this season, will have surgery Friday (Saturday, PHL time) and will be evaluated in one to two weeks. He has never played more than 64 games in a season and won't again this season after he was hurt Monday night (Tuesday, PHL time) in a victory over Oklahoma City. Embiid injured the radial collateral ligament in the ring finger in the first half, a grotesque injury that made teammate Ben Simmons say "I nearly threw up" when he saw the finger. Embiid's finger overlapped his pinkie to the point that it seemed he had his fingers crossed. He played most of the game with his finger taped and said he "couldn't go up with two hands." "There were a couple of times I could have grabbed with both hands but I just couldn't. I just kept tapping it," Embiid said Monday (Tuesday, PHL time). The Sixers had braced for the worst, though they were certainly used to playing without their 7-foot big man. He was hindered by illness and knee injuries during last season's playoff run, and the Sixers worked this season to balance his minutes with the proper amount of rest. They usually go as far in the postseason as Embiid can take them -- a small sigh of relief he was hurt before the All-Star break and not headed into the postseason. Mike Scott slid into the starting rotation for Thursday's (Friday, PHL time) game against Boston, along with Al Horford, Tobias Harris, Josh Richardson and Simmons. "All of a sudden, we're different," 76ers coach Brett Brown said. "We're just different. I look at this as an opportunity. Nobody's crying. This is not a 'woe is me' moment, not for me, at all. And not for my players. We'll take what we have, and what we have, I love." The 25-year-old Embiid has struggled with injuries ever since he was drafted with the No. 3 pick of the 2014 draft. He missed his first two seasons with foot injuries and hasn't played more than 64 games in any of the last three. He suffered a broken bone around his left eye and missed games in the 2018 playoffs. The Sixers signed Embiid, a native of Cameroon, to a $148 million, five-year extension that kicked in at the start of the 2018-19 season. He didn't pick up a basketball until he was a teenager, when a friend informed him that very few 7-footers succeed in soccer. A few months later, Embiid was lured to a basketball camp in the capital of Yaounde run by NBA veteran Luc Mbah a Moute, one of just two players from Cameroon to have played in the NBA. Mbah a Moute persuaded Embiid's parents to let him move 6,000 miles to Florida, and helped enroll him at Montverde Academy, one of the best high school programs in the country. He played just 28 games in his lone season at Kansas before he left for the NBA. "How does he get his health where he's back and feeling cocky and comfortable and ready to go where he's healthy, not just for this playoffs but for many playoffs," Brown asked. "I care for Joel and his future. What's best for him and his future.".....»»
Category: sportsSource: abscbnRelated NewsJan 10th, 2020
Home | Latest News | Entertainment | Sports | Finance | Lifestyle & Fashion | Filipino News
About us | Disclaimer | Privacy Policy
© NewsNow.ph


Superfoods: Nutrient-rich foods for Health & Well-being.
Thanks to brands such as Synergy, Lucy Bee, Tree of Life, Greens Organic, and Hesh (to name but a few), superfoods have become more popular than ever in the UK, with many people already enjoying their benefits. Sources of Food that have been recently elevated to 'superfood status' include those rich in Antioxidants (such as vitamins A, C & E) and omega-3 fatty acids.
Superfoods are a varied assortment of nutrient-rich natural foods such as Nuts & Seeds, berries, algae, grains, and fruit & vegetables. Unlike most healthy foods, which normally contain 2-3 particular nutritional properties, superfoods contain a much larger percentage of Vitamins, Minerals, Amino Acids, enzymes, and antioxidants.
How do I consume superfoods?
For best results it is advised to consume superfoods in their raw and original state. Cooking them on a high heat may cause damage to water-soluble vitamin & antioxidant content within them. However, most superfoods are pretty versatile, and can be easily added to your favourite foods & Drinks.
What are the benefits of regular superfood consumption?
You don't need specific foods for specific conditions. Combining a healthy diet with a variety of superfoods could help you to maintain and/or lose your weight, fight colds & illness, aid Digestion, and reduce Inflammation in the Body.
What Superfood products can I buy at Natures Healthbox?
Whether its Superfood Shots, powders, tablets, capsules or simply supergreens, Natures Healthbox have you covered for all your superfood needs. So check out our great range of products (below) today and get your body kick started with a well-earned super boost!


text:
Hometown Star, Soprano Ailyn Pérez, Returns to the Windy City for Solo Recital
Wednesday, September 7, 2016 by Stephen Raskauskas
Ailyn P
Soprano Ailyn Pérez (Photo: Rebecca Fay)
Chicago-born soprano Ailyn Pérez returns to her hometown for a solo recital presented by the Collaborative Arts Institute of Chicago on Thursday, September 8, 2017. "They tell you a career in opera is a gypsy life," Pérez said in a recent interview, "and boy, they weren't kidding!"
Pérez grew up on the South Side of Chicago and later Elk Grove, Illinois. Since, she's travelled the globe performing alongside the likes of Plácido Domingo. Though humble about her own success, Pérez said that when she's had the opportunity to work alongside some of her heroes, like Domingo, "I definitely fan-girl out!"
Plácido Domingo and Ailyn Pérez at the 11th Annual Opera News Awards (Source: zimbio)
In 2006, she met Plácido Domingo when she won second prize in Operalia, a singing competition which the tenor founded. "Around the same time, I had sung for Luciano Pavarotti, and that was a huge honor. So after Operalia, when maestro Domingo invited me to tour with him, I thought, 'What else can there be?' But then, Jose Carreras invited me on a concert tour. I just died!"
"It was exciting watching my mom meet Plácido Domingo. Years ago, he cancelled a performance in Chicago to go help his family and all those affected by the earthquake in Mexico City."
She said working alongside artists like Domingo has taught her that, "It's more than just your life on stage that matters. It's who you are as a person, how you're contributing to humanity, and staying grounded, and being generous towards the public and upcoming artists."
Working with young artists is one reason Pérez is so glad to be back in Chicago. Besides connecting with her family and friends during her time in the Windy City, she paid a visit to her alma mater, Elk Grove High School. She said her early music education was a "life-changing experience" that provided her with "the foundation to have a career in opera."
Our @EG_Choir is unbelievably fortunate to meet the amazing @AilynPerez1 of @ElkGrove_HS & the @MetOpera! #WeAreEG pic.twitter.com/kF0pWMrQUB
— Paul Kelly (@EGPrinciPaul) September 2, 2016
Being from Chicago, "You have to declare your baseball team," Pérez said. "The White Sox made it really easy for me: they invited me to sing the national anthem and I gave a jersey with my name on it and the year." She admits, "technically I was born on the North Side, so I should pick the Cubs. But I'm a fan of all Chicago's sports teams."
Her other favorite things about being back in Chicago? The food! "I love Portillo's and Lou Malnati's. And I'm definitely Italian beef crazy. Of course for Mexican food, I just eat at home with my family." One of her favorite family traditions is making tamales at Christmas and being able to "just graze all day, catch up, and watch the kids play."
You certainly can't replace family, and if there's anything Pérez is proud of, it's hers. "I put Mexican-American on my Twitter feed because of all the political stuff going on," she said. "I don't want to be scared and I don't want to fearful. When I stand, I stand on the shoulders of my parents and their energy and their beliefs and dreams, but also in the quality of their culture and who they are as people and their long history."
.@santafeopera Don't mess up your #wigsandmakeup or else….‼😂🍾🙌🏼💃🏻 #romeoandjuliet #AshleyRobinson ❤ pic.twitter.com/7v5dWAL5KB
— Ailyn Pérez (@AilynPerez1) August 26, 2016
"Growing up and trying to find my place," she explained, "I gravitated towards theater and music because there, you belong, you're part of something bigger, and you're telling a story. I think it also has something to do with my culture, as a Mexican-American. But I also enjoy creating a culture, which is what we do in opera."
Pérez feels, "We need more representation and more diversity on stage. When you can create harmony with others onstage from different backgrounds, it feels so good because it feels like you're giving goodness to humanity, or is putting up a mirror to an audience and say think about these issues," she said. "I think that's what art can do is – it's meant to move us, to make us feel and to think and to work and to strive for a better day for one another."
To learn more about Pérez, including upcoming engagements, visit her website.
« Previous Post: In Wake of Historic Flooding, New Orleans Opera & Louisiana Philharmonic Team Up for Benefit Concert
Next Post: A 1968 Review of Greektown's Parthenon Restaurant from the WFMT Guide »

redpajama_set_name: RedPajamaCommonCrawl


As explained in last week's column, the old confession box was invented for the confession of sin and was never an adequate place for the celebration of the liturgy of reconciliation in its present form.
When a parish decides to take seriously the setting up of a space that is appropriate for celebrating the revised form of individual reconciliation, it is often faced with several difficulties.
In many older churches, an old three-stall confessional has been converted for the purpose. The result is often a space no larger than a closet and without any windows. On the other hand, if the room is large, it can be hard to resist the temptation to use it for storage or other purposes. A lady at Mass recently was surprised when told that she could not use the reconciliation room to change her baby's nappy.
As is the case with any other sacred object or area, the reconciliation room should not be used for anything except the celebration of the sacrament. It is a worship space, a place where liturgy takes place. It is not just an ordinary room such as might be used for counselling or administration. Hence the appropriate title for this part of the church building is "Reconciliation Chapel".
The Reconciliation Chapel needs to be designed and arranged as a worthy and comfortable place for the celebration of reconciliation, which includes the reception of the penitent, reading of the word of God, confession of sins, prayer, offering of moral counsel and the imposition of hands. It should be large enough to hold two or three chairs, a small table, a kneeler and a screen. A full-length opaque curtain or rice paper screen partially dividing the room would serve this latter purpose. A kneeler placed in front of the screen offers anonymity for those who wish it.
The chair for the confessor is placed behind the screen so that he is unable to see the penitent entering the chapel and yet is sufficiently in view for those who choose face-to-face contact. An open lectionary or bible for the proclamation of scripture can be placed on a small table. A cross, a candle and suitable art work appropriately placed decorate the space.
While it is regrettable that windows or glass walls are now required in chapels of reconciliation to protect both confessor and penitent, there is a positive aspect to this development. A closed room with an unknown layout can be frightening or disconcerting to some people. Greater visibility and accessibility encourage people to approach the sacrament. They can see if the priest is present and if he is celebrating the rite with another penitent. No more need for "stop - go" lights or "vacant – engaged" door locks!
More importantly, the openness of such a chapel emphasises the fact that, while it is a private rite that is celebrated there, it is nevertheless an ecclesial, communal event. People in the main worship space are aware of fellow sinners in the reconciliation room and feel empathy with them. Penitents can see, and feel connected with, members of the church community and the table of the Eucharist with which they have been reconciled.


"Scheme" – an offer by the Police to complete an educational driver training programme as an alternative to receiving a fine, penalty points or prosecution.
"course" – the particular online module or printed/downloadable Workbook offered in relation to the Scheme.
"Conditional Offer of Fixed Penalty" – the fixed penalty notice sent to you by the Police.
"Completion Deadline Date" – 28 days from the date of the course invitation letter.
"Ticket Number" – the unique number printed on your course invitation letter.
"PIN Number" – the unique 4 digit number printed on your course invitation letter.
"we" and "us" means the National Driver Offender Retraining Scheme (NDORS).
"you" – the customer who is the subject of the offence.
NDORS – Creators of this scheme for Police forces of England, Wales and Northern Ireland.
DriveTech – Service Provider administering this scheme on behalf of NDORS.
a) Course completion: You must pay for and successfully complete your course by the Completion Deadline date. Failure to pay for and successfully complete your course by the Completion Deadline date will result in the offer of the Scheme being withdrawn and you will have to pay the fine notified on the Fixed Penalty issued to you by the Police.
b) Payment:We accept payment by most credit and debit cards via our website or our Customer Care Team. We cannot accept payment by cheque, cash or by instalments. Payment for your course is non-transferable and non-refundable, including in the event that you do not successfully complete your course. In the event that you pay both the fine and course fee the relevant Police force will refund the fine.
c) Website:In order to access the course, you will be required to enter your Ticket Number and PIN Number into the Your Belt/Your Life Scheme website – www.roadsafety.police.uk. If you cannot find your Ticket Number or PIN Number or have difficulty logging onto the course website, please contact our Customer Care Team on 0344 264 6349.
d) Collection and use of information: In deciding to offer you this course we have checked your details against a national database to establish if you have completed a similar course within the last 3 years of this offence. If you decide to accept the course, we may ask you to give additional information so we can process the course booking. If you complete the course, your details relating to this course will remain on the system for road safety research purposes for a further 6 years from the date of the offence, after which any personal reference to you will be erased. Your details will not be released to any other parties except a Police force if they are considering making an offer of a course in the future. Your personal details will not at any time be made available to the public. If you fail to complete the course or if the offer is withdrawn your personal details relating to this matter will be erased from the national database.
f) Warranties:To the maximum extent permitted by law, we give no warranties and make no representations of any kind relating to the course including, without limitation, any implied warranties of fitness for a particular purpose, or merchantability.
2) our liability to you arising out of any and all claims (whether arising from any Course, from your participation in, or inability to participate in, any Course, or otherwise) will not in any circumstances exceed in aggregate the total amount of the sums paid by you to us for the Course to which that liability relates.


A few days ago, we talked about how some experts have determined that English people are of one-third Anglo-Saxon ancestry. Well, a new research has hinted how the genetic distribution in Britain before the Anglo-Saxon migrations/invasions was not that heterogeneous, even after the impact of the Roman Empire. This study interestingly comes from further analysis of the decapitated skeletons of (what seems as) male gladiators in ancient Britain.
The headless specimens were originally discovered from a Roman burial site in Driffield Terrace in York. Unsurprisingly dating from 2nd to 4th century AD, the remains conform to an area which was better known as Eboracum – the provincial capital of Roman Britain's northern reaches. Now in terms of standout features, other than just their decapitated states, the archaeologists also found evidences of physical trauma in the skeletons, including cut marks to arms and fingers. Moreover, all of the males were found to be younger than 45 years, while displaying heights taller than the average. Added to these injury marks, the historians have also been able to detect possible infections and childhood stress in these 'Roman' skeletons.
These physical and (possibly) psychological effects suggest that the men were probably gladiators (read more about gladiators here). Though the other possibility remains that they served as Roman legionaries, where men above a certain height threshold were only inducted (read more about Roman legionaries here). In any case, the archaeologists from the University of York were able to collect high-quality DNA samples from a particular ear-region of the seven skeletons. They also salvaged some DNA samples from two other skeletons – an Iron Age female and later-dated Anglo-Saxon male. On comparative analysis, the York 'gladiators' were found to have a similar genome to that of the Iron Age specimen, but were markedly variant from the Anglo-Saxon genome. This suggests that the genetic makeup of the British people really didn't change that much under Roman rule.
In fact, most of the York 'gladiators' were assessed to be pretty similar to the present day Celtic population in Britain, like the Welsh. Now we must stress on the word 'most'. That is because, among the seven skeleton specimens, one was found to have a fascinatingly different genome, with its origins from the Middle East, possibly Lebanon or Syria. This certainly alludes to the dynamic society that the Roman Empire stood for. And if we stretch the ambit a bit, some researchers have even talked about how the legendary King Arthur was possibly related to the Sarmatian horsemen (from South Russian steppes) stationed in Britain during the Roman times. Simply put, while the Romans might not have made their genetic mark on the native British populace (at least as much as the later Anglo-Saxons did), their periodic cultural influences sometimes brought forth 'foreigners' into the land.
The excitement is, we are now technologically able to do this kind of work, which is mind-boggling when you consider the great achievement of sequencing the first human genome was less than 15 years ago, and now we can sequence the genomes of Romans from York and Anglo-Saxons in Cambridge. It's just absolutely extraordinary.
The study was originally published in Nature Communications.


text:
» Columnists » Claude Julian » Coverstory: Robin Power Royal
Coverstory: Robin Power Royal
Posted by stunner3baby | On April 15, 2014 | Leave a comment | Under: Claude Julian, Columnists, Coverstory
by Claude Julian | ARCHIVES
ROBIN "POWER" ROYAL STATS
Height: 5'6 1/2
Measurements: 34DD-26-36
Ethnicity: Black
Hometown: Chicago, IL
SOMETHING ABOUT ROBIN "POWER" ROYAL
Stunner Baby Magazine is very proud, humble, and tremendously thrilled to receive the opportunity to provide an exclusive interview opportunity on the talented, beautiful, exotic and sex appeal driven, Robin "Power" Royal. "Power" is our March/April 2014 cover girl. She has transcended many levels of stardom in Hollywood before Chicago's own Salli Richardson and LisaRaye McCoy, arrived years later to make their imprint in the movie entertainment industry in Hollywood.
I've had the pleasure of discovering her beauty and dancing skills many years ago at the Taste Entertainment Center nightclub on the Southside of Chicago. "Power" stood out due to her bold dancing moves, confidence, sex appeal, and ability to mesmerize a large crowd of men and women lusting after her sexuality.
"Back in the day, I provided encouragement to live out her dreams in Hollywood. I had a vision that Soul Train would one day be a part of her life." Power starred in a music video by the renowned gangster rap group, N.W.A. (Appetite For Destruction) captures her lighting up the entire short film that will keep you spell bounded. An in-your-face gangster rap music video of high-voltage reality showcases all of "Power's" brilliance. "Power" provides an uncensored (R-Rated), bold, and candid look into her fascinating evolution as an ex-NBA wife, movie actress, recording artist, Playboy model, and an eye candy entertainment industry owner. Let's turn on the switch to unlock the World of Robin Power Royal!
CJ: How did you start your modeling, acting, and dancing career in Chicago? What was your child like growing up in Chicago?
POWER: "It is a pleasure providing an exclusive interview for Stunner Baby Magazine. I am very excited about the re-launch of my career and featured cover opportunity. I started my modeling career in my twenties from a real close friend, mentor, and ex-boyfriend. I owe a lot to him in preparing my mind to approach a successful modeling career and staying on the right track. He motivated me to prepare myself for each photo shoot, be on time, push my sexuality, and make love to the camera for the ultimate sex appeal. I started acting at Chicago's Curie and South Shore premiere Performing Arts high schools in all the talent shows. I use to act around the house with my family like the Crosby's Show. I use to sing and act out characters with my brothers (Reginald & Reynard). We use to sing, "Al Green" songs. Acting is part of a family thing. Also, I am a product of the Boys & Girls Club. I've been dancing as high school pom-pom girl at South Shore High School, and any hot dance club with hot beats. "Dancing is in my blood, I've been dancing all my life!"
"My childhood was extremely hard. My mother had somewhat of a horrific childhood. The only thing I can say about her is that she was the best mother that she knew how to be. She is a survivor and taught me how to be survivor. I am somewhat of what you might call a product of the streets. My mother was a queen of the streets. She was a gang-banger, dominatrix, drug dealer, a pimp, gun runner for both the El Rukns and Gangster Disciples street gangs growing up on the southeast side of Chicago. Unfortunately, because of her insecurities and because of that the Queen of the streets became a victim to drug abuse. I was that cute little six-year-old girl sent out to play and come back when the streets lights came on. My struggles in Chicago have taught me to survive. I wouldn't change anything about what I've experienced because it has shaped the woman that I am today."
CJ: Why do you feel this is the perfect time to relaunch your acting, modeling, reality show, and music career? What direction do you want to take your career? What was it like working as an actor in Hollywood?
POWER: "Well! I feel that it is a perfect time to re-launch my acting, modeling, reality show and music career because "I feel that the world is finally ready for me." I truly do feel that I was before my time. So now, I feel you guys have finally caught up. The direction that I would like to go with my career including acting, reality television, modeling and music along with fashion is the adult entertainment world. I have a production company named, Chocolatetiger Productions which specialize in all of these areas. It is time for the world to have a multicultural empire that is able to present adult music, exotica, photos, movies, play toys, fashions for adults to enhance their sexual relationships and their own sexuality. Thus, hopeful more procreation in the world! It was absolutely wonderful acting in Hollywood. A childhood dream came true. I was in the movie, "Graffiti Bridge" as a lead actress with Prince. The movie was the sequel to "Purple Rain." I played, Morris Day's girlfriend and the daughter of Billy who own the club in Purple Rain. Also, I appeared in "Coming to America" (Eddie Murphy, Arsenio Hall, James Earl Jones) and "House Party" (Kid & Play, Tisha Campbell, Martin Lawrence). It has been a wonderful rollercoaster ride."
"The thing about all of this is that it is the beginning of the next segment of my life because I have barely scratched the surround of all the things I plan to do in this entertainment industry. So look out for Chocolatetiger Productions because there's a "TIGER" on the loose LOL."
CJ: What insightful details can you share with your fans about working in his films, touring, and living with Prince? How long did you tour? What countries? What doors opened appearing in his movies?
POWER: "I've learned how to make a movie while working on "Graffiti Bridge." It taught me a lot about lighting, set design, actor preparation, and cast dynamics. I studied how Prince interacted with his entire cast and created a role in the film for me. The original script didn't include my character, so I was honored that he recognized something special in my talent to include me in such a major film project. Touring was such a fantasy! It was a roller coaster dream ride coming true. I had such a fabulous time with him. We traveled to Paris and London. In London, we performed before 75,000 people chanting my name at Wembley Stadium. Prince urged the crowd on, while I danced to every beat. Actually, I didn't exactly live with Prince but spent a lot of time at Parsley Park studio, and at his home at the Purple mansion. Prince and I spent a lot of time together, once I relocated from Los Angeles. I actually lived at a Minneapolis hotel for awhile, and later shared an apartment with roommates. Playboy… Playboy opened a major door that opened up after filming, "Graffiti Bridge." Prince called Playboy to let them know he wanted me in the magazine. Playboy built a $10,000 set for my photo shoot. I've appeared in four romance videos and two major photo shoots. Working with Playboy, was a dream come true. I had been fantasizing about working for Playboy since the tender age of 16."
CJ: What was life like as an ex-NBA wife? What were some of the pros and cons of an NBA wife's world? How did you deal with all the NBA gold-diggers?
POWER: "My ex-husband (Donald Royal) played for the National Basketball Association's Minnesota Timberwolves, San Antonio Spurs, Golden State Warriors, Orlando Magic and played overseas. Life as an NBA wife was back to normal. I walked away from that situation back to Chicago with three bags of clothing and $20.00. Being an ex-NBA wife provided plenty of accolades when discussing my experience. Prior to my marriage, I was a former Chicago Bulls Cheerleader dancing as a Chicago Luvabulls. I've been involved in the NBA for a number of years. Some of the pros of being an NBA wife is the notoriety, money, success, and being able to travel to places you never been before. Also, buying the things you always wanted to have. It was a wonderful experience! I love a very athletic man that stays in shape. I love going to the games and being part of a family of winners and strivers. People that want to be the best. I really enjoyed the lifestyle, and wouldn't trade it for the world!"
Gold-diggers… There is a difference between a groupie and a gold-digger. Let's not forget beautiful women in search of the best in life. They make sure they put themselves in a position that they meet someone that can support them financially, take care of children, provide for a family, athletically fit, and some women like "giants" needing a whole lot of man to handle a whole lot something! Trust me I can relate. Yes! There are Gold-diggers in the NBA. There were young ladies around me all the time. Some were my friends, most were my lovers since I am bisexual. I really enjoyed their company. It was very easy to gather wonderful harem of beautiful women. It was very simple thing which I enjoyed, prior to becoming an NBA wife but the gold-diggers are the ones who pretend to be your friend but they really want to push you off a cliff to take your place. Unfortunately, as kind as I was, I still had those leeches and bloodsuckers around me. I'm just glad God reveal to me who they really represent. I'm moving on to create new chapters in my life. To be honest, I love groupies over gold-diggers any day. Groupies show tremendous loyalty and dedication!"
5) How would you describe your experience as a famed Soul Train dancer? How did you make it to the main platform to be view by millions on Soul Train? How many years did you dance? What were some of your memorable moments with Don Cornelius?
POWER: "I had a magnificent experience dancing on Soul Train. I remember when I was a little girl like so many of us glued to the television on Saturday morning to watch, Soul Train. I remember as a little girl being raised without a father in the home, so (Don Cornelius) was like this Saturday morning daddy or babysitter. Don Cornelius was like a godfather image to me. He was a powerful role model on television showcasing our talents of our people. I really appreciated being given the opportunity to dance on the platform. When I moved to Los Angeles, I danced at various nightclubs where a lot of dancers from Soul Train frequent. I became friends with some of the dancers who took me down to Soul Train as a guest. As soon as I got there I walked directly up to the coordinator name (Eric) on the first day, I told him that I was from Chicago. I ask him if I could dance on the platform, "He said what makes you think you deserve to dance on the platform?" I said because I am from Chicago; that's where Soul Train started, and thirdly, I am a really good dancer and deserve to be on the platform. He said wait a minute while he spoke with Don. Eric said, Don would like to see what you can do. He instructed me to dance on the floor near the famous Soul Train Scramble Board. I started dancing, within 3 minutes (Eric) came rushing over to inform me that I can dance on the platform. So it took me 3 minutes to show, Don Cornelius that I was worthy to be on the platform as a famed Soul Train platform dancer. I danced on Soul Train for two seasons because we shot over the summer. My most memorable moment with (Don Cornelius) was when I was leaving to go to Minneapolis, Minnesota to live and record at Parsley Park Records with Prince. He walked up to congratulate me, said he was very proud of me while putting his hand on my shoulder he said that, "You're going to would be bigger than, (R&B/Pop singer) Jody Whatley ever was!" Jody Whatley was one of his protégés, so I really took that as the most ultimate compliment. I am not here to take anything away from Jody Whatley's brilliant career but I don't plan to want let him down."
CJ: How would you describe your career as a famed music video vixen? How many music videos did you appear in? What was it like to work with Ice Cube, Young MC?
POWER: "I didn't claim a lot of fame as a music video model. A lot of people never realized that I appeared in over 18 music videos. My versatility provided me opportunities on Soul Train; working with Ice Cube, and Young MC's music video projects. I never acquired fame in music videos because no one could ever connect me from project-to-project. But if you think about it, I've been seen by millions over the years with my appearances on Soul Train and appearing in major movies."
CJ: How would you describe you exotic beauty and sexuality? How do you manage to keep your (size 3) shapely figure? How does it feel to have both men and women desire your beauty, sex appeal, and love?
POWER: "I would describe my beauty as God-given. My mother possibly procreated with a handsome man to pre-arrange how I looked. She wanted and prayed for an angel with light-skin with long flowing hair and attractive features. I've never met my biological father. My sexuality is very natural. I was born sexy which has always attracted people to my beauty. I keep my shapely figure due to dancing, strict seafood vegetation diet (no animals), stay active, get plenty of rest, and keep moving because fat loves an inactive person. I am very proud to have my same size 3 figure. I am a dancer at Atlantis Gentlemen's Club (Chicago) which keeps me active daily. I've had this same figure since I was 17 years old. I take a great deal of proud in this lifelong accomplishment. I love that people love me and want to be around me. I've had meaningful relationships, friendships, and sexual relationships with some interesting people. I am very comfortable with my sexuality. No! I am not a groupie! I have had many sexual partners due to there personalities traits such as celebrities, businessmen, female and male eye candy, and regular guys who make me laugh. If you ever want to know the truth about me, just ask!"
CJ: How would you describe your daughter's accomplishments in her life? Is she currently taking classes to become a hair stylist? What was it like raising a daughter in the limelight of being a celebrity?
POWER: "I am very proud of my daughter. She's grown into a confident, faithful, athletically focused, and independent young woman. Yes! She is studying to be a hair stylist. She's wonderful with hair, beauty, fashion, poetry with a blend of street and book smarts. While growing up a baby in an NBA household, it didn't effect my daughter's growth or personality. She's very proud of both her mother and father's accomplishments. It has motivated her due to her parents' ability to strive for a dream and accomplish great results."
ROBIN "POWER" ROYAL GALLERY
Robin "Power" Royal Favorites:
Fragrances: Angel
Food: Sushi, Salmon
Snacks: Ice cream with chocolate
Vacation Spots: Paradise Island (Atlantis Bahamas)
Movies: "Coming to America", "Graffiti Bridge"
Cars: Masetrati, Rose Royce
R&B/Rap/Pop Artists: R. Kelly, Drake, Usher, Katy Perry, Madonna
Books: The Bible, "Blood of the Lamb"
Reality Shows: "The Making of an Empire, Power Royal."
For more about sexy Robin "Power" Royal, visit
www.chocolatetigerproductions.com
www.facebook.com/robinpowerroyal
www.twitter.com/POWERANGELBABY
www.modelmayhem.com/3300499


text:
2 Chainz, Anthony Hamilton, Charlie Wilson, Elle Varner, Fantasia, Ginuwine, John Legend, Keyshia Cole, Leah LaBelle, Miguel, Ne-Yo, New Edition, Rapheal Saadiq, Stevie Wonder, Tank, Tyrese
WATCH THE SOUL TRAIN PERFORMANCES FROM @KEYSHIACOLE @2CHAINZ & MORE
Last night saw the Soul Train awards hit the TV screens, Filmed in Las Vegas this year instead of Atlanta where it is usually held, with some great performances from the likes of Keyshia Cole, Ne-Yo, Miguel, 2 Chainz and more. Watch the performances after the jump via BET.
Music,Tv Shows,Videos
BET Honours, Jennifer Hudson, Jermaine Dupri, Kelly Rowland, Mariah Carey, Patti LaBelle, Spike Lee, Stevie Wonder
[VIDEO] BET HONORS MARIAH CAREY + MORE
Last night BET Honoured Mariah Carey, Spike Lee, Stevie Wonder, Beverly Kearney and Maya Angelou with performances from Patti LaBelle, Kelly Rowland, Jennifer Hudson and more. Mariah was honoured for her work ethic as an entertainer since 1990 and still working currently in the studio recording her 14th studio album with Jermaine Dupri. After selling an impressive 200+ Million albums worldwide it was only right she was honoured in this way. Watch below for the full show and performances.
Album Review,Music,Videos
40, Big Sean, Birdman, Boi-1da, Chris Brown, Drake, J. Cole, Jo Jo, Jon B, Juvenile, Kendrick Lamar, Lil' Wayne, Nicki Minaj, Pusha T, Rick Ross, Rihanna, Stevie Wonder, The Weeknd, Trey Songz, Wale
@DRAKE 'TAKE CARE' ALBUM REVIEW
November 15th is shortly upon us will Drizzy kill the game again or has the likes of J. Cole, Big Sean and Wale taken his shine? Say Somethin' reviews 'Take Care' after the jump!


text:
Fondation d'entreprise Hermès
Exhibitions at La Verrière from 2008 to 2012
The Foundation's exhibitions
Exhibition "Cliffs", Stéphane Erouane Dumas, La Verrière, Falaise nocturne, oil on paper / huile sur papier, 2009 © Stéphane Erouane Dumas
Installation view of "Vibrato con sordino", Charlotte Charbonnel, La Verrière, 2011 © Fabien de Cugnac
Installation view of "Ideal Circus", Claude Lévêque, La Verrière, 2010 © Fabien de Cugnac
Installation view of "Toiles et twils", Claude Viallat, La Verrière, 2010 © Fabien de Cugnac
Installation view of "J'aime trop Baugin", Côme Mosta-Heirt, La Verrière, 2012 © Fabien de Cugnac
Installation view of "There are no circles", Lionel Estève, La Verrière, 2012 © Fabien de Cugnac
Installation view of "Whisper", Monique Frydman, La Verrière, 2008 © Fabien de Cugnac
From 2008 until 2012, curator Alice Morgaine oversaw the artistic direction of La Verrière. Every year, she invited a number of artists to present original works created especially for the Brussels exhibition space. Ever since La Verrière opened its doors with the support of the house of Hermès, it has sought to give precedence to the production of new work over the presentation of pre-existing projects. In a model of patronage and support of original creation that has since been reproduced at other art venues opened by the house of Hermès throughout the world, the work produced for La Verrière remains the property of the artist. Seeking to address the broadest possible audience, all of these spaces offer free entry.
Since its inauguration in 2000, this impressive space beneath a pyramidal skylight has played host to a wide range of exhibitions. From 2008, when La Verrière became part of the programme of the newly created Fondation d'entreprise Hermès, until 2012, when Guillaume Désanges took on the role of head curator, Alice Morgaine organised sixteen solo exhibitions. Sixteen exhibitions; sixteen original projects conceived specially for this unique space and its ever-changing light, and sixteen unique moments in the careers of the invited artists. Over the course of the months and years, different creative worlds were revealed, each with their own forms and questions. While the curator intentionally allowed the artists free rein in their projects, certain traits lend a distinct colour to the programming over this five-year period. A diverse group of artists living and working in Europe were featured, from internationally renowned figures to early-career artists exhibiting work in a solo capacity for the first time. Often working with various forms of abstraction, they pursued their work along sculptural or pictorial lines, with the exception of Fabien de Cugnac, who marked the ten-year-anniversary of the space with a retrospective of exhibition views.
Identifying and playing upon paradoxes, the artists' interventions at times combined the monumental with the discreet: Lionel Estève created a pearlescent constellation that descended from the space's skylight, whilst Charlotte Charbonnel's radial strings formed an instrument that was alternately sonorous and silent. The geometrical volumes of Jean-Gabriel Coignet and the letters erected by Peter Downsbrough brought to mind the radical gestures of seminal minimalist art. Other projects, such as those of Danae Stratou and Jean-Charles Pigeau, seemed to be anchored in a dialogue with the space's architecture. From the interplay with the shifting light of La Verrière instigated by Monique Frydman and Aïda Kazarian to the immense cliff-face created by Stéphane Erouane Dumas, and from the instantly recognisable work of Claude Viallat to the manifold contradictions of Christian Bonnefoi's, the medium of paint thrived in this space. In the same year, Patrick Neu marked out traces in soot that seemed to respond to the black, interlacing forms created by Côme Mosta-Heirt. Situated at the heart of the capital of the European Union, La Verrière also hosted socially engaged installations by Barthélémy Toguo and Claude Lévêque.
From 2008 to 2012, Alice Morgaine invited several artists each year to present original works created especially for the Brussels exhibition space.
Sixteen personal exhibitions were presented at La Verrière by curator Alice Morgaine between 2008 and 2013.
Since its opening, La Verrière has sought to give precedence to the production of new work over the presentation of pre-existing projects.
50, boulevard de Waterloo
1000 Brussels Belgium
Free admission,
Tuesday to Saturday
from 12 p.m. to 6 p.m.
Alice Morgaine
Dates of the exhibitions
"Ballistic Poetry": an exhibition series at La Verrière
"L'héritage des secrets": a series of exhibitions at La Grande Place
"L'Esprit du Bauhaus", a major exhibition
Aloft at Hermès Exhibition Cycle in 2018
Exhibitions at Atelier Hermès in 2018
Exhibitions at Le Forum in 2018
See all the Foundation's projects
Keep informed of the Foundation's
latest news, events and programmes
J'accepte de recevoir des informations de la part de la Fondation d'entreprise Hermès et
que mes données soient traitées conformément à la Politique de Confidentialité.


text:
T-Shirts & More
Home>All Products > Kids in Action CD
Kids in Action CD
Part Number:1_GS017-CD
1. Kids In Action
2. The Way We Do It
3. Bop 'Till You Drop
4. Goin' On A Bear Hunt
5. Beanie Bag Dance
7. Get Ready, Get Set, Let's Dance
8. Conga Line
9. Can't Sit Still
10. My Aunt Came Back
11. Can You Leap Like A Frog?
12. Beautiful World
A must have, Kids in Action is packed with movement songs that direct themselves. Some teachers call it, "P. E. in a box!" Kids get moving again and again. Movement, sing along, repetition. Goin' On A Bear Hunt; Get, Ready, Get Set, Let's Dance; Beanie Bag Dance and more.
With more than four million recordings sold to date, Grammy nominated Greg & Steve hold the rank of the number-one children's music duo in the country. It's easy to see why – their singable lyrics and catchy melodies are set to a contemporary beat. Parents and teachers alike find Greg & Steve's tunes a fun way to teach children basic concepts such as colors and numbers as well as friendship and cooperation. Greg & Steve have received numerous accolades, including 10 Parents' Choice Awards, 2 Dr. Toy Awards, and an Early Childhood NEWS Award.
Ready, Set, Move! CD
Kids In Motion CD
Greg & Steve Teddy Bear
Follow @Greg_and_Steve
Songs by Subject
Privacy, Terms and Conditions
Copyright Greg & Steve. All Rights Reserved. eCommerce Software by 3dcart.


text:
What to Eat in Delhi's Shahpur Jat Neighborhood
India Delhi
All Delhi
Sharell Cook
Sharell Cook lives in Mumbai full-time and has been writing about India travel for TripSavvy since 2008.
Potbelly Rooftop Cafe.
Wondering what to eat in Delhi's Shahpur Jat neighborhood? This cool urban village and designer hub attracts a lot of health-conscious hipsters. Hence, wholesome vegetarian food is popular, along with gourmet teas and coffee. In addition, look out for some groundbreaking restaurants serving cuisines that you might not be familiar with!
Bihari Cuisine: The Potbelly Rooftop Cafe
The Potbelly Rooftop Cafe
Top Floor, 116 C, behind UCO Bank, Shahpur Jat, Siri Fort, New Delhi, Delhi 110049, India
Phone +91 11 4161 2048
It's not often that you get the opportunity to try authentic regional cuisine from Bihar in India, let alone in such a funky environment as the Potbelly Rooftop Cafe. No wonder this cafe is a hot-spot for foodies in Delhi! Its owner was a fashion designer before deciding to diversify into the restaurant business. She opened the cafe in 2011 using her mother's recipes, which have been handed down over generations—so you know the dishes will be homely and delicious.
Order the Baggia Basket (pockets of rice flour stuffed with spiced channa daal and served with chutney), Litti Chokha (a trademark Bihari dish of whole wheat balls stuffed with spiced flour), Fish Chokha (spicy fish salad served on crispy poori bread with chutneys), mustard fish curry or prawn curry.
Do note, there's no elevator and you'll have to climb four flights of stairs to reach the roof. The cafe serves lunch and dinner daily, from noon to 11.30 p.m.
All Day Breakfast and Continental Cuisine: Ivy and Bean
Ivy and Bean
119, Sishan House, Shahpur Jat, Siri Fort, Shahpur Jat, Siri Fort, New Delhi, Delhi 110049, India
This cozy cottage-feel restaurant has an eclectic menu packed with sumptuous English breakfasts, pancakes, burgers, Italian mains, and bit of modern Australian fare thrown in. The restaurant's owner is also the chef, and she spent a decade in Australia working closely with celebrity chef Matt Preston. The restaurant gets its name from an Australian children's book series, and books are part of the theme there. One of the walls is lined with a huge bookshelf that's been turned into an honesty library. Take a book and return it, or swap it with one of your own. Choose from indoor or outdoor seating, tables or sofas, and get comfortable. Opening hours are 11 a.m. to 11 p.m. daily.
Healthy Food: Garden House Cafe
Garden House Cafe
Working as a celebrity fitness trainer inspired the cafe's owner to set up a kitchen for the home delivery of healthy food in 2015. Such was the demand that he opened the Garden House Cafe in 2018. It's a cute little cafe that offers salads, super food bowls, fitness meal boxes, sandwiches, smoothies, health tonic teas and coffees, and cold-pressed juices. Not everything on the menu is strictly healthy though. There's pasta, pizza, and Oreo shakes for those who want to indulge. The cafe often hosts live events including stand-up comedy and solo music performances. Opening hours are 9 a.m. to 11 p.m.
Nepalese Cuisine: Darjeeling Steamers
Darjeeling Steamers
Darjeeling Steamers brings "delicacies of the hills" to Delhi. Momos (stuffed dumplings) are the specialty and you can even have them for desert, with chocolate fruit and nut or apple cinnamon fillings. Health-conscious customers can select outer coverings made from buckwheat, red wheat (beetroot), and green wheat (spinach) four. However, if you're really hungry, order a tempting Nepalese Thakali meal that comes with a variety of dishes. There are Nepalese snacks, noodles and soups to try too. The restaurant is open daily from noon to 10 p.m.
Korean Cuisine: The Layer Cafe & Bistro
The Layer Cafe & Bistro
One of the newest additions to Shahpur Jat's dining scene, The Layer Cafe & Bistro opened in early 2020 and serves tasty Korean food for breakfast through dinner. The menu includes Korean fried dumplings, sushi, noodle bowls, and sausage teok (fried sausage with sweet and sour sauces). Finish off with the restaurant's signature "puffy and airy" souffle pancakes. Intrepid gastronomes should make an advance reservation to sample little-known local Korean dishes. Kick back and relax with a Korean magazine to complete the experience. Continental comfort food and fabulous coffee will satisfy less-adventurous eaters. The young owners of this friendly restaurant are very focused on customer satisfaction, and it shows. Opening hours are 9 a.m. to 10 p.m. daily.
Tea and Cakes: The Mad Teapot @ The Wishing Chair
The Mad Teapot @ The Wishing Chair
86 A, Ground Floor, Near UCO Bank, Shahpur Jat, Siri Fort, New Delhi, Delhi 110049, India
Take break from shopping for quirky home decor at The Wishing Chair and recharge at their whimsical Mad Teapot cafe, situated in-store. Both the store and the cafe have been inspired by Enid Blyton's children's books, and this has extended to the names of the dishes on the menu. The cafe's collection of tea pots is also fitting. And, of course, there's an assortment of boutique teas to go with it from Tea Trunk, Jugmug Thela, and Anandini Himalaya Tea (they also have a tea room in Shahpur Jat). Pair them with a freshly baked cake from the display, or a more substantial vegetarian salad, sandwich, pasta or flatbread. Coffee aficionado are catered for as well.
Sundar Nagar Restaurants
9 Things to Eat in the Hauz Khas Neighborhood, New Delhi
The Best Things to Eat in Delhi's Nizamuddin Neighborhood
What to Eat in Delhi's Connaught Place Neighborhood
14 Foods You Need to Try in Udaipur, Rajasthan
The 13 Best Restaurants in Udaipur
Where to Eat and Drink in Delhi's Paharganj Backpacker District
The 7 Best Restaurants in Delhi's Lodhi Colony Neighborhood
48 Hours in Udaipur: The Ultimate Itinerary
The 14 Best Restaurants in Casablanca
The 15 Best Restaurants in Mumbai
The Best Things to Eat in Delhi's Sundar Nagar Neighborhood
What to Eat in Mumbai's Fort Neighborhood
The Top 12 Restaurants in Dubai
The 15 Best Restaurants in Marrakesh
The 15 Best Restaurants in Sao Paulo
15 Best Restaurants in Scottsdale, Arizona


Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.
Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia.
This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest.
Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).
Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.
This article belongs to a Special Issue on Imaging for CNS drug development and biomarkers.
Mitul A. Mehta and Sukhi S. Shergill are joint senior authors.
The online version of this article ( https://doi.org/10.1007/s00213-018-5134-y) contains supplementary material, which is available to authorized users.
Patients with schizophrenia commonly experience positive symptoms such as hallucinations and delusions and negative symptoms such as lack of motivation and flattening of affect. In addition, patients also suffer from impairments in cognitive functioning, which are often profound and evident across a range of cognitive domains including learning, attention, memory and executive function (Heinrichs and Zakzanis 1998). Despite the prevalence of these cognitive deficits, there are currently no approved treatments for cognitive impairments in schizophrenia. Cognitive impairments are highly correlated with functional disability (O'Carroll 2000; Green et al. 2004) and in some domains to a greater degree than clinical symptoms (Bowie et al. 2006), so there is a significant need to develop novel therapeutic interventions to improve cognition in these patients (Gilleen et al. 2014; Gilleen 2017).
Many compounds and non-pharmacological techniques have been tested for their potential to treat cognitive deficits in schizophrenia (Wallace et al. 2011). While there have been some promising results, the dominant picture is of mixed findings and overall modest effect sizes. Pharmacological approaches include the use of agonist compounds, which may be useful in the short term, but present a theoretical limitation of adaptation of the neurotransmitter system or tolerance at the target receptor site. Compounds that indirectly alter target neurotransmitter systems may offer a more feasible approach. These include allosteric modulators, or those that inhibit enzymes, which breakdown components of neural signalling cascades.
Recently, there has also been considerable interest in the potential for inhibitors of the enzyme phosphodiesterase (PDEs) to improve cognitive functioning. PDEs are a large family of intracellular enzymes that hydrolyse the cyclic nucleotides cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). cAMP plays an important role as a second messenger molecule controlling multiple cellular processes (Conti and Jin 1999). Currently, 11 PDE families (PDE1–PDE11) have been identified that differ in substrate specificity, sensitivity to inhibitors and expression in different cell types. Areas of high PDE localisation are widespread, including hippocampus, prefrontal cortex, striatum and amygdala supporting a role for these enzymes in cognition (Wallace et al. 2011; van der Aart et al. 2017).
Within the PDE family, PDE4 holds specificity for cAMP and inhibition of this enzyme has demonstrated some potential for improving cognition. Rolipram, a highly selective inhibitor of PDE4 (Conti and Jin 1999), which enhances intracellular availability of cAMP (Pérez-Torres et al. 2000), has been shown to improve memory in rats (Barad et al. 1998; Hosseini-Sharifabad et al. 2012; Rutten et al. 2006; Vanmierlo et al. 2016) and reverse MK-801-induced (Zhang et al. 2000) and scopolamine-induced (Egawa et al. 1997; Zhang et al. 2000) deficits in working memory, latent inhibition (Davis and Gould 2005), as well as scopolamine-induced deficits in short-term memory (Imanishi et al. 1997; Rutten et al. 2009; Zhang et al. 2000). Rolipram attenuates PCP-induced impairments in object retrieval in monkeys (Rutten et al. 2008), and cognitive flexibility in rodents (Rodefer et al. 2012). Rolipram is a non-selective PDE4 inhibitor, and these effects may be due to the involvement of cAMP in memory as PDE4A, 4D and to a lesser extent 4C are expressed in rat hippocampal CA1 (Peng et al. 2014). Rolipram increases cAMP response in hippocampal slices and serves to facilitate persistent long-term potentiation in CA1 (Barad et al. 1998) and may do so by lowering the threshold at which LTP occurs (Bach et al. 1999).
In humans to date, there is no published assessment of the ability of rolipram to improve cognition, which may in part be due to its emetic side effects likely, in turn, due to its non-selectivity. Another PDE4 inhibitor, roflumilast, currently used to treat chronic obstructive pulmonary disease, has also shown potential to be a cognitive enhancer and has a more favourable side-effect profile perhaps attributable to its greater relative selectivity (for PDE4B/D). Although roflumilast has been used in fewer neurological studies than rolipram, the reported effects to date are favourable. Roflumilast (and rolipram) significantly reverses time-induced memory deficits in a novel object recognition task (Jabaris et al. 2015) and also enhances spatial Y-maze performance in mice (Vanmierlo et al. 2016). In healthy volunteers, Van Duinen et al. (2015) demonstrated that a single dose of 100 μg roflumilast improved verbal memory and P600 (late event related potentials) during verbal learning significantly more than placebo. Further, the same group reported that roflumilast improved verbal learning in elderly healthy volunteers (Van Duinen et al. 2017).
Cognitive deficits in schizophrenia are broad and notably include prefrontal dysfunction in addition to hippocampal-dependent memories (Heinrichs and Zakzanis 1998). Dopamine dysfunction has also been implicated in the frontally mediated deficits through the dopamine D1 receptor (Goldman-Rakic et al. 2004). D1R binding in PFC is reduced in schizophrenia, and this reduction is associated with poorer cognitive performance (Okubo et al. 1997). PDE4 can modulate dopamine signalling via its effects on cAMP, which is increased with dopamine D1 receptor agonism (Cooper 2003). Indeed, PDE4 is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons and modulates the level of D1 receptor signalling and DARPP-32 phosphorylation in the frontal cortex (Kuroiwa et al. 2012). As working memory is impaired in schizophrenia (Heinrichs and Zakzanis 1998), is functionally subserved in part by prefrontal D1 (Goldman-Rakic et al. 2004) and is disrupted by dysregulation of cAMP signalling (Taylor et al. 1999), roflumilast may be expected to improve cognition via this pathway.
In this study, we aimed to demonstrate that roflumilast, as an add-on to second-generation antipsychotics (SGAs), would improve working memory and episodic memory functioning in schizophrenia patients. We reasoned that the domains of working memory and verbal episodic memory, consistently impaired in schizophrenia, would be sensitive to modulation of PDE4 activity based on previous animal studies and the known role of cAMP in these processes. We included functional imaging of a working memory task to test the hypothesis that prefrontal cortex activity would be modulated by roflumilast, and to our knowledge, this is the first three-period crossover fMRI neuroimaging study designed to assess a cognitive enhancer in schizophrenia. We anticipated that roflumilast would enhance cognitive performance compared to placebo. Specifically, we hypothesised that there would be a significantly greater positive change in performance of verbal episodic memory (as measured by the HVLT) and working memory (as measured by the Spatial Span task), and significantly reduced dorsolateral prefrontal cortex activity during spatial working memory (as measured by the Dot Task with fMRI) following 8 days of treatment with roflumilast compared to 8 days with placebo. We also additionally explored dose-response effects of roflumilast for these cognitive and neural outcomes.
This was a phase 1, randomised, double-blind, placebo-controlled, single-site, three-period crossover study to evaluate the effect of roflumilast as an add-on to SGA in attenuating cognitive deficits associated with schizophrenia. In each of the three periods, placebo and 100 or 250 μg roflumilast were administered once daily to patients with schizophrenia for eight consecutive days to achieve steady state (Fig. 1). The time course of study participation was consistent and conformed to Fig. 1 for all participants. All patients received all doses, and the treatment order was determined by random allocation to one of three treatment sequences according to a Latin Square design (ABC, BCA or CAB), with a 2-week wash-out between phases (see Table 1).
Cognitive testing with the Hopkins verbal learning test-revised (HVLT-R) and spatial span (SS) from the MCCB MATRICS test battery (Nuechterlein et al. 2008) was performed on the first (pre-drug on D1) and last day (D8 post-drug) of each phase to assess change in cognition, and fMRI was conducted on the eighth day of each phase (see fig. 1). One week prior to the first drug or placebo testing phase, all participants underwent two practice training sessions for the cognitive tests and an fMRI familiarisation session. Prior task administration is a standard approach to minimise, or 'wash-out', practice or learning effects. These effects were further reduced by using the five available parallel versions of the HVLT-R (forms 1, 3, 4, 5 and 6), and the order of HVLT form administration was randomised and counterbalanced across participants. The DOT task trial-set is randomly generated with each test administration. For the spatial span task, no parallel versions exist however as there was at least 7 days between assessments trial-specific retention (learning effects) would not be expected to occur for such complex spatial sequences. There were three outcome measures: change in accuracy on the HVLT-R, span on the SS and neural activity change during a spatial working memory test (the Dot Task (Marquand et al. 2011)) as measured with fMRI. Performance on the Dot Task was trained to achieve a 70% correct threshold, and only correct trials (hence successful working memory) were included in the analysis. FMRI was carried out while subjects performed the Dot Task in the MR scanner while the other cognitive tasks, the HVLT and spatial span task, were performed just prior and outside the scanner.
This study took place at the Institute of Psychiatry, Psychology and Neuroscience, Kings College London. This research was conducted in accordance with the protocol procedures complied with the Declaration of Helsinki, the International Conference on Harmonisation (ICH) E6 GCP guidance, and all applicable local or regional regulatory requirements. The study was pre-registered with clinicaltrials.gov (identifier: NCT02079844), and hospital ethics approvals were given by NRES Committee South Central Berkshire (reference 12/SC/0443).
Patients who had consented to be contacted about participating in research were recruited from local outpatient services. Following the study inclusion/exclusion criteria, men or women, aged 18 to 60 years, who met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), criteria for schizophrenia, and who were receiving stable doses of second-generation antipsychotics for at least 2 months prior to screening (see supplementary materials for inclusion/exclusion criteria) were eligible to take part. Twenty-one patients were consented and randomised to one of the treatment groups. Participants were randomised to one of three treatment sequences according to a blinded computer-generated allocation schedule. Six did not complete the study: five participants withdrew without reason, and one was unable to attend dosing and so was withdrawn. Demographics and clinical information for the 15 participants who completed are shown in Table 2, and additional information on participants is shown in supplementary materials. Only data from completers is reported. Seven participants were receiving olanzapine (2 at 20 mg, 2 at 10 mg, 1 at 15 mg, 1 at 10 mg, 1 at 2.5 mg), four were receiving aripiprazole (2 at 20 mg, 1 at 15 mg, 1 at 10 mg), one quetiapine 300 mg, one paliperidone 50 mg and two risperidone depot 25 mg.
It has been demonstrated that single doses of roflumilast 100 μg (but not 300 or 1000 μg) administration improves episodic memory in both healthy volunteers; with the same pattern—single dose 100 μg (but not 300 or 1000 μg)—showing significant effects on P600 values with EEG (24,25, 40). In following, 100 and 250 μg in multiple dosing to achieve steady-state condition were chosen for this study to explore the effective dose window in patients with schizophrenia. Dosing on all days took place at site in front of a research team member to ensure compliance—confirmed post hoc via pharmacokinetic/metabolite analysis of blood samples. Plasma concentrations, roflumilast exposure and safety data are reported in supplementary materials. Both doses were compared to placebo. Blinding and randomisation procedures were conducted by Quintiles CRO Ltd. Blindings for this study were not broken for any participant.
The Hopkins verbal learning test-revised (HVLT-R) is a subtest of the MATRICS Consensus Cognitive Battery (MCCB (Nuechterlein et al. 2008)). It assesses verbal memory and consists of a list of 12 words from 3 taxonomic categories. The words were presented orally, and the participants are asked to recall as many words as possible after each of three trials. The key outcome variable for the HVLT-R was the total number of correct responses over three trials. The test was administered on day 1 (pre-drug) and day 8 (post-drug), and each drug period made use of the alternate HVLT-R forms from the MATRICS to avoid practice effects.
The spatial span test assesses working memory. Participants are presented with a board containing blue blocks arranged in an irregular pattern. The rater taps out a pattern on the blocks and participants are tasked with tapping the same pattern in response. Trial spans become longer in length and also consist of both forward and reverse patterns, the latter requiring patients to tap in the reverse order to the administrator. Scores are the sum of the correct responses in both the forward and backward trials.
In the DOT task (see Fig. 2), a rewarded delayed-response working memory task (Marquand et al. 2011), participants are instructed to remember the spatial location of a target stimulus (a dot) relative to a fixation cross after a delay period, which includes a noise mask (numerous moving dots). Half of the 40 trials carried a monetary reward, indicated by the colour of the stimulus, and the order of the trials was randomised and counterbalanced across subjects. In each trial, the target stimulus was presented for 750 ms (encoding), followed immediately by a mask for a further 750 ms to disrupt visual iconic memory; after a 7- or 9-s interval (delay), the target stimulus and a distracter stimulus are presented, and participants indicated which of the stimuli matches the target location by a left- or right-button press on a two-button response box (retrieval; 2 s). Feedback indicating success or failure is provided at the end of each trial. Patients received training on the task to ensure they understood the instructions, were able to respond appropriately and could achieve a threshold performance of 70% correct trials—well above chance. Only correct trials were used in the analysis as we were interested in successful spatial working memory (evident from correct trials only)—hence performance changes per se were not examined, only BOLD response changes during spatial working memory. FMRI was only conducted on D8 (post-drug), and these sessions were compared between drug arms. Strict criteria were used for acceptance of valid data available in all three sessions.
Symptoms were assessed at days 1 and 8 using the PANSS (Kay et al. 1987), although the study design was focussed on, and powered for, the cognitive outcomes.
Statistical analyses were performed to examine the effect of each dose of drug and placebo on change in cognitive test scores from day 1 (baseline) to day 8 (post-drug assessment) for the endpoints involving cognitive test results relative to change in the placebo phase from day 1 (baseline) to day 8 (post-drug assessment), and by day 8 comparison for the fMRI endpoints. Data processing and voxelwise brain image analysis was performed by the investigators, with the analysis of the primary endpoints performed by an independent statistician.
Pairwise comparisons were made between each roflumilast dose level and placebo using LS means estimated via analysis of variance (ANOVA) with sequence, period and treatment as fixed effects and subject nested within sequence as a random effect. The effect size for each roflumilast dose level was calculated using Cohen's d from which an effect size of 0 to 0.2 is considered small, 0.3 to 0.7 is considered moderate, and ≥ 0.8 is considered large.
We collected a high-resolution T1-weighted image on one session for each participant, for normalisation to a standard space (TR = 7312 ms, TE = 3.016 ms, FoV 270 mm, voxel size 1.05 × 1.05 × 1.2 mm, 196 slices, TI = 400 ms). The functional time series used the following parameters (TR = 2000 ms, TE = 30 ms, FoV 211 mm, voxel size 3.75 × 3.75 × 3.3 mm, 39 slices).
The fMRI task data acquisition started 5 h after day 8 dosing. The Tmax is up to 3 h after ingestion of a single dose and its N-oxide metabolite demonstrates a plateau-like Tmax after about 8 h. The median effective half-life of roflumilast is 17 h. Steady-state plasma concentrations following repeated dosing with 500 μg Roflumilast is estimated to be reached after approximately 4 days (83 h) for roflumilast and after 6 days (148 h) for the N-oxide metabolite. Roflumilast and its N-oxide show linear repeated-dose pharmacokinetics over the dose range of 250 to 1000 μg. Thus, assessment after 8 days of treatment ensured steady-state plasma concentrations required for cognitive testing.
Preprocesing steps are reported in the Supplementary materials. Single-subject, single-session fixed-effects GLM analysis was conducted to model responses during the DOT task. The DOT task consists of three parts: encoding, delay and retrieval, and additionally, trials were either rewarded or unrewarded. Thus, the following regressors were modelled: non-rewarded encoding and delay, non-rewarded retrieval, non-rewarded feedback, rewarded encoding and delay, rewarded retrieval and rewarded feedback. Because of the proximity in time and the brief, fixed presentation time of the cues, the encoding and delay periods were modelled together. The six movement regressors from the motion correction were also included in the model. A high pass filter of a period of 128 s was applied to the model to eliminate low-frequency signals such as scanner drift. For the purposes of reporting the data here, contrasts for the encoding and delay period were combined across the rewarded and non-rewarded trials as the primary outcomes were based on working memory-related activity.
The individual contrast maps from the first level were entered into a second level, random-effects analysis with subject as the random effect and session (drug/placebo) as a within-subject effect. Linear contrasts were used to describe the main effect of task across all drug conditions and the effect of roflumilast on the a priori defined region of interest.
fMRI performed well across participants in relation to the cognitive task and data collected, although data from some were removed due to poor quality. Quality was assessed for the fMRI data by visually inspecting coverage within the field of view and calculating movement. Excessive movement (> 1 voxel > 20% volumes) in any one session resulted in removal of the participant from the fMRI analysis. A high response rate was required for the task (> 60%), and no participant was removed due to low response rate.
A dorsolateral prefrontal cortex (DLPFC) ROI was chosen due to its known involvement in working memory (Curtis and D'Esposito 2003) defined as 6-mm spheres centred on the peak co-ordinates from Marquand et al. (2011) (Left − 43, 33, 25, Right 38, 44, 32), which utilised the same task.
LS mean HVLT total scores on day 8 (compared to Day 1) were increased with roflumilast 100 and 250 μg (0.27 (SE = 1.06) and 1.07 (SE = 1.08), respectively) and decreased with placebo (− 1.67, SE = 1.08) (see Table 3). LS mean differences in change from baseline between high-dose roflumilast and placebo were statistically significant (p = .044, ES = 0.77 (large effect size)), but not between low-dose roflumilast and placebo (p = .14, ES = 0.55 (medium effect size)). We also conducted an ITT (Intention To Treat) analysis which revealed the following effects: 100 μg (N = 17) vs placebo (N = 16): ES = .45 (95% CI interval = − 0.25 to 1.14); and 250 μg (N = 16) vs placebo: ES = 0.55 (95% CI interval = − 0.16 to 1.26). These differences were not significantly different.
Post hoc examination of the three HVLT trials revealed that performance on the high-dose roflumilast and placebo was maximally different on the third and last recall test of the three HVLT-R word list repetitions (effect size for trial 1 = 0.32, trial 2 = 0.47, trial 3 = 0.73).
LS mean total score change from D1 to day 8 with roflumilast 100 and 250 μg were 0.07 (SE = 0.51) and − 0.13 (SE = .52), respectively, while scores decreased with placebo (− 0.20, SE = 0.52). Change under both roflumilast doses were not significantly different to placebo (low dose p = .74; high dose p = .93). An ITT analysis (placebo: N = 16, 100 μg N = 17, and 250 μg N = 16) also revealed no significant drug effects vs placebo (100 μg (N = 17) vs placebo (N = 16): ES = 0.11 (95% CI interval = − 0.57 to 0.79), and 250 μg (N = 16) vs placebo: ES = 0.06 (95% CI interval = − 0.63 to 0.76).
Complete data were acquired for ten participants. Participants were as evenly distributed across the treatment orders as possible. For the comparison of placebo with 100 and 250 μg, there was change of activity with effect sizes of − 0.03 and − 0.671, with p values of 0.948 and 0.154 respectively. A voxelwise analysis was additionally conducted, and this again showed a reduction in activity from placebo to 250 μg roflumilast (shown in Fig. 3a, b) although this did not survive FWE-correction for multiple comparisons in the DLPFC. An additional exploratory whole-brain analysis was performed, and this revealed that no other brain regions were significantly affected by roflumilast; thus, no changes outside the DLPFC were observed. A separate analysis of the same data but including all 13 patients who completed the task (at any time point) showed effect sizes of − 0.006 for 100 μg (p = .98) and 0.500 for 250 μg (p = 0.082). The mean difference in BOLD response for the low and high doses is illustrated in Fig. 3c. While these analyses are in line with our prediction of reduced activity in the DLFPC with roflumilast, the differences were not significant. Post hoc analyses of the rewarded and unrewarded trials separately showed the same pattern of results: less activity associated with the high dose, most with placebo and the low dose producing intermediate activity. Behaviourally, as participants were trained to perform well on the task (to a threshold of ~ 70%) and only correct trials were used in the analysis performance was intended to be matched across treatment arms. As shown in Table 3, this was the case, and differences were not statistically different.
PANSS ratings did not change from day 1 to 8 for either dose of drug on either the positive or negative scale (ps > 0.434).
This study tested the hypothesis that the addition of roflumilast, a PDE4 inhibitor, would improve cognitive function and modulate frontal brain activity in patients with schizophrenia treated with atypical antipsychotics. The performance on verbal learning from the HVLT was significantly improved with the higher dose of roflumilast compared to placebo; however, working memory measured with the spatial span test did not show improvement. Reductions in PFC activity during working memory were evident with increasing doses of roflumilast in bilateral DLPFC, and the effect size for the higher dose was 0.5.
There is considerable preclinical evidence suggesting that inhibition of the PDE4 enzyme improves cognition, particularly memory processes (Bach et al. 1999; Barad et al. 1998; Hosseini-Sharifabad et al. 2012; Rodefer et al. 2012; Rutten et al. 2006; Rutten et al. 2008; Rutten et al. 2009; Vanmierlo et al. 2016; Zhang et al. 2000). Performance on verbal list learning was significantly enhanced by roflumilast in patients with schizophrenia—and these effects were greatest on the third and final learning presentation. Strikingly, Van Duinen et al. (2018) have also recently reported improvement in verbal learning performance following a single-dose 100 μg of roflumilast in healthy adults—and also showing greatest effects on the third trial in healthy adults as demonstrated here. The P600 peak as measured by EEG during verbal learning was also significantly increased, again only on the third trial at 100 μg, not at 300 or 1000 μg, of roflumilast. The authors suggest these findings may indicate that roflumilast affects information processing during memory (word) encoding.
There is now emerging and converging evidence that PDE4 inhibition can enhance memory via its action on long-term potentiation (LTP). Rolipram specifically induces late-phase LTP (L-LTP) not early-phase LTP (E-LTP) in rat hippocampus (Barad et al. 1998), and similarly specifically modulates late-long-term memory (LTM) not early-LTM (Rutten et al. 2009). It has been proposed that increasing cAMP signalling may improve memory by raising the probability that long-lasting synaptic plasticity occurs (Barad et al. 1998; Blokland et al. 2012). In line with this, mice with impaired long-term object recognition, due to being carriers of truncated CREB-binding protein, show reversal of deficits with rolipram (Bourtchouladze et al. 2003). In humans, the hippocampus is active during memory, which requires longer-term storage, including verbal learning (Johnson et al. 2001). Thus, as potential for LTP will be maximal with an increased number of stimuli presented over a time period, elevation of L-LTP/L-LTM by roflumilast is a potential neurobiological mechanism by which verbal learning performance improvements may occur.
Roflumilast was associated with reduced cortical demands during spatial working memory assessed using fMRI. This modulation was dose-dependent with a medium effect size for the higher dose, suggesting improved neural efficiency. We proposed that roflumilast would improve working memory as PDE4 inhibition increases intracellular cAMP levels in striatum and frontal cortex. These alterations increase dopamine synthesis and turnover in striatum and enhance the dopamine D1 receptor/PKA/DARP-32 signalling cascade in frontal cortex. Inhibition of PDE4 by rolipram increases dopamine D1 receptor signalling in cortical pyramidal neurons (in mouse) in frontal cortex (Kuroiwa et al. 2012), and dopamine D1 receptor signalling is known to improve working memory performance in rodents and non-human primates (Goldman-Rakic et al. 2004). The preclinical evidence also indicated that PDE4 inhibition reverses MK-801-induced (Vanmierlo et al. 2006) and scopolamine-induced (Egawa et al. 1997) deficits in working memory. As an example, activation of NMDA receptors produces a CA2-dependent increase in cAMP that may play a role in the induction of LTP in CA1 of the hippocampus (Zhang et al. 2000).
Roflumilast did not, however, lead to significant change in cognitive performance on spatial span compared to placebo at either dose. The pattern of data in the prefrontal cortex fits with previous neuroimaging studies of catecholaminergic stimulant medication (e.g., Mehta et al. 2000) with reductions in task-related activity accompanied by improvements, or even lack of significant change in performance. Future studies could investigate the specific PDE4 neurotransmitter interactions, which may account for pro-cognitive effects of PDE4 inhibition in working memory, changes in neural efficiency, and other cognitive processes.
The main limitation of this mechanistic study was the relatively low subject numbers, partly due to attrition because the patients found the frequency and complexity of assessments within the study somewhat demanding. As this study is exploratory in nature, the sample size was not based on statistical considerations. The sample size is based on the desire to gain adequate efficacy data on the primary and secondary outcomes as well as on published literature reporting pro-cognitive effects of drug candidates using the same pharmacological model and similar study. However, using a within-subject, crossover design rescues some statistical power by reducing degrees of freedom.
A primary goal of the study was to provide evidence of improved cognitive function following PDE4 inhibition in patients for the first time, and to assess the underlying impact on frontal brain activation, In both respects, it was successful and demonstrates the utility of combining cognitive and imaging markers in studies of novel mechanisms in patient populations. Since the outcomes were only measured at one time point, we are unable to determine if the drug effects are in fact greater earlier after an acute medication administration, or alternatively, if longer-term treatment leads to more robust effects in patients.
The delayed-response working memory fMRI task was based on one of the most widely used working memory paradigms, is sensitive to pharmacological manipulation and incorporated reward and no-reward conditions in order to parallel both the human and animal research into working memory processes. This also allows for secondary analyses to examine the role of reward; however, there was no differential effect of roflumilast on reward. This could reflect either a real lack of effect, or poor sensitivity due to the low sample size.
Additionally, for the purposes of this initial trial, we minimised the number of endpoints and chose to examine only the DLPFC during administration of the DOT task as this aligned with the predicted effects in schizophrenia and the predicted effects of PDE4 inhibition on the prefrontal activation seen during the encoding and delay periods on the task; however, subsequent work could investigate additional brain regions.
The age at illness onset ranged from 17 to 44 years, and the mean age of participants was 32 years old which is relatively later than in other patient studies. An older average age of patients is, however, more likely to be expected in drug trials as clinical and medication stability are inclusion criteria, and this is somewhat more likely in older patients. Despite this, the higher mean age may also be due to the relatively small sample size and could potentially limit the generalizability of the findings to younger onset samples.
The significant mean score differences between high-dose roflumilast and placebo on the HVLT-R were contributed to in part by a decline over time in the placebo arm. Despite this, the trend from placebo to high dose was significantly greater improvement with the high dose than placebo. Decline in the placebo group may additionally be attributable to study fatigue, which may be modified in the treatment periods.
Individuals with schizophrenia have significant cognitive deficits across many domains of functioning including memory, learning and working memory. Improvements in cognitive functioning are associated with better overall outcomes in individuals with schizophrenia (Bowie et al. 2006), yet there are no currently approved drugs for the improvement of cognition in schizophrenia. This study investigated the potential for roflumilast, a PDE4 inhibitor, to provide pro-cognitive effects in patients with schizophrenia concurrently treated with second-generation antipsychotics. The results showed that high-dose roflumilast significantly improved verbal learning relative to placebo. There was also a trend for roflumilast decreasing activation in the DLPFC during working memory suggestive of an impact via improving neural efficiency. These results are in line with previous studies with experimental animals indicating that PDE4 inhibition may improve memory function through its impact on intracellular mechanisms. Memory may be enhanced via the effects of cAMP on two systems—one, fast-acting on prefrontal neurotransmission to improve online memory processes, and a second, enhancing the capacity of L-LTP to encode learning targets (Kuroiwa et al. 2012). In summary, this clinical study provides support for increasing the use of combined neuroimaging and cognitive testing to validate models developed in experimental animals. We suggest that this research also supports further evaluation and clinical trials of this well-tolerated, off-patent and widely prescribed treatment as a potentially repurposed medication from respiratory medicine to neuropsychiatry. It should also be noted for subsequent studies that cAMP gradients and responses are highly varied among PDE isoforms (Fertig and Baillie 2018); thus, future work may better couple specific targeting of PDE4 subtypes with cognitive effects, potentially avoiding the need for multiple days of dosing to achieve steady state, as well as potential optimisation of side-effect profiles.
We would, firstly, like to acknowledge and thank the patients who participated for the time and effort they gave to the study. We acknowledge the on-going support from the NIHR-Wellcome Trust King's Clinical Research Facility and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. We also thank South London and Maudsley NHS Foundation Trust for supporting participant recruitment. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
The funding source for this study was Takeda Pharma A/S, London.
This research was conducted in accordance with the protocol procedures complied with the Declaration of Helsinki, the International Conference on Harmonisation (ICH) E6 GCP guidance, and all applicable local or regional regulatory requirements. The study was pre-registered with clinicaltrials.gov (identifier: NCT02079844), and hospital ethics approvals were given by NRES Committee South Central Berkshire (reference 12/SC/0443).
SSS has received grant funding for clinical trials and/or honoraria for educational input from EnVivo Pharmaceuticals, Takeda, AbbVie and Janssen Pharmaceuticals. He is supported by a European Research Council Consolidator Award (Grant Number 311686) and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. MAM has acted as a consultant for Cambridge Cognition, Lundbeck and FORUM pharmaceuticals in the past 5 years. He also has or has held research funding from Shire, Roche, Lundbeck and Takeda in the past 5 years. JG has acted as consultant for Quintiles CRO Ltd. YF, CD, SK, LV, AR and SCW have no disclosures or conflicts of interest to report. TU, GL and FO are employees of Takeda Development Center Americas, Inc., Chicago, U.S.A.MT is employed by Eli Lilly, Indianapolis, USA.


text:
Hyaleucerea fusiformis är en fjärilsart som beskrevs av Walker 1856. Hyaleucerea fusiformis ingår i släktet Hyaleucerea och familjen björnspinnare. Inga underarter finns listade i Catalogue of Life.

Källor

Björnspinnare
fusiformis

redpajama_set_name: RedPajamaWikipedia