text:
Monthly Report for October '09
Expand Messages
- After mulling over several different ways to measure the success
(or lack thereof) of the list, I now think that a simple metric may be
best. An average rate of 1.5 messages per day would yield 45 per
month (simplifying each month to 30 days), which seems neither
too much for the reader to handle, nor too little for conversation to
dry up (as it has, unfortunately, the last 10 days or so). Such an
average rate would yield 540 messages per year, which would be
above the totals for three of the last six years (2003-08), and close
to a fourth, so it seems like a goal which is achievable, but not
so easily that it would come without effort.
So how are we doing so far? October was below par, with 34
messages (partially my own fault, but my absence was largely
unavoidable). For the year, we now have 441 messages over
10 months, less than the goal of 450, but within striking range.
I hope, then, for a November posting of 54 messages, which
would bring us up to par.
On the matter of my (Thomas) website, it remains at Geocities awaiting
the availability of my new domain-name, which is still in limbo. For some
reason, Melbourne IT (which is apparently the license-agent for
Yahoo) hasn't yet released the name so that I can re-request it.
The Yahoo people said it would take some time, but I didn't
anticipate that it would take this long. If the Yahoo techies can't
figure a way around this problem pretty soon, I may have to decide
whether to change the first part of the domain-name (from 'gospel-
of-thomas') or choose an alternate ending. ('.info' instead of '.net'?
Seems odd but appropriate, eh? Suggestions welcome.)
Best wishes to all our subscribers,
Mike Grondin
Your message has been successfully submitted and would be delivered to recipients shortly.


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My Content
Membership has its privileges! Sign up or sign in to gain full access to both All About Jazz and Jazz Near You. Learn more.
Last February, Wayne Shorter and his quartet played the Portland Marriott ballroom, christening the city's inaugural jazz festival with a performance that over the next 12 months remained a source of inspiration for musical circles on both sides of the Willamette River. This year it was Charlie Haden's turn to make waves.
The venerable Grammy-winning bassist led a parade of big-name jazz artists appearing at the 2nd annual Portland Jazz Festival, a nine-day procession (Feb. 11-20) that featured the Dave Holland Quintet, Patricia Barber, Andy Narell, Luciana Souza, Joe Locke, John Patitucci, Danilo Perez, Dianne Reeves, and The Bad Plus. Mr. Haden, center stage in dark clothes and light spirits, commended Oregon's blue state status in the 2004 election before embarking on a seven-tune, two-hour set with tenor man Ernie Watts, pianist Alan Broadbent, and drummer Rodney Green (filling in for Larance Marable). Astonishingly, Quartet West succeeded in trans-forming the Marriott's cavernous, 150x150x11 square-foot ballroom into an intimate musical venue, to the delight of its 600-plus occupants.
Charlie's subtle, understated double-bass'"warm in tone, clear in pitch'"balanced melody and space during solo passages like the steady meditative breathing of a body at rest. In this environment the audience's collective mind was free to consider a thousand subjective details of the musical narrative. The random audible snap of right index finger completing its journey from plucked E-string to open palm only heightened the hypnotic effect.
Ernie Watts, playing yin to Haden's yang, provided rapid-ï¬re solo sweeps on tenor sax. His how-many-notes-can-squeeze-into-this-measure approach to the music garnered scattered ovations for technical ability. Drowned, however, in his tsunami of sound was any semblance of creative inquiry. Watts' solos on Charlie Parker's "Dexterity and "Segment left this listener gasping for air, flailing in a swell of arpeggios, and praying for the lifeline of Haden's bass strings.
Alan Broadbent brought a decidedly classical influence to the evening's material, employing a cascade of block chords across the entire keyboard during his solo on Ornette Coleman's "Lonely Woman. For his part, Rodney Green proved an expert rhythm accompanist; his pianissimo brush and cymbal support was especially appreciated.
But this night belonged to Charlie Haden. His encore rendition of "Body and Soul (with Watts laying out) revealed a tapestry of melodic beauty that punctuated a special night in the young life of the Portland Jazz Festivalone likely to produce ripples of praise up and down the Willamette for months to come.
Personnel: Ernie Watts - saxophone, Alan Broadbent - piano, Charlie Haden - bass, Rodney Green - drums
Develop a column, write album reviews, cover live shows, or conduct interviews.

subset: commoncrawl


text:
Custom designed, eco-friendly, all natural 100% soy wax candles. These premium candles are hand poured into stylish "Status" glassware and feature a crackling wooden wick.
Scent Description: Awake your senses with this amazing blend of Espresso, and Vanilla scents stirred with a touch of Hazelnut Cream. A perfect way to start or end your day.
Size: Medium 8oz.


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We've always been able to click on PrntScrn to take a snapshot of the full screen. Unlike the old MS-DOS days, where PrntScrn actually sent the screen to the printer, as of the first version of Windows, it copied the screen to the Windows Clipboard.
From the Clipboard, you could paste it into a Word document, a WordPad document, a spreadsheet, into Paint (the Windows image editor in Accessories), or into many other programs. From those, you could actually print the image.
Windows also has had the Alt-PrntScrn combination, which does the same things except with an image of only the active window.
Windows 7 has a really nice tool for taking a snapshot of a user-specified portion of the screen. It's called the Snipping Tool.
Like Paint, it's found in the Accessories sub-directory of All Programs. Left-click on the Windows Orb, then hover over (or click) All Programs, the hover over (or click) Accessories. Now you can left-click on the Snipping Tool, as shown below.
In the image below, you can see the Snipping Tool dialog box. Notice that the entire screen has been overlaid by a soft white mask.
The next step is to decide where you want to start your image — left-click at that point and drag the crosshair pointer to the opposite corner of the portion that you want in the image you are creating.
As you can see below, as you drag the selection tool, the white mask is removed from the area to be in the resulting image.
After selecting the image with the Snipping Tool pointer, release the mouse button.
That will result in the Snipping Tool dialog box showing up again, this time with an image it in. That image has already been copied to the Windows Clipboard, so you can immediately paste it into WordPad, Word, your graphics editor, or whatever.
The Tools item on the Snipping Tool menu bar includes the Pen (Red, Blue, Black or Custom), the Highlighter, the Eraser, and an Options selection.


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I have just started working with a 2 monitor PC system.
I am running Windows XP locally, and connecting to the Linux server over XMing, or PuTTy. When I start icfb, the CIW and all pop-ups from the CIW are placed between the 2 monitors, as opposed to either the right or left monitor.
How do I rectify this, so that icfb opens in one monitor or the other? I am assuming that there is some way of specifying either the position, or the screen in either the .cdsenv, or .cdsinit files.
Many Thanks
Look in <ICinstDir>/doc/dfIIconfig/dfIIconfig.pdf and search for formPlacement and optionFormPlacement (also formRelativeTo and optionFormRelativeTo).
Thanks, that pointed me in the right direction. The CIW now opens where I want it, still can't get Dialog boxes to open where I want them, but at least I know where to look for the answer now :-)


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April 22, 2005
Environmentalists are quick to admonish, "Every Day is Earth Day" -- a mild reproach to the general public that everyone ought to daily consider how their actions affect the planet. While a variety of environmental problems exist, the fact is that the environment has improved markedly since the first Earth Day in 1970, says H. Sterling Burnett, a senior fellow with the National Center for Policy Analysis.
For 10 years now, the Pacific Research Institute in conjunction with the American Enterprise Institute has published an annual "Index of Leading Environmental Indicators."
Among the good news this year is that air pollution is at an all time low:
- The 2005 Index shows that since 1976, aggregate emission of air pollutants measured by the Environmental Protection Agency (EPA) all substantially declined.
- Indeed, pick a pollutant, its levels have declined: Ozone is down 31 percent; sulfur dioxide is down 72 percent; nitrogen dioxide is down 42 percent, carbon monoxide is down 76 percent, particulates are down 31 percent and lead has declined 98 percent.
- For the first time since air pollution has been monitored, virtually the entire nation has achieved clean air standards for four of the six pollutants regulated under the Clean Air Act.
Much of the decline is due to the fact that cars are getting cleaner every year. Indeed, the EPA estimates that emissions from the auto fleet will decline by more than 80 percent over the next 25 years.
Environmental improvement is a worthwhile goal and more should and will be done. However, the public ought to celebrate how much the environment has improved. And if any day is a good day for that, Earth Day certainly is, says Burnett.
Source: H. Sterling Burnett, "Every Day Is Earth Day," Washington Times, April 22, 2005; and Steven F. Hayward, "2005 Index of Leading Environmental Indicators," Pacific Research Institute, April 2005.
Browse more articles on Environment Issues


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Today we are celebrating your local independent bookstore. I love Nicola and her bookstore, not only because they have a fantastic kids' section that goes well beyond the standards and celebrity lit, but also because they do great author events, supply all the books for my school visits, always have my book in stock, and have given me tons of ARCs when I was researching what's out there. If you are an author, seriously, you've got to love on your local indie. If you are a book lover, especially one who likes to read things that aren't what every single other person on earth likes to read, you must love on your local indie, who is far more likely to carry mid list books than the chains. If you love someone who loves books, you must love on your local indie because they can help you find great gifts. If you hate books, you should love on your local indie anyway because it's just good karma.
What's that you say? You do all your shopping at Amazon. Okay, that's fine. I am no Amazon hater. BUT, I am in LOVE with IndieBound. Have you seen IndieBound's "Shop Local Online" feature? Click on that link. Search for the book you want. A window will pop up, asking if you want to shop local online. Type in your zip code and it will direct you to a listing of your local indies who have online ordering. Voila. As easy as Amazon. Try it. You can even set up a wish list. And make friends. Find me!
What? Are you still there? Sorry. I got distracted at the Indie Next List. Mmm. Books. Me like books. Nom nom nom.
Wednesday, December 10, 2008
5 comments:
You are so right about indies. We lost our last best indie to a buyout by Borders. The place was called Thackeray's and wa reader friendly plus.
Tons of books, marvelous children's section, and like Nicola's, chairs and corners and nooks to curl up in and look at books.
Also knowledgeable staff. I sure miss them. There is one very small children's book store. It has a limited inventory and just doesn't take the place of Thackeray's. Boo Hoo.
- December 10, 2008 at 10:09 AM
- Brenda said...
I'm ashamed to admit that I did not know there were any Indie bookstores near me...I thought Books-A-Million and Barnes & Noble were it...but I put in my zip and found out I have several within 30-45 minutes from me...
Thanks for the site!
- December 10, 2008 at 6:16 PM
- Jacqui said...
Boo hoo, indeed Sharon. That stinks.
Brenda! I'm so glad you found them!
- December 10, 2008 at 8:42 PM
- Mary Witzl said...
I am with you 100%. I would go out of my way to support an independent book shop.
If you ever go to England, go and visit Hay on Wye! This is an ENTIRE town stuffed to the gills with independent book shops. Really: you can't go half a block without finding a dozen or so. In Scotland, it's Wigtown. I could cry just thinking about them...
The books here are all in Turkish, of course. It's the strangest feeling, seeing a book fair and thinking -- Yay! -- then suddenly realizing the horror of it. Books in English are carefully passed around and you can find yourself reading a genre you might have turned your nose up at before...
- December 11, 2008 at 3:12 AM
- Jill Corcoran said...
thanks for the link, jacqui!
- December 11, 2008 at 12:48 PM


text:
Vaidyaratnam Amruthotharam Kashayam: Very effective in all types of rheumatic diseases especially which affect the lower part of the body.
Vaidyaratnam Amruthotharam Kashayam: Very effective in all types of rheumatic diseases especially which affect the lower part of the body.Amrutottara kashayam is an effective Ayurvedic medicine in liquid form. It is extensively used in the treatment of fever by Ayurvedic doctors. It is also known by the terms Amrutottar kashay, Kwath, Amrutottara kashaya, Amruthotharam kashayam etc.
Benefits: It is used in all types of fevers.It contains Indian tinospora,which is a known immune booster and antimicrobial herb.It improves digestion strength and appetite.
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You have to send us DD for the order amount to process the order. Note: We will process your order only on the receipt of payment. In case of Cheque, the order will be processed after the cheque clearance.
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Disclaimer: All products & Logo copyrights owned by their respective companies / manufacturer.
The information presented at this page is not intended to replace the services of a health practitioner licensed in the diagnosis or treatment of illness or disease. Any application of the material in this text is at the readers discretion and sole responsibility. If you have a persistent medical condition or your symptoms are severe please consult a physician. Statements on this web site about health conditions and remedies have not been evaluated by the U.S. Food and Drug Administration.


text:
Peep Show
Seattle SuperSonics: These are usually the words they inscribe on the tombstones of old coaches. "Right now, I'm not reaching these guys," Sonics head coach Nate McMillan said in the Seattle Post-Intelligencer. But he wasn't finished after his team lost their fourth in a row. "You've got to play with some heart," McMillan said. "This is the third game I've seen a loose ball, and we've had guys to reach for it, and they've had guys dive for it. For whatever reason why we're playing this way, I certainly have to take responsibility for that. Because you've got to come up with something to say, something to do to get them fired up, and they haven't responded to that." That wasn't the end of it, either. "I know what I'm giving it, that I'm giving it my all," McMillan said. "I've got to figure out what to do. Which are the right buttons to push, because I feel that this is the team where the right buttons have to be pushed."
New York Knicks: Once upon a time, Allan Houston called himself the best shooting guard in the NBA. Well, now he has another bold statement. "We're going to make the playoffs," Houston said in the New York Times. "Whatever happens, I don't care, we want to make the playoffs." And he wasn't the only one sounding so optimistic after the Knicks won their third game in a row. "This is probably as talented a team on paper as I had in New Jersey since we reached the finals," Keith Van Horn said.
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- Haberstroh: NBA's best duo?
- Ford/Pelton: Is Russell a future Lakers star?
- Pelton: Curry a unanimous MVP?
- 5-on-5: Celtics boast best second-half upside
- Ford: Ben Simmons or Brandon Ingram?


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MUNICH-BASED former Socceroo Paul Agostino has urged Mathew Leckie not to ditch the Bundesliga.
Agostino a legend with Bavaria's 1860 Munich after a decade with the German outfit watched Leckie perform admirably for FSV Frankfurt against his old club this month.
Former Adelaide United striker Agostino returned to Munich last year to head the flourishing Bavarian youth academy Munich Soccer Camp.
Agostino believes Leckie has all the traits to be a huge success in the Bundesliga.
Leckie, 21, is currently on loan to second-tier club Frankfurt from the Bundesliga's Borussia Moenchengladbach.
"The last thing he should do is come back to Australia to play,'' Agostino said after Leckie told The Advertiser he was finding life tough in Germany.
"You don't leave Germany on your own decision.
"You only leave Germany when they kick you out. This place, the Bundesdhliga, is absolutely on fire the professionalism, the biggest crowds in the world and the excellent youth development.
"Mathew Leckie has unbelievable speed.
"He's getting better technically, and if he's looked after ... I watched him against 1860 and gee, the pace, he's unbelievable.
"Even in Germany if you don't quite have the skill, (with) that sort of lethal pace you can get away with it.
"Mathew Leckie is making an impression. He's not far off, he's got that special spark."
Agostino said he would be in Adelaide next year with some of Germany's finest young coaches, including Martin Max, a 400-game Bundesliga veteran, and ex-Czech international Roman Tyce.
The UEFA coaching licence holders will hold their first soccer camp outside Germany. It will be hosted by rebadged FFSA club Eastern United Saints.
Agostino said the Munich Soccer Camp's Tyce was a qualified scout.
"Tyce works as a scout for the Bavarian football federation," he said.
Agostino said the team would be made up of active coaches who would teach youngsters through demonstration.
"We're not coming to Adelaide to reinvent football," he said.
"We want to give kids in South Australia an insight into what it's like training in Germany.
"We want to coach children from a young age until under-20s and we want to give them a personal feel of what it is actually like in a German (soccer) environment."
Originally published as Leckie urged to stay put in Germany


text:
Sears dropped from campaign probe
Company agrees to cooperate as the case proceeds
Published 6:30 am, Saturday, January 1, 2005
AUSTIN - A third-degree felony charge accusing Sears, Roebuck and Co. of making an illegal corporate contribution of $25,000 to influence a state election was dismissed Thursday by Travis County prosecutors.
A grand jury had accused Sears of making an illegal donation to Texans for a Republican Majority, a group founded by U.S. House Majority Leader Tom DeLay, R-Sugar Land. DeLay has claimed the investigation is politically motivated by a Democratic prosecutor.
Sears became the second corporate defendant to receive a dismissal from Travis County District Attorney Ronnie Earle in his investigation into corporate financing of Republican campaigns during the 2002 elections.
Diversified Collection Services Inc. of California received a dismissal earlier this month.
As in the Diversified case, Sears agreed to fund a program on corporate responsibility regarding political campaign donations. Sears officials said they are funding the program through the LBJ School of Public Affairs.
"We welcome this dismissal as an appropriate action ... as we have maintained all along that there was no illegal action on the part of the company in this matter," said Sears Vice President Robert J. O'Leary.
"At the same time, we have taken steps to further clarify our contributions policy and will initiate a program to foster education and awareness concerning campaign finance and the debate surrounding it," O'Leary said.
The District Attorney's Office declined to comment. But in its filing with District Judge Bob Perkins seeking the dismissal, Earle said the indictment involved a single incident. He said Sears made the donation based on "false and misleading information provided by the fund-raiser."
Earle and Sears said the company has agreed to cooperate as the case proceeds against other defendants.
Sears and Diversified were among eight corporations indicted in the case. Also indicted were DeLay political associates John Colyandro, Jim Ellis and Warren RoBold. Ellis runs DeLay's Americans for a Republican Majority, and RoBold is a fund-raiser for DeLay's political committee.
RoBold's lawyer, Rusty Hardin of Houston, said he believes all the corporate defendants will be dismissed eventually, and he doubts any will ever testify that RoBold misled them.
"No one has ever gotten his side of the story," Hardin said.
Colyandro is asking Perkins to dismiss the case against him because he is not a candidate, officeholder or political committee.
Colyandro has a court appearance scheduled before Perkins on Tuesday. Ellis and RoBold have court appearances set for Thursday.


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> Drug Interactions And How To Stay On Top of Things


text:
The review of this product is based on a re-released version of the game. Because of this change of medium and the passage of time, it is possible that there are slight factual differences between the original retail product and the version reviewed. The following review should be used as a reference for how well the game stood up over time rather than an evaluation of how it would have scored based on its original release date.
I don't know what this is, but I think I like its premise. Some of the best and most memorable gaming experiences over the past few decades have simply defied classification. Games like Katamari Damacy or Mr. Mosquito. Games that are just so ridiculously odd that you can't help but smile at the preposterousness of it all -- Bravoman is one such game. This side-scrolling 2D fighter from the TurboGrafx is one of the weirdest and wackiest games of its day, and it's almost worth a try just to see how purely insane it really is.
Bravoman is a super-suited superhero, some kind of costumed avenger like the Power Rangers. In place of a Megazord, though, Bravo's gifted with a more extendable type of crime-fighting tech -- his own stretching appendages. This game plays something like a Street Fighter II spin-off would, if Dhalsim were given the starring role. Bravoman attacks his enemies by stretching out his arms, his legs, and even his neck for limb-elongating action.
That would be enough weirdness in itself, but Bravoman's nonsense extends beyond the self-extending hero and touches the rest of the game as well. His world is a parodical take on modern Japan. His enemies are spinning, grinning totem poles, robots, and knife-throwing dancer girls. His arch-nemesis is a man named Dr. Bomb, whose hairstyle looks like something out of your local organic food store's cauliflower section.
Add on to all of this a heaping of classic poorly-translated Japanese dialogue, and the stage is set for a winning experience. Bravoman's gameplay capitalizes on the presentation, too. It's not revolutionary, but it is sometimes entertaining -- you run and jump through side-scrolling levels, scoring points and eating rice balls to recover health. You can also collect "Luck Symbols" to redeem for power boosts with sidekick character Lottery Man at the end of certain stages. And, mixing things up, Bravoman occasionally goes underwater, transforming himself into a submarine. These stages alter the gameplay into something more similar to a spaceship shooter like Gradius.
The icing on this kooky cake comes in assaulting the help. When loyal, friendly characters appear onscreen to offer you aid, you can relentlessly punch or kick them without warning. They'll be insulted at the offense and verbally retaliate, threatening not to help you if you keep it up. And, if you keep it up, they'll make good on their threats -- Lottery Man, for example, will stop supplying life-replenishing rice balls if you smack him around one time too many. It's an extra touch of detail that rounds out the wacky adventure, but it doesn't push the gameplay much of anywhere.
The TG-16 has previously seen a few other side-scrolling brawlers from the likes of Vigilante and Splatterhouse. Bravoman proves to be a good companion to these titles, as together they form a picture of what a staple the genre was back in the early '90s. Given the choice between the three, I'd likely give a slight nod to Bravo (even if it doesn't do anything particularly well beyond its kookiness). But it's worth considering a purchase of any one of them to get a sense of that part of Hudson company history.


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I love a good chilidog.....I live in South OC (San Clemente), and I don't mind driving, so anyone know of a great place to get a chilidog n fries? Only place Ive been to is Der Weinerschnitzel. And you know, they're good in a pinch, but I'm looking for GREAT!!.....Any recommendations would be greatly appreciated, thanks!
Andrew in OC
2205 W Chapman Ave, Orange, CA 92868


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Una Leopard Attack: Forest official almost mauled to death by injured cat as team lacked tranquilizer-guns or defensive firearm
The proposal for the guns is pending for years and officials are either forced to hire shooters or beat the animal to death in defense, in case of encounters.
UNA- An ill equipped team of Himacal Pradesh Forest Department in district Una that tried to rescue a injured leopard fell victim to the fury of threatened animal. The leopard died a brutal death as guards and some locals had to beat it to death with wooden sticks to rescue the Range Officer Rajesh Kumar in Una district. The cat almost crushed the skull of the Range Officer and injured six people including two locals and four forest guards to arrived for rescue of the officer. Shockingly, the team had not even a single tranquilizer-gun or firearms for defense in such encounters.
The Leopard had reportedly pounced on the R.O. during a search operation and grasped his head between his jaws and claws for about 10 minutes.
View More Photos in Gallery Below:
This another example of government's apathy and lethargy that has cost a lot to this forest official, who is fighting for his life in hospital after receiving grieve injuries in his head and limbs. The Govt. has not equipped the forest guards with basic equipment used in animal rescue like tranquilizer-guns. The proposal for the guns is pending for years and officials are either forced to hire shooters or beat the animal to death in defense, in case of encounters.
Most recent example was witnessed in district Bilaspur where, probably, the world's longest leopard, after it attacked few villagers, was shot dead instead of capturing it.
Take a Look
The team that had arrived to rescue the leopard after some locals informed the forest department of sighting the animal sitting on a roadside in injured condition. The R.O. and four forest guards, namely Sanjeev Kumar, Pawan Kumar, Kapil and Sachin, arrived at the spot unequipped. The team was empty handed and didn't even have a tranquilizer-gun.
The forest department, when asked about the tranquilizer-guns, told media that the only gun is not available as it is sent for servicing.
Team Ignored Facts about Animal Behavior!
Another shocking fact is that the team didn't display any sign that they have received training about animal behavior, specially the cat family. It's a well known fact about cat behavior that in injured condition they become highly defensive and aggressive. Then, why the team followed the animal without any preparation?
Moreover, the team failed to prevent the people from gathering around the spot as the leopard felt more threatened.
Cat Further Fell Threatened by Huge Crowd
The Leopard was scared by noise that the increasing crowd of people who had started to gather to watch the leopard were making. Surprisingly, the team followed the big injured cat unwisely during which the animal attacked the R.O. Other than the guards, only two youth, Ankush and Munish Kumar, displayed enough courage and ran to rescue the R.O. They beat the leopard with wooden sticks during which they also received injuries. At last, the Leopard was put to death with a 'Daraat' (a sharp, rural metal tool used to cut wood and bushes).
A youth carried the critically injured R.O. on his back upto the road and thereafter rushed him to district hospital of Una in a vehicle. The officer was reported to be in serious condition and received several stitches all over his head and limbs. Doctors were unable to tell whether the injured R.O. is out of danger or not.
Further, recently, the issue of lack of tranquilizer-guns and defensive fire-arms, and vehicles for the forest staff in Himachal was raised by the department and the media. However, the government is busy knitting strategy for the upcoming Legislative Assembly Elections. The forest minister is reported to be indulged in matters like beating driver of the public transport bus for not letting his VIP car over-take. The government has shown no sign that it is serious about alarming rise in man-animal conflict in the hill state and equipping the forest department with even basic equipment to deal with it.
Stay updated on the go with Himachal Watcher News App. Click here to download it for your android device.


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Oakland University
College of Arts and Sciences
Post-Master's Graduate Certificate in Health Care Administration
520 O'Dowd Hall
520 O'Dowd Hall
Rochester, MI 48309
United States
Program Information
Degrees Offered:
Post-Master's Graduate Certificate in Health Care Administration
Format: Campus
Program Description:
The Post-Master's Graduate Certificate in Health Care Administration program is designed to provide students who have already earned an M.P.A. or a similar degree with additional education and training in the specialized area of health care administration. Students will be required to take at least 16 credits of graduate work beyond the master's degree. The health care administration specialty area is based on elective coursework currently offered by the M.P.A. program.
Accreditation:Oakland University is accredited as a doctoral degree-granting institution by the Higher Learning Commission of the North Central Association of Colleges and Schools.
International Student Requirements:International applicants requiring an I-20 for a visa must also submit additional documents, including an International Student Supplemental Application, financial documents, transcript evaluations, and proof of English language proficiency (TOEFL, IELTS or MELAB).
Facts & Figures
Financial Aid: Yes
International Financial Aid: Yes
Classification: Doctoral/Research University—Intensive
Locale: Large Suburb
Size & Settings: 10,000-19,999


text:
Phantom II Aerosol Spray
Buy Now
Yuen writes,
what is the difference between bed bug treatment kit with phantom spray and bedlam spray?
I bought the bed bug treatment with the phantom spray but I found that your q and A seems to recommend the bedlam spray. What are the factors I should pay attention to when using the phantom spray. What are the advantages of using one spray over the other.
There are many factors that we considering when answering a customer submitted question. Phantom is one of the top products on the market for bedbug infestations but for some customers it is too costly. Phantom is a non-repellent insecticide which means that bedbugs would not be able to detect that it is there and they will readily walk through treated areas. In the Q&A that you are referencing the other customer could have been using other synthetic pyrethroids in the same are which would have interfered with the non-repellent qualities of Phantom or there could have been a budget concern. Also the customer who submitted the Q&A you are referring to may have lived in a state where Phantom is restricted.
Answer last updated on: 07/17/2011
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text: Well the Gophers host the SDSU Jackrabbits tonight and St Cloud native Nate Wolters who is coming off a 32 point 11 assist performance in the Jackrabbits first game of the year. Gophers will have a huge size advantage inside and the Jackrabbits gave up 32 points to their last opponent on the low post. Should be a big night for Trevor Mbakwe and the Gophers but they will need to limit the open loods by SDSU from the outside.


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The stage is set, and the City of Visalia Parks & Recreation Department is ready once again to see the best home grown teen talent that Visalia has to offer!
Gracing the stage of the L.J. Williams Theater, tomorrow's top teen stars will face a panel of celebrity judges to compete for the title of Visalia Teen Idol 2017 and you're invited. Taking place September 9th, doors to the L.J. Williams Theater open at 5:30 p.m. and the show starts at 6 p.m.
Will your pick win big? Tickets are on sale now from your favorite Idol contender or at the Visalia Parks & Recreation Business Office, located inside the Anthony Community Center. Pre-sale tickets are $7; tickets at the door will be $10.
For more information on Visalia Teen Idol, call 559-713-IDOL, email email@example.com.
Visalia Teen Idol is not associated with Fox Broadcasting's American Idol, 19 TV Limited or & Fremantle Media Enterprises.


text:
Hi guys,
After reading all of the threads, tutorials and ... unfortunately i could not get unbanned by changing mac address or ip address.
so i want to know if there is any way to get unbanned ?
whats the way??? thats not patched??
My friend told me that the funniest things are here www.***********

Sign by Danasoft - For Backgrounds and Layouts

why are u still playing MW2?
There is no way, all these tuts are fake.
Change to a diferent SO, like if you are on windows 7 you go to XP or Vista
Especially since you're appealing your ban; alterIWnet • View topic - Get new router, and game says im banned......
Last edited by aIW|Convery; 11-16-2010 at 12:10 AM.


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Ellis University
Ellis University
Master of Arts (MA) in Teaching - Teacher as a Leader
Program Information
Degrees Offered:
Master of Arts (MA) in Teaching - Teacher as a Leader
Format: Online
Program Description:
The Master of Arts in Teaching is designed to complement core proficiencies that are consistent across most National Board of Professional Teaching Standards (NBPTS) certificates. The goal of this program is to increase teachers' abilities to engage students in effective and efficient learning experiences that produce measurable gains in student achievement. This degree program is designed for licensed, practicing P-12 classroom teachers and early childhood educators who want to advance their knowledge and skills to improve their classroom practice and demonstrate their skill and qualifications as a master teacher or are seeking to advance their research skills as they study an area in the field of Education in depth. The teacher as a leader specialization engages students in case-based and problem-based learning activities and assignments that require them to implement and integrate strategies and techniques within their own classroom and engage in inquiry that assesses the outcomes and effectiveness of their efforts. In addition to the core courses, 4 of the following 5 courses are required: introduction to school leadership and administration; school law and ethics; developing, motivating and supervising teachers; curriculum design and development; and issues facing elementary and secondary teachers. A capstone course is also required. Students must complete 39 credit hours to obtain this degree.
Accreditation:Ellis University is regionally accredited by the Higher Learning Commission of the North Central Association of Colleges and Schools and is nationally accredited by the Distance Education and Training Council.
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Jailbreak Apple TV 3
Unlock 04.11.08
iPhone Carrier Checker
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Googles new Plan To develop App obsolete
Mountain View-based Company showed off quite some potentially revolutionary mobile tech news at its I/O developer conference held on Thursday. The conference was concentrated on Jump and Brillo, but also on the evolution of cutting-edge tech that is almost three years old. The company went to great lengths to showcase how making apps is obsolete and is doing its best to get the users back onto the web, where of course
is the absolute king. Even
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Recent Posts
Author Archives: matthewryanward
For all the money…
My Biggest Baddest Bucket List Entry – My Destination is Nashville
Nashville is the home of America's music and so much more. For My Destination's Biggest Baddest Bucket List, I take you around Music City, USA in just a day's time and show you the landmarks, the local favorites and flavor, … Continue reading
Why we quit…
"What nobody tells people who are beginners — and I really wish someone had told this to me . . . is that all of us who do creative work, we get into it because we have good taste. But … Continue reading
I'm old enough that I can start recalling decades. Good god.
A Decade in Music and Films. My Favorites. Top 50 Albums of the past decade: Radiohead – Kid A Sufjan Stevens – Age of Adz (w/ADP) Radiohead – Hail to the Thief Sufjan Stevens – Illinois Arcade Fire – Funeral … Continue reading
What you give up in 140 Characters or Less: Reflections on the Tucson Shooting and the Compromised Immune System of our Democracy
Early on the day of the shooting in Tucson in which 22-year-old Jared Lee Loughner shot 19 people, wounding Congresswoman Gabrielle Giffords and killing Federal Judge Judge John McCarthy Roll and five others, including a young girl, I posted two tweets in response. Celebrated … Continue reading
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We've been working on getting another Toolkit release done. Unfortuantely, we discovered an issue in the June CTP of Atlas that caused some problems.
You could ask "why didn't you catch this before the June CTP went out?" To which I would reply "that's a very good question."
There's actually two answers (and two issues): one we didn't catch because we were missing a test case, but the other is more interesting.
One of the things that is nice to do is to be able to bind to properties values. In a repeater, it would be nice to say:
<myExtenderProperties TargetControlID="Label1" Value="<%# Eval("ID") %>"/>
But unfortunately that dosen't work because you can only databind to Controls....usually. So we tested the June CTP bits with our current builds and everything was fine. Making the databinding work required some changes to Microsoft.AtlasControlExtender.dll, so we made that change.
When we rebuilt that against the new Atlas, poof, we had a problem that we couldn't work around. See, Atlas added an override to a method, but our old code was still bound against the base definition. When we recompiled, we started calling the override instead, and got the behavior change.
So, anyway, the Atlas team is currently working on a new CTP that should be ready shortly. As soon as we get those bits, we'll crank out another release, update the atlas.asp.net website, etc.
But man oh man are there some cool things coming down the pipe in the Toolkit. If you go back to our last full release (60504), we've added eight new components, and have some more stuff almost ready. But what's even cooler is that this will be our first release with non-Microsoft contributor components included!
I know I can't make too big of a splash here - from the forums it's clear that folks are already just picking stuff up directly from CodePlex and partying on it, even when it's just in our prototype tree! Early feedback is good but we've seen forum posts within an hour of a checkin. Wow!


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Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, "Advancing Drug Discovery for Schizophrenia" was held March 9–11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia.
Session chairs: Stephen R. Marder and Bryan Roth
Though pioneering pharmacotherapy for the treatment of schizophrenia occurred in the 1950s with the introduction of antipsychotics, there have been decidedly few major innovations in the intervening years. Indeed, the current classes of drugs available largely involve the same mechanisms of action and the same neurobiological targets. Compounding the lack of progress has been the systemic pull-back of the pharmaceutical industry from research and development of new treatments for schizophrenia.
With the advent of successful methods for identifying anomalies at the genetic level, schizophrenia and other neuropsychiatric disorders stand to benefit immensely from incorporating these approaches and broadening our understanding of the pathogenesis of these illnesses.
"Advancing Drug Discovery for Schizophrenia" convened with an opening session of keynote lectures moderated by session chairs Stephen R. Marder (University of California, Los Angeles) and Bryan Roth (University of North Carolina School of Medicine). Marder called for a change in the way schizophrenia treatment has previously been conceptualized by moving away from focusing only on treating symptoms in individuals who are in the acute phase of the illness. Innovative drugs may emerge from improving our understanding of the pathologic processes that occur early in the development of the illness, thus providing strategies for altering the course of the disorder. Importantly, genetic and epigenetic approaches present a very promising means by which to accomplish this goal.
Patrick F. Sullivan (University of North Carolina at Chapel Hill) introduced the advantages of genetic approaches to schizophrenia by listing several benefits: the temporality of exposure to genetic risk factor preceding disease can be reasonably assumed; attempts at unbiased searches are possible; and, in the past two years, there has been substantial progress in uncovering the genetic basis of schizophrenia. He suggested that the purpose of employing genetic techniques is to look both for genetic variance that confers risk or prevention and for whether multiple genes work in concert to form pathways to an illness. To illustrate this point, he offered the analogy of a match to a forest fire—genetic studies seek to identify the initiating event in a disorder, or in other words, the "match" that sparks the fire.
This line of work has begun to make progress.1,2 Sullivan noted that there are novel and robust findings that include common variation in the major histocompatibility complex, the region encoding the microRNA miR-137, and four predicted targets of miR-137. Copy number variants that are rare but have high penetrance with robust results include regions on 1q21.1, 15q13.3, 16p11.2, 22q11.2, and NRX1. At this point, up to 15 possible genetic loci for schizophrenia have been identified. Further, Sullivan stressed that the accumulated data suggest that schizophrenia is relatively highly polygenic, which may be a general feature of complex traits. For example, various genes may actually code at the symptom level versus the disorder level (Table 1).
The results to date are notable, Sullivan underscored, in that the novelty of findings correspond relatively poorly to prior ideas about the etiology of schizophrenia. Empirical data suggest that both common and rare variations are involved in the etiology of schizophrenia. Rare variant–only models have been evaluated and are not consistent with the data. Sullivan suggested that with genome-wide association studies (GWAS), we can, however, estimate that increasing sample sizes are likely to produce more significant loci and considerably better pathway analyses. He likened GWAS to a powerful centrifuge that allows for the separation of specific genes. Most heartening, he suggested, is the likelihood that the discovery profile for schizophrenia has a linear trajectory—increasingly larger samples will lead to an increasing number of loci identified.
Edward M. Scolnick (Broad Institute of MIT and Harvard University) began by suggesting the great importance of unraveling the full genetic architecture of schizophrenia and bipolar disorder as the critical step in establishing their underlying neurobiology. While the overarching theme of the conference pointed to a general stagnation in the field of schizophrenia treatment, Scolnick lauded the significant strides made recently. In other words, the field has become "unstuck." This movement could also be attributed to the application of three new technologies: human genetics, optogenetic methods to manipulate specific circuits in the brain, and induced pluripotent stem cells.
Scolnick noted the apparent disparity between developments in schizophrenia versus cancer treatments. Bolstering this swell in cancer drug development is the increased understanding of the genetic and molecular aspects of various forms of cancer, something that, given the limited knowledge of its genetic basis, is not yet possible for schizophrenia.
In the past three years, however, using detailed maps of the human genome and doing association studies, a number of risk genes for schizophrenia and bipolar illness have been identified. CNVs (copy number variants) and genomic associations have been identified with a high degree of statistical certainty; some of the CNVs are de novo and some are inherited. Scolnick referred to characterizing diseases by the frequency of variants in addition to penetrance. For example, Mendelian diseases possess high penetrance and are deterministic of the development of the disease. However, many diseases posses a mixture of high- and low-frequency variation, indicated Scolnick. Increasingly, GWAS methodology is being used to investigate the penetrance of diseases and is appropriate for application to schizophrenia. Pathways involving synaptic proteins, the WNT signaling pathway, as well as miR-137 have been identified, which now provide clues about the biology of some illnesses. In addition, it has become clear that schizophrenia and autism may share some risk genes in common. Though the outcomes are very different, it may be possible, Scolnick suggested, that causative DNA variants may someday be used diagnostically.
Scolnick concluded by posing the idea that the full-scale application of genomics is now limited only by money and time to unravel the full genetic architecture of these illnesses. Further, given the burden of these illnesses, he reasoned that there is "no excuse" for NIH and NIMH funds not to be made available to perform the needed genetic studies and to finally enlighten their etiologies. He continued by saying that until we understand fully the genes that cause these illnesses the field will remain a "backwater of medicine." Funding for neuroscience is certainly needed to understand their pathophysiology, but without an understanding of the genetic bases, he cautioned, scientists will continue to guess at what to work on to elucidate the illness and discover new targets for treatment.
Applying genetic methodologies to psychiatric disorders presents unique challenges, suggested Eric J. Nestler (Mount Sinai Medical Center). These include that they are categorically defined by behavioral abnormalities and that the genetic risks involved are likely to be a combination of multiple genetic variations. Thus, progress in understanding the etiology and pathophysiology of schizophrenia has been frustratingly slow, as has been the discovery of significant, novel therapeutic mechanisms. The exceedingly challenging neurobiology of higher brain function and the ethical and practical difficulties of examining the living human brain have no doubt contributed to this relatively slow progress. Another important factor is the extremely challenging nature of modeling schizophrenia in laboratory animals.3 This is due to the inaccessibility, in animals, of many of the key symptoms of schizophrenia, the subjective nature of the symptoms, the lack of objective biomarkers, and the early state of knowledge of the underlying genetics and neurobiology of the syndrome.
What we have learned from genetic studies of schizophrenia thus far, Nestler argued, is especially complicating vis-à-vis animal models, because most genes of relatively strong effect implicated in schizophrenia are also implicated in bipolar disorder and even autism. Moreover, Nestler proposed that what can be learned from placing genes of very small effect into laboratory animals is itself questionable. Indeed, Nestler continued by saying that most available animal models of schizophrenia have significant limitations, ranging from weak validation to poor predictive power for drug efficacy in humans.
Illustrating the complications that arise from translating models of human disorders in, for example, murine models, Nestler explored difficulties for establishing construct validity. For example, though genes may be associated with schizophrenia, abnormalities in these specific genes may cause schizophrenia but may also cause other disorders. Moreover, there is difficulty in making animal models as complicated as human models, and this too may require experimentally manipulating multiple genes.
Nestler also discussed two other forms of validity in respect to the limitations of animal models. Perhaps the most obvious limitation is the lack of face validity—there are simply features of psychiatric disorders that are not accessible in animals. Second, Nestler referenced the lack of predictive validity of animal models. Not only are there no new medications to test for efficacy in animals, but we must also interpret any response to drugs with great caution. In contrast, there may be better face validity for some of the negative symptoms associated with schizophrenia (e.g., social withdrawal and anhedonia), which have been modeled successfully, but may not be unique to this illness.
Concluding his talk, Nestler remained optimistic that, with time, the genes that confer risk or resilience in mental illness will be determined, citing advances in autism as support. The generation of convincing and useful animal models of schizophrenia thus represents a major set of challenges that will not have easy answers. On the other hand, given current limitations of clinical studies, Nestler concluded that it is hard to imagine significant progress in schizophrenia pathophysiology or therapeutics without good animal models.
Session chair: Mark A. Geyer
The discovery of genes associated with risk for schizophrenia holds promise for identifying therapeutic targets based on etiopathogenesis. Daniel R. Weinberger (National Institute of Mental Health) reported recent work from his lab documenting an association with schizophrenia to the hERG family potassium channel gene, KCNH2.4 Risk-associated variants predict expression of a novel brain and primate specific isoform, KCNH2 3.1, which both has unique physiological properties and is upregulated in schizophrenia prefrontal and hippocampal cortices. Because many antipsychotic drugs bind to KCNH2 channels, accounting in some cases for QT prolongation, and atypical agents such as clozapine are particularly potent KCNH2 inhibitors, Weinberger and coworkers hypothesized that activity at KCNH2 channels may be a therapeutic mechanism of antipsychotic drugs. As a result, targeting the 3.1 isoform not expressed in the heart would have a particularly favorable therapeutic-to-toxic ratio. Weinberger stated, "We have tested the first hypothesis in two independent samples of patients who underwent placebo controlled studies of antipsychotic therapy, including an inpatient sample from the CBDB/NIMH experimental therapeutics unit (n = 59) and Caucasian subjects treated with olanzapine as part of the CATIE trial from whom we also had drug clearance data (total N = 89)." In both groups, Weinberger and colleagues found that the KCNH2 genotype predicted response to treatment (e.g., positive symptoms P < 0.0007, thought disturbance P < 0.0004 in the CBDB sample, positive symptoms P < 0.04 in CATIE). Currently, Weinberger's group is testing the second hypothesis in human and model cell lines that over-express KNCH2 3.1 and also in a mouse model that overexpresses KCNH2 3.1 in cortex and shows predicted abnormalities in K+ channel kinetics and in working memory.
Structural variation in the genome in the form of copy-number variants (CNVs; submicroscopic gains or losses of segments of DNA) has now been identified as a major contributing genetic factor in schizophrenia.
Maria Karayiorgou (Columbia University) discussed the importance of examining low-frequency alleles with moderate effects, as they are easier to characterize and potentially more likely to contribute to the development of the disorder. Further, exploring the genetic variation in the landscape de novo may have great utility in delineating sporadic versus inherited types of schizophrenia. Importantly, Karayiorgou suggested that inherited CNVs are more disrupting than those that are de novo.
Karayiorgou focused on one such CNV on chromosome 22q11.2. Recent studies are beginning to paint a clearer and more consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. In contrast to previous talks stressing the uncertainty of associating schizophrenia risk with any specific gene or CNV, Karayiourgou maintained that 30% of individuals with a deletion on 22q11 develop schizophrenia or schizoaffective disorder. Indeed, parallel studies in humans and animal models have begun to uncover the complex genetic and neural substrates altered by this microdeletlon. For example, Krayiorgou illustrated studies that have begun to identify CNVs that may explicate some of the working memory-related processing deficits seen in schizophrenia, because they occur in regions that oversee microRNA, thus affecting prefrontal cortex neuronal synaptic transmission and plasticity. In addition to offering a deeper understanding of the effects of this genetic lesion, Krayiorgou ended her presentation with the hope that these findings may guide analysis of other CNVs associated with psychiatric disorders.
Alessandro Guidotti (University of Illinois at Chicago) began by stating that the efficacy of current drugs is limited and that, without new developments, there is little hope for progress in the treatment of schizophrenia. An area of research that holds promise is exploring the role of the fundamental interaction between GABAergic interneurons and pyramidal neurons and how this function is compromised in schizophrenia and bipolar disorders. Schizophrenia and bipolar disorder patients show a downregulation of GAD67, reelin, and other genes expressed in telencephalic GABAergic neurons, likely associated with promoter hypermethylation mediated by an overexpression of DNA methyltransferase (DNMT).5 The inhibitory action of DNMT on gene expression may also occur through formation of chromatin repressor complexes that include histone deacetylases (HDAC) or histone methyltransferases, thereby shifting chromatin from a conformation permissive for transcription to one that is repressive. Guidotti has concentrated on a pharmacological strategy to reduce the hypermethylation of GABAergic promoters and to induce a permissive chromatin conformation. This strategy is to administer drugs such as the HDAC inhibitor valproate (VPA), which induces DNA demethylation when administered at doses that facilitate chromatin remodeling.6
Studies employing this strategy in mice, as presented by Guidotti, suggest that when combined with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation (Fig. 1). Olanzapine and quetiapine (two similar atypical antipsychotic drugs) also facilitate chromatin remodeling, but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, Guidotti suggested the synergistic potentiation of VPA's action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors. Furthermore, the administration of clozapine in conjunction with VPA reverses the downregulation of the GAD67 expression induced in mice by seven days of methionine administration.5
Guidotti concluded by positing that chromatin remodeling mechanisms may be altered in the brains of schizophrenia and bipolar disorder patients. Thus, by activating DNA demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors could be considered a promising prevention and treatment strategy to normalize the GABAergic promoter hypermethylation and GABAergic gene expression downregulation detected in the postmortem brain of schizophrenia and bipolar patients.
Prompted by epidemiological research that shows advanced paternal age increases risk for schizophrenia in offspring,a Jay Gingrich (Columbia University Medical School) discussed potential epigenetic mechanisms behind this effect. With each round of sperm production, epigenetic marks are erased and then reprogrammed—a process that may become degraded with advanced paternal age. To explore this, Gingrich and colleagues compared the offspring from older mouse fathers to those from young mouse fathers. Several behaviors differed between the two, including measures of an open-field ambulatory test, startle responses, and paired pulse inhibition. These mice showed distinct methylation patterns on their genomes at 0.4 % of the methylation sites. At these sites, the offspring of older males were less methylated than those of the younger males in introns, exons, and promoters. These findings suggest that differences inboth the promoter activity and alternative splicing patterns may drive some of the changes observed in the mice. Notably, hotspots of altered DNA methylation could be found in schizophrenia-related genes, though, Gingrich noted, the researchers didn't select the mice for disease-related behaviors.
Alterations in chromatin structure and function, including changes in levels or distribution of histone lysine methylation markings and other epigenetic regulators of gene expression, could affect neuronal signaling in schizophrenia and other major psychiatric disease.8 However, to date, relatively nothing is known about the regulation of neuronal and other cell type–specific epigenomes in the diseased brain. Schahram Akbarian (University of Massachusetts) opened his talk by pointing out the potential for neuroepigenome mapping approaches to advancing the epigenetic field through focusing on the postmortem human brain. Specifically, he discussed work exploring the genome-wide distribution of trimethylated histone H3K4 (H3K4me3), an epigenetic histone mark associated with actual or potential transcription, in neuronal nuclei collected postmortem from prefrontal cortex (PFC) across a wide age range (0.5–70 years).
Neuronal nuclei from postmortem prefrontal cortex were immunotagged with NeuN antibody, NeuN+ and NeuN− nuclei were sorted separately via fluorescence-activated "cell" (nuclei) sorting (FACS), and purified mononuclesomes were enriched for H3K4me3 analyzed by massively parallel sequencing using an Illumina Solexa platform.9 Akbarian's group has identified 16,000–22,000 H3K4me3-enriched regions (peaks), the majority located proximal to (within 2 kb of) the transcription start sites (TSS) of annotated genes. These included signatures specific to neurons as well as signatures specific to individual subjects (Fig. 2). Preliminary analyses presented by Akbarian provided evidence for a large-scale remodeling of histone methylation landscapes in immature PFC neurons during early infancy, with comparatively minor changes during subsequent periods of maturation and aging. Further, he predicted that epigenome mapping in defined cell populations of the diseased human brain, in conjunction with RNA and transcriptome profilings, could reveal important information about gene expression alterations at specific loci. These approaches, he stressed, will also be important to unravel the genetic and epigenetic risk architectures of specific cases and, furthermore, reveal insight about developmental regulation of chromatin structures in specific cell populations.
Session chair: Robert W. Buchanan
Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. Jeffrey A. Lieberman (Columbia University and New York State Psychiatric Institute) stressed during his talk that, as a result, while these drugs can be effective at ameliorating psychosis, they are largely ineffective at treating negative and cognitive symptoms, can produce serious side effects involving different organ systems, and may even contribute to gray matter volume reduction. The differences between the majority of the current drugs, Lieberman suggested, are primarily due to side-effect profiles, with pronounced side-effects often outweighing the therapeutic potential; additionally, considerable heterogeneity in response to treatment exists.
For years, psychiatric researchers and pharmaceutical companies have sought to develop mechanistically novel antipsychotic drugs based on targets other than dopamine receptors. For example, Lieberman highlighted the considerable amount of work that has been devoted to precedented targets and mechanisms (D-2, D-3 dopamine, and 5-HT2A serotonin antagonism); novel mechanisms (partial agonism, functional selectivity); and novel targets (glutamatergic, cholinergic, GABAergic), including intracellular signaling mechanisms (AKT, GSK). Unfortunately, drugs targeting many of these mechanisms were abandoned before they were tested in clinical trials.
In addition, Lieberman offered the observation that increasing attention is being focused on the complex genetics of schizophrenia as well as the signaling pathways implicated in its pathophysiology. Lieberman's presentation reviewed the limitations of existing therapeutic agents and development strategies, including several of the major genetic findings that have identified signaling pathways representing potential targets for novel pharmacological intervention—for example, genes in the 22qll locus, DISC1, Neuregulin1/ ErbB4, and components of the Akt/GSK-3 pathway.
Lieberman concluded that it may be critical both to consider the necessity of multiple medications that treat different aspects (or domains) of schizophrenia and to renew commitment to research and development of pharmacotherapy for the illness.
P. Jeffrey Conn (Vanderbilt University) presented work demonstrating the path between hypotheses and actual treatments of schizophrenia. The glutamate/NMDA receptor function hypofunction hypothesis has garnered wide attention because of its significant potential in targeting the range of symptoms presented in schizophrenia, including positive, negative, and cognitive symptoms. Further supporting this hypothesis, a large number of cellular and behavioral studies suggest that selective agonists of the metabotropic glutamate receptors (mGluRS) could provide a novel approach to treatment of schizophrenia.10 Unfortunately, it has been difficult to develop compounds that act as selective orthosteric agonists of mGluRS and that have properties likely to be suitable for development of therapeutic agents. Conn presented work from his group, which has been successful in implementing a novel approach to activation of these receptors by developing highly selective allosteric potentiators of mGluR5.These compounds do not activatemGluR5 directly, but rather potentiate the response of these receptors to the endogenous agonist. Thus, these allosteric potentiators offer high selectivity for the targeted receptor and provide an exciting new approach to development of novel selective activators of mGluR5 and other G protein–coupled receptor (GPCR) subtypes.10
In vivo studies reveal that these compounds have robust effects in animal models, which have been used to predict efficacy of novel antipsychotic agents. Conn showed findings that demonstrate that introduction of these compounds reduces amphetamine-induced motor hyperactivity, a putative animal model of limbic hyperactivity and positive symptoms of schizophrenia. In addition, mGluR5-positive allosteric modulators (PAMs) enhance multiple forms of synaptic plasticity in the central nervous system (CNS) and have cognition-enhancing effects in animal models.11 These studies, therefore, provide an exciting new approach for discovery of novel, highly selective activators of specific GPCR subtypes for treatment of schizophrenia and other CNS disorders. In conclusion, Conn suggested that recent advances in the discovery of a broad range of mGluR5 allosteric modulators with different functional profiles will allow the development of a more complete understanding of the properties of individual mGluR5-PAMs with the hope of determining which may be most suitable for development as novel therapeutic agents.
A critical need exists for gaining insight into the underlying etiology and pathophysiology of schizophrenia and other neuropsychiatric disorders in order to advance the development of new types of targeted therapeutic interventions. Surveying recent work, Stephen J. Haggarty (Harvard Medical School, Broad Institute of MIT and Harvard University) presented studies of the Disrupted in Schizophrenia 1 (DISC1) gene, which is disrupted by a balanced chromosomal translocation t(1;11)(q42.1;q14.3) in a single extended Scottish family with a high incidence of schizophrenia, major depression, and bipolar disorder. Studies have revealed a key role for DISC1-mediated signaling in diverse aspects of neuroplasticity. One of the direct binding targets of DISC1 is the multifunctional serine/threonine kinase GSK3, which is known to play a key role in the regulation of neurogenesis and synaptic function.12 GSK3 has also been shown to be inhibited in vivo directly, and indirectly, by the mood stabilizer lithium and indirectly through the activity of antipsychotics at various GPCRs.13
On the basis of these findings, as well as emerging human genetic studies implicating other components of the GSK3 signaling pathway in the etiology of schizophrenia, Haggarty discussed the advent of chemical genomic approaches to identify small molecule probes that target known and novel components of DISC1/GSK3 signaling.
Using pharmacological and viral-mediated gene expression to modulate AKT kinase activity, Haggarty presented work demonstrating a key role for AKT kinase activity in determining the cellular and mood-related behavioral effects of lithium.13,14 In contrast, selective and direct GSK3 inhibition by an ATP-competitive, highly selective, brain penetrant GSK3 inhibitor (CHIR-99021) was found to bypass the requirement for AKT activation (Fig. 3).14 In order to try to develop pathway-selective inhibitors of GSK3 and to develop small molecule probes that enable the selective targeting of individual DISC1 domains, Haggarty's group has used small molecule microarray screening to measure the interaction of DlSC1 variants in a high throughput manner.
Finally, Haggarty presented efforts to use induced pluripotent stem cell (iPSC)–derived human neurons for use in high-throughput screening for small molecule probes of DISC1/GSK3 signaling. Haggarty showed findings that demonstrated the ability to identify known and novel small molecules that regulate TCF/LEF–dependent transcription that is under control of GSK3 signaling in iPSC-derived human neurons. Collectively, he noted, through the use of genetically accurate cell models and in using iPSC-derived human neurons, these studies will enable a better understanding of the role of DISC1/GSK3 in regulating signaling pathways implicated in schizophrenia, as well as potentially lead to the identification of new targets and improved treatments.
Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in genetic risk for schizophrenia, but the biological mechanisms are unknown. Amanda J. Law (National Institute of Mental Health) presented work testing the hypotheses that aberrant PI3K/AKT signaling represents a pathogenic consequence of schizophrenia-associated genetic variation in ErbB4 and that pharmacological manipulation of this pathway may represent a novel therapeutic avenue for the treatment of psychosis. She explained that her group has used an "integrative translational neuroscience approach" to test the hypothesis, incorporating data from patient-derived Iymphoblastoid B cells, human brain mRNA expression profiling, clinical genetics, and pharmacological studies in rodents. These results pinpoint a genetically regulated pathway associated with schizophrenia and with ErbB4 genetic risk variation involving upregulation of a Pl3K-linked ErbB4 receptor CYT-l and of a specific phosphoinositide 3-kinase (PI3K) subunit. Law presented intracellular signaling data collected in human Iymphoblastoid cells showing that NRG1-mediated phosphatidyl-inositol,3,4,5-triphosphate [PI(3,4,5)P3] production (and cell migration) is associated with ErbB4 risk genotype and PI3K enzyme levels and is significantly impaired in patients with schizophrenia. In the human brain, the association of ErbB4 genotype and PI3K subunit expression was confirmed, and antipsychotic drug administration was found to downregulate expression of the PI3K subunit, implicating the PI3K pathway as a novel therapeutic target. Specific inhibition of the PI3K subunit using a small molecule inhibitor blocks the effects of amphetamine in a mouse pharmacological model of psychosis. Law posited that these studies provide novel insight into how ErbB4 may contribute to the pathophysiology of schizophrenia, reveal a previously unidentified link between NRG1-ErbB4 and PI3K signaling in the disorder, and suggest that a specific PI3K merit further consideration as a molecular target for rationally designed drugs for the treatment of psychiatric disorders.
Representing work conducted in the private sector, Brian Campbell (Pfizer) discussed recent work on a naturally occurring NMDA agonist, kynurenic acid (KYNA). KYNA is a biologically active byproduct of tryptophan metabolism that is reported to act as an endogenous antagonist of NMDA receptors and may also interfere with nicotinic α7 receptor function. Since KYNA levels are elevated in schizophrenic patients, it has been hypothesized that this may contribute to the cognitive deficits observed in schizophrenia. Though inhibitors of kynurenine aminotransferase 11 (KAT II), the primary enzyme involved in brain KYNA synthesis, have been proposed as targets to treat symptom domains in schizophrenia, research into this hypothesis has been hampered by lack of potent, selective, and brain penetrant tools. Campbell reported on the discovery and pharmacological characterization of a new class of KAT II inhibitors with nanomolar potency, >1000-fold selectivity over other kynurenine pathway enzymes, and excellent brain penetration. Systemic administration rapidly decreased KYNA by as much as 80% in brain dialysates in a dose-dependent manner. In addition, Campbell detailed the profiling of these compounds through a range of animal models relevant for domains of schizophrenia, which revealed efficacy in models of working memory in both rodents and non-human primates and also in a rat model of attention (i.e., a sustained attention task). Furthermore, Campbell and the group at Pfizer have found activity in an anhedonia model (chronic mild stress), which may suggest therapeutic utility for the negative symptoms of schizophrenia. These compounds are inactive in classical models of antipsychotic activity, suggesting that KAT II inhibitors may be suitable as adjunctive agents, given along with antipsychotics, to treat the cognitive and negative symptoms associated with schizophrenia that are so poorly managed today.
Session chair: John H. Krystal
Bita Moghaddam (University of Pittsburgh) opened the final session of the meeting. Dissatisfied with how simple circuit versions of the glutamate hypothesis of schizophrenia fail to deliver for the whole brain, she proposed an alternative way of thinking about the disorder. Instead of seeing the main clues we have for schizophrenia—NMDA receptor hypofunction and decreased GAD67, an enzyme that synthesizes GABA—as factors that contribute to the disorder, she suggested that decreased GAD67 may instead reflect a compensation for abnormal levels of glutamate. If markers of disease like these are compensatory, rather than primary, then trying to correct them would give opposite effects than expected. With this in mind, she cited a tightly regulated GABA shunt in mitochondria that recycles GABA molecules from glutamate. Moghaddam suggested that imbalances in GABA and glutamate levels could stem from improper mitochondrial function—something with repercussions for excitatory and inhibitory signaling throughout the brain.
Seeking to better simulate the molecular processes underway in neurons in disease, Akira Sawa (Johns Hopkins University) reported on the "garden of human neural cells" growing in his lab. He has had some success in maintaining olfactory neurons from humans obtained through a relatively noninvasive nasal biopsy,15 deriving human neurons from iPSCs,16 and deriving neurons directly from human skin cells.17 After two weeks of treatment in media, these latter neurons, called induced neurons (iN), showed neuron-specific markers and fired action potentials.
As an example of the dividends these approaches may provide, Sawa showed a comparison of mRNA profiles in olfactory neurons between people with schizophrenia and controls. The groups differed in genes related to actin binding, the NF-κB protein complex involved in DNA transcription, intracellular protein transport, and immune and stress responses. Consistent with these changes, olfactory neurons from patients with schizophrenia show abnormalities in association with cytoskeletons and oxidative stress (Table 2).
The last three speakers discussed whether there might be ways to refine dopamine signaling in the brain to treat schizophrenia more effectively and with fewer side effects. Starting with D2Rs, the target of all antipsychotics, Marc Caron (Duke University) noted that D2Rs engage both a G protein–coupled pathway and one involving the scaffolding protein β-arrestin-2, which in turn activates the AKT/GSK3β signaling independently associated with schizophrenia.
To probe how much this β-arrestin-2 pathway mediates psychosis-like behaviors in mice, he disabled it by removing GSK3β in D2R-containing neurons. This interfered with apomorphine-induced rearing as well as amphetamine-induced hyperlocomotion and prepulse inhibition, but not cognitive tasks. Removing GSK3β's target, β-catenin, from D1R-containing neurons induced more amphetamine-induced psychosis, whereas removing it from D2R-containing neurons induced less. Together, the results implicate this pathway in psychosis-like behaviors and antipsychotic response, and the extent of its contribution may be further delineated with D2R mutants engineered to selectively signal through either the G protein or the β-arrestin-2 pathway.
In a later talk (see below), John Allen (University of North Carolina) reported new efforts to discover D2R ligands that selectively activate the β-arrestin-2 pathway but not the G protein pathway. In a chemical biology effort in Bryan Roth's laboratory (University of North Carolina), the group screened hundreds of new compounds and came up with two that are biased for their signaling activity at the D2R-β-arrestin-2 pathway. When administered to mice, these arrestin-biased compounds decreased PCP- or amphetamine-induced hyperlocomotion without increasing catalepsy. These results suggest that selective D2R-β-arrestin-2 signaling and recruitment may contribute to antipsychotic activity without motor side effects.
In another twist for dopamine signaling, Susan George (University of Toronto) presented her evidence for a novel dopamine receptor made up of a D1R and a D2R. This combination receptor offers a new mode of signaling for dopamine because it activates a G protein pathway that is not induced when either receptor is activated alone. The D1-D2 heteromers occur endogenously in the brain and are enriched in the nucleus accumbens and globus pallidus of rats. Using a competitive binding assay to detect a high-affinity state for a D2 agonist in the D1-D2 heteromer, George found this state is enhanced in rats treated with amphetamine and in the globus pallidus of the postmortem brain in schizophrenia. The work suggests both that abnormal coupling between D1 and D2 could be a molecular marker for pathological states in the brain and that this coupling may be a new treatment target—something that has already been explored in mouse models of depression.
Serotonin signaling is also thought to contribute to schizophrenia symptoms, and the atypical antipsychotics have been designed to also target 5-HT2A serotonin receptors, following suggestions that this activity set clozapine apart from the typical antipsychotics. Prompted by a rare CNV found in the caveolin-1 (CAV1) gene in a case of schizophrenia,18 John Allen explored the state of serotonin signaling in knockout mice missing CAV1. CAV1 encodes a scaffolding protein involved in clustering diverse signaling molecules together, including 5-HT2A receptors.19 Loss of CAV1 resulted in an increased sensitivity to PCP-induced hyperlocomotion and disrupted prepulse inhibition, suggesting a propsychotic-like effect in the mice. Loss of the CAV1 gene also attenuated the activity of atypical antipsychotics and 5-HT2A antagonists in behavioral studies (Fig. 4). Similarly, these mice made fewer head twitches in response to a hallucinogenic 5-HT2A agonist and also disrupted 5-HT2A signalingin cortical neurons. The number of 5-HT2A receptors was normal in these mice, which suggests that loss of the CAV1 scaffold mislocalized 5-HT2A receptors and their downstream effector molecules, compromising their function and resulting in compromised antipsychotic activity.20
Although the crowd was dwindling, energy remained high at the end of the talks, with several people saying that they felt optimistic about the prospects for discovering truly innovative drugs for schizophrenia. One participant raised the issue of specificity, asking how disturbances to intracellular signaling pathways available to all cells can produce the malfunctions in specific brain circuits observed in schizophrenia. Moghaddam suggested that patterns of metabolic activity, combined with aberrant signaling, somehow target certain circuits for dysfunction. John Krystal (Yale University) suggested a genetic explanation, noting that susceptible brain regions in schizophrenia are the most recently evolved and thus could be the most genetically labile. Either way, a challenge will be to deliver treatment to ailing brain circuits without disrupting those that are functioning normally.
In his closing remarks, Krystal called the meeting "a next-generation conference" with research beginning to meet the urgent need for mechanistically novel compounds. "What's exciting is not how far we've come, but the possibility that we might be getting to the point where we can use science to guide psychiatry.
aSee the SRF hypothesis: http://www.schizophreniaforum.org/for/curr/Malaspina/default.asp
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.


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My Nonprofit Reviews
Review for Operation Snowball, Inc., Springfield, IL, USA
I have seen Operation Snowball make a great difference in teens lives. Many of the teens that I have worked with have become more confident, open and developed leadership. They have gone on to college and continued to make healthy lifestyle choices. Many of the participants as teens have come back to be a part of Operation Snowball as adults. It continues to have an impact in their lives long after they experience it as participants. Because alumni return to the fold, the event has an even bigger impact on the current teens taking part. My sons have experienced the impact on their lives as Operation Snowball participants and now as adults. Both of them have entered the Social Work arena. My oldest son is a professor of Social Work at a college and does therapy for addicted teens. My other son has become a Counselor at another local college and continues to have a very strong impact on Operation Snowball.
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I've personally experienced the results of this organization in...
I continue to speak with past participants. They always relate to me the impact that Operation Snowball has had on their lives. The reasons that they come back as adults to contribute to the organization are: "It set me on a path that kept me successful," " I would not be where I am today if it weren't for Snowball," and "The confidence that I gained from Operation Snowball helped me to be the person that is before you today, confident, happy, healthy, and excited for the future."
If I had to make changes to this organization, I would...
I would like to see Operation Snowball grow. The organization is already International, but I would like to see a stronger domestic presence. I would focus some more of the organization's resources locally.
Will you volunteer or donate to this organization beyond what is required of advisors?
How much of an impact do you think this organization has?
Will you tell others about this organization?
How did you learn about this organization?
I became involved when my son attended an event for middle school kids.
What is this organization's top short-term priority?
Teach children to be drug and alcohol free.
What is its top priority in the long run?
Not sure.
When was your last experience with this nonprofit?


text:
I'll start: Yo mama has so many teeth missing, that it looks like her tongue is in jail.
MAMA - do I have to sleep in your bed again - I am 54 now
Yo mama is like a hockey player, she only showers after three periods.
Yo mama is so stupid she got hit by a parked car.(That's my favorite because I got hit by a parked truck, but I get really good grades.)
MAMA can I soon go on solids - I am 52 now
Yo mama is like a chicken coop, s fly in and out all day.
Mammy are you sure we should be doing this?
MA - can I go and play with someone else now I am 33
Yo mama is so hairy you almost died of rugburn at birth!
Yo mama's mouth is so big that she speaks in surround sound.
Yo mama is so old her social security number is 1!
Yo mama is so grouchy that the McDonalds she works in doesn't even serve Happy Meals.
Yo mama is so lazy she thinks a two-income family is where yo daddy has two jobs.
You suck... yo mama does too, but she charges.
Yo mama is so nasty she made right guard turn left.
Yo mama is like a paper towel, she picks up all kinds of slimy wet stuff.
Yo mama is so stupid she sold her car for gasoline money!
Yo mama is like Bazooka Joe, 5 cents a blow.
Yo mama is so poor when she goes to KFC, she has to lick other people's fingers!(its been fun but I gotta get back to work)
Yo mama is like a telephone, even a 3 year old can pick her up.Have a good day.
Dad... DAD.... The Dog's thrown up and Mum's getting all the big bits!
Yo mama is so fat, she sat on the beach and Greenpeace threw her in.
by mayhmong8 years ago
Yo mama jokeathon! THIS IS NOT INTENDED TO HURT ANYONES MAMA AND MAY NOT BE USED AS FOUL PLAY OR BLAMING OTHERS MAMA UNLESS THEY REALLY DESERVED ITNot really in a good mood now. No it was not my mamas fault for me...
by R.S. Hutchinson6 years ago
Post it.Yo mama is like HTML: Tiny head, huge body.
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