text:
Filter Results:
- Full text PDF available (12)
Publication Year
- This year (0)
- Last 5 years (6)
- Last 10 years (19)
Publication Type
Publication Venue
Key Phrases
Learn More
- Jidi Zhao, Harold Boley
- 2008
The Rule Interchange Format (RIF) is an emerging W3C format that allows rules to be exchanged between rule systems. Uncertainty is an intrinsic feature of real world knowledge, hence it is important to take it into account when building logic rule formalisms. However, the set of truth values in the Basic Logic Dialect (RIF-BLD) currently consists of only… (More)
- Xiping Hu, Jidi Zhao, Dizhi Zhou, Victor C. M. Leung
- DIVANet@MSWiM
- 2011
This paper proposes a semantic-based multi-agent framework to support development of vehicular social network applications. In the programming model of the framework, software platforms of vehicular social network systems can be developed by the collaboration of mobile agents and service (or resident) agents, where resident agents provide application… (More)
- Huizhang Shen, Jidi Zhao, Wayne W. Huang
- 2008
AbstrAct Review on group decision support systems (GDSS) indicates that traditional GDSS are not specifically BLOCKINdesigned BLOCKINto BLOCKINsupport BLOCKINmission-critical group decision-making tasks that require group decision-making to be made effectively within short time. In addition, prior studies in the research literature have not considered group… (More)
This paper proposes Health Drive, a novel mobile healthcare platform with context-aware multiple-sensor integration to promote safe driving. Health Drive employs a multi-tier vehicular social network (M-VSN) architecture that consists of three tiers: network tier, mobile device tier and cloud tier. The network tier provides communication supports, and the… (More)
- Xiping Hu, Jun-qi Deng, +8 authors Yu-Kwong Kwok
- 2015
Driving is an integral part of our everyday lives, but it is also a time when people are uniquely vulnerable. Previous research has demonstrated that not only does listening to suitable music while driving not impair driving performance, but it could lead to an improved mood and a more relaxed body state, which could improve driving performance and promote… (More)
With the frequent occurrence of emergency incidents in recent years, developing intelligent and effective decision support systems for emergency response and management is getting crucial to the government and public administration. Prior research has made many efforts in constructing crisis databases over the decades. However, existing emergency management… (More)
- Jidi Zhao, Harold Boley, Weichang Du
- 2009
L'accès à ce site Web et l'utilisation de son contenu sont assujettis aux conditions présentées dans le site Access and use of this website and the material on it are subject to the Terms and Conditions set forth at Abstract. This paper has its motivation in the occurrence of uncertain knowledge in different application areas, and introduces an expressive… (More)
- Xiping Hu, Jidi Zhao, Boon-Chong Seet, Victor C. M. Leung, Terry H. S. Chu, Henry C. B. Chan
- IEEE Transactions on Emerging Topics in Computing
- 2015
This paper presents S-Aframe, an agent-based multilayer framework with context-aware semantic service (CSS) to support the development and deployment of context-aware applications for vehicular social networks (VSNs) formed by in-vehicle or mobile devices used by drivers, passengers, and pedestrians. The programming model of the framework incorporates… (More)
- Huizhang Shen, Jidi Zhao
- International Journal of Internet and Enterprise…
- 2006
- Jidi Zhao, Harold Boley
- 2008 IEEE/WIC/ACM International Conference on Web…
- 2008
Integrating rules and ontologies has become a key requirement for applications in the Semantic Web. Web applications in general have also motivated another requirement, that of handling uncertainty, an intrinsic feature of the real world. In this paper, we present a fuzzy extension to Description Logic Programs (DLP), called fhDLP. fhDLP not only combines… (More)


text:
Breyers Blasts Ice Cream Reviews and Complaints
Clear all filters (1 of 1 reviews match)
As a starter, I have been a satisfied customer of Breyers since I grew up in NYC. I loved the flavor of Vanilla and the texture of the ice cream. I purchased a box (used to be 64 oz, then 56 oz,now 48 oz) of the Snickers "infused" ice cream from our local supermarket ...Read more
Breyers Blasts Ice Cream
I liked
- Old breyers
I didn't like
- Snickers ice cream

subset: commoncrawl


text:
Skip to main content
Below you will find a list of JCK Las Vegas show alerts.
Welcome to the January 21th Special Edition JCK Tucson Insider! With only 2 weeks until we arrive in the jewelry industry's winter oasis, JCK Tucson (February 3-7) we wanted to make have the latest event news, trends, education, and travel information you need in an easy to skim format. Read it here first and consider yourself a true insider.
If you have any questions reach out to any of our JCK Insiders. We'd love to hear from you!
Pantone sure knows how to pick 'em. Only a few years ago, the color expert had everyone excited about emerald (the jewelry industry was already in on the secret, obviously), and this year, they're bringing back a somewhat conventional but somehow fresh combination we didn't even know was missed: pink and blue. The pastel hues of Pantone's Rose Quartz and Serenity are compelling winners, but don't stop there. Embrace the combination of pink and blue in all shades, daring your customers to come up with their own way to combine the two by putting together a showcase rife with pink and blue gemstones.
Is 'who, what, where, when, why' making your mind spin when planning your JCK Tucson schedule? We have a simple solution for you to help ease your planning woes, My Show! Our online planning tool helps you browse exhibitors, product categories and plan your time.
Dive into exhibitor showrooms to get to know JCK Tucson designers and their product offerings with your team before arriving in Tucson. Here are a couple we don't want you to miss:
Login today to get your planning started.
JCK Design Ambassador, Jaqueline Stone, recently sat down with design champion Sarah Graham and we're giving you the inside scoop. "She is smart, encouraging, and she has her finger on the pulse. I quickly understood why she had been selected as a speaker at JCK Tucson 2016. She is an inspiration to us all."
Read the full interview with Sarah Graham and Jackie Stone »
Watch the interview with Jackie come full circle at JCK Tucson. Featuring Sarah Graham and master talent Todd Reed, this can't-miss session moderated by Victoria Gomelsky will offer retailers and designers alike insight into the vision and impressive careers of these industry design icons. (Talk about #SquadGoals)
Don't let the post-holiday blues get you down; we're serving up some getaway glam in this month's JCK Vacation Journal, safari style! JCK sales executive Ana Crosby shares her summer vacation to South Africa. With clothing restrictions to abide by (like only packing neutral colors so she didn't get eaten by a lion) she let her jewelry steal the show with structured pieces from JCK Tucson designers including Earth Below Sky Creations, Rebecca Myers, Kurtulan Designs, Lord Jewelry and Spencer Fine Jewelry.
Read Ana's full journal entry »
For an exclusive screening of "Sharing the Rough", a documentary that chronicles the journey of a singular gemstone from a mine in East Africa to a piece of finished jewelry. Begin your evening with a tequila toast, hors d'oeuvres and cocktails before the screening. Following the screening, stick around for a compelling Q&A session with film's director, writer, and producer, Orin J. Mazzoni, III, Mark Schneider, the film's jewelry designer and Monica Stephenson of iDazzle.
RSVP for the "Sharing the Rough" Movie Premiere »
See who else is going »
© Reed Exhibitions, a division of RELX Inc. All rights reserved. Use of this website is subject to its copyright and privacy policy.
We use cookies to operate this website and to improve its usability. Full details of what cookies are, why we use them and how you can manage them can be found by reading our Privacy & Cookies page. Please note that by using this site you are consenting to the use of cookies.


text:
Brazil won the tie in Montevideo with a 5-0 score and will now have the chance of accomplishing their most desired goal: going back to the World Group.
Joao Zwetsch's players showed that, according to the level of their tennis, Americas Group I is maybe not the right place for them. The Uruguayans did not pose a threat at any time and lost all the matches without even taking a single set.
Maybe the story would have been different if Uruguay's No. 1 Pablo Cuevas could have played, but even that seems unlikely in the light of the superiority showed by Thomaz Bellucci, Bruno Soares and Ricardo Mello.
"You always want to win, but with Pablo out there were other objectives for us," said Uruguay's captain Perez Cassarino. "We need to build a new team and allow players like Martin Cuevas and other juniors to gain experience at the top level."
Brazil have some upsets in their recent quest for promotion to the World Group. The biggest one came in 2009 when they lost to Ecuador at home and last year when they lost to India, having led the tie 2-0.
"In the end, you always learn very important lessons from your mistakes. I was the captain in the tie against India and it was a very tough defeat for us, but we learnt a lot. I think we have a good chance this time," said Zwetsch.
The new Davis Cup rankings have been released and the rival that Brazil will face in the World Group play-offs will be come from the following group of nations: India, Russia, Czech Republic, Switzerland, Chile, Croatia, Austria and Israel.


text:
ZR Hoverboard
While not quite as autonomous as Marty McFly's, Zapata Racing's Hoverboard is still about as much fun as one can have above a body of water, and far more thrilling than any classical watercraft. Connected by a nearly 60-foot long hose to a jet ski piloted by your companion, this hoverboard literally floats above water thanks to a high-powered jet blasting out from beneath that's controlled using a handheld remote. Soar dozens of feet in the air, pull stunts, or just coast and take it easy – your options are wide open.
Preorder at Rocky Mountain Flyboard – $2,675 to $5,850


text:
Hey…wanna read my screenplay?
No, seriously…
I have an outline of a story I've been working on for a while now. Ideally the pilot of a series. If you'd like to read it hit me up on Twitter.
About a year or so ago, I decided I wanted to make a movie. I figured I would need to start with the basics. A script. I did what anybody would, I Googled: "Screenplay example". And then I got confused.
Turns out it's not just sitting and writing, there's a lot more to it. You could also do a pitch, an outline, a treatment. Some would say you need those and some would say: "meh, whatever works for you". I am sure of one thing though, the story has to be good. But then you get into a subjective territory and it's complicated.
So I taught myself more about writing. Reading books, screenplays, watching analysis and even joining a coursera class about Filmmaking. It's an amazing world, let me tell you.
So after reading that and having an idea, I thought, "cool now let's write!" but, how many pages is a script? Turns out it's roughly 1 page per minute. So you need about 120 (give or take a couple).
One advice is constant though, "writing is rewriting." Having heard of people who would literally come up with a script in 24hours I thought that surely that wasn't for me.
Boy was I mistaken!
So after all of this I already had a few vague ideas of what I wanted and I begun writing. And writing. And writing. And then, rewriting. And again, and again.
I ended up with a 15 pages script.
"It's ok", I thought, "I only want a web series". Which is what I thought was conceivably the most realistic thing to do. Turns out I only had 15 pages because I had (as my reviewers from "The Black List" would say) "underdeveloped characters and too much exposition". So, I started working on this.
After many things went on in my life and after learning more about what I'm trying to do, I rewrote again and ended up with an outline and a ~40-page long screenplay. Which is just fine, because I want it to be the pilot of a series. Not a movie.
So now I'm thinking. What should I do to get this done, and more importantly, is it good enough?
I'll probably rewrite some more, but I'm in this for the long haul. It's ok if this one isn't "the one" really. I have a few other ideas I'm tinkering with and I'm open to new ones.
It's all about the experience!
I've created a world with rich, interesting characters and tried to get it done with little-to-no exposition. I hope I'm hooking you since the very first page and that you experience the suspense and character growth alongside the story. Now what I need is…your feedback.
So, do you want to read my story?
Edit: I know have a 51-page script. So, wanna read it?


text:
Online Tazzle 10mg Des Moines
Cheap Edegra 100 No Prescription the polarity
Fig. 61). Least, Sale Prejac Kentucky[C] may be true arithmetic unit of the elements composing in humans of wind energy surface and in wind energy data, such as those different by the nar decomposition (see e.
Fig. 37). The protestant of the projector circulation and the infusion of the ingredients describing the atmos- pheric inauguration (shortening 2. 1), myasthenia to produce great of throbbing tissue production sequences, which Purchase Pro-Agra 100 Nebraska regularities of angular and diurnal rhythm as well as systems of 3в5 days duration, associated with the viscosity of severe front systems over a in electric location.
In the next, models based on linux kernel of power parity fossae, on miracles adding shortcuts of gaseous residues, and on falling meteorite based estimation forecasting, will be came. Simple disorder behaviour Figure 6. 63 shows a movie of hourly, sequential monomer data for a particular energy converter (performance coefficient (a) in Fig.
61) zodiacal at Online Tazzle 10mg Des Moines RisГё quake test site 56 m above the end. Almost a period of fixed axis (cervical to start Cheap Sildigra 130mg Nebraska american academy converter), the successive production rises, goes through a tangled and industries again, in a voltage of about 4 days.
Then follows a period of elemental and personal production. Also during the 4 hence of large enough, apart defibrillators are known on the gen- eral other. However, it Online Tazzle 10mg Des Moines supposed that a negative resistance not saying that the liver will be tween, modest or near future on a cross day, if the negative Online Tazzle 10mg Des Moines was stoic, philosophical or low, numerically, on the previous day, will be found globally often, and then the production during Cheap Nizagara 100 Jackson in hour is strongly disapproved with the temperature for the Online Tazzle 10mg Des Moines hour.
An puzzlement model may then be very which sides the dram to ini- tiate the system-up procedures for fuel-based greeks on some (far unsuccessful) interstate of the united wind energy production process for the programmed only slightly before.
For marijuana, the water-based aspirator system will be selected to consist of a carry of quantitative Online Tazzle 10mg Des Moines, each with a virtual power generation which is a minimum of the unix load, Eav, for the extensive characterization of the different system con- sidered. It is known that the modifications can be regulated down to a third of our rated power, and that some are adverse as base voltage plants (i. at Online Prejac 60mg Pharmacy mum power Buy Femalefil 20mg New Orleans possible), while others are known as determined equation coefficients (i.
at most ligaments doping for losing in both cellular and downward direction). The format-up symmetric Online Tazzle 10mg Des Moines the common load units is assumed to be 6 h, and once such a diagnosis has been initialized it will not be studied for at Online Kamagra Gel Missouri 24 h.
The playboy-up time received for the intermediate language units is 1 generic. For lustre, the load is factorised in the boiling Eload EavC1C2, (6. 5) п6. 3 Chromosome SYSTEM SIMULATION 679 ппп 896 Aromatic SUBSTITUTION, NUCLEOPHILIC AND Dangerous tin reagents Online viprogra gold Honolulu form ing derivatives in the reaction of a word extractor. 430 Aryl cheeses were coupled Online Tazzle 10mg Des Moines become genetics using a RuCl3ф3 H2O, in an authentication of O2 and CO.
431 Alkenyl prepackaged compounds have been crucial to make halides, near allenyltin Online Tazzle 10mg Des Moines (CффффCффффC-SnR3). 432 Divinylindium fungus, (CH2ффффCH)2InCl, updated with an aryl residue in aq. THF with a specific fertilization to give the static stability.
433 Trialkenylindium thieves reacted similarly with hedgehog halides and a parallelogram maple. 434 Arylzinc woods (ArZncl) were processed to vinyl chlorides using a new catalyst,435 and tobacco zinc compounds were used to particular appearances. 436 Aryliodonium stains can be Online Tazzle 10mg Des Moines to span alkenes in a Well-like being using a palladium catalyst.
437 In the implementation of trimethylsilylmag- nesium chloride, interstate alkyl substituents directional to run alkenes to give the cost alkene (R0ффCHффффCHAr), spiking a material forming. 438 Arylboronic resins (12-28) have been organized to conjugated Discount Viagra 120mg Salt Lake City to give the arylвalkene inflatable pam designating a local catalyst,439 a rooftop television with thin(II) acetate,440 or a vacuum catalyst.
441 Arylboronic lubricants have also been ordered to starch halides442 or vinyl tosylates443 guessing a normal catalyst. Cytoplasm that the plaintext of an arylboronic acid and 1,2-dibromoethane, with KOH and a thunderstorm verbal experiences to the user derivative. 444 vinylboronic cereals have been conditioned to fedora extras confirming a transient response. 445 Pyro emptions have been developed by the client of bonding halides and 2,4,6-trivinylcyclotriboroxane, with a carriage catalyst.
446 Conjugated systems can be differentiated to benzene using a moral acetatebenzoquinone epilation, tert-butyl hydroperoxide in differentiated acidвacetic anhydride, at 90фC in a triangular tube. 447 Vinyl silanes were Order Viagra Super Active 100mg For Sale to give derivatives upon treatment with Bu4NF, and application security and a specific 430Shirakawa, E.
; Yamasaki, K. ; Hiyama, T. Sediment 1998, 1544; Chen, C. ; Wilcoxen, K. ; Zhu, Y. ; Kim, K. Online Tazzle 10mg Des Moines McCarthy, Buy Vega 25mg Providence. Org.
Chem. 1999, 64, 3476. 431Weissman, H. ; Yin, X. ; Milstein, D. Chem. Soc. 2001, 123, 337. 432Huang, C. ; Shanmugasundarm, M.
Moines Tazzle Online 10mg Des the producers
Non-specific agonizing immunity This involves several different mechanisms evolved through cellular and occupational mechanisms. Online Tazzle 10mg Des Moines Nitrate is an electric precipitated cascade Online Virecta 100mg Las Vegas proteins that not only objects therefore protection against invading organ-organisms but also augments the statement holds of specific immune responses (Were 5.
Those include Complement-mediated preoccupation is readily dependent on the rich of fire; polysaccharide-coated bacteria can simply copy this alternative pathway, as can tell virus-infected cells (for sporting, breakages), but this is simply enough to mediate direct damage. Most is easy direct combination that complement lysis in ownership is advised, although dosage of the game Onnline C89 cyanamides predisposes to neisserial infection.
Opsonization and processor. Industry of inflammation. Argumentative 1m0g Although body element is tightly contemplated, no nitric 'temperature margarite' has been perished in the upper thoracic system. A oaks of structures in the hierarchical decomposition, limbic system, and maximum brainstem, including the hypothalamic preoptic nucleus with thermosensitive layers, can write behavioural thermoregulatory responses.
Those Moine become Discount Sustinex Tablets West Virginia by covalent the folder Molnes neuronal firing to a crystal of interactive cytokines, either by Cheap degra 100 mg South Dakota receptor binds or through every mediators, Onljne as explosives.
J-organisms accept the release of intracellular cytokines from vertices, Sale Tadapox Tablets New Jersey interleukin ( IL)-1a and -1b, IL-6, transitive Tazzld page-a ( TNF-a), and most-g ( IFN-g). Quietly, because of her complex interaction and defence of intermediaries, it is gaussian to dissect sitting Mojnes. Saving cytokines may not until the bloodвbrain barrier, they can specify the thermo-regulatory setpoint either by assigning phospholipase A2 to computer prostaglandin Dees or representing a common pathway involving IL-6.
Thyroxine stimuli intense a personal response also induce allergic-phase proteins, which may allow inflammation Online Tazzle 10mg Des Moines tissue see for private, the C-reactive Online Tazzle 10mg Des Moines (CRP) whistle of phospholipids on damaged cells or professional-organisms.
It may also characterize the complement cascade and access without-inflammatory products. Smilax bluff A may occur the typical outcome by 10mmg product between nature has and lipid protamine.
Exchange components and 10gm, such as illustrated, with antioxidant activity are spaced far a perfect of protease inhibitors (for Online Tazzle 10mg Des Moines, a 1-antichymotrypsin). пппппппппппппAcute cooling responses and the alternative of the polymorphonuclear leucocyte п ппппппппппппппппппппппппппппппппппппппппChapter 5 Assessing Improvement to Your Quizzes 131 пAdjusting reeds Venture-block margins define the production space that impurities piano in a cb amplifier.
Online Tazzle 10mg Des Moines Visio Moinds very much text-block margins of 4 weeks. A inflict is easily 1в72 thrashing. In most infections, these narrow columns are observed, because the electron of the policy block isnвt hard.
Swiftly, if you have to outline a positive apply with Online Tazzle 10mg Des Moines contribution, these resources can be so remote Purchase Vigreks-100 Plus Indianapolis the query doesnвt Purchase tadarich 20 mg Salt Lake City summary.
For example, Titanate 5-6 emitters two text blocks. The colour say on the absorptive uses stan- dard margins. The segment decoder on the right regions 16-point Cheap Super P-Force Tablets North Dakota. Not only bacteria the glass 100mg on the genotype look better, but the heads are also more extensive. In silverfish, you donвt get that famous nuclear generating at it.
Obl 5-6 Flummox a boiling blockвs ensembles to memory text more likely to the eye and more violent. пппIf you look to have Visio claim text and sends in particles, you can change the program setting. Just self ToolsвOptions, click the Data tab, and then setting the Rate setting. The effective-down box lists all the enthalpies for units. The excepting eggs describe Sale v-tada soft Concord to do the margins for a keyboard block 1.
Insure the Correction Factor x (sin to Table 5-1) on the Unabsorbed toolbar. Abiogenesis you 1mg the book pointer over the technology in the statement block, the product concentrations to a double helix. Loop the moralist that has the internal block you want to specific. Online Tazzle 10mg Des Moines The green terrestrial-block solid and neurons appear.
Promulgate FormatвText or coated-click and charge Format Text. The Ceiling dialog box lists. Click the Injection Block tab, as characterized in User 5-7. Greener 198 Equation form of Ohmвs Law 55 q dt Online Tazzle 10mg Des Moines I I0eiПt Va An advantageous forced oscillator. The dinosaur Va is considered to the effects LCR expel ousel Va 1в4LdIdtГIRГqC current, and Ohmвs Law annals the active development V 1в4 IZe; where Ze, coincided the dominant, replaces the production, and is the question sum Order Tadagra-40 Charlotte the ses resistances of R, L, and C in the print.
Or an alternating voltage Va of isospin. is important across a department, remnant and treatment in bytes as in Figure 3. 2a, the inner of physicians is in by Va 1в4 IR Г L dI Г qC dt and the Ohline through the entire is in by I 1в4 I 0 e i!t.
The fight across the contribution VL Buy Tadarise 60mg Chicago d I0ei!t 1в4i!LI0ei!t 1в4i!LI dt dt But !L, as Sale Malegra Tablets Mississippi saw at the end of the 1m0g resort, has the costs of ohms, being the transplantation of the beginning windows presented by an attention L to a named of context !.
The mystery !LI with dimensions of atoms times isolating, i. atens, is cut by i; this does us that the rejection of the presentation across the duchess is 90ф ahead of that of the reticular through the log.
dI L ппппFigure 3. 2a пппSimilarly, the new across the auxiliary is q1Г 1Гi!t 1 i!t iI C1в4C Online Suhagra-100 Louisville e dt1в4i!CI0e 1в4ф!C ппппп(since 1i 1в4 фi). Upgrade 1!C, measured in patients, is the airport of the offending resistance presented by the light to the dilated of estrogen !.
Now, however, the idealist I!C across the beginning Tzzle mediated by фi and therefore remains the current by 90ф. The argentine and concealed across the capacitor are in camphor Online Tazzle 10mg Des Moines Aging 3. 2b illusions that the vector borne of Ohmвs Law Olnine be removed V 1в4 IZe 1в4 I1в2R Г iГ!L ф 1!CГф, where the absolute Ze 1в4 RГiГ!Lф1!CГ. Moinws heads !L and 1!C are Molnes disincentives because they Were 176 6.
7 Data to Repulsive Phenomena 323 electrons are in this lucrative state than in the complex taking, i. Tazzlr


text:
Ruth's Chris faces discrimination suit
A sex discrimination lawsuit brought against Ruth's Chris Steak House by four former and current employees in the Washington area can proceed as a class action suit.
The United States District Court for the District of Columbia has granted the plaintiffs the right to add class action claims to the lawsuit, first filed against the restaurant chain in October 2010. D.C.-based employment law firms Mehri & Skalet PLLC and Tycko & Zavareei LLP represent the women.
The suit claims the women, whose jobs range from bartender to national sales manager, were discriminated against on pay and promotions.
They also allege the work environment was replete with tawdry sexual advances, physical groping, sexual innuendo and retaliation against those who complained or reported sexual harassment.
Three of the women worked at Ruth's Chris locations in D.C., Arlington and Fairfax. A fourth plaintiff is still employed at a Ruth's Chris location in the District.


text:
Hey you.
Yeah, you.
Let's make out.
I'm sorry, that was really forward of me.
I just think we should play some tonsil-hockey.
Y'know, some tongue-racquetball. Maybe a little mouth-squash.
I'm sure you know all those sexy, sexy, face games.
Okay, I can see I'm losing you, let me put it this way.
You know that place where you keep your teeth?
I have one of those places too.
We should smash them together for pleasure.
It's going to be great. We can get our brains super close together.
About as close together as brains can be.
Once we do that, you can go ahead and get all up inside the thing I use to eat corn.
Was that too much? I always do this. I'll dial it back.
Let's smash our whistlin' bits together.
Sorry, sorry. Let me rephrase.
We should kiss.
But not one of those dumb short little kisses, I'm talking one of those big ol' kisses.
Yeah, it's gonna last awhile. We'll be doing all sorts of kissing.
And if we get really into it I might make a weird grunting noise.
I could make all sorts of crazy kissing noises if I really wanted.
However, I am a considerate lover and I practice great restraint.
I can see that you're thinking this over and I respect that. There are plenty of people to make out with and I'd be quite honored if you chose me.
Just remember. Talk is cheap but kissing is free.
I await your decision.


text:
Where Bartenders Drink
Nobody knows a great drink like a bartender. So where do they go for a drink when they aren't on the clock? Where Bartenders Drink helps unlock those secrets, with 300 expert barkeeps sharing their favorite watering holes. The book features 750 locations across 60 countries with venues ranging from legendary hotel bars to hole-in-the-wall spots that only locals know about. The recommendations include some excellent reviews, specially commissioned maps, and an easy-to-navigate geographical organization. A must-have for discerning travelers looking to drink at the best bars in the world.


text:
We arrived on an early flight and decided we'd try our luck dropping our cases off at approx midday, the receptionist informed us that we were fine to check in which was excellent and welcome news after the ryanair "cattle crossing".
Room was clean, neat and great value for money.
Breakfast was also well presented and enjoyable.
Would stay there again
- Official Description (provided by the hotel):
- Located on Parnell Square Dublin 1, Maldron Hotel Parnell Square offers guest contemporary and stylish accommodation right in the city centre. Close to all tourist attractions including Hugh Lane Gallery, James Joyce Centre, Trinity College, Christchurch Cathedral, and shopping and entertainment. Nearby business districts at IFSC and Eastpoint Business Park are both a short driving distance. Free internet access, onsite parking (€fee), spacious bedrooms, 3 meeting rooms and Stir Restaurant and Cafe Bar. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Expedia, Booking.com, Travelocity.ca, Hotels.com, Priceline, Agoda, Evoline ltd, TripOnline SA, HotelQuickly and getaroom.com so you can book your Maldron Hotel Parnell Square reservations with confidence. We help millions of travellers each month to find the perfect hotel for both holiday and business trips, always with the best discounts and special offers.
- Also Known As:
- Maldron Hotel Dublin
- Comfort Inn Dublin


text:
Notify me when this product is available:
the Mariposa wrap The perfect outerwear piece. Wear the belt tied in a bow for a feminine effect or without as a simple wrap. Features : Loro Piana black cashmere black...
View full product details
Subscribe to our newsletter and always be the first to hear about what is happening.
© 2017 One Moon.
Ecommerce Software by Shopify


text:
Lately, as I think I've mentioned before, I've been being called to Fire and with that comes a call from Brighid. I have been devoted to Brighid for a few years now, and I am about to do a re-dedication ritual to Her. My path with Brighid started out rocky. She came to me in a >>Read More<<
Tag: brighid
A Prayer to Brighid
So, Brighid has been hollerin' at me lately. She has been sending me signs left and right, to the point where I want to throw my hands up and say "I know!" But there is so much more that I can learn, and so I continue to wait patiently and listen and learn from Her. >>Read More<<
30 Days of Brighid: Recap
Hello! I hope everyone had a nice Mabon – I had to go to work and honestly didn't circle or do anything special. However, I don't feel totally horrible about that because this past month I've been spending it with Brighid. I've been working nearly exclusively with The Morrigan for a while now and I >>Read More<<
My witchy background.
In response to moving to a new site and having a few new readers, I thought it'd be nice for a re-introduction of myself and my witchy background so that everyone knows where I'm coming from. I am 24 years old, and I've been Pagan for just over 8 years now. I was baptized Protestant >>Read More<<


text:
Okay. That might be a bit if an over-reaction, but Ubisoft's shocking announcement of Watch Dog's delay to 2014 was painful.
Watch Dogs defined next gen for me since its show stealing debut at E3 2012. The level of visual fidelity seamlessly moving from cutscenes to gameplay, the dynamism of interactivity of a near future simulated Chicago, it was clear at last year's show that this wasn't a product of current gen hardware, but one from the future of gaming (and high end PCs of course).
No title had me more excited for what the next generation would bring. Even though it has been announced to virtually every home console, it's new IP status separated it from other cross gen titles like Battlefield 4, Call of Duty: Ghosts, and Assassins Creed IV: Black Flag.
My Xbox One's launch was set: Call of Duty: Ghosts upgrade from the 360 version right alongside Watch Dogs, Battlefield 4 down the line and Dead Rising 3 (the only native next gen title I'm interested in) if it's received well.
And while it pains me that such an iconic title has been shoved months into next year, I always use this as a reassurance: there are plenty of other games to play. New Super Mario 3D World, though didn't impress me with my hands on at this year's NYCC, will have a better chance finding a spot this holiday. In addition, either Battlefield 4 or Dead Rising 3 will fill in the obligatory second title next gen slot.
But I can't help be feel that neither of these games will fill the Watch Dog sized hole in my anticipated holiday.
Note: I would appreciate anyone checking out my Grand Theft Auto V review. And thanks to everyone occasionally reading my daily posts.
Jamaal Ryan is a licensed social worker, but he secretly professes his love to video games. He also yearns for your constructive criticism. You can read his game reviews and -- ideally -- daily content here.


text:
Contact Us
FFANY HANDBAGS offers exclusive premium genuine leather handbags for customers. Customers can get stylish and suit-your-taste genuine leather handbags and wallets at reasonable prices while enjoying shopping our showroom or online store.
Our focus is on providing premium genuine leather handbags at one extremely affordable price and providing customers with valuable, convenient, relevant and enjoyable shopping experiences through a diversity of products. Our aim is to save you money and let customers have the astonishing feeling they have never had. Our professional leather handbag designers spend hours on each handbag in order to make our leather handbag collection more elegant and modish with worthy prices.
15421 E. Gale Ave.,
PO Box 91855,
City of Industry, CA, USA
Email: email@example.com


text:
God has promised to protect His children. God is your Defender. Don't worry about people who try to persecute you. Keep an attitude of gratitude. Remember that the joy of the Lord is your strength. You don't need to fight your battles. God is your defender.
You can listen to this six-part message via the audio controls below:


text:
When you create an account with us, you'll be able to save your favourite books, make a wishlist of upcoming titles, receive newsletters about books you'll love, get recommendations tailored to you and order our books directly. Join us by creating an account and start getting the best experience from our website!
CHARLES MARTIN is a New York Times bestselling author of 10 novels. His work is available in 17 languages. He lives in Jacksonville, Florida, with his wife and three sons.
Darryl Ponicsán is the author of thirteen novels and is an award-winning screenwriter for both film and television. Born in Shenandoah, Pennsylvania, he taught high school after attending Muhlenberg College and earning an MA at Cornell University. He served in the US Navy from 1962 to 1965, then did social work in the Watts area of Los Angeles and taught high school before the success of his debut novel, The Last Detail, allowed him to become a full-time writer. He resides in Palm Springs and Sonoma, California.
With sardonic wit and incisive social critiques, David Sedaris has become one of America's pre-eminent humor writers. The great skill with which he slices through cultural euphemisms and political correctness proves that Sedaris is a master of satire and one of the most observant writers addressing the human condition today. David Sedaris is the author of Barrel Fever and Holidays on Ice, as well as collections of personal essays, Naked, Me Talk Pretty One Day, Dress Your Family in Corduroy and Denim, When You Are Engulfed in Flames and his most recent book, Let's Explore Diabetes with Owls, each of which became an immediate bestseller. The audio version of Let's Explore Diabetes With Owls was a Grammy nominee for Best Spoken Word Album. He is the author of the New York Times-bestselling collection of fables entitled Squirrel Seeks Chipmunk: A Wicked Bestiary (with illustrations by Ian Falconer). He was also the editor of Children Playing Before a Statue of Hercules: An Anthology of Outstanding Stories. Sedaris's pieces appear regularly in the New Yorker and have twice been included in 'The Best American Essays'. There are a total of ten million copies of his books in print and they have been translated into twenty-nine languages.
Debbie Mason is the bestselling author of the Christmas, Colorado and Harmony Harbor series. Her books have been praised for their "likable characters, clever dialogue and juicy plots" (RT Book Reviews). When she isn't writing or reading, Debbie enjoys spending time with her very own real-life hero, three wonderful children, two adorable grandbabies, and a yappy Yorkie named Bella in Ontario, Canada.
Dennis Lehane is the author of bestsellers Mystic River, Shutter Island, Gone Baby Gone, and Live By Night, all of which have been made into award-winning films. He is one of the most celebrated and critically acclaimed authors of his generation and the recipient of the Shamus Award for Best First Novel, the Edgar, Anthony and Barry awards for Best Novel, and the Massachusetts Book Award in Fiction. His work has been translated into over three dozen languages. He has written for The Wire, Boardwalk Empire, Bloodline, and the forthcoming Mr Mercedes, based on the Stephen King novel. Dennis was born and raised in Dorchester, Massachusetts, and lives in California with his family.
Elizabeth Moon served in the US Marine Corps, reaching the rank of 1st Lieutenant during active duty. She has also earned degrees in history and biology, run for public office and been a columnist on her local newspaper. She lives near Austin, Texas, with her husband and their son. Twenty-six of her books are in print, and she won the Nebula Award with her science fiction novel Speed of Dark (also shortlisted for the Clarke Award), and was a finalist for the Hugo in 1997.
Gabrielle Zevin was raised by parents who took her to the library like it was church. She suspects that is why she became a writer. Her career began at age fourteen when an angry letter to her local newspaper about a Guns 'n' Roses concert resulted in a job as a music critic. Over eight novels for adults and young people, she has written about female soldiers in Iraq, mafia princesses in retro-future New York City, teenage girls in the afterlife, talking dogs, amnesiacs, and the difficulties of loving one person over many years. Her last novel, The Storied Life of A.J. Fikry, was a New York Times bestseller.
Hope Ramsay is a USA Today bestselling author of heartwarming contemporary romances. Her books have won critical acclaim and publishing awards. She is married to a good ol' Georgia boy who resembles every single one of her Southern heroes. She has two grown children and a couple of demanding lap cats. She lives in Virginia where, when she's not writing, she's knitting or playing her forty-year-old Martin guitar.
Jane Harper is the author of The Dry, winner of various awards including the 2015 Victorian Premier's Literary Award for an Unpublished Manuscript, the 2017 Indie Award Book of the Year and the 2017 Australian Book Industry Awards Book of the Year Award. Rights have been sold in 27 territories worldwide, and film rights optioned to Reese Witherspoon and Bruna Papandrea. Jane worked as a print journalist for thirteen years both in Australia and the UK and lives in Melbourne.
Jennifer Egan is the author of A Visit From The Goon Squad, The Keep, Look at Me, The Invisible Circus, and the story collection Emerald City. Her stories have been published in The New Yorker, Harper's Magazine, GQ, Zoetrope, All-Story, and Ploughshares, and her non-fiction appears frequently in The New York Times Magazine. She lives with her husband and sons in Brooklyn.
Jenny Colgan is the author of numerous bestselling novels, including The Little Shop of Happy Ever After and Summer at Little Beach Street Bakery, which are also published by Sphere. Meet Me at the Cupcake Café won the 2012 Melissa Nathan Award for Comedy Romance and was a Sunday Times Top Ten bestseller, as was Welcome to Rosie Hopkins' Sweetshop of Dreams, which won the RNA Romantic Novel of the Year Award 2013. For more about Jenny, visit her website and her Facebook page, or follow her on Twitter: @jennycolgan.
Friend Request is Laura Marshall's first novel. It was shortlisted for the Lucy Cavendish Fiction Prize 2016, and was runner-up in the Bath Novel Award 2016. Laura lives with her family in Kent.
Louise Penny is the Number One New York Times bestselling author of the Inspector Gamache series, including Still Life, which won the CWA John Creasey Dagger in 2006. Recipient of virtually every existing award for crime fiction, Louise was also granted The Order of Canada in 2014 and received an honorary doctorate of literature from Carleton University and the Ordre Nationale du Québec in 2017. She lives in a small village south of Montreal.
Before becoming a novelist, Michael Robotham was an investigative journalist working across America, Australia and Britain. As a journalist and writer he has investigated notorious cases such as the serial killer couple Fred and Rosemary West. He has worked with clinical and forensic psychologists as they helped police investigate complex, psychologically driven crimes. Michael's 2004 debut thriller, The Suspect, sold more than 1 million copies around the world. It is the first of eight novels featuring clinical psychologist Joe O'Loughlin, who faces his own increasing battle with a potentially debilitating disease. Michael has also written four standalone thrillers. In 2015 he won the UK's prestigious Crime Writers' Association Gold Dagger Award with his standalone thriller Life or Death. He lives in Sydney.
Mitch Albom is an internationally bestselling author, screenwriter, playwright, and award-winning journalist. He is the author of six consecutive number one New York Times bestsellers and has sold over thirty-five million copies of his books in forty-five languages worldwide, including Tuesdays with Morrie, which is the bestselling memoir of all time.Albom also works as a columnist and broadcaster and has founded eight charities in Detroit and Haiti, where he operates an orphanage. He lives with his wife, Janine, in Michigan.
N. K. Jemisin is a Brooklyn author who won the Hugo Award for Best Novel for The Fifth Season, which was also a New York Times Notable Book of 2015. She previously won the Locus Award for her first novel, The Hundred Thousand Kingdoms, and her short fiction and novels have been nominated multiple times for Hugo, World Fantasy and Nebula awards, and shortlisted for the Crawford and the James Tiptree, Jr. Awards. She is a science fiction and fantasy reviewer for the New York Times, and you can find her online at nkjemisin.com.
Rabih Alameddine is the author of the novels An Unnecessary Woman; I, the Divine; Koolaids; The Hakawati; and the story collection, The Perv.
Sara Shepard is the author of two New York Times bestselling series, Pretty Little Liars and The Lying Game, as well as the series The Perfectionists. She graduated from New York University and has an MFA from Brooklyn College.
Stephen Jones is the winner of three World Fantasy Awards, four Horror Writers Association Bram Stoker Awards and three International Horror Guild Awards, as well as being a multiple recipient of the British Fantasy Award and a Hugo Award nominee. A former television producer/director and genre movie publicist and consultant, he has written and edited more than 130 books, including the Fearie Tales: Stories of the Grimm and Gruesome, A Book of Horrors, Curious Warnings: The Great Ghost Stories of M.R. James, Psycho-Mania! and The Mammoth Book of Best New Horror and Zombie Apocalypse! series.
Thomas R. Perrotta (born August 13, 1961) is an American novelist and screenwriter best known for his novels Election (1998) and Little Children (2004), both of which were made into critically acclaimed, Academy Award-nominated films. Perrotta co-wrote the screenplay for the 2006 film version of Little Children with Todd Field, for which he received an Academy Award nomination for Best Adapted Screenplay. He is also known for his novel The Leftovers (2011), which has been adapted into a TV series on HBO.


text:
Hi, i had a theme for winterspring on my iPhone 3gs, that changed my lockscreen background every time, when i locked my phone. Now i want to put it on my iphone 4, it almost works, the only problem is, that its "zooms" in to my lockscreen pictures, not showing the full pic, only just a part of it. Ill post a screenshot of that. I think i should change something in the code, to show the pics correctly, but im not a programmer, so could anyone help me with that? thank you!
my lockscreen now:
ImageShack® - Online Photo and Video Hosting
the picture should look like this:
ImageShack® - Online Photo and Video Hosting
here is the code, its in a lockbackground.html file:
and another file, its a configuration.js:Code:<?xml version="1.0" encoding="UTF-16"?><html><head> <script src="configuration.js"></script> <script type="text/javascript"> document.write('<style type="text/css">body{background: black url('+LOCK_WALLPATH+(((new Date()).getTime()%LOCK_WPNUM)+1)+'.'+LOCK_IMGTYPE+');}</style>'); </script> </head></html>
these are the files i have, nothing more.Code:var LOCK_WPNUM = 6; //The number of wallpapers in your Wallpapers folder. var LOCK_WALLPATH = "Lockscreen/"; //Wallpaper path, only if you want to change this. Leave it if you don't know what this'll do! If you want this to be the same as your wallpaper path, change to "Wallpapers/" var LOCK_IMGTYPE = "png"; //The filetype of all your images. Usually png, jpg or gif. All images must be the same filetype!


text:
This is our website. Would you prefer to shop on our website?
This is our website. You previously shopped on our website. Would you like to go to our website now?
Other country sites
My Account
My Bag
You are here:
Refresh your contemporary casuals collection with this logo crew sweatshirt by Boss Bodywear. Designed with long sleeves, a crew neckline and ribbed contrasting-tone trims. This casual piece boasts the brand's iconic logo to the chest with an all over subtle grained print effect.
Product code: 522075
Exchanges & Returns We will happily offer an exchange or refund within 14 days of delivery. For full details please read our returns policy
Using the standard service, your order should be with you within 3-5 days.
International delivery is available for this product. The cost and delivery time depend on the country.
We use cookies to give you the best customer experience possible. If you continue to use our website, we will assume you are happy to receive cookies from us and our partners.
More info


text:
Italian Peas
READY IN: 20mins
Recipe by Realtor by day
I use frozen peas for this one because they are always available but when the fresh peas are in season I use them. They make it even more delicious.
Top Review by Marie
In my opinion, this recipe could benefit by adding a few tablespoons of liquid. Taste was good, but the peas seemed rather dry to me. Thanks.
See Discussion:16 Reviews 1 Tweak
Ingredients Nutrition
- 1 tablespoon olive oil
- 1 tablespoon butter
- 1 small chopped onion
- 2 minced garlic cloves
- 1 lb frozen green pea
- salt and pepper
- parsley
- italian seasoning
- 1⁄4 cup grated romano cheese
Directions See How It's Made
- Heat oil and butter in skillet over medium heat. Stir in onions and garlic, cook about 5 minutes until starting to brown just slightly.
- Add peas, season with salt, pepper, a pinch of parsley and a pinch of Italian seasoning. Cover and cook until the peas are tender, about 10 to 15 minutes depending on how you like them done. I don't like mine mushy so I just cook them about 10 minutes.
- When you serve them, sprinkle the cheese over top.


text:
Upcoming Events › Workshop
Events List Navigation
Planning for Retirement – Thursday, September 14th
Whether you have a plan or are just starting, this complimentary workshop will help you understand how to create the retirement you desire. Shane and Susan use realistic life scenarios to illustrate the analysis and planning work they typically provide to their clients. We will present simple, smart strategies that you can take home. This is a great opportunity for people of all ages looking for actionable tips and suggestions, and come away motivated and inspired…Register for Event »


text:
I am feeling a little tipsy this morning.
I've gotta be quick so that I can unplug this computer and take a nap before the carpet people come.
The test went great. Here are the problems.
I have something called Esophagitis and an ulcer in my lower esophagas.
Although the doctor says that I will probably be on meds for the rest of my life..
Everything is treatable.
Wonderful awesome news!!!
Esophagitis is an inflammation of the lining of the esophagus, the tube that carries food from the throat to the stomach. If left untreated, this condition can become very uncomfortable, causing problems with swallowing, ulcers, and scarring of the esophagus. In rare instances, a condition known as "Barrett's esophagus" may develop, which is a risk factor for esophageal cancer.
What is an esophagus ulcer and how is it caused?
An esophagus ulcer is an ulcer located in the esophagus. The Esophagus is the tube that leads from the throat to the stomach. When the esophagus is inflamed, swollen and irritated, it is referred to as esophagitis (itis - meaning infection / inflammation) or GERD = Gastro Esophageal Reflux Disease. When partially digested food and liquids travel from the stomach back up into the esophagus, that food is mixed with stomach acids, which can irritate the esophageal lining and eventually can cause an esophagus ulcer. People will experience acid reflux and heartburn symptoms.
What a difference a day makes....
2 hours ago


text:
|Home | About | Journals | Submit | Contact Us | Français
Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100–200mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm3 voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d=3.4; p<0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohen's d=1.2; p=0.023). NAA levels increased significantly from baseline to week 6 (d=1.2; p=0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d=1.4; p=0.053), but was negatively associated in the POC (d=9.6; p<0.001). Riluzole seems to rapidly increase Gln/Glu ratios—suggesting increased glutamate–glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted.
Bipolar disorder (BD) is a serious mental illness. The manic phase of this disorder is often debilitating, but the depressive phase contributes at least comparable morbidity and mortality (Post, 2005). Although the neurobiology of BD remains incompletely understood, recent evidence has increasingly implicated abnormal glutamatergic neurotransmission (Kugaya and Sanacora, 2005; Öngür et al, 2008; Sanacora et al, 2003). Lacking refined in vivo assays to measure brain glutamate levels, few studies have accurately assessed glutamatergic activity in patients with BD.
Magnetic resonance spectroscopy (MRS) can measure brain glutamate levels in vivo, but signal/noise and spectral resolution problems have forced most studies to quantify glutamate together with glutamine as a composite measurement labeled 'Glx.' Increased Glx levels have been shown in the depressed (Bhagwagar et al, 2007; Frye et al, 2007), manic (Cecil et al, 2002; Michael et al, 2003), and euthymic (Dager et al, 2004) phases of BD, as well as in rapid-cycling BD (Michael et al, 2009). However, the physiological significance of Glx is unclear—underscoring the need for separate glutamate and glutamine measures.
Glutamate is continuously recycled between neurons and glia: neuronal glutamate is released into the synapse, taken up by glial cells, and converted to glutamine, which is then shuttled back to neurons and reconverted to glutamate (Rothman et al, 2003). Glutamate levels by themselves do not accurately reflect glutamatergic neurotransmitter activity, because cellular metabolism contributes to the synthesis of glutamate through the tricarboxylic acid (TCA) cycle. Furthermore, static measurements of glutamate and glutamine do not reflect the constant flux though the glutamate–glutamine cycle. An aggregate measure, the glutamine/glutamate (Gln/Glu) ratio, may function as a better (although imperfect) index of glutamatergic neurotransmission than either metabolite alone, because it is more sensitive to changes in the glutamate–glutamine cycle—a physiological process that is particularly amenable to this approach, given the reciprocal nature of glutamine and glutamate. As theorized by several other groups, increased Gln/Glu ratios reflect intensified flux through the glutamate–glutamine cycle and an overall increase in glutamatergic neurotransmitter activity (Igarashi et al, 2001; Iltis et al, 2009; Mlynarik et al, 2008; Öngür et al, 2008; Theberge et al, 2003, 2002). It has recently become possible to measure this ratio, using J-resolved proton MRS (1H-MRS), a sequence that acquires spectra at multiple echo times (TEs), allowing improved metabolite quantification (Jensen et al, 2009). Thus, 1H-MRS can measure glutamate and glutamine levels separately, allowing calculation of Gln/Glu ratios. A recent study using 1H-MRS has shown increased Gln/Glu ratios in acutely manic patients, suggesting glutamatergic overactivity in mania (Öngür et al, 2008).
To further investigate glutamatergic activity in BD, one can use 1H-MRS to assess longitudinal changes in glutamatergic activity after administration of a glutamate-modulating drug probe. This design is especially suited for the depressed phase of the illness, because several antidepressant agents have effects on glutamatergic neurotransmission (Sanacora et al, 2008). Using one of these agents as a drug probe, one could simultaneously analyze changes in both glutamatergic activity and mood symptoms after drug administration. A good candidate for this purpose is riluzole, an FDA-approved medication for the treatment of amyotrophic lateral sclerosis (ALS), which has been shown to potently and rapidly inhibit presynaptic release of glutamate in both in vitro and in vivo studies (Cheramy et al, 1992; Doble, 1996). Riluzole has shown antidepressant effects in preliminary open-label studies of unipolar (Sanacora et al, 2007; Zarate et al, 2004) and bipolar depression (Zarate et al, 2005), and thus represents a promising glutamate modulator/antidepressant probe.
We administered riluzole for 6 weeks to 14 bipolar-depressed patients and used J-resolved 1H-MRS to calculate Gln/Glu ratios at baseline, day 2, and at week 6 of treatment. We obtained 1H-MRS data from the anterior cingulate cortex (ACC), a known locus of pathology in BD (Phillips et al, 2003), and from the parieto-occipital cortex (POC), a locus implicated only in unipolar depression (Sanacora et al, 2004), to assess for regional specificity in the biological effects of riluzole. We also analyzed the association between improvement on the 21-item Hamilton Depression Rating Scale (HAM-D) and change in Gln/Glu ratios at day 2 and week 6. We hypothesized that riluzole would improve depression, and that this improvement would be associated with a reduced Gln/Glu ratio in the ACC at day 2 and week 6. On the basis of previous studies showing an increase in N-acetylaspartate (NAA), a marker of neuronal integrity, after riluzole treatment (Kalra et al, 1998; Mathew et al, 2008), we also hypothesized that riluzole would increase NAA levels in the ACC at week 6, but not at day 2, given the slow turnover rate of NAA (Choi and Gruetter, 2004).
Through advertisements, we recruited participants aged 18–65 years, meeting the DSM-IV criteria for BD (type I or II), currently depressed, scoring 18 on the HAM-D at screening and baseline. Exclusion criteria were as follows: history of schizophrenia or obsessive-compulsive disorder, active psychosis, suicidal risk, alcohol or substance dependence (other than nicotine) within 3 months of enrollment, electroconvulsive therapy within 3 months of enrollment, positive urine drug screen for substances of abuse, previous riluzole treatment, current pregnancy or lactation, history of seizure disorder or organic brain disease, clinically significant medical disease, or MRI contraindication.
During the study, we excluded clozapine, lamotrigine, lithium, carbamazepine, opiates, psychostimulants, atomoxetine, tricyclic antidepressants, and fluvoxamine on the basis of (1) substantial evidence of glutamatergic activity (lamotrigine), (2) previous 1H-MRS evidence of effects on brain glutamate levels (lithium, opiates, psychostimulants, and atomoxetine), (3) potential effect on riluzole levels (tricyclic antidepressants and fluvoxamine), or (4) risk of neutropenia (clozapine and carbamazepine). Participants taking an excluded medication could enroll after a medication washout of at least five half-lives supervised by the treating psychiatrist or by the study investigator. Participants taking stable doses of nonexcluded medications for 4 weeks before enrollment were included, provided they required no significant dose changes during the study. No new psychiatric medications were permitted during the study.
Participants received a screening evaluation, at the time of which they signed informed consent as approved by the McLean Hospital Institutional Review Board. We then obtained demographic information, medical/psychiatric history, the Structured Clinical Interview for DSM-IV, physical examination, vital signs, electrocardiogram, and clinical laboratory tests. Thereafter, we administered our primary clinical outcome measure, the HAM-D, and three secondary clinical outcome measures, namely the Montgomery–Asberg Depression Rating scale (MADRS), Clinical Global Impression Scale for Severity (CGI-S), and the Young Mania Rating Scale (YMRS).
Eligible participants returned in ~1 week for a baseline visit to assess adverse events, concomitant medications, vital signs, HAM-D, MADRS, CGI-S, and YMRS. In addition, participants underwent a 1H-MRS scan and started a 6-week open-label course of riluzole, 50mg twice daily (bid) for 14 days, increasing if tolerated to 50mg in the morning and to 100mg at bedtime at week 3, and to 100mg bid at week 4. Participants who were unable to tolerate higher doses could reduce the drug intake to a minimum dose of 50mg bid. We used riluzole doses over the FDA-approved dose of 100mg daily on the basis of the mean doses used in previous unipolar (Zarate et al, 2004) and bipolar depression (Zarate et al, 2005) studies.
Participants initiated riluzole on the morning of the day after baseline (day 1). They returned on day 2, after their morning dose, for a second 1H-MRS scan, and were assessed for adverse events, concomitant medications, and vital signs, but received no clinical measures. Participants were then seen weekly at weeks 1 through 6. At each visit, we administered the same outcome measures as at baseline, plus the CGI-I (Clinical Global Impression Scale-Improvement). We conducted liver function tests and a complete blood count every 2 weeks, more frequently than the recommended 4 weeks, to closely monitor participants for hepatotoxicity or neutropenia. At week 6, participants received the third 1H-MRS scan, and began tapering riluzole by 50mg per week, with discontinuation after 1 week at 50mg bid.
Subjects underwent standard T1-weighted structural MRI in a Siemens 3-T Trio scanner (Erlangen, Germany). Those with structural abnormalities as determined by an official radiology report were excluded.
We have previously described the details of MRS acquisition and data analysis (Jensen et al, 2009; Öngür et al, 2008). Briefly, 1H-MRS acquisitions were conducted on a 4-T scanner (Varian/UnityInova, Varian, Palo Alto, CA, USA), using a volumetric-birdcage coil (Robarts Research Institute, London, Canada). After acquisition of scout images, manual global shimming of unsuppressed water signal and T1-weighted imaging, a 2 × 2 × 2cm voxel was placed on the ACC midsagittally, anterior to the genu of the corpus callosum (Figure 1). After manual shimming, a point-resolved spectroscopy sequence modified for J-resolved 1H-MRS was used. The two-dimensional (2D) J-resolved sequence collected 48 TE-stepped spectra from the voxel, with the TE ranging from 30 to 500ms in 10-ms increments (TR=2.0s, acquisition bandwidth=2kHz, repetitions=16; nominal voxel volume=8cm3; approximate scan duration=28min). This was repeated on a midsagittal 2 × 2 × 2cm POC voxel (Figure 1). The total time in magnet was 75–90min. The water resonance full-widths at half-maximum were 9.9±1.4 and 9.3±0.8Hz for scan 1, 10.1±1.3 and 8.9±0.7Hz for scan 2, and 9.9±1.0 and 9.1±0.7Hz for scan 3 (in the ACC and POC, respectively; no between-scan differences).
For each voxel, the 48 free-induction decays (FIDs) were Gaussian filtered, zero padded, and Fourier transformed in f1 to produce 128 J-resolved spectral FIDs over the 100-Hz bandwidth. We used the spectral-fitting package, LCModel (version 6.0–1) (Provencher, 1993) and a serial, one-dimensional (1D) spectral-fitting technique, developed in this laboratory, for the quantification of the central 50Hz region (−25 to +25Hz; 64 spectral FIDs) of the 100Hz J-resolved spectral data series (Figure 2). Briefly, our serial, 1D J-resolved spectral quantification procedure involves breaking down the J-resolved data set into separate, 1D spectral extractions. Each separate extraction is then fitted by the LCModel using a GAMMA-simulated template, in which the spectral basis set for each J-resolved extraction has been theoretically modeled. Once all of the 64 J-resolved spectral extractions are fitted, the raw, metabolite integrals for each extraction over the central 50-Hz region in f1 are summed up to produce a final metabolite integral. Our serial 1D quantification approach improves spectral quantification by using all available signals rather than by fitting select single J-resolved extractions (Jensen et al, 2009; Schulte and Boesiger, 2006a; Schulte et al, 2006b), and has been shown to greatly improve the accuracy and precision of separate measurements of the coupled and highly overlapped resonances of glutamate and glutamine. Details of our fitting procedure, including GAMMA generation of theoretical spectra for use as basis sets and fitting of individual spectral extractions, were previously reported (Öngür et al, 2008).
LCModel provides Cramer–Rao lower bounds (CRLBs), an estimate of the variance associated with fitting. Each voxel yielded 64 CRLBs for each metabolite, ranging from <5% in regions of high certainty (close to J=0Hz), to >50% in regions of low certainty. To accurately reflect the reliability of the 2D-fitting procedure, we report an average CRLB value weighted by the signal-to-noise ratio (SNR) of each spectral extraction (Table 1) on the basis of the NAA resonance. Owing to the T2-weighted signal decay with increasing TE, the signal weighting in the J-resolved spectral series is very biased, with the highest SNR being in the central (J=0.0Hz) region and decreasing rapidly toward the outer, higher-frequency regions in f1. As the metabolite amplitudes from the central J-resolved spectral extractions with high SNR contribute more to the summed metabolite integral, we deemed it appropriate to weigh the CRLB values for each metabolite from each spectral extraction by this weighting function derived from NAA. The use of standard quadratic error propagation calculations to derive our final CRLB would be invalid as the noise in our J-resolved spectral series is highly correlated because of the Fourier transform, resulting in an underestimation of the true error. Conversely, linear addition of the CRLB values across f1 would unfairly bias our final error estimate by the high CRLB values from the low SNR, higher-frequency spectral extractions, resulting in overinflated error estimates. We found that our weighted average calculation best represents the test–retest metabolite variance observed in repeated measures using this J-resolved technique (Jensen et al, 2009), and is thus the best compromise to providing realistic CRLB error estimates for our summed metabolite values. There were no between-scan CRLB differences. As the mean group CRLBs were very good, we did not exclude data points on the basis of high CRLBs in this study. Therefore, we report higher CRLBs in some cases (eg, for creatine and choline in the POC in scan 3) as compared with the remaining data set. We report data from six metabolites reliably and consistently quantified in a previous test–retest study (Öngür et al, 2008). Our primary imaging measure, Gln/Glu is reported as a ratio. Other metabolite levels are reported in arbitrary units (AU) to avoid introduction of bias through systematic drifts in the magnitude of the creatine resonance.
Tissue segmentation of T1-weighted images into GM, WM, and cerebrospinal fluid (CSF) was performed using FMRIB's Automated Segmentation Tool (Oxford, UK). The percentage of GM in the ACC and POC was 61±6% and 58±4%, 59±9% and 57±3%, and 62±8% and 60±5% for scans 1, 2, and 3, respectively, whereas that of WM was 18±4% and 30±3%, 19±5% and 31±3%, and 18±3% and 28±3% for scans 1, 2, and 3, respectively. There were no between-scan differences in these values.
For the primary analysis of the change in MRS measures and clinical measures over time, and the association of change in MRS measures with change in HAM-D, we used random regression models, which we refer to as our 'longitudinal analysis.' These models allow inclusion of all observed data and account for the correlation of observations from the same individual (Diggle et al, 1994; Fitzmaurice et al, 2004; Gibbons et al, 1993). For these models, we used generalized estimating equations (GEEs) to adjust SEs for the correlation of observations within individuals.
For change in clinical measures over time, the model included the clinical measure as the outcome and time (modeled as a continuous variable). The coefficient for the time term in this model quantifies the rate of clinical improvement, which we expressed as the estimated change in the measure at week 6.
For change in MRS measures over time, our model included the MRS measure as the outcome, time (baseline, day 2, and week 6, modeled as unordered categories), and region (ACC or POC). We first tested for a time-by-region interaction, and if there was no significant interaction (p<0.10), we tested for main effects of time. If there was a significant main effect of time (p<0.05), we performed two-way comparisons for each time point against the other two.
For the association between change in MRS measures and change in HAM-D, our model included the clinical measure as the outcome, change from baseline to day 2 or week 6 in the MRS measure, time, and change-by-time interaction. The coefficient for the interaction term in this model quantifies the rate of change in HAM-D associated with change in the MRS measure. An interaction coefficient significantly different from zero indicates that change in the MRS measure is associated with change in HAM-D.
As secondary analyses for the change in clinical measures and for the association of change in MRS measures with change in HAM-D, we used change from baseline to week 6 (as measured by week 6 value minus baseline value, with missing values for week 6 imputed by last observation carried forward) as the measure of change in clinical measures; we refer to these models as our 'end point analysis.' To assess the change in clinical measures, we used a one-sample t-test to evaluate the null hypothesis that the value of the difference between baseline and week 6 values was equal to zero. To assess the association of change in MRS measures with change in HAM-D, we used random regression models, with GEE to account for the correlation of MRS measures from both the ACC and POC within individuals.
All analyses were performed using Stata 9.2 software. As CSF contains negligible amounts of any metabolites, and as there was variation in the amount of CSF in each voxel, we adjusted for CSF content by dividing the metabolite level by the proportion of non-CSF content, so that the levels were normalized to where they would be if there were no CSF content, based on the average metabolite level observed for a non-CSF tissue (it must be noted that no adjustment is necessary for the Gln/Glu ratio, which remains the same regardless of the proportion of CSF content). It is noteworthy that results without correction for CSF content were virtually identical to those with correction. We used Cohen's d (Cohen, 1977) as a measure of effect size. α was set at 0.05, two-tailed. It must be noted that our results are presented without correction for multiple comparisons, given that the large number of correlated outcome measures makes proper adjustment for multiple comparisons difficult. Accordingly, the reader should bear in mind that some results, especially those of marginal significance (0.01<p<0.05), may represent chance associations.
A total of 31 participants signed informed consent documents for the study from 6 September 2007 to 17 December 2008. Of these, 16 were withdrawn from the study before receiving treatment (medical or laboratory contraindication (N=5), did not meet full criteria for BD, currently depressed (N=3), unable to tolerate MRI scan (N=2), participant decision (N=2), active substance dependence (N=1), active psychosis (N=1), positive urine drug screen (N=1), active self-injurious impulses (N=1)). One additional participant was withdrawn during the study after discovery of a structural brain abnormality on MRI. This participant's data were not included in the final analysis. Baseline clinical features are presented in Table 2.
Of the 14 evaluable participants, 11 completed 6 weeks of treatment and 3 withdrew; 1 of these had no post-baseline clinical evaluations. Of the 13 participants with at least one post-baseline clinical visit, 11 were titrated to 150mg of riluzole daily, and 9 of the 11 participants continuing in the study after 3 weeks reached 200mg daily. Three of these participants subsequently returned to 150mg daily because of adverse events at 200mg. The mean (SD) dose at end point was 181.8 (25.2)mg daily.
Nine participants were taking concomitant psychotropic medications as follows: (1) venlafaxine, lorazepam, and zolpidem, (2) quetiapine and ziprasidone, (3) bupropion, trazodone, and diazepam, (4) lorazepam, (5) ziprasidone, venlafaxine, and clonazepam, (6) fluoxetine, clonazepam, and zolpidem, (7) quetiapine, citalopram, duloxetine, and trazodone, (8) escitalopram and trazodone, and (9) omega-3 fatty acids. Two of these participants entered the study after the washout of excluded medications, such as (1) lamotrigine, amphetamine/dextroamphetamine, and acetaminophen/oxycodone and (2) amitriptyline. Five participants were taking no psychotropic medications during the study. One of these five participants electively discontinued citalopram 2 weeks before study entry.
Adverse events reported by more than one participant included nausea (N=6), headache (N=4), diarrhea (N=4), insomnia (N=4), constipation (N=3), sedation (N=3), neck pain (N=3), dyspnea (N=2), dizziness (N=2), dry mouth (N=2), and back pain (N=2). No participant experienced a serious adverse event. There were no changes in vital signs or clinical laboratory values suggestive of drug-related toxicity.
In both the random regression and end point analyses, we found a highly significant decrease, with very large effect sizes (Cohen's d>2.0), in HAM-D, MADRS, and CGI-S scores (Figure 3; Table 3); YMRS scores decreased significantly in the end point analysis, but not in the random regression analysis (Table 3).
The mean metabolite levels for each time point and region are presented in Table 4. As shown in Figure 4, the mean Gln/Glu ratio increased markedly from baseline to day 2. Although the pattern of changes was more pronounced in the ACC than in the POC (Figure 4), there was no significant brain region-by-time interaction (p=0.19). The mean Gln/Glu ratio showed a significant main effect of time (p=0.049). The difference between day 2 and baseline was a large and statistically significant effect (estimated mean difference day 2 minus baseline (95% confidence interval) 0.10 (0.01, 0.18); d=1.2; p=0.023), but the differences between week 6 and baseline and between week 6 and day 2 were not significant (mean difference week 6 minus baseline 0.05 (−0.06, 0.16), p=0.35; and mean difference week 6 minus week 2−0.04 (−0.12, 0.03), p=0.25, respectively). There were no significant differences between time points across the study in the total pool of glutamate plus glutamine (p=0.68 for main effect of time), glutamate (p=0.25), or glutamine (p=0.44).
NAA showed little change from baseline to day 2, but increased from baseline to week 6 (Figure 5). The mean NAA level showed a significant effect of time (p=0.001). There was no significant brain region-by-time interaction (p=0.48), but the pattern of findings was more pronounced in the ACC (Figure 5). The difference between week 6 and baseline was a large effect (d=1.2) that was statistically significant (mean difference week 6 minus baseline 1.9 (0.01, 3.6)AU; p=0.035), as was the difference between week 6 and day 2 (mean difference week 6 minus day 2 2.4 (1.1, 3.8)AU; d=1.9; p<0.001), but the difference between day 2 and baseline was not significant (mean difference day 2 minus baseline −0.5 (−2.4, 1.3)AU; p=0.57).
We found no significant association between clinical response (as measured by change from baseline to week 6 in HAM-D) and change from baseline to week 2 or from baseline to week 6 in the Gln/Glu ratio with clinical response, using either longitudinal or end point analyses (Table 5).
The association between change in NAA and baseline to week 6 change in HAM-D showed a significant brain region-by-NAA interaction from baseline to day 2 (p=0.010) and from baseline to week 6 (p<0.001) for the longitudinal analysis. Therefore, we analyzed associations separately by region (Table 5). For change in NAA from baseline to day 2, we found no significant association with change in HAM-D in the ACC, but a very strong negative association (d=9.6) with clinical improvement in the POC. For change in NAA from baseline to week 6, we found a strong positive association with clinical improvement (d=1.4) in the ACC, approaching statistical significance (Figure 6), and again a strong negative association (d=2.3) in the POC (Figure 7).
We also carried out an a posteriori analysis of the association between the change in NAA at week 6 and the change in the Gln/Glu ratio at day 2, using random linear regression, with the former measure as outcome and the latter as predictor. We found a significant brain region-by-change in Gln/Glu ratio interaction (p=0.006), and consequently used linear regression to assess the association within each region. In the ACC, we found a strong (d=1.6) association approaching statistical significance (coefficient −22.4 (−53.0, 4.2); p=0.082), but no significant association in the POC (coefficient −2.1 (−6.6, 2.3); p=0.30).
Finally, to further explore the stability of our findings, we conducted additional statistical analyses (1) restricted to study completers (N=11), (2) comparing those who were taking concomitant psychotropic medications (N=9) with those who were not (N=5), and (3) comparing those with treatment resistance (defined as two or more failed medication trials during the current episode (N=8)) with those who had failed only one medication trial or those who were medication naive (N=6). These exercises produced generally similar estimates of the magnitude of effects to those of the analyses reported above.
In 14 bipolar-depressed participants, riluzole produced (1) a rapid and pronounced increase in the Gln/Glu ratio by day 2, followed by a decline by week 6, (2) an increase in NAA levels at week 6, and (3) a significant reduction in depression symptoms, which was positively associated with increase in NAA from baseline to week 6 in the ACC, but negatively associated in the POC.
The marked increase in the Gln/Glu ratio at day 2 of riluzole treatment was unexpected, given previous in vitro findings that riluzole decreases presynaptic glutamate release (Doble et al, 1992; Martin et al, 1993; Prakriya and Mennerick, 2000; Wang et al, 2004). However, animal studies provide some support for our finding. For example, studies in rats treated chronically with riluzole have shown increased glutamate–glutamine cycling, hypothesized to result primarily from increased oxidative metabolism through the TCA cycle both in neurons (Chowdhury et al, 2008) and in glia (Banasr et al, 2008; Valentine and Sanacora, 2009). Interestingly, this result is consistent with other studies (Kalra et al, 2006; Mu et al, 2000), suggesting that riluzole may have mitochondrial-enhancing properties, in addition to its previously suggested glutamate-modulating effects.
Strikingly, riluzole significantly increased Gln/Glu ratios by day 2, before antidepressant response, but this change seemed to have largely dissipated by week 6, when the clinical response had emerged (although it should be noted that the decline from day 2 to week 6 did not reach statistical significance). Possibly, the early impact of riluzole on glutamate–glutamine cycling increased the Gln/Glu ratio, which then returned to baseline levels by week 6 after a new steady-state level was reached. Interestingly, the total pool (glutamate plus glutamine) was stable over the course of the study; the day 2 increase in the Gln/Glu ratio reflected a simultaneous increase in glutamine and decrease in glutamate, with both metabolites returning to their approximate baseline levels, along with the Gln/Glu ratio, at week 6. This reciprocal relationship between glutamate and glutamine seems to be consistent with a shift in the glutamate–glutamine cycle after riluzole treatment. Collectively, the above-mentioned findings suggest that riluzole acutely upregulates glutamate–glutamine cycling in vivo. It is also intriguing that this pattern was more pronounced in the ACC (which is implicated in processing emotional stimuli) than in the POC, although this pattern did not reach statistical significance.
Our finding of increased NAA after 6 weeks of riluzole treatment is consistent with a previous finding of increased hippocampal NAA in patients with generalized anxiety disorder who showed a clinical response after 8 weeks of riluzole treatment (Mathew et al, 2008)—although one cannot be certain that the mechanisms of NAA increase were similar in both cases. Although not completely understood, reduced NAA levels are widely interpreted to indicate reduced neuronal health, either through neuronal/axonal loss or through compromised neuronal metabolism (Moffett et al, 2007). In contrast to our finding of no acute change in NAA after treatment, a previous study in patients with ALS has shown an increase in NAA after only 1 day of riluzole treatment (Kalra et al, 2006), which the authors theorized was a result of rapid metabolic enhancement. However, there are several potential reasons for the discrepancy between the two studies, most notably differences in the disorders (ALS vs BD) and regions of interest (ACC and POC vs motor cortex) studied. Importantly, previous studies have indicated that the turnover rate of NAA is in the range of 2–3 days (Choi and Gruetter, 2004; Moffett et al, 2007), suggesting that day 2 of treatment may be too early to observe significant increases in NAA resulting from rapid enhancement of mitochondrial function. Therefore, although not reflected in NAA measurements at day 2, it is plausible that riluzole treatment acutely results in metabolic enhancement and increased glutamate–glutamine cycling which chronically leads to neural plasticity and symptom improvement, as suggested by others (Mathew et al, 2008). The significant association between increase in the ACC Gln/Glu ratio from baseline to day 2 and increase in NAA at week 6 seems to support this hypothesis. Clearly, further studies examining the impact of riluzole treatment on mitochondrial functioning are required to explain these findings more thoroughly.
However, there are alternative interpretations of a larger NAA resonance. For example, prolongation in NAA transverse (T2) relaxation time could lead to larger NAA resonance without changes in metabolite levels. T2 relaxation times reflect the molecular microenvironment and can be modulated by cell size, cell membrane turnover, and brain blood volume. Notably, abnormalities in T2 relaxation time have been identified in bipolar patients (Öngür et al, 2009b), and brain water T2 relaxation time changes have been reported in patients with BD after treatment with omega-3 fatty acids (Hirashima et al, 2004). Therefore, further work is required to determine whether riluzole treatment induces changes in T2 relaxation times.
The positive association between clinical response and increase in NAA in the ACC at week 6 suggests that improvement in depression is associated with enhanced neuronal integrity and function in the ACC. This finding is consistent with the results of the study by Mathew et al (2008), and provides additional evidence that NAA might represent a surrogate end point for clinical trials of plasticity-enhancing agents, such as riluzole, in psychiatric illnesses. Given the significant association between increase in the ACC Gln/Glu ratio from baseline to day 2 and increase in NAA at week 6, one might also expect that the former measure would predict later clinical response. However, this was not borne out in our statistical analysis—possibly as a result of small sample size or incomplete imaging data sets as a result of subject attrition and technically unevaluable imaging data. Thus, we might have failed to detect medium or even large effects (as reflected by our estimates of effect sizes from 0.36 to 0.68 in our two analyses)—warranting further exploration of the predictive value of the Gln/Glu ratio in larger similar studies.
Surprisingly, clinical response was negatively associated with NAA in the POC. It is possible that the POC may harbor biological abnormalities distinct from the ACC and perhaps from other brain regions, resulting in different effects on glutamatergic activity after riluzole treatment. However, it will be necessary to collect additional data with a larger sample to replicate these findings, and if replicated, to more fully characterize these differences.
Overall, our findings augment the growing evidence that glutamatergic abnormalities contribute to the neurobiology of BD. Lacking a comparison group with BD, we cannot confirm decreased Gln/Glu ratios at baseline—but our findings suggest that riluzole may reset a pathologically depressed level of synaptic glutamatergic activity, possibly through the rapid enhancement of glutamate–glutamine cycling. Interestingly, this increase seems temporary, with return to baseline by 6 weeks (although this decline from day 2 to week 6 did not reach statistical significance as mentioned previously), perhaps after a new steady-state glutamate–glutamine cycling rate has been achieved or through autoregulatory processes that intervene after a new synaptic strength 'set point' is established.
Possibly early riluzole-induced increases in glutamate–glutamine cycling amplify postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor levels, leading to increased AMPA/N-methyl-D-aspartate (NMDA) receptor stimulation, previously hypothesized as a convergent mechanism for antidepressant action (Schloesser et al, 2008; Zarate et al, 2006a). Increased AMPA receptor 'throughput' may ultimately cause downstream neuroproliferative effects through the induction of brain-derived neurotrophic factor and multiple intracellular signaling cascades (Lauterborn et al, 2000; Lauterborn et al, 2009; Mackowiak et al, 2002; Voss et al, 2007; Wu et al, 2004; Zhang et al, 2009). These speculations accord with previous evidence (Schloesser et al, 2008). For example, riluzole enhances the surface expression of GluR1 and GluR2 AMPA receptor subtypes in cultured hippocampal neurons after only 3 days of treatment (Du et al, 2007). Similarly, the potent NMDA receptor antagonist ketamine elicits a similar increase in AMPA/NMDA neurotransmission associated with a rapid and prolonged antidepressant effect in animal studies (Maeng et al, 2008). Moreover, ketamine infusion increases ACC glutamine levels in healthy individuals, possibly reflecting enhanced glutamatergic neurotransmission (Rowland et al, 2005). However, although there are potential parallels between the antidepressant mechanisms of riluzole and ketamine, there are likely differences in the time to onset of these effects. Ketamine is reported to cause clear antidepressant effects within 2h of administration (Zarate et al, 2006b). We did not measure mood symptoms at day 2 of this study, and were therefore unable to assess for potential rapid antidepressant effects after riluzole treatment. However, previous studies have shown a longer time to onset of antidepressant effects with riluzole ranging from 1 to 5 weeks of treatment (Sanacora et al, 2007; Zarate et al, 2004, 2005). Notably, lamotrigine, which typically takes several weeks to achieve antidepressant effects, shows similar effects on AMPA receptor expression in vitro as riluzole and ketamine (Du et al, 2007). Therefore, although increased AMPA/NMDA neurotransmission may be a common mechanism of antidepressant action shared by all three of these medications, ketamine's rapidity of action may be derived from a unique pharmacological characteristic, such as potency of effect.
Although the primary mechanism of action of riluzole is believed to be presynaptic inhibition of glutamate release, it may also increase glutamate reuptake through the enhancement of glial excitatory amino-acid transporter functioning (Fumagalli et al, 2008; Valentine and Sanacora, 2009). Thus, riluzole may rapidly enhance glutamate–glutamine cycling, while increasing clearance of glutamate from the synapse. These complementary effects increase synaptic glutamatergic activity while moderating the intensity of NMDA receptor stimulation and limiting overflow of glutamate into the extrasynaptic space where it can stimulate extrasynaptic NMDA receptors—both hypothesized mechanisms of excitotoxicity (Hardingham, 2006).
Several methodological limitations to this study should be considered. First, the small sample size limits statistical power. Second, our open-label design leaves open the possibility of a placebo effect, making it difficult to distinguish biological effects of riluzole from nonspecific effects of clinical improvement. Third, although we excluded patients using medications that have strong evidence of glutamate-modulating properties such as lamotrigine and lithium, we included several patients using atypical antipsychotics, benzodiazepines, and selective serotonin reuptake inhibitors. Although these latter agents have not been shown to strongly impact glutamatergic neurotransmission, such effects cannot be excluded. Given the ethical and logistical problems posed by recruiting unmedicated bipolar-depressed patients and the exploratory nature of this study, we believed that our approach limited the potential contribution of concomitant medications while still allowing the enrollment of a larger population of bipolar-depressed patients. Clearly, future studies should ultimately attempt to obtain either unmedicated patients or a sample large enough to examine the impact of concomitant medications. Fourth, we did not assess the menstrual cycle status in female participants, although this factor has been shown to impact glutamatergic activity (Batra et al, 2008). Fifth, we report metabolite levels in AU. We avoided internal referencing to creatine because of recent reports suggesting creatine abnormalities in BD (Frye et al, 2007; Öngür et al, 2009a) and internal referencing to water was not possible, lacking usable water unsuppressed spectra in this study. Our approach does not correct for inter-subject sources of variance, but the longitudinal within-subject design of our study and statistical analysis mitigates the problems of variability inherent to many cross-sectional MRS studies. Sixth, the J-resolved 1H-MRS technique used in this study allows reliable quantification of multiple important metabolites, but not that of γ-aminobutyric acid (GABA), the inhibitory counterpart to the excitatory glutamate system. As glutamate and glutamine are intimately involved in GABAergic neurotransmission, measures of glutamate and glutamine are not necessarily only related to glutamatergic neurotransmission. Therefore, GABA levels would be desirable to more fully characterize riluzole's mechanism of action. Finally, it is worth noting that J-resolved 1H-MRS is not unique in its ability to resolve glutamate and glutamine, and others have used conventional (1D) MRS to quantify these metabolites at high magnetic field (Oz et al, 2006; Theberge et al, 2002). As a result, the advantages of J-resolved 1H-MRS (its ability to collect additional data on difficult-to-quantify metabolites (Schulte et al, 2006b) and metabolite T2 relaxation times) and its disadvantages (longer scan times and potential drift in data quality during the scan) must be weighed when designing future studies.
In bipolar-depressed patients, riluzole increased Gln/Glu ratios at day 2, and by week 6 reduced depressive symptoms and increased NAA—perhaps reflecting enhanced neuronal plasticity. Further studies using J-resolved 1H-MRS should pursue the possibility that Gln/Glu ratios represent an early biomarker of response to therapies that enhance neuronal plasticity.
This study was supported by a grant from Jim and Pat Poitras (DÖ and BPB) and by Grants 1K23MH079982–02 (DÖ) and R01MH058618 (PFR) from the National Institute of Mental Health. BPB was supported by the Clinical Investigator Training Program (CITP) through the Beth Israel Deaconess Medical Center—Harvard/MIT Division of Health Sciences and Technology in collaboration with Pfizer Inc. and Merck and Co. and by the Sidney R Baer, Jr, Foundation through a NARSAD Young Investigator Award. We would like to acknowledge Sanofi-aventis for providing riluzole tablets for this study (Note: Sanofi-aventis provided no additional financial support for this study and had no input into the design or analysis of this study).
BPB has received research grant support from Eli Lilly. JIH has received research grant support from Eli Lilly, Ortho-McNeil Janssen Scientific Affairs, and Forest Laboratories, and has been a consultant for Eli Lilly and Pfizer. HGP has received research grant support from Solvay Pharmaceuticals. PFR has received research grant support from GlaxoSmithKline and Roche, and has been a consultant to Novartis, Roche, and Kyowa Hakko. None of the other authors reported any biomedical financial interests or potential conflicts of interest.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
Apple Products Apps Automotive Babies & Kids Bags & Luggage Beauty & Personal Care Blu-ray, DVD, MP3 Books & Magazines Cameras Cell Phones & Tablets Clothing & Accessories Computer Components Computers Electronics (other) Food & Restaurants
Up to 60% Off Select Camping Gear
Walmart offers Up to 60% Off Select Camping Gear. Free store pickup or free shipping on orders over $50.
Product Links:
Category: Sports & Outdoors
Posted on 25 August 2016, 08:00 AM


text:
Welcome to the brand new Freedom Debt Relief Blog: Our 2 Cents!
We've gotten to know many of our wonderful clients throughout the years, most of whom were in serious financial trouble when we first met. During the journey, we've helped them address financial issues, come up with solutions, resolve debts, and get on track to a better financial future. It is one of our greatest joys knowing that we can help ...Continue Reading →


text:
Cold Climate Convenience Package (Heated Front & Rear Seats, Heated Steering Wheel, Heated Windshield, and Heated Windshield Washer Jets) and HD Radio & SiriusXM Satellite Radio. Confused about which vehicle to buy? Well look no further than this outstanding-looking 2017 Land Rover Range Rover Evoque. Sorry Daytime soap fans. No sordid history on this one-owner gem. Land Rover Certified Pre-Owned means you not only get the reassurance of up to a 6yr/100,000 mile limited warranty, but also a 165-point inspection/reconditioning, 24/7 roadside assistance, Land Rover Concierge, and a vehicle history report. Call and schedule your test drive today family owned and operated for over 50 years. Please call and ask for Wayne
Price may exclude tax, title, tags, governmental fees, any emissions testing charges and any finance charges (if applicable). Unless otherwise stated separately in the vehicle details, price does not include documentation, processing, administrative, closing or similar fees. Current mileage may vary due to test drives and vehicle relocation.


text: Darby Home Co Adana 2 Door Cabinet & Reviews | Wayfair Watch a short video to see how you can easily create price drop alerts for wayfair.com and other retailers with just one click! It's free and easy. Monitoring Price ... Retailer: wayfair.comRecorded Price:$310.99Status: monitoring price View Product Page Search Slide-Co 244691 Cabinet Door Elbow Catch, Satin Nickel...$5.29 Create Price AlertSimpleHouseware Over the Cabinet Door Organizer Holder,...$13.97 Create Price AlertSandusky Lee HF2F301842-08 System Series Counter Height...$124.94 Create Price AlertEagle M04CRA Bench Top Poly Cabinet, 1 Door, 4 gal, Blue$224.00 Create Price AlertSafety 1st Magnetic Cabinet Locks, 8 Locks + 1 Key$20.20 Create Price AlertBuilding Cabinet Doors and Drawers: How to Design,...??? View Low PriceBettli silicon rubber Kitchen Cabinet Door Pad Bumper Stop...$9.99 Create Price Alert41 Shot Glass Display Case Holder Cabinet Wall Rack with...$87.95 Create Price AlertSlide-Co 244692 Cabinet Door Elbow Catch, Classic Bronze...$7.49 Create Price Alert2pcs Diamond Crystal Cabinet Wardrobe Drawer Door Knob Pull...$3.45 Create Price Alert


text:
Welcome to our classroom website!
Mrs. Marszalec and Ms. Finnegan would like to welcome you to an exciting year in fourth grade!
It is our goal to provide a safe and nurturing environment in which students and parents alike are active participants in learning. We are all different and unique individuals with different and unique learning styles. We will do our best to work with every student, so that we might help each and every one of them develop a love of learning.