#denae fritz

[marcorossi]

denae fritz leaving isu is so crazy and it’s like. you don’t wanna harp on a 20 year old making what she thinks is the best decision for her athletic career but also what the fuck happened

[juniperpublishers-toxicology]

The Importance of Dose-Time-Response Relationships for Hazard Identification and Limitation of Animal Experiments

JUNIPER PUBLISHERS-

Open Access Journal of Toxicology (OAJT)

 Author: Henk A Tennekes

Introduction

Historian Heiko Stoff has recently sketched a fascinating controversy in the 1950's on chemical risk assessment [1]. Two renowned scientists in the Farbstoffkommission (Dye Committee) of the Deutsche Forschungsgemeinschaft (DFG, German Research Community), pharmacologist Hermann Druckrey and biochemist (and Nobel Prize winner) Adolf Butenandt, were advocates of a preventive risk approach. This approach was largely determined by a groundbreaking study conducted by Druckrey during the war years with the carcinogenic dye 4-dimethylaminoazobenzene (also known as "butter yellow") [2], and Druckrey's un-intentional cooperation with the electrophysicist Karl Küpfmüller in an American detention camp in Hammelburg, Bavaria [3].

    The History of the Druckrey-Küpfmüller Equation

Druckrey demonstrated in 1943 that the carcinogenic action of "butter yellow" was determined by the total dose, and completely independent of the daily dose (Table 1). The product of daily dose D and exposure time (up to liver cancer manifestation) T was always the same:

D. T = constant (1)

and found to be about 1000mg (1 gram) in the case of butter yellow (Table 1).

This dose-effect relationship is known as Haber's rule (or law) [4], named after the German chemist Fritz Haber, who played a key role in chemical warfare in the Great War. Haber's rule originally described the relationship between gas concentration c and time to death t. The smaller the c.t product, the higher the toxicity. Druckrey's observation that Haber's rule also described the dose-response relationship of a carcinogenic substance was remarkable in view of long latency periods. Druckrey concluded from this study that the harmful effects of a carcinogen were cumulative and that thresholds of toxicity for carcinogens do not exist.

Druckrey and Kupfmuller also explained this dose-response relationship theoretically with a mathematical analysis of receptor kinetics, as shown in Table 2 [5]. It was assumed that the carcinogenic effect of butter yellow was due to irreversible interactions with a specific receptor. We now know that the receptor is DNA, and that cancer is the result of cumulative damage to DNA, but that was not known in those years. However, Druckrey and Kupfmuller also postulated that when the effect of receptor binding is irreversible as well, effects would be amplified over time (Table 2). In 1956, when Peter Magee and John Barnes linked the carcinogenicity of dimethylnitrosamine to alkylation of nucleic acids [6], Druckrey took the initiative to investigate the dose-time relationship of diethylnitrosamine (DENA) in rats to verify possible reinforcement of effects by exposure time. After all, irreversible DNA alkylation results in irreversible mutations, and nitrosamines therefore appeared to be perfect model substances. This study confirmed potentiation of carcinogenicity by time [7] which could be expressed as follows:

D. T n = constant (2)

TR is the time constant for the reversibility of receptor binding.

Tr is the time constant for the reversibility of the effect.

C is the concentration of the compound at the site of interaction with the receptor.

CR is the concentration of bound receptors.

E is the effect.

* if C remains constant.

with a value ofthe time exponent n of 2.3. This dose-response relationship is now known as the Druckrey-Kupfmuller equation. The equation explains the harmful effects of low exposure levels of a poison during prolonged exposure (Table 3). The lower the daily dose, the lower the total dose required for the damaging effect, even though the adverse effect occurs only after a long exposure period.

    Risk Prevention is Displaced by Risk Management

It is not surprising therefore that Druckrey and his influential friend Butenandt became major advocates of risk prevention. Only substances with a reversible mechanism of action and dose-dependent toxicology (Table 2) were acceptable in their eyes because safe exposure concentrations below a threshold of toxicity could be defined. By contrast, substances with an irreversible mechanism of action which followed equations (1) and (2), had no threshold and exposure should, where possible, be avoided.

However, in the 1960's, this approach was displaced by the ADI (acceptable daily intake) concept, which defines an acceptable level of exposure for a substance, independent of the mechanism of action. The ADI concept was mainly propagated by French professor René Truhaut [8] and received a lot of support from the chemical industry, because it was seen as a manageable concept for product development. This had major consequences for toxicological research. The primary objective of animal experiments was no longer clarification of the dose-response relationship and the mechanism of action, but determination of the dose that did not cause any harmful effect, in comparison to control animals, the so-called No-Observed-Adverse-Effect Level (NOAEL). The NOAEL is then divided by a safety factor, usually 100, to take account of possible differences in sensitivity between experimental animals and humans, and individual variation in sensitivity between humans. That exposure level (NOAEL: 100) is then considered as the ADI, the permissible daily human exposure. An exception was made for substances with mutagenic (DNA-damaging) properties, which were not allowed unless used to treat life-threatening diseases.

    The Druckrey-Küpfmüller Equation is Generally Applicable

In 2009, Francisco Sanchez-Bayo showed that the toxicity of the neonicotinoid insecticides imidacloprid and thiacloprid for arthropods was not only dependent on the dose but also on the duration of exposure [9]. Henk Tennekes, who was mentored by Hermann Druckrey in his time at the German Cancer Center in Heidelberg, recognized the dose-response relationships as Druckrey-Küpfmüller equations [10]. The lower the exposure concentration, the lower the total dose required for the damaging effect (Table 4). The subsequent collaboration between Tennekes and Sanchez-Bayo provided additional examples of substances with time-cumulative toxicity (Cartap, Diphacinone, organic mercury) [11,12]. All of these substances cause irreversible receptor binding and irreversible effects, and there are no indications for a threshold [13], so that the ADI for these substances underestimate the actual risks. In any case, it became clear that the theories of Druckrey and Küpfmüller are generally applicable and that equations (1) and (2) are of importance to the risk analysis of chemicals.

    The Risks of an Irreversible Mechanism of Action are Underestimated

The widely used neonicotinoid insecticide imidacloprid binds virtually irreversibly to nicotinic acetylcholine receptors in the central nervous system of insects and causes irreparable damage to nerve cells [14,15]. The substance is very slowly decomposed in the soil (half-life 200 days), and may leach into the groundwater, or run-off to surface water [16]. In water, the substance can only be degraded by ultraviolet light (photolysis). In many areas of intensive agriculture, surface water is contaminated with imidacloprid [16]. As a result, nontarget insects are exposed to an extremely toxic substance for a long time, which can lead to massive insect mortality and a break in the food chain [16]. Studies of the Universities of Utrecht and Nijmegen showed that the pollution of surface water with imidacloprid quantitatively correlated with decline of invertebrates and insects-dependent bird species [17,18]. Research in the National Park Dwingelderveld, The Netherlands, and in a nature reserve in Krefeld, Germany, showed that, since the introduction of imidacloprid in the mid-1990's, at least three-quarters of the ground beetles and flying insects have disappeared [16,19]. The risks of imidacloprid have been completely underestimated, with catastrophic consequences for insects and insectivores.

    Review of Risk Analysis is Urgently Required

Hermann Druckrey and Adolf Butenandt seem to have defined the correct approach to risk analysis of chemicals in the 1950's, as the new insights of recent years show. The ADI concept of René Truhaut is in any case unacceptable for substances with action mechanisms described by Haber’s rule or the Druckrey- Küpfmüller equation. Dose-response relationships are of much greater importance than a NOAEL in an experimental experiment because irreversible effects can be identified. In addition, dose- response relationships can make accurate estimates of the risks in the real world. This may make risk management more restrictive, but at least a lot safer. And there is another important perspective. Dose-response relationships can make a significant contribution to a strong reduction in the use of laboratory animals (Table 4).

    Analysis of Dose: Response Relationships Can Make Many Animal Studies Superfluou

The development of a new pesticide now costs almost $300 million [20], and expenditure for international market authorization procedures have risen exponentially in recent years. This development reflects the increasing concern about harmful effects of pesticides on farmland biodiversity. Imidacloprid is a case in point. The general applicability of the theories of Druckrey and Küpfmüller means that analysis of dose- response relationships can identify and eliminate hazardous substances at an early stage of product development [21]. Dose- response studies can be performed in a short period of time, for example with Daphnia magna (water fleas). In doing so, product development is shifted to substances with dose-dependent toxicology (Table 2). Long-term experimental experiments to determine a NOAEL are no longer necessary, as exposure time has no effect. In combination with a multitude of available in vitro studies (http://www.oecd.org/env/ehs/testing/adopted- testguidelines-toxicity-testing-3r-relevance.htm), this strategy can make a major contribution to the implementation of the 3R Principles (Replacement, Reduction and Refinement) that Russel & Burch first described in 1959 to limit the use of experimental animals [22].

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[biofunmy]

After Misty Comes Marie. Breaking Barriers in ‘The Nutcracker.’

She may not remember it, but during the first summer of her life Charlotte Nebres canvassed for Barack Obama with her mother, Danielle, who carried her in a sling. She attended political rallies. And on a frigid day in January 2009, she accompanied her parents and older sister to his inauguration.

When Charlotte was 6, Misty Copeland became the first female African-American principal at American Ballet Theater. That, she remembers.

“I saw her perform and she was just so inspiring and so beautiful,” Charlotte, 11, said. “When I saw someone who looked like me onstage, I thought, that’s amazing. She was representing me and all the people like me.”

Now Charlotte, a student at the School of American Ballet, is breaking a barrier herself: She is the first black Marie, the young heroine of “George Balanchine’s The Nutcracker,” at New York City Ballet. It’s a milestone for the production, which dates to 1954.

It isn’t lost on Charlotte that she “got to grow up in a time when it wasn’t just like, oh yeah I can do this, but not do this,” she said. “There was nothing holding you back.”

But the cultural shift reaches beyond Charlotte, whose mother’s family is from Trinidad (her father’s side is from the Philippines), as her school works to diversify its student body. In addition to Charlotte, the other young leads this season are Tanner Quirk (her Prince), who is half-Chinese; Sophia Thomopoulos (Marie), who is half-Korean, half-Greek; and Kai Misra-Stone (Sophia’s Prince), who is half-South Asian. (The children are always double cast.)

City Ballet, which takes most of its members from the School of American Ballet, its affiliate, is also showing signs of change. Over the past seven years, 62 S.A.B. students have become City Ballet apprentices; of those, 21 identify as nonwhite or mixed; and of those, 12 refer to themselves as black; four of those are women. That carries weight: Since the 1970s, City Ballet has largely had only one black female dancer at a given time.

For Charlotte’s debut, that context is meaningful. Her mother described what happened when Charlotte, who is quiet and artistic — she loves to draw and sing — emerged from her “Nutcracker” audition: “With that poker face of hers, she said, ‘Well, I’m Marie,’ And I just thought, oh my goodness — they really did it. I couldn’t believe it.”

The importance of the casting hit Ms. Nebres, who herself danced growing up: “What does this mean in a larger context? That was just a whole different conversation than that initial, oh my gosh, you’re going to do this thing.”

When she told Charlotte that she was the first, Ms. Nebres said, her daughter’s response was: “Wow. That seems a little late.”

The children at the school, no matter their ethnicity, are growing up with role models like Mr. Obama and Ms. Copeland to guide them. Ms. Nebres, who has three children enrolled at the school — Charlotte, whom she called “a free spirit,” is the middle child — said she tries to be mindful of that. “It’s tough because we have past hurts, past injuries and disappointments,” she said, “and you don’t necessarily want to color their worldview that way. You want them to approach it with their fresh perspective.” She added: “It really gave me chills thinking about it.”

She’s not alone. Kai’s mother, Kavita Misra, said she was proud that her son was cast this season. “It’s a historical moment and he is privileged to be a part of it,” she said, later adding: “I think at some point they’re just dancers. And that’s what trumps everything else.”

Casting for “The Nutcracker” is not a casual act. Dena Abergel, the children’s ballet master of City Ballet, considers many things, from a dancer’s size and dependability — how often does an 11-year-old hold a Lincoln Center stage? — to dramatic finesse. Tanner, at 13, is older than the others with, Ms. Abergel said, an “inborn princely quality,” while Kai, 11, has “a really sensitive soul — his demeanor is so open.”

Sophia, 12, and Charlotte each have a delicacy. Ms. Abergel said both are quiet in class but stood out to her onstage — Sophia in the party scene of the “Nutcracker” last year and Charlotte as Little Red Riding Hood in “The Sleeping Beauty.” Charlotte ran away with the role — and even surprised her mother, who hadn’t realized she was so theatrical.

“I just thought, they picked the wrong child,” Ms. Nebres said. “She is introverted in a way. But then when I saw her, I thought, O.K., I’m the one that doesn’t know Charlotte.”

Ms. Nebres laughed. “I think that’s the most interesting thing about this experience for me,” she said. “You don’t know what people are seeing in your child, and they are definitely seeing something in her.”

But kids have opinions, too. Earlier this month, this year’s Princes and Maries took a break from rehearsals to talk about the dedication and fun of training to become ballet dancers.

What follows are edited excerpts from that conversation.

What is it like to represent the changing face of S.A.B.?

Charlotte It’s pretty amazing to be not only representing S.A.B., but also representing all of our cultures. There might be a little boy or girl in the audience seeing that and saying, hey, I can do that, too.

How do you feel about Misty Copeland?

Sophia Honestly, if I see an African-American dancer, it doesn’t really make a difference of how I think of them or anything, but I think it’s pretty amazing how she represents something — that maybe a lot of other African-American dancers wanted to be this, but they felt too afraid or something. She just went out there and did what she loved no matter what.

Do you think that ballet needs to change?

Kai I think that it should because stuff is always evolving and the more it changes, the more opportunities people will have.

Is it a big deal for you to be the first black Marie?

Charlotte It is. But to me, it’s just how I grew up so it’s not really different to me.

Does this feel like a sacrifice of your time?

Sophia It can be hard, especially with all the rehearsals to get homework done. But I think overall I’m getting used to the schedule and the whole experience is going to be really fun. I think I will have time to do homework.

What are you most excited about for “The Nutcracker”?

Charlotte I think the part that I’m most, most excited about is at the end when they’re on the sleigh.

Could you describe what happens?

Charlotte Marie and the Prince go offstage and sit on this sleigh. Then, they get to float up in the air and they fly away — they leave the Land of Sweets. I don’t know where they go. It’s like a one-in-a-million chance to do that and it looks so fun.

Kai The snow is really magical. It’s really fun in rehearsals to do the scene waking Marie up, but I think with the snow it will give it more of a magical feel. What does it feel like? I think it might be paper.

Sophia I remember a lot of Princes and Maries from the past like to collect the snow that would fall in their hair for, like, a souvenir.

Charlotte [Sighs happily] I’m so excited about that part.

Kai I’ve heard things about them going to a bucket? And when they’re not looking, they just take a handful and put it somewhere. [The girls squeal in delight.]

Charlotte Last year, Tenzin [Niles, a former Prince] was like, “This is a secret.” There’s water backstage so he took a cup and opened up this barrel of what looked like a trash can and took a scoop of it and it was, like, snow. He showed us how. He was like, “Just put it on this piano and once you come offstage, take it.”

You’ve spent a good deal of your lives onstage. What is that experience like?

Sophia I think “Nutcracker” has a different feel to it than if you’re in another show. It’s very magical, like the whole part of it being close to Christmas and the holidays.

Are you nervous?

Kai I’m quite nervous about it. But then I think once I do a couple of shows, it will get more natural. I’m also really excited about the backstage process. I remember having a lot of memories about having fun backstage and going in the hallways — I’m sorry to give secrets — but we would run around.

Charlotte It’s not allowed, but everyone does it.

What did you do?

Charlotte Unspeakable things.

Tanner We would dare ourselves to go into this little room and just scream.

Who is Marie to you?

Charlotte I never really thought about that, but I guess to me, literally, she’s a little Victorian girl who experiences magic.

How do you relate to that?

Charlotte Everyone experiences Christmas magic. She’s a girl on Christmas Eve and almost anyone can relate to that — being happy, getting a little doll and playing with your friends. I think of it as having Christmas every day. That’s the best way to think about it. It’s Christmas! Be happy.

Kai Can I add a little bit to the Marie stuff? I think, honestly, Marie is almost just a normal girl, who is young and has that spirit and then suddenly she gets into this magic world with all of her nightmares, like the mice, but also, all of her dreams, like the Sugarplum Fairy, come true.

What about the Prince?

Kai The Prince is this character that develops. In the beginning, he is Drosselmeier’s nephew and then it’s almost as if he transforms into the Nutcracker and then goes back to being the Prince. He comes out of his shell and just opens up and is like: Here I am.

Do you watch “Stranger Things”? Are you into the supernatural?

Kai Yes. I mean I don’t like many shows like that, but “Stranger Things” is an exception. I started watching it when I was 8. My mom was like, “Oh my God” to my sister and she was like, “Oh, he’ll be fine.” I was — kind of fine? But I kind of wasn’t.

Tanner, as a former Fritz [Marie’s bratty little brother], you have probably studied Princes over the years.

Tanner I definitely think that the Prince is very brave and compassionate especially toward his Marie, which is what I aspire to be like in real life, too.

Charlotte And the pink suit. It never gets old. He transforms from the Nutcracker Prince — sword-fighting, mouse-killer, victorious — to the Prince who is the ruler of the Land of the Sweets and wears a pink suit.

Sophia Although we don’t get to see the big transformation. We’re asleep on the bed. But you can hear it in the music.

Charlotte And everyone’s clapping.

Why ballet? Why is it important to you now?

Charlotte To me, it just feels like when I dance I feel free and I feel empowered. I feel like I can do anything when I dance. It makes me happy, and I’m going to do what makes me happy. You don’t need to think about anything else.

Sophia It’s kind of the same thing. You feel really free and open when you dance and to me, the dance world is almost a separate world. You’re not thinking about school. As much as I like the technique and all of that, I really like the moments when you get to move through the air and feel the music.

Tanner I feel like I’m in another world. I love to perform.

Kai What I like about it is you do something, and you do something well, but then there’s always something you need to perfect more. I think that’s a life lesson for regular day life. Nothing’s ever perfect, but in ballet you do your best. You try to make it beautiful. But really you just learn from it.

George Balanchine’s The Nutcracker

Through Jan. 5 at the David H. Koch Theater, Lincoln Center; nycballet.com.

Other Notable Nutcrackers in the Area

‘MY FIRST NUTCRACKER’ An introductory production for kids aged 3-8. Saturdays and Sundays through Dec. 22 at Theater Row, 410 West 42nd Street, Manhattan; nycchildrenstheater.org.

‘NUTCRACKER ROUGE’ This sexy version for adults mixes burlesque and circus arts with ballet. Through Jan. 26 at Théâtre XIV, 383 Troutman Street, Bushwick, Brooklyn; companyxiv.com.

SALZBURG MARIONETTE THEATER’S ‘THE NUTCRACKER’ The venerable Austrian company brings its handcrafted puppets to Queens. Dec. 4 at 7 p.m. at Flushing Town Hall, 137-35 Northern Boulevard, Flushing, Queens; flushingtownhall.org.

‘GREAT RUSSIAN NUTCRACKER’ Local children join professional dancers from the Moscow Ballet in a Russian-influenced production. Dec. 7 at 2 and 7 p.m., Kings Theater, 1027 Flatbush Avenue, Brooklyn; kingstheatre.com.

‘THE YORKVILLE NUTCRACKER’ Dances Patrelle’s production, set in New York City in the late 19th century, features New York City Ballet principal dancers. Dec. 13-15, the Kaye Playhouse at Hunter College, East 68th Street, Manhattan; dancespatrelle.org.

JOFFREY BALLET SCHOOL’S ‘THE NUTCRACKER’ A student performance of the full two-act ballet. Dec. 13-15 at LaGuardia Performing Arts Center, 31-10 Thomson Avenue, Long Island City, Queens; joffreyballetschool.com.

‘KEITH MICHAEL’S “THE NUTCRACKER”’ New York Theater Ballet’s production has an Art Nouveau design and hourlong running time. Dec. 13-15 at Florence Gould Hall, 55 East 59th Street, Manhattan; nytb.org.

‘THE BROOKLYN NUTCRACKER’ Brooklyn Ballet combines ballet with hip-hop and other dance styles from around the world. Dec. 14 at 2 and 7 p.m. at Kings Theater, Brooklyn brooklynballet.org.

NATIONAL BALLET THEATER OF ODESSA’S ‘THE NUTCRACKER’ A traditional version from the Ukrainian company. Dec. 14 at 2 and 7 p.m. at the New Jersey Performing Arts Center, Newark; njpac.org.

‘NUT/CRACKED’ The Bang Group’s vaudevillian take on the classic. Dec. 19-21 at the Flea Theater, 20 Thomas Street, Manhattan; thebanggroup.com.

‘NUTCRACKER WINTER SUITE’ A showcase for the dancers of the Valentina Kozlova Dance Conservatory. Dec. 20-21 at Symphony Space, Manhattan; vkdcny.com.

VICKY SIMEGIATOS DANCE COMPANY’S ‘THE NUTCRACKER’ The New York City Ballet principal dancers Maria Kowroski and Ask la Cour are featured. Dec. 22 at 1 and 6 p.m. at St. George Theater, 35 Hyatt Street, Staten Island; vspac.com.

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