text:
in the previous ep kouga completely forgot his promise to
marry ayame. a hair demon attack them all. kouga saved
kagome and left the rest of the inu gang on the cliff.
ayame and kouga had a long conversation of the past and
when he promised hed marry her. inu and the rest of them
are on the move to catch up to kagome an dkouga. while the
demon quickly approaches them all. at the beginning of this
ep we see inu running and miroku and sango riding on
kirara. miroku wonders if this hair demon has anything to
do with naraku. sango says in a determined that they will
know when they capture the demon. shippo thinks that the
demon might know narakus location as well. inu says that we
will find out after we save kagome. kouga is sitting on a
rock brooding with a funny expression on his face. he looks
ticked off. kagome watches kouga for a bit then aska ayame
if the yourou tribes leader is her grandfather. ayame
having finally calmed down from crying answers kagome, yes
i call him grandpa. kagome asks her if there is any reason
she came down from the mountain now. ayame sits right next
to her and says, it was recent but, fomr the mountain came
a weird evil energy, grandpa said something about the smell
of an ogre, the north east west yourou tribes statred
fighting,for the fight to settle down, grandpa wanted me to
find a young man with power, and get the allies together.
kagome is shocked and says, a forced marriage!??!!??!?!?!?!
ayame looks down with her eyes closed saying, kouga and i
already have a marriage promise. kouga abruptly turns
around from the rock behind them shouting BUT I DONT
REMEBER IT. ayame explains to kagome that she and grandpa
tought kouga had the power to settle down their allies.
kagome eyes r bulging while she thinks, oh so it wasnt just
a forced marriage. kouga is moving around the rock like he
has a wedgie and has both has on his head saying, grrr all
of this because of some evli energy. to get them to settle
down it would be easier to TALK IT OUT. ayame quickly
stands up with her fist by her hips shouting, ITS NOT THAT
SIMPLE OF A SITUATION. to gather them together they need to
trust one person. they need to have faith and reliability.
kouga says in a annoyed voice, then that shouldnt be a job
for me. what i must do right now is take narakus neck. i
dont have time to deal with this other situation. ayame
asked why not. kouga turns completely around shouting, SHUT
UP AND GO BACK TO THE MOUNTAIN. kagome shouts at kouga.
ayame is speechless and begins to get upset again. kouga
says in a softer voice, ayame wouldnt it be better to stop
listening to grandpa and do what u want to do? the hair
demon is approaching. kouga announves that this
conversation is over. they all sense demon energy. kouga is
annoyed and says, inu yasha mustve let the demon go, i can
smell it, it is nearby. kagome is scared and looks for it
in the trees. kagome runs over to kouga and tells him to go
back to inu yasha. kouga grabs her hands, gazes into her
eye and says passionately, dont worry kagome, i will
protect u. kagome responds, uh uh thanks for saying ur
feelings but........ (kagome thinks to herself that this
isnt the time to be talking about this) ayame is watching
them and says, kouga said heluvs her, perhaps this girl
kgome.... the demon finally arrives ayame gte out of the
way in time and kouga saves kagome. kouga tell the demon
that he will be his opponent, either way i needs answers.
inu ysah and them stop in the middle of the forest. they
see the hair left on the branches of the trees. inu wonders
which way to go then finally find the right directoin. but
just then the hair on the branches attacks him and inu
dodges. everyone start attacking the hair. miroku tell inu
to go find kagome while the stay here with the hair. inu
yasha understand and goes off. he jumps into the air
saying, kagome wait for me. back with kouga kagome and
ayame. the demon laughs and says tht he wont let them
escape and eat them along with the shards. kouga tells
ayame to take care of kagome. ayame goes, say what? me? he
tells kagome to wait over with ayame. kouga jumps at the
demon takes a lock of its hair pull it around a tree (the
demon notices kougas shards) and kick the demon in the
teeth. 2 of the demons teeth crack in half and breka off.
kouga charges at the demon again and demands that he tell
him narakus mysteries. just as kouga gets close to the
demons huge mouth a bright light come from its mouth and
kouga is blinded. some hair cam eoff and is attacking ayame
but she destroys them. the demon squeezes kouga na dhe cnat
move anymore. ayame run over to save him but the demon has
er in a tight squeeze and she cant move. kagome takes her
bow and arrows and get ready to shoot. as kagome is about
to shoot her arrow turns pink and it hits the hair
squeezing ayame and ayame falls down still being squeezed.
ayame wonders if kagome is a priestess. kouga tries with
all his strength to get out of its clutches. kagome runs
over to ayame aska if shes ok and uses the arrow to melt
the hair away. ayame tell her to runs away and that kouga
is only fighting fo rkagome. kagome responds , he isnt that
type of guy, he is fighting for both of us. jsut as another
couple locks of hair attack inu comes jus tin time and does
iron reaver. kagome couldnt be anymore happier to c him.
inu yasha lands infront of her asking if she is safe.
kagome smiles even wider and says she is fine. ayame
wonders if inu yasha is her ally. inu yasha turns around to
kouga saying, what r u doing, she was put in a dangerous
situation. kouga tells him to shut up and that its inus
fault cuz he let go of the monster. inu says that HE will
protect kagome and demands that kouga stay back. kouga stay
being dragged near the monster mouth trying to use all his
strength to escape says, I'LL protect kagome. inu shout
back that kouga doesnt have what it takes to protect
kagome. kogua grits his teeth. inu makes this *u r too
stupid look while pointing at his head* lol kagome says
with a smile to kouga, inu yasha came so dont push urself.
kouga gets angry by her comment. kagome warns inu that it
damgerous to get in the monsters hair. inu takes out his
sword and says for her not to worry. inu in a bragging tone
says that he'll defeat it with wound of wind. kouga gets
angry and says that HE will be the one to defeat this
demon. ayame wonders why kouga is acting like this. her
though r interrupted when the demon starts to drag her and
kouga closer to its mouth. the demon with a smile says that
he will eat them and teh shards. kaogme tell inu to hurry
and that he must save them both. inu looks at her and says
me? i do? kagome yells in his face and says WHO ELSE? LOOK
HTEY R ABOUT TO BE EATEN. kagome pushes inu. inu smiles and
says that he doesnt care about what happens to kougas life.
inu says that he wont let the demon have those shards, he
jumps up into the air the demon send hair after him. inu
is shocked noticing that the hair just flew off. the hair
squeezes him. the demon laugh saying that he wont lte
anyone interfere now that he was finally released from
naraku. with the shards he can get back to his original
form. shippo miroku sango and kirara arrive. sango asks if
she is ok. sango sees ayame and asks who she is. kagome
says that she is kougas fiance. eveyrone says together,
huh? his fiance? kagome tell them that she will explain
later. miorku asks what they will do about the mosnter.
kagome tells them that this monster was released by naraku.
inu ysha demands the demon to tell him what he meant. the
demon says that when naraku left teh castle, he left him as
well. sango figures out that this monster isnt a clone that
naraku made. kaogme and shippo are disappointed that he is
useless. inu say, that explains it, i thought u were to
weak to be naraku clone. inu frees himself looks at kouga
and says, so kouga u were trapped by this useless garbage.
at that moment kouga break free goes over to ayame and
frees her and throws her into the air. she lands righ by
kirara and miroku. kouga tells her to stay there and that
he will protect her too. kouga gives inu the 'hand' and
tell him that he will play with him later.lol. kouga
charges at the demon yelling that it didnt know anything of
narakus mystery. kouga punches it and cause the demon the
break in hal above its mouth. everyone is surprised by his
strength. miroku tells kouga not to destroy it yet. they
still need ot sak it some questions. kouga responds, heh
dont worry i went easy. purple smoke is coming out from the
monster where kouga injured him. kouga demands that the
monster tell him everything he knows. th4e monster laughs
and says that naraku went to a place where no one can reach
him. everyone has a shocked expression. kouga asks the
monster what he means by that comment. the monster laughs
and says he knows nothing else besides that and has no way
to communicate with naraku. the monster laughs again
saying, heheheh thats all u'll get. miroku doesnt think
the monster is lying. inu and kouga agree that tihs monster
is totally useless. kouga cracks his knuckles and says,
hehe there is one thing a useless demon is good for....
kouga goes to punch its mouth again but hte monster
swallows most of his arm. kouga calls him a bast@rd. ayame
is worried about kouga, takes her purple flower and stabs
the monster in the lips. sango is surprised about ayame
powers. ayame flew off the evil energy. miroku sayd it must
be the flower. the monsters says that he will eat them all.
kouga pulls his arm out, goes to save ayame, and they both
get eaten. inu get angered and says that now he cant kill
the monster with wound of wind. teh mosnter is happy that
he now has 2 shikon shards within him. the monster screams
in agony sevreal rays of white light come out of it. the
monster swells up and explodes. everyone else wonder why in
the world this happened. teh demons remain fall to the
ground all arounf them. in the center where the monster was
is kouga with his leg up in a kick position. kouga says,
yea right like I can be defeated. blood is dripping from
kougas arms and ayame is worried about him again. kouga
says that its nothing and pick up one of the remains od the
demon. just then hakkaku and ginta (kouga s peeps) catch up
to them out of breathe as usual. lol. kouga lifts up the
monsters remain stares at it and throws it at them. he tell
them and the wolves to memorize that scent. miroku says
that if the wolves memorize they scent they can randomly
look arounf for naraku. inu approaches kouga from behind
saysing. KEH what kind of help is that. kouga just galres
at inu. inu bragging again closes his eyes and says, if the
wolves could smell them out i wouldve have already smelled
them. inu opens his eyes to find kouga is gone. he looks
around frantically geting angrier each second then find him
with kagome. lol. kouga holds her hands azer into her eyes
and says in a passionate voice, kagome, i have to leave for
now but, next time i will bring u narakus neck. ayame is
facing the opposite direction from them. there is tension
in her eyes. she stares at tehm still facing away thinking,
kouga ur in a one sided luv. cant u see that? kagome has
the most hilrious expression, she shakes her head and says
in a quiet voice, but i i i dont want his neck. lol kouga
says , dont make that expression kagome, u r going to be my
bride. inu yasha still watching them shouts
WHAAAAAAAAAAAAAAAAAAAAAAAAAAAAT. kagome get back to her
senses gets out of his grip and yells at kouga saying, WAIT
(ayame is still pouting refueing to look at them) DID U
FORGET ABOUT THAT AGAIN?!?!?!?!?. kouga is feaked out by
her response and back away from her. kouga says that he
cant remeber. kagome tries to heplp him. kouga thiks hard
about the moon rainbow. kouga does remeber a bit of it but
then the memory fades away. *flashback of kouga saving
ayame and carrying her in the rain, and the moons rainbow*
kouga lies to kagome and says that he doesnt remeber
anything. kagome tries to hepl him but kouga refuses and
says he cant remeber a thing. kouga starts to feel guilty.
ayame plays with her red hair finally turns around and tell
him to forget about it. she says that she understands that
his desire to go after naraku. sango whisper to miroku
about kagome is stuck in anothre luv triangle. miorku says
no not like that. ayame just came to get kouga. shippo
whispers into mirokus ear the kouga only likes kagome. and
that kagome wont be in 2 relationships. inu ysaha punches
shippo in the head. shippo falls to the ground with a huge
bump on his head. lol.shippo demands to knwo why inu did
that. inu just looks away and tell him to shut up. ayame
finally smiles and tell kouga that until he takes care of
narkau she and grandpa will try to do something about the
tribes. she puts her hand to her heart close her eye and
reopens them say that she will never forget him and tell
him not to forget about her and that she will be his bride
and no one else. kouga totally freak out and says that he
will only have a wife that can see shikon shards. kouga
reaches over grabs kagome points to her head ans says with
a HUGE smile, kagome can see them. ayame takes in his words
and shouts I WILL ELARN HOW TO SEE THEM TOO. everyone
becomes all bugged eyed. LOL. kougas still kinda freaked
says, uh uh learn how to see them? (he finally calms down)
u cant learn. ayame yells in his face, I WILL. kouga yells
in her face, U WONT. its goes on aand on. I WILL U WONT I
WILL U WONT I WILL U WONT. ayame starts to laugh. this
confuses kouga. ayame pats both his shoulders winks at him
and tell him to wait for that day. she turns into a
tornadoe and leaves. shippo wonders if anyone can really
learn how to see shards. miroku says that he doubts it.
they r impressed by her confidence. kouga calls ayame an
idiot. inu demands that kouga give up the shards in his
legs. inu attack but punche the ground since kouga dodged.
kouga tell kagome good bye and leaves. inu is enraged
gritting his teeth. miroku says that if kouga allies
increase the better hteir chances r of finding narkau. inu
says that its to easy, if the scent was our clues then why
did narkau leave this behind, (inu stands up) the scent as
a clue would be to easy. eveyrone is amazed that inu
actually said something smart for once. inu syas that this
means that naraku has great confidence that he wont be
found.everyone agrees with inu. inu smiles but then it
faces when miroku aska him if he has an idea where naraku
went to. there is complete silence. inu yasha walk backward
toward them turns around and tell him that he should think
about the rest. lol. sango thinks, oh so he wasnt think
about it. shippo think that he should be more responsible.
kagome says that what inu was saying is no mistake. naraku
went ot a place where no one would find him. she wonders
where they should search. its night now. u can hear cricket
chirpin and see several fireflies near teh water. kouga is
standing by the river. teh fireflies fly around him. (very
beautiful scene ^_^) kouga looks into the water and notices
a rainbow. kouga says that he has no intension of losing to
naraku. once he gets his revenge there is no assurance that
he'll be alive. kouga looks into the rainbow again as it
fades away and reappears. he looks off into the distance
and says, forget about the moon and the rainbow ayame.
kouga looks down and slowly walks away. back to ayame. she
lgazes upware to the moon and stars with he hand on her
heart thinking that she will never forget how kouga saved
her evne when the rainbow disappears. back with inu yasha.
inu is lying down on the grass with kagome beside him. inu
is annoye dhta he was fianlly able to cut through narakus
barrier. kaogme with hope in her voice says that they will
find naraku if the all search together. inu sits up and
demands to know what she means by together and if she means
kouga. inu says, r u thinking about someone who has a
fiance and still tries to hit on u. kagome smiles at him
and says, r u still jealous? inu eyes bulge and he says i
am not jealous. kagome glares at him saying, oh so ur not
jealous. inu says that doesnt matter. kagome glares at him
and says in an accusing voice, u started it. inu just sits
there about to explode form embarrassment. niether inu or
kagome take their eyes off each other. miroku sango and
shippo r enjoying this moment from behind. a sweatdrop
falls down from inus cheeck. LOL. inu look away form her
lies back down complete facing the opposite direciton form
her saying , thats enough. lol. kagome thinks that this
isnt good and if only inu was honest about kouga nad ayame.
kagome smiles and looks up at the moon. inu syas that
rainbows dont show up at night. kagome tells them it will
for those who can see it. inu tries but fails to see
anything. they all look up to the starry night sky.


text:
Fall classes coming soon!
Newspace's Summer classes run until the end of September, but we're already excited about our Fall offerings! Newspace's classes offer something for everyone and we'll reveal our Fall offerings with you very soon!
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- Newspace also offers One-on-One Private Training for students interested in tailoring their photography education to their needs and receive private training from Newspace's expert educators in commercial, fine art, and contemporary practices.
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- Corporate Training through Newspace's offers customized instruction for businesses that are interested in training their staff in creating more dynamic images for marketing.
Look for our Fall catalog of classes soon!

subset: commoncrawl


text:
Sweethearts Challenge winner
The winner of our Snowflakes challenge
picked by Bj, owner of Cheery Lynn Designs is
#3 Lindsay
Congratulations, Lindsay. Please contact me for your $20 shopping spree to Cheery Lynn Designs. And thank you to everyone who joined in on the challenge. We hope to see you again in this week's Tickled Pink challenge.


text:
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Kimber McGray
Always a crafter of some kind, Kimber McGray started scrapbooking 5 ½ years ago and has never looked back. Obsessed would be a mild way of describing her love of paper crafting. Kimber's 1st book, Scrapbook Secrets, was released in May 2009. She co-authored Remember This with Summer Fullerton, which was released June 2010. Her 3rd book with F&W Publications, 175 Fresh Card Ideas was recently released in August 2010.
Kimber enjoys working with all different aspects of the industry by designing in all realms. She is currently designing for three different Manufacturers: Jillibean Soup, Unity Stamp Company and Core'dinations Cardstock. This helps her keep her work fresh and new as well as challenge her to use different products daily.
We asked Kimber to share a little about herself and here is what she had to say...
My favourite colour combination is... kraft, teal and orange
My absolute three favourite products are… We R Memory Keepers Corner Chomper, Jillibean Soup Corrugated Alphas, Kraft Cardstock
My favorite sport is…Football (both College-Ohio State and NFL--Indianapolis Colts)
I absolutely cannot live without… Chocolate. Just not possible and why would I try ;)
My favorite non scrapbook related website is… decor8blog.com or etsy.com
I organize my scrap supplies by…. color
If I could get on a plane to go anywhere, I would go to… New York City because I've never been and I would love to go.
Over the past four years, Kimber's work has been published in Scrapbook & Cards Today magazine regular issues, Memory Makers, Creating Keepsakes, BHG Scrapbooks Etc., Scrapbook Trends, Cards, CardMaker, as well as featured in different Idea Books. Her work has also appeared in major ad campaigns for We R Memory Keepers and Core'dinations. Kimber was also announced as a Hall of Fame 2007 winner with Creating Keepsakes.
She lives in Carmel, Indiana, with her husband Bill of 10 years and two children, Andrew (7) and Laura (5).
You can see more of Kimber's great designs at www.kimbermcgray.blogspot.com.
Kimber has also written all of these wonderful books:
back to the design team


text:
Headquarters Nestorville
Barbour County W.Va
April 26, 1865
His Excellency A.I. Boreman Governor W.Va.
It is made my duty to inform you of the death of our Captain M.T. Haller who was killed by rebel Bushwhackers on Monday the 27th instantly whole pursuing those marariders who had sabed [sic] a citizen near our camp for the purpose evidently of entering us inside a trap that they had set for; in which they only too well succeeded. There were three in our company killed the captain Groderly Nester & one private [?] T. Martin The number of the rebels that [?] the[?] is variously estimations from the best information he caught on the subject there could not have been less than fifty of them.
There were [?] five our men engaged Governor in time of the calamity it will be necessary for you if it is pleasure to continue the company to appoint a captain to command it we deem it necessary to have the number of men to at least fifty in view of the demonstration that the rebels are making on this county recently and we should not be willing to attempt to continue our service here with a less number. He would respectfully petition you Excellency Therefore to isue [sic] an order to this effect if you think is best not to comply with this request then we position your Excellency to release us from further service.
I have consulted the company with regard to whom they would prefer as captain & they have selected Moose Mcneel as their choice. If it is your please then to increase this company we would most cheerfully recommend him as a suitable person to take command If what we have requested should meet with your probation we would further request that you allow us to have one Lieutenant
I have the honor Sir to subscribe myself your most obedient servant,
John W. England
Sergt. Comdg Barbour Co
State Troops
Transcription by Chad Story, undergraduate student enrolled in Dr. Billy Joe Peytons Fall 2010 Introduction to Public History at West Virginia State University
Militia Box 01, Folder 4


text:
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Investor Relations


text:
Shakespeare Electronic Conference, Vol. 3, No. 241. Friday, 2 October 1992.
Date: Thursday, Oct. 1, 1992, 18:32:14 EDT
Subject: NEACH Oct 23 (New Date)
NEACH: Northeast Association for Computers & the Humanities
We have changed the dates of the October and December programs
to Friday, Oct. 23, and Tuesday, Dec. 15. The topics and place are
not changed. Meetings will take place as before at 1:30 p.m. in
the IBM Building in New York City, 57th Street and Madison Avenue.
Friday, Oct. 23 (previously Tuesday, Oct. 13):
E-mail, E-news, E-groups, E-research (Louie Crew, Rutgers)
Wed. Nov. 11: Computers and Composition (Robert Royar, NYIT)
Tuesday, Dec. 15 (previously Dec. 8):
Electronic Text Archives and Libraries (Anita Lowry, Columbia)


text:
U.S. District Judge Milton Shadur sentenced a former part-time Postal Service letter carrier to 6 months of home confinement and 2 years of probation for failing to deliver more than 8,400 pieces of mail last year.
Larry J. Mack, 39, was arrested Jan. 1 by Chicago police after a neighbor informed authorities he had seen Mack burning mail in two trash cans behind his Chicago home. A third can was brimming with mail, and postal inspectors discovered additional mail in his home and cars, said Assistant U.S. Atty. Theodore Chung.


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Pregnenolone and Dehydroepiandrosterone as an Adjunctive Treatment in Schizophrenia and Schizoaffective Disorder: An 8-Week, Double-Blind, Randomized, Controlled, 2-Center, Parallel-Group Trial
Michael S. Ritsner, MD, PhD; Anatoly Gibel, MD; Tatyana Shleifer, MD; Igor Boguslavsky, MD; Ahmad Zayed, MD; Rachel Maayan, PhD; Abraham Weizman, MD; and Vladimir Lerner, MD, PhD
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Objective: Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) are reported to have a modulatory effect on neuronal excitability, synaptic plasticity, and response to stress; they are associated with mood regulation and cognitive performance. We investigated the influence of PREG and DHEA on psychotic symptoms and cognitive functioning as an add-on to ongoing antipsychotic treatment of patients with chronic schizophrenia or schizoaffective disorder.
Method: This 8-week, double-blind, randomized, placebo-controlled, 2-center study compared 30 mg/d of PREG (PREG-30), 200 mg/d of PREG (PREG-200), 400 mg/d of DHEA, and placebo as an adjunctive treatment of 58 chronic schizophrenia or schizoaffective disorder patients (DSM-IV). The data were collected from February 2005 until June 2007. The outcome measures were symptomatic and neurocognitive changes, functioning, and tolerability as assessed primarily by the Clinical Global Impressions-Severity of Illness scale and the Positive and Negative Syndrome Scale. Analyses are presented for 44 patients who completed 8 weeks of treatment and for 14 noncompleters.
Results: Compared with subjects who received placebo, those administered PREG-30 had significant reductions in positive symptom scores and extrapyramidal side effects (EPS) and improvement in attention and working memory performance, whereas subjects treated with PREG-200 did not differ on outcome variable scores for the study period. The general psychopathology severity and general functioning of patients receiving placebo and PREG-30 improved more than that of those subjects treated with DHEA, while EPS improved more in subjects treated with DHEA than in patients receiving placebo. Negative symptoms and akathisia were not significantly benefited by any treatment. The administration of PREG and DHEA was well tolerated.
Conclusions: Low-dose PREG augmentation demonstrated significant amelioration of positive symptoms and EPS and improvement in attention and working memory performance of schizophrenia and schizoaffective disorder patients. Further double-blind controlled studies are needed to investigate the clinical benefit of pregnenolone augmentation.
Trial Registration: clinicaltrials.gov Identifier: NCT00174889
J Clin Psychiatry
Submitted: January 2, 2009; accepted April 23, 2009.
Online ahead of print: June 15, 2010 (doi:10.4088/JCP.09m05031yel).
Corresponding author: Michael S. Ritsner, MD, PhD, Acute Department, Sha'ar Menashe Mental Health Center, Mobile Post Hefer 38814, Hadera, Israel (firstname.lastname@example.com).
J Clin Psychiatry 2010;71(10):1351–1362
© Copyright 2010 Physicians Postgraduate Press, Inc.
Despite the effectiveness of antipsychotic medications in a substantial proportion of schizophrenia patients, the overall clinical response remains insufficient and incomplete. Consequently, the development of more effective treatments is an important research goal. One promising direction is the use of neurosteroids (substances produced in the brain) and neuroactive steroids (produced in the adrenal glands and gonads), both of which affect the brain.
Neurosteroids such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA) and their sulfates (PREGS and DHEAS) are reported to have a modulatory effect on neuronal excitability and synaptic plasticity.1,2 These neurosteroids may be suitable candidates in the treatment of schizophrenia and schizoaffective disorder patients, since PREG and DHEA have many functions associated with response to stress, mood regulation, and cognitive performance.3,4 In particular, they may act as potential signaling molecules for neocortical organization during brain development, regulating the neuronal function by affecting the neuronal excitability through prominent modulatory effects on the γ-aminobutyric acid type A (GABAA), N-methyl-d-aspartate (NMDA), sigma-1,5–9 cholinergic,10,11 and dopamine systems.12 These modulations may lead to important changes for neuronal excitability. Neurosteroids demonstrate cognitive-enhancing effects and they have been reported to improve memory.11,13 In preclinical studies, memory-enhancing effects of PREGS and DHEAS have been attributed to their NMDA-agonistic properties.14,15 Finally, PREG may be relevant to the beneficial effects of antipsychotic agents, since both clozapine and olanzapine elevate PREG in rat hippocampus, cerebral cortex, and serum.16 These findings, however, need to be replicated.
The main effect of PREG and DHEA and their sulfates is neuroprotective.17–20 The specific mechanisms by which PREG and DHEA exert their neuroprotective actions are just beginning to be clarified. In particular, they may regulate the growth of neurons and cerebral brain-derived neurotrophic factor levels and enhance myelinization and synaptogenesis in the central nervous system. Pregnenolone and DHEA have shown a dose-dependent protective effect of hilar neurons against kainic acid.21 Pregnenolone has neuroprotective effects against both glutamate and amyloid β protein neuropathology, and it also prevents glucocorticoid receptor localization to the nucleus, which may be involved in the observed neuroprotective effects of PREG against glutamate neurotoxicity.17
There is accumulating evidence that neurosteroids may be involved in the pathophysiology of schizophrenia, mood disorders, dementia, and substance abuse.2,22,23 Previous clinical studies have demonstrated low circulating levels of PREG in the elderly, including those with dementia,24 and in individuals with schizophrenia.25
Early human trials with PREG conducted on healthy volunteers under stressful conditions demonstrated significant improvements in mood, general well-being, psychomotor performance, and learning.26–28 Low-dose oral PREG (30 mg/d) was generally well-tolerated in 17 healthy volunteers receiving PREG for 4 weeks.29 It has been suggested that PREG might antagonize acute benzodiazepine effects by enhancing arousal via its GABAA receptor antagonism.29 To the best of our knowledge, no clinical trials examining the use of PREG as an add-on to ongoing antipsychotic treatment in schizophrenic patients have been published. In addition, there are conflicting data concerning the potential utility of DHEA augmentation (50–200 mg/d) for a period of 1 to 12 weeks in the treatment of schizophrenia patients.30–33
In the first clinical trial, 27 adult schizophrenia patients were drawn from an inpatient population and were randomly assigned to receive either DHEA daily (n = 15) or a placebo (n = 12) in addition to a constant dosage of antipsychotic agents for the 6-week trial period.32 The starting dose was 25 mg/d, which was increased to 50 mg/d for the next 2 weeks and then to 100 mg/d for the remainder of the trial. The authors noted a decrease in anxiety, depression, and negative symptoms among the DHEA-treated patients.
In a second study, Nachshoni et al30 investigated the effect of DHEA administration during a period of only 7 days on medication-induced extrapyramidal side effects (EPS) among inpatients with schizophrenia or schizoaffective disorder. Patients were randomly assigned in double-blind fashion to receive either 100 mg DHEA or placebo in addition to a constant dosage of antipsychotic medications. Analysis was performed on 30 patients (15 patients in each arm). The authors reported that DHEA caused a significant favorable effect on parkinsonism.
A third study33 performed by the same research group included 40 patients with chronic schizophrenia stabilized on olanzapine therapy. The subjects were randomly assigned in double-blind fashion to receive either DHEA (150 mg/d) or placebo augmentation for a period of 12 weeks. Sixteen patients receiving DHEA and 15 patients receiving placebo completed the study. DHEA augmentation was not superior to placebo in improving scores on the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), measures of side effects (the Simpson-Angus Scale [SAS] for extrapyramidal side effects, the Barnes Akathisia Scale [BAS], and the Abnormal Involuntary Movements Scale [AIMS]), cognitive performance (Mindstreams battery), and aggressive behavior (the Life History of Aggression scale). These cross-sectional DHEA trials30,32,33 did not replicate one another in terms of depressive and anxiety symptoms and in medication-induced adverse side effects. The trials did not show a consistent and unequivocal significant favorable effect for DHEA administration on negative symptoms compared to placebo.
In order to resolve some of the concerns that have arisen in the cross-sectional trials, Ritsner et al31 conducted a randomized, double-blind, placebo-controlled crossover study in 2 mental health centers. During this trial, 55 patients received either DHEA (200 mg/d) or placebo in identical capsules for 6 weeks, following which they were switched to either placebo or DHEA for a further 6 weeks. Patients continued to receive their regular treatment with daily doses of antipsychotic medication kept constant for at least 2 weeks prior to entering the study and throughout the study period. The crossover analysis revealed no statistically significant treatment effect of DHEA on severity of illness symptoms (PANSS), side effects (AIMS and ESRS), or quality of life measures compared with placebo treatment. However, this investigation, while preliminary, does support some improvement noted in visual sustained attention and visual and motor skills due to DHEA administration.
Here we report for the first time the results from a randomized, placebo-controlled, double-blind comparative trial with 2 neurosteroids (PREG or DHEA) added to ongoing antipsychotic treatment in patients with schizophrenia and schizoaffective disorder for 8 weeks. Given the potential neuroprotective roles of PREG, we hypothesized that PREG augmentation to ongoing and unchanged antipsychotic therapy would improve psychotic symptoms and cognitive performance in chronic schizophrenia and schizoaffective disorder patients compared to DHEA and placebo administration.
Study Design
This was an 8-week, controlled, double-blind, randomized, 2-center, parallel-group trial with 30 mg/d and 200 mg/d dosages of PREG and 400 mg/d DHEA augmentation to ongoing antipsychotic treatment. Since it is unknown if higher or lower doses produce greater or lesser therapeutic effects, 2 daily doses of PREG were used in this study. The low dose of PREG (30 mg/d) was chosen in order to increase the patient's circulating PREG levels to at least the range of the typical physiologic peak in young, healthy subjects. The high dose of PREG (200 mg/d) was chosen because PREG's behavioral effects in humans and animals may be more apparent at larger doses.13,28 In previous studies with DHEA administrations of 90–450 mg/d, an improvement was demonstrated in depressive mood in humans.34–36 The effect of high dose (400 mg/d) DHEA was examined in the current trial, since the use of 50–200 mg/d of DHEA had not previously revealed conclusive findings in the treatment of schizophrenia patients.30–33
Eligible patients had had schizophrenia or schizoaffective disorder (according to DSM-IV criteria) for longer than 2 years. The subjects' ages varied from 18 to 60 years, and they were able and willing to sign an informed consent. Major exclusion criteria included an unstable medical condition, any significant medical (including prostate illness) or neurologic illness, pregnancy, or receiving mood stabilizers or any steroid or hormonal supplement (eg, estrogen). The absence of medical or neurologic illnesses was verified by means of a routine laboratory investigation (including prostate-specific antigen level in men older than 50 years), a physical and neurologic examination, reports of the treating physician, and medical records. No change in the doses of antipsychotic medications or addition of any other psychoactive medication was permitted before study entry or throughout the study period. Prior to the study entry, all subjects provided written informed consent after receiving a full explanation regarding the nature of the study and the potential risks and benefits of study participation. The study was approved by the Institutional Review Boards of the Sha'ar Menashe Mental Health Center (Hadera, Israel) and the Be'er-Sheva Mental Health Center (Be'er-Sheva, Israel) and the National Ministry of Health Ethical Review Board.
Data were collected from February 2005 until June 2007. An initial evaluation of the patients included a review of medical and psychiatric history and current medications; blood was collected for laboratory assessment, and written informed consent was obtained for participation. Eligible patients were examined by senior psychiatrists (M.S.R., A.G., T.S., and V.L.) who conducted a confirmatory psychiatric evaluation. After screening and baseline assessments, patients were randomly assigned (by means of random number generation) to receive 30 or 200 mg/d of PREG (PREG-30 and PREG-200, respectively), 400 mg/d of DHEA, or placebo in identical capsules (Biosynergy, Boise, Idaho), each for 8 weeks in a double-blind manner. The randomization procedure was performed using the Random Allocation Software, version 1.0 (M. Saghaei, MD, Department of Anesthesia, Isfahan University of Medical Sciences, Isfahan, Iran: http://mahmoodsaghaei.tripod.com/Softwares/randalloc.html). The pharmacist conducted randomization of participants by using a random and equal block size for placebo, DHEA, and PREG-30 arms (with ratio 1.5:1 for PREG-30 and PREG-200 arms, respectively) and conducted the blinding of the trial. The patient allocation details were coded and kept confidential until the trial was completed.
The outcome measures, except neurocognitive tasks, and serum samples of hormones were collected over 5 visits: at baseline before starting therapy, and then after 2, 4, 6, and 8 weeks. All observed or self-reported adverse events that appeared during the study or exacerbations of preexisting illnesses were recorded. Adverse events were evaluated for severity, duration, and possible relation to the drug under study. When a trial was discontinued, for any reason, the patients who did not complete the trial ("discontinued") were observed according to the protocol until the end of the study.
We screened 70 outpatients with ongoing residual symptoms in 2 large state referral institutions: the Sha'ar Menashe Mental Health Center (Hadera, Israel) and the Be'er-Sheva Mental Health Center (Be'er-Sheva, Israel). Of all screened subjects, 12 patients did not enter the study. Two subjects who were excluded had organic brain damage, 4 patients had comorbidity with substance abuse, 1 patient had a serious medical illness (hepatitis), 2 patients had low comprehension skills, and 3 patients declined to participate. Thus, a total of 58 patients were randomly assigned to treatment.
The study sample consisted of 13 women and 45 men, with a mean age of 35.8 years (SD = 8.3; range, 23–55) and a mean duration of education of 11.0 years (SD = 2.0; range, 6–15). Of the participants, 15.5% were married, 61% were single, and 23.5% were divorced or widowed. Mean age at illness onset was 23.6 years (SD = 6.1; range, 12–45), mean duration of disorder was 12.2 years (SD = 7.5; range, 2–28), and mean number of lifetime hospitalizations was 7.0 (SD = 7.5; range, 1–20). Of the total of 58 patients, 43 subjects met DSM-IV criteria for schizophrenia, paranoid type, and 15 met DSM-IV criteria for schizoaffective disorder. At baseline, 26 patients were treated with first-generation antipsychotics (FGAs): chlorpromazine, haloperidol, haloperidol decanoate, perphenazine, zuclopenthixol, zuclopenthixol decanoate, or fluphenazine decanoate; 23 patients were treated with second-generation antipsychotics (SGAs): clozapine, risperidone, olanzapine, quetiapine, ziprasidone, or amisulpride; and 9 patients received both types of antipsychotic medications (combined therapy). Mean ± SD chlorpromazine (CPZ) equivalents were 556 ± 106 mg/d for FGAs, 470 ± 64 mg/d for SGAs, and 481 ± 102 mg/d for combined therapy. In addition to the antipsychotic medications, the patients continued to take anticholinergics and benzodiazepines that they had received prior to the study recruitment.
Outcome Measures
At the screening visit, the investigators collected background and demographic data, family and personal histories, details about the present illness, medications, and psychiatric and general medical history, conducted a physical examination, and obtained samples for laboratory analysis. Senior psychiatrists at each site enrolled patients and established diagnoses according to DSM-IV criteria.
The primary rating instruments were the Clinical Global Impressions—Severity of Illness scale (CGI-S)37 and the Positive and Negative Syndrome Scale (PANSS).38 Secondary outcome measures included the Global Assessment of Functioning scale (GAF),37 the Extrapyramidal Symptom Rating Scale (ESRS),39,40 and the Barnes Akathisia Rating Scale (BARS).41 Raters were trained before the study to produce acceptable levels of interrater reliability, estimated by intraclass correlation coefficient (ICC), for the primary diagnosis and CGI-S, PANSS, GAF, ESRS, and BARS scores (ICC = 0.89, 0.90, 0.87, 0.92, 0.88, and 0.90, respectively).
Neuropsychological assessment was conducted with the computerized Cambridge Automated Neuropsychological Test Battery (CANTAB).42,43 Measures were collected at the baseline visit and at the end of the study (or at discontinuation of treatment). The CANTAB battery tests, which run on an IBM-compatible personal computer with a touch-sensitive screen, are grouped into the following cognitive domains: attention, memory, and executive functions. In particular, the Matching to Sample Visual Search (MTS) is a speed/accuracy trade-off task, testing the subject's ability to match visual samples. The Delayed Matching to Sample (DMS) is a test of perceptual matching and immediate and delayed visual memory in a 4-choice simultaneous and delayed recognition memory paradigm. Other components of the CANTAB include Pattern Recognition Memory (PRM); Rapid Visual Information Processing sustained attention (RVP A′); and the Stockings of Cambridge (SOC). The nonverbal nature of the CANTAB tests makes them largely language-independent and culturally blind. Performance on neurocognitive tests was presented using the standard z score, which is the number of SDs from the mean performance computed relative to an extensive database of raw scores for healthy adult subjects matched by age and sex. The CANTAB program calculated z scores on the basis of the extensive normative database included in CANTAB. A negative value of the z score indicates poorer than average performance. (For a description of the nature of these tests, the performance measures used, and how the test scores are derived, see http://www.camcog.com/science/default.asp.)
Laboratory Testing
Blood samples were collected between 8:00 and 9:00 am after 20 minutes of rest, and serum was separated. Subjects were instructed to abstain from unusual physical activity or stress for a period of 24 hours prior to blood sampling. Hormone levels in all samples were measured simultaneously to avoid interassay variability.
Pregnenolone was evaluated using Immune Biological Laboratories direct ELISA kit DB52031 (Immune Biologic Laboratories, Hamburg, Germany), DHEA was evaluated using DHEA-DSL 9000 Active, DHEAS was evaluated using DHEA-S-DSL-3500 Active (Diagnostic Products Corporation, Los Angeles, California), progesterone was evaluated using Progesterone RIA DSL-3900 Active, 17α-OH progesterone was evaluated using 17α-OH progesterone DSL-5000 Active, androstenedione was evaluated using Androstenedione DSL-3800 Active, 3α−androstanediol glucuronide (3α−androstane-3α−17β−diol-glucuronide; 3α−Diol G) was evaluated using DSL 9200 Active, testosterone was evaluated using DSL 4000 Active, and estradiol (E2) was evaluated using DSL 4300 Active. All these kits were coated-tube-radioimmunoassay (RIA) kits (Diagnostic Systems Laboratories, Webster, Texas). Cortisol was evaluated using Cortisol-TKCO1 Coat-A-Count coated tube RIA kit (Diagnostic Products Corporation, Los Angeles, California). The sensitivity of the commercial RIA kits was 0.05 ng/mL for pregnenolone, 0.07 nmol/L for DHEA, 46 nmol/L for DHEAS, 0.12 ng/mL for progesterone, 0.01 ng/mL for 17α-OH progesterone, 0.1 nmol/L for androstenedione, 0.4 ng/mL for testosterone, 0.08 ng/mL for 3α−Diol G, 6.5 pg/mL for estradiol, and 5.5 nmol/L for cortisol. The cross-reactivity of PREG with progesterone was 6.0%, with DHEA was 5.2%, and with all other steroids was less than 1.0%; the cross-reactivity of DHEA with DHEAS was 0.88% and with all others was negligible; the cross-reactivity of DHEAS with DHEA was 41% and with all others was negligible; the cross-reactivity of progesterone with similar hormones was negligible; the cross-reactivity of 17α-OH progesterone with similar hormones was negligible; the cross-reactivity of androstenedione with similar hormones was less than 0.4%; the cross-reactivity of 3α−Diol G with similar hormones was 2%–10%; the cross-reactivity of testosterone with similar hormones was less than 5.8%; the cross-reactivity of estradiol with similar hormones was negligible; the cross-reactivity of cortisol with prednisolone was 76%, with 11-deoxycortisol was 11.4%, with prednisone was 2.3%, with cortisone and corticosterone was 1%, and with all others was < 0.3%.
Specificity (assay variability) was 9.6%–14.5% for pregnenolone, 10.2% for DHEA, 10% for DHEAS, 4.8%–8.0% for progesterone, 8.1%–9.5% for 17α-OH progesterone, 6.0%–9.8% for androstenedione, 6.4%–7.2% for testosterone, 8.4%–9.1% for 3α−Diol G, 4.9%–9.4% for estradiol, and 4.0%–6.4% for cortisol, between runs, and 7.8%–10.6% for pregnenolone, 5.6%–10.6% for DHEA, 6.3%–9.4% for DHEAS, 9.2%–13.1% for progesterone, 6.3%–10.8% for 17α-OH progesterone, 2.8%–5.6% for androstenedione, 4.9%–5.7% for testosterone, 7.8%–9.6% for 3α−Diol G, 5.3%–19.2% for estradiol, and 3.0%–4.8% for cortisol, within runs according to level.
Statistical Analysis
Patients who completed the study (completers) were included in the statistical analysis. The LOCF procedure was used to analyze those subjects who completed at least 4 weeks (selected a priori) but failed to complete all 8 weeks of the study (noncompleters).
Effects of PREG and DHEA administration on the outcome measures were determined by analysis of covariance (ANCOVA) with 2 kinds of variables: (1) rating scale scores at all time points (at baseline, weeks 2, 4, 6, and 8, time factor); and (2) the changes of the outcome measures during the study period, which were calculated as an absolute difference value for each subject (2, 4, 6, and 8 weeks minus baseline) controlling the baseline scores of each outcome measure, and duration of illness (years). Post hoc analyses were carried out in cases of significant outcomes, using the Tukey-Kramer method and the Bonferroni correction for multiple comparisons.
In particular, rating scales data were analyzed by using repeated-measures ANCOVA model 2 [or 3, or 4] × 5 × 2 with a main factor of treatment (separately 2, 3, or 4 treatment conditions) by time factor with comparison between completers and discontinued patients controlling the baseline scores of each outcome measure, and the duration of the illness (years). Other ANCOVAs models applied, with either sex or drug treatment (FGAs, SGAs, combined therapy controlling daily dose as CPZ equivalent, mg/d as covariate) or DSM-IV diagnosis (schizophrenia versus schizoaffective disorder) being added to the models.
Changes in the performance of the CANTAB tasks (z scores) from baseline to endpoint were analyzed with ANCOVA model 4 × 2 × 2 (without and with the sex effect or type of antipsychotic agents) controlling education (years) and a daily dose of antipsychotics (CPZ equivalent, mg/d). Distribution of the types of antipsychotic agents (FGAs/SGAs/combined therapy patients) in the groups was placebo (8/6/2), PREG-30 (5/8/3), PREG-200 (8/2/0), and DHEA (5/7/4).
Finally, an ANCOVA model with 3 main factors (treatment group, time, and sex) controlling for age (years) and daily dose (CPZ equivalent, mg/d) was performed for comparison of the serum hormonal concentrations throughout the study period.
Effect sizes (Cohen d with CI) were calculated for changes in outcome variables from baseline to endpoint examination by the estimated pooled standard deviation, with a small effect size defined as 0.2, a moderate effect size as 0.5, and a large effect size as 0.8.44 Effect size is simply a way of quantifying the effectiveness of a particular intervention relative to some comparison. As the name suggests, an effect size estimate can place an easily interpretable value on the direction and magnitude of an effect of a treatment, a difference between 2 treatment groups, or any other numerical comparison or contrast.
Baseline values of rating scales and cognitive tasks among 4 treatment groups of patients were compared by a multivariate analysis of variance (MANOVA) with Hotelling test.
Continuous variables were compared using the 2-tailed t test or the Wilcoxon signed rank test (z) for assessing the difference in medians. Differences in the frequency of categorical variables were examined with the χ2 test. For all analyses, the level of statistical significance was defined as an α less than .05. We performed the statistical analysis using the Number Cruncher Statistical Systems (Kaysville, Utah).45
Sample Composition
Figure 1 presents a flow diagram of the study population. Fifty-eight enrolled patients were randomly assigned to receive 30 mg/d of PREG (n = 16), 200 mg/d of PREG (n = 10), 400 mg/d of DHEA (n = 16), or placebo (n = 16).
Click figure to enlarge
The allocation into the experimental groups was independent of the antipsychotic drugs used by the subjects (classified as FGA, SGA, and combined therapy; χ26 = 8.3, P = .21). There were no notable imbalances among 4 treatment groups in age, sex (χ23 = 1.8, P = .62), marital status (χ26 = 7.5, P = .28), body mass index (BMI), age at illness onset, number of hospital admissions, duration of disease, or the distribution of diagnoses (schizophrenia or schizoaffective disorder, χ23 = 1.7, P = .63).
Of the 58 patients randomly assigned to this trial, 14 patients dropped out. Discontinuation of the treatment occurred in 2 patients in the PREG-30, 4 patients in the PREG-200, 3 patients in the DHEA groups, and 5 patients assigned which received placebo. More specifically 1, 1, 2, and 3 patients assigned to receive PREG-30, PREG-200, DHEA, and placebo, respectively, dropped out between 4 and 6 weeks, and 7 patients dropped out between 6 and 8 weeks. The treatment was discontinued due to reasons not related to the neurosteroids: lack of efficacy (n = 4), change in the antipsychotic drugs (n = 3), loss to follow-up (n = 5), and noncompliance (n = 2).
Forty-four patients (12 of 13 women and 32 of 45 men) completed the trial. Ten patients met DSM-IV criteria for schizoaffective disorders; all other subjects met DSM-IV criteria for schizophrenia. The baseline characteristics of the 44 subjects who completed the study are listed in Table 1. As can be seen, there were no notable differences in the completers among the 4 treatment groups in age, sex, marital status, BMI, age at illness onset, number of hospital admissions, duration of disease, the distribution of diagnoses (schizophrenia or schizoaffective disorder), or antipsychotic medication daily dose.
In this study, 7 discontinued patients were examined at the end of the trial; the missing data of the other 7 discontinued patients were imputed using LOCF. Among patients who were randomly assigned to receive PREG-30, PREG-200, DHEA, or placebo and who completed this study, there were no significant between-group differences in baseline mean scores on the CGI-S scale, PANSS subscales, GAF scale, ESRS, and BARS (MANOVA, Hotelling test, F21,98 = 0.71, P = .75). Outcome measures are described in Figure 2 and Tables 2 and 3.
Neurosteroids compared to placebo. Compared with placebo, PREG-30 augmentation significantly improved PANSS positive symptom scores (F1,148 = 6.8, P = .010), whereas no significant effects were observed on the other PANSS subscales, the CGI-S scale, or GAF scale scores (Table 2). A mean reduction on the PANSS positive subscale score was –2.6 among PREG-30 subjects compared with −0.9 among placebo subjects with a small effect size (F3,219 = 5.9, P = .006, power = 0.95; d = 0.28; CI, −1.7 to 0.51) (Figure 2A). Patients who were treated with PREG-200 did not differ on the outcome variable scores compared to placebo for the study period (all P values > .05).
The condition of patients receiving placebo improved more than DHEA-treated subjects as measured in the reduction on CGI-S scores (F1,148 = 7.2, P = .008; d = 0.61; CI, –0.20 to 1.42) and on PANSS general psychopathology scores (F1,148 = 4.9, P = .028; d = 0.24; CI, –0.56 to 1.05), and in an increase on GAF scores (F1,148 = 8.2, P = .005, d = 0.41; CI, –1.22 to 0.40; Table 2). Since 4 comparisons were significant (see Figure 2), Bonferroni correction for 4 tests was applied (P = .05/4 = .0125). After Bonferroni correction, improvement in the PANSS positive and general psychopathology subscales remained significant (P < .05).
PREG compared to DHEA. An ANCOVA model yielded a significant reduction in the CGI-S, PANSS positive, PANSS negative, and PANSS general psychopathology scores and an increase in GAF scores among patients receiving PREG-30 compared to those receiving DHEA (Table 2, Figure 2B). PREG-30 augmentation was significantly superior for ameliorating PANSS positive symptoms compared to PREG-200 augmentation (F2,191 = 6.2, P = .002, power = 0.89). The treatment with PREG-30 and PREG-200 significantly improved GAF scores compared to DHEA augmentations (P = .001, power = 0.92); the differences between PREG-30 and PREG-200 groups were not significant. When multiple comparisons between the groups of patients who received any augmentation were analyzed, 5 comparisons were significant (Table 2, far right column), Bonferroni correction for 5 tests was applied (P = .05/5 = .01). After Bonferroni correction, improvement in PANSS positive and general psychopathology subscales and GAF scores remained significant (P < .05).
Tolerability and Safety
A significantly favorable effect on EPS compared to the placebo group was observed among subjects treated with PREG-30 and DHEA (for both groups F1,148 = 3.9, P = .049, power = 0.74; Table 2). As indicated by changes in the ESRS total scores from baseline to week 8, PREG-30 (d = 0.44; CI, –1.24 to 0.36) and DHEA (d = 0.59; CI, –1.41 to 0.23) patients who completed the study had significantly lower ESRS total scores than patients receiving placebo (F3,219 = 3.2, P = .024, Table 3). No significant interactions between group × time, or group × type of antipsychotics were found (all P values > .13). With regard to the analysis of the BARS scores, no differences between the 4 groups were noted. During the trial, no significant adverse events (such as oily skin, acne, voice deepening, or hirsutism) were observed. Thus, the administration of PREG and DHEA was well tolerated.
Analysis of Covariates
No significant main effect of the type of antipsychotics or type of antipsychotics × time interaction on CGI-S, PANSS subscale, GAF, ESRS, and BARS scores was observed for patients receiving PREG-30, PREG-200, DHEA, or placebo (all P values > .05). No relation was found between the diagnosis and any differences between treatment arms in the changes on the CGI-S, PANSS subscale, GAF, ESRS, and BARS scores (all P values > .05). The analysis of between- and within-group gender differences did not show any significant main effect on the outcome variables.
Neurocognitive Functioning
No significant between-group differences in the performance of CANTAB attention, memory, and executive function tasks (MTS, DMS, PRM, RVP, and SOC) at the baseline assessment were observed (MANOVA, F15,290 = 1.45, P = .12). At the end of the trial, PREG-30 augmentation significantly improved z scores compared to placebo in the DMS (F1,25 = 4.3, P = .049; d = 0.79; CI, 0.04–1.69) and in the MTS (F1,32 = 5.0, P = .035, d = 0.75; CI, 1.57–0.07) tasks; Figure 3). None of the treatment effects, in pairwise comparisons on other cognitive tasks, were significant (all P values > .15), and no significant differences between the groups in the cognitive performance were detected when only 3 treatment groups (PREG-30, PREG-200, and DHEA) were compared (ANCOVA, F2,42 = 0.2–1.5, all P values > .05). The type of the antipsychotic agents and sex did not have a significant effect on cognitive performance.
Completers Versus Noncompleters
In this clinical trial, there were no significant differences between the discontinued patients and completers in the mean values for age, education, age at onset, number of admissions, duration of illness, BMI, and CPZ equivalent daily dose (2-way MANOVA; F7,47 = 0.47, P = .85 for completers vs discontinued patients by 4 treatment groups: F21,137 = 1.09, P = .36). Baseline CGI-S, PANSS subscale, GAF, ESRS, and BARS scores did not differ between 44 completers and 14 discontinued patients (2-way MANOVA; F7,47 = 0.68, P = .69) across 4 treatment groups (F21,137 = 0.71, P = .81). However, after the treatment had begun, completers had significantly lower PANSS positive, PANSS general psychopathology, and ESRS scores than patients who discontinued prior to the end of the study (Tables 2 and 3, Figure 2). The completers also showed a significant improvement on GAF scores compared to the discontinued subjects (F1,219 = 8.2, P = .005, Table 3). There were no significant differences between the completers and discontinued patients in the performance of CANTAB tasks (MTS, DMS, PRM, RVP, and SOC; MANOVA, F5,94 = 0.76, P = .58).
Blood Hormone Levels
No significant difference was observed among the groups in the baseline values of the tested hormones (MANOVA, F27,95 = 1.1, P = .35). Figure 4 presents blood concentrations of hormones throughout the study period.
According to an ANCOVA (F3,204 = 12.4, P < .001), serum PREG level was significantly higher among the patients treated with PREG-30, PREG-200, and DHEA compared to the placebo group (P < .05). Blood PREG level was also higher among the PREG-200 group compared to the PREG-30 and DHEA groups (P < .05; Figure 4A). The main time effect of augmentation with PREG and DHEA on blood PREG levels was observed by the fourth week (F4,204 = 4.4, P = .014).
Serum levels of other hormones among subjects treated with both PREG-30 and PREG-200 were similar to placebo throughout the study period (all P values > .05). The DHEA treatment revealed a significant elevation of the blood levels of DHEA (F3,240 = 28.0, P < .001), DHEAS (F3,240 = 54.6, P < .001), androstenedione (F3,204 = 31.9, P < .001), 3α-androstanediol glucuronide (F3,240 = 56.5, P < .001), and estradiol (F3,240 = 10.3, P < .001) compared to PREG-30, PREG-200, and placebo conditions (Figure 4B–4E). There was no significant between-group difference in levels of progesterone (F3,201 = 0.5, P = .66), 17-OH-progesterone (F3,240 = 1.0, P = .39), testosterone (F3,204 = 2.4, P = .073), and cortisol (F3,204 = 0.8, P = .50).
A sex effect was noticeable in the blood levels of pregnenolone (F1,2046 = 25.9, P < .001; females > males), 3α-androstanediol glucuronide (F1,240 = 5.6, P = .019; males > females), testosterone (F1,204 = 210.8, P < .001; males > females), estradiol (F1,240 = 5.5, P = .004; females > males), progesterone (F1,201 = 15.3, P < .001; females > males), and 17-OH-progesterone (F1,240 = 36.8, P < .001; males > females), but not in levels of DHEA, DHEAS, and androstenedione (all P values > .05).
In this randomized double-blind, placebo-controlled trial, we report for the first time that, compared with placebo, an 8-week low-dose PREG (30 mg/d) augmentation of an ongoing antipsychotic treatment showed a statistically significant reduction in positive symptoms and improvement in attention, memory, and EPS in chronic schizophrenia and schizoaffective disorder patients, whereas subjects who were treated with PREG-200 did not differ on outcome variable scores for the study period. Cohen d effect sizes demonstrated slight beneficial effects for PREG-30 versus placebo in positive symptoms (d = 0.28) and EPS scores (d = 0.44). This is especially noteworthy considering the fact that the baseline scores of the outcome measures, duration of illness, and education were controlled. Since there was no overall significant effect of diagnosis, sex, or type of antipsychotic drug on the therapeutic effects of PREG-30, the results of the covariance analyses suggest that the favorable therapeutic effects of PREG-30 are achieved, at least partially, due to direct effects of the augmentation.
Interestingly, a significant effect of DHEA augmentation was observed with 50–150 mg/d32,33 but not with 200 mg/d31 or 400 mg/d in the present trial. Moreover, the augmentation of 400 mg/d of DHEA resulted in significantly less improvement on CGI-S and PANSS general psychopathology scale scores compared to placebo. Therefore, we suggest an inverted-U clinical response with a daily dose of PREG and DHEA augmentations (although there could be other reasons for the inconsistent results: methodological issues, different sample characteristics, different baseline severity of illness, and varying durations of combination treatment).
The present study showed a slight improvement in cognitive performance in the MTS (Cohen d = 0.75), and in the DMS (Cohen d = 0.79) tasks of CANTAB among the patients receiving a low dose of PREG augmentation compared with placebo. It should be noted that the MTS is a speed/accuracy trade-off task testing the subject's ability to match visual samples, while the DMS measures the ability to remember a target stimulus (a complex, multicolored pattern). Theoretical analysis suggests that strategic ability, attention, and working memory are critical to the performance of these tasks.46 No significant improvement on CANTAB tasks was observed among patients receiving 200 mg/d of PREG or 400 mg/d of DHEA compared with placebo.
The mechanisms by which neurosteroids influence cognitive functioning have been studied in various species. The beneficial effect of PREG and PREGS on the cognitive functioning of animals has been shown in several preclinical studies. Experiments with animals show enhancement of the posttraining memory processes after the injection of low doses of PREG or PREGS.13,47,48 In particular, the memory-enhancing effects of PREGS and DHEAS in preclinical studies have been attributed to their NMDA-agonistic properties14,15 or cholinergic activity.10,11 Furthermore, a systemic or intracerebral administration of PREG and PREGS enhances memory in rodents by increasing the animal's natural performance or antagonizing pharmacologically induced amnesia.49 PREG treatment of rats during the neonatal period influences the cortical dopaminergic and adenosinergic systems and behavioral responses.50
While the precise mechanisms of action of PREG that result in the improvement of positive symptoms remain unclear, some researchers ascribe them to the stimulation of the hippocampal dopaminergic system,12,51 mixed modulatory effects (positive and negative) on the GABAA receptors,8,52 and neuromodulatory effects on NMDA53–55 and sigma-16 receptors. It should also be noted that PREG and its sulfate demonstrate potent neuroprotective qualities and play an important role in neurodevelopment.17,56 Although we do not have any definitive explanation for the mechanisms underlying the beneficial effects of the addition of neurosteroids to antipsychotics, the neuromodulatory effects of PREG may be relevant to the clinical activity, as has been demonstrated to be the case with clozapine.16
The findings of this study indicate a significant beneficial effect of low daily doses of PREG administration on EPS but not on akathisia. The beneficial effect of DHEA on EPS is consistent with a previous preliminary trial30 but not with a crossover study.31 Mechanisms by which PREG might have an EPS-lowering effect remain unclear, but several intriguing possibilities exist. One such possibility is that PREG's positive modulatory influence on dopamine neurotransmission50,51 may counter the dopamine-blocking effect of antipsychotic-induced EPS as has been suggested for the favorable effect of DHEA on neuroleptic-induced EPS.32
As recommended by the CONSORT guidelines,57 we developed ANCOVA models with comparisons between 44 completers and 14 noncompleters using the LOCF method. This approach provides a more valid assessment of the treatment effectiveness, because it relates to actual clinical practice.58,59 Although there was no significant difference in the baseline scores between these subgroups of participants, they were followed throughout the study. In particular, the patients who discontinued the study early appeared to have less improvement on the PANSS positive, PANSS general psychopathology, ESRS, and GAF scales than did completers, whereas no significant differences between these subgroups were found in the performance of the CANTAB tasks.
Circulatory PREG was found to be significantly higher among the patients treated by either neurosteroid compared to the placebo group; however, it was significantly higher among those receiving 200 mg/d of PREG compared to the PREG-30 and DHEA groups. This study demonstrates no effects of PREG administration on the other hormones measured in this trial, while the treatment with DHEA significantly elevated blood levels of PREG (but to a lesser extent than PREG 200 mg/d) and DHEA, DHEAS, androstenedione, 3α-androstanediol glucuronide, testosterone, and estradiol compared to PREG-30, PREG-200, and placebo. No differences between groups in the levels of progesterone, 17-OH-progesterone, and cortisol were demonstrated. Our findings that circulatory DHEA and DHEAS increase after DHEA administration (400 mg/d) are consistent with a previous report,31 although among the patients treated for a period of 12 weeks with DHEA (150 mg/d) blood DHEA and DHEAS levels failed to reach significance compared to the placebo group.33 Blood levels of 3α-androstanediol glucuronide, testosterone, and 17-OH-progesterone were increased in men, while blood levels of pregnenolone, estradiol, and progesterone were increased among women. No sex differences were indicated in levels of DHEA, DHEAS, or androstenedione. Thus, the patients receiving PREG are not at risk for elevation of androgenic metabolites, like DHEA, which may in turn potentially predispose to various problems such as prostatic hypertrophy in men and hirsutism in women. The treatment effects of PREG cannot be explained by an impact of their neuroactive metabolites like DHEA, DHEAS, androstenedione, 3α-androstanediol glucuronide, testosterone, and estradiol. Considering the lack of any significant effect of PREG on the measured hormonal profile in this study, the therapeutic effects of PREG noted here may be mediated by other mechanisms, including further potential hormonal influences not investigated in this study. In addition, PREG's effect may be mediated by its direct neuromodulatory effects on the GABAA, NMDA, sigma-1, dopaminergic, cholinergic, or neurotrophic systems.
Last, since no persistent new adverse effects or unfavorable drug interactions were observed, the combination of these neurosteroids with antipsychotic drugs appears to be safe and well tolerated, confirming the results of previous trials with PREG26,29 and DHEA31,32,60 as additions to ongoing antipsychotic treatment.
Limitations of this study include the relatively small sample size and the relatively short duration of the study. Long-term, large-scale studies are required to obtain greater statistical significance and more confident clinical generalization. In addition, it would be important in such larger sample sizes to investigate whether any interaction exists between PREG and any specific medication and to compare responses to PREG and DHEA in those receiving typical and atypical antipsychotics within the context of a standardized medication regimen.
In conclusion, the present data, although based on a relatively small sample size, suggest that low-dose PREG treatment for 8 weeks, used as an adjunct to antipsychotics, has the valuable effect of ameliorating positive symptoms and attention and memory impairments and antipsychotic-induced EPS in chronic schizophrenia and schizoaffective disorder patients. Although the results of this study are notable, it is crucial to replicate the trial with a larger sample of chronic and nonchronic schizophrenia or schizoaffective patients for a longer duration of treatment. Further double-blind controlled studies are needed in order to investigate the clinically significant benefits of PREG augmentation.
Drug names: clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon).
Author affiliations: Department of Psychiatry, The Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa (Dr Ritsner); Sha'ar Menashe Mental Health Center, Hadera (Drs Ritsner, Gibel, Boguslavsky, and Zayed); Division of Psychiatry, Faculty of Health Sciences Ben-Gurion University of the Negev, and Ministry of Health Mental Health Center, Be'er-Sheva (Drs Shleifer and Lerner); Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva (Drs Maayan and Weizman); and Research Unit, Geha Mental Health Center, and Sackler Faculty of Medicine, Tel Aviv University (Dr Weizman), Israel.
Potential conflicts of interest: None reported.
Funding/support: None reported.
Author contributions: Dr Ritsner contributed to study design, data analysis, and, with Dr Lerner, oversaw data collection. Drs Gibel, Shleifer, Boguslavsky, Zayed, and Lerner contributed to data collection. Drs Maayan and Weizman contributed to biologic testing. Dr Ritsner was primarily responsible for manuscript preparation, with contributions from Drs Weizman, Maayan, and Lerner. All authors contributed to and have approved the final version of the manuscript.
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Quinta to release Chromophobia in France
Quinta Distribution will release Cannes closing film Chromophobia in France, Quinta president Tarak Ben Ammarconfirmed last week. The company also has world rights to the film directed byMartha Fiennes; Ammar is also producer on the film.
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Game Boy RGB Backlight | Pocket and Original
$ 12.99
How did we ever play our Game Boys without an illuminated screen? Unless you had a clunky attachment and some extra batteries, this task was not easy for a 90's kid who just wanted to play Pokemon at night.
- 7 rich color options
- Thinnest backlight available at 1.23mm
- >90% uniformity
- Four 28 gauge tinned wires included
- 3 resistors included (2x 100 ohm, 1x 150 ohm)
- DMG and Pocket compatible
This RGB (Red, Green, Blue) backlight can change color based on which connections are grounded. Mix your ground connections to make a variety of colors! Now you can play both consoles in the dark or give your Game Boy a makeover! You can also display your screen in an "inverted" orientation to give your pixels a retro look.
Colors created:
- Red
- Green
- Blue
- Teal (Green + Blue)
- Yellow/Green (Green + Red)
- Purple (Red + Blue)
- Ice Blue White (Red + Blue + Green)


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Contact: OBFS Training Team 217-265-9275Instructor: Megan Wells
COURSE PREREQUISITE(S): FN 100: Finance Systems Overview (on-line) AP 100: Accounts Payable System Overview (on-line) PO 101: Requisition Processing
COURSE DESCRIPTION:This course covers the receiving process, including how to do adjustments, overrides, and returns. Also covered is how to query in Banner, how to view the receiving status and the resources available to departments needed to appropriately receive and log in purchases.
CPE CREDIT:The Office of Business and Financial Services is an Illinois Public Accountant Continuing Professional Education (CPE) sponsor and will offer 3 hours of CPE to Certified Public Accountant (CPA) participants in this course.
BRING TO SESSION (REQUIRED):Printed copy of RC 101 Participant Guide
LOCATION:Green Street Building - 111 East Green Street, Champaign, Lab #11
The building hours are 8:30am - 5:00pm.Please check in with the receptionist near the back door before proceeding downstairs to the lab.
PARKING:There is no visitor parking available in the Green Street Building Lots or at Presidential Towers. There are metered spaces on Second Street as well as along the Boneyard Creek Path behind Garcia's and Papa Dels. These spaces have a two (2) hour time limit, so meters must be fed accordingly. It is strongly recommended that you consider other transportation arrangements to the Green Street Building such as walking, car-pooling, or use of the bus. You may ride the MTD bus for free by showing your University ID. Maps and schedules are available on the MTD web site.


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About Us
Main content
The cosmology group led by Prof. Alexandre Refregier seeks to answer fundamental questions about the Universe: What is the nature of Dark Matter and Dark Energy? What are the initial conditions for the formation of cosmic structures? Is General Relativity valid on cosmological scales?
Since its formation in July 2011, the group has grown to incorporate a broad range of expertise including observations, data analysis, theoretical interpretation, software development, hardware design and teaching. The group thus endeavors to play a leading role in cosmology, a dynamic field entering a new phase of high precision that calls for a broad and integrated approach. Please visit our people page for a list of group members.


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In a large saucepan set over moderate heat, warm the oil until it is hot, add the onion, carrot, salt and pepper and cook, stirring occasionally, for 5 minutes. Add the garlic and cook 1 minute. Add the tomatoes, gingerroot, curry powder or Garam Masala, lemon pepper seasoning, herbs de Provence and bay leaves, and cook, stirring occasionally for 2 minutes. Add the water and bouillon cube and cook, stirring occasionally, for 5 to 7 minutes more, or until mixture has thickened. Add the lentils, and simmer, stirring occasionally, for 5 to 7 minutes more, or until flavors have blended. Discard bay leaves.
Before serving, stir in the lemon juice and drizzle with the extra-virgin olive oil.
Recipe courtesy of Padma Lakshmi


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CARPENTER'S SQUARE or
MARYLAND FIGWORT (Scrophularia marilandica)
Family: Figwort family
Location: Woodlands
Season: Summer and fall
Flower: Tiny brownish, irregular flower with two upper lips and a lower lip that is turned under. Held in loose cluster at end of stem. Seeds in pod roughly the same size as flower.
Leaves: Opposite, egg-shaped, toothed.
Click here for larger pictures.


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Welcome to IDS!
Welcome to the industry-leading management tool offering the best web-based Dealership and Enterprise management reporting solution on the market! Access to the system is also available via leading mobile platforms.
We work tirelessly to improve the tools and reporting systems used by our clients to run their operations - whether from a corporate, consolidated view to a store-level view to a department manager view, we put the information you want and need to see at your finger tips.
We listen, we learn, and we deliver!