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If you grew up in the 90s or early 2000s and played PC games, you've undoubtedly heard of the Heroes of Might and Magic franchise - a series of turn-based strategy games by New World Computing. Heroes of Might and Magic 2 was the first truly amazing game of the series, followed by HOMM3 with improved graphics, and then going to crap starting with the 4th one. I think HOMM2 and HOMM3 collectively stole not months, if not years, of my time, and I am still just as excited to play either of them as I was back in the day - the replayability factor of these games is through the roof.
Update: It's up for sale yet again today, Saturday, May 7th.
Woot.com, Internet's favorite a-deal-a-day site that I personally religiously check daily, is offering up an Android tablet deal today that may be hard to pass up for those looking for a beefy, yet budget, Android tablet.
The very hackable ViewSonic gTablet, which sports a speedy dual-core 1GHz Tegra 2 CPU, a 10.1" 1024x600 TFT display, a front-facing camera, 512MB RAM, 16GB ROM, and USB host capabilities, is sitting there for the next 12 hours (or until it's sold out) for the very low price of $279.99 + $5 shipping.
The enTourage eDGe Dualbook is one of the more interesting devices released last year due to its 2 screens - a 7" touchscreen LCD and a 6" e-Ink. Similar to the Spring Design Alex eReader, the Dualbook lets you read ebooks on one screen while simultaneously Googling, browsing Wikipedia, checking email, and doing anything Android lets you do on the other screen. However, if you find yourself reading late at night, just throw the book over to the LCD screen, and suddenly you can read in the dark.
Ok, so we have some good news and some not-as-good-as-you-would-like-it-to-be news for Notion Ink Adam owners. Let's start with the good: according to the official Notion Ink blog, the kernel source code for the Adam has been released. Great, right? Now all of the custom fun that you've been waiting for is just around the corner, you just have to wait on developers to download the code and get to work.
Well, it looks like the good old FCC has given their stamp of approval to the Wifi-Only HTC Flyer. As you can see in the image below, the sticker is ready for deployment and I, for one, couldn't be happier.
Now that the red tape has been cut through, we could start seeing the Wifi-only Flyer in Best Buys stores all across the land any time now (hopefully sooner rather than later).
If you head over to Amazon's Facebook page right now and press "Like," you'll find the first product in Amazon's ongoing A-Z Sweepstakes, a Motorola XOOM, is up for grabs. Eight of them - to be precise. All you have to do is give Amazon your name, email address, and phone number to enter. This is a US residents-only contest, though (unlike our super-awesome Motorola XOOM Wi-Fi Giveaway.)
The Barnes & Noble NOOK Color has been the e-reader of choice for many Android power users because of its hackability, making it easy to transform it into a full featured tablet. B&N must've taken note from the Android dev community, because an update has just been released for the NOOK Color that brings Froyo, apps, flash player, and more to this budget friendly device.
Before you get too excited, though, it's not exactly what you think.
In case you aren't sold on any of the current crop of Honeycomb tablets, Lenovo is about to throw their hat in the ring with the ThinkPad Tablet (also called the Think Slate). The folks at This is my next got ahold of a PowerPoint with all the specs, and this tablet can certainly hold its own amongst the competition:
- NVIDIA Tegra 2 processor
- Android 3.0 with custom Lenovo UI
- 1280 x 800 IPS 10.1" display
- 16, 32, and 64 GB models
- USB, micro USB, mini HDMI ports
- Full SD card reader
- 3G and possible 4G connectivity
Interestingly enough, the Think Slate will also ship with two key optional accessories: a pen and a "keyboard portfolio case," which seem to mimic the HTC Flyer and Asus Transformer, respectively.


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"I was looking for something quick and easy that didn't require a trip to the store and found this recipe. I substituted bulk sausage and omitted the olive oil, cooking the onions and garlic directly in the sausage pan. I'll probably make this again with more tomatoes and perhaps a little spicier sausage or some red pepper flakes. (I wanted just..."
"A very nice, very easy dish that was well received by everyone at my Thanksgiving table this year. I used the Grand Marnier as recommended and had good success. A light, tasty sauce."


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We set out for Rock Creek with temperatures above freezing and very little wind. When it gets cold this winter the Rock Creek trip may not be possible for me unless I am wrapped in an insulated bubble with a 70 degree thermal layer inside.
This trip uplake was magical as it seemed the gentle breeze was always at out back. Fog clouds were wrapped around cliff tops with occasional sunlight spotlighting cliff walls. It was absolutely beautiful and unique for the always dramatic scenery from Padre to Rock Creek.
As we headed toward the back of main Rock Creek the gentle breeze lessened and flat calm conditions prevailed. The trip was already a success so we turned around and went back, NO! That was not going to happen since there was another plan to be completed.
In the back of the canyon there is a deep trench that runs from 50-70 feet but on the right hand side there is a bench that averages 35 feet. For the last month or longer, the magic holding depth for striper schools has been 35 feet. So we started there.
My basic technique is to troll a deep diving Thunderstick and a mid depth Shad Rap. The graph is studied while trolling and a floating marker is in hand ready to mark the location of any large striper schools that are passed over. We could just graph and then stop on a school and drop spoons, but it is also necessary to get the school activated. The best way to do that is to hook a fish which excites other schooling fish almost as much as it energizes me. As the hooked striper is reeled in, the curious school often follows to see if there is more free food close at hand. As the troll-caught fish is lifted into the boat the striper school pauses under the boat wondering where the hooked fish went and more specifically where they might find free food.
This time the first fish hit the shad rap which allowed me to reel in my Thunderstick and quickly deploy the spoon rod. Sure enough! As soon as the first fish was hoisted in, the school appeared and my spoon was eaten on the way down to the bottom. I played my fish until another spoon was in the water. Then I flopped my 3-pound striper on the deck by holding the spoon and the jerking it while letting the weight of the fish disengage the hooks from the lip. Luckily it worked that time and I could immediately put the spoon back in the water as my partner played his spoon caught fish.
We deployed a marker at the spot where the first fish was caught. We worked this school over for about 10-15 minutes before they left us. Then we picked up the fish off the deck, and put them in the cooler on ice. We had drifted about 200 yards away from the marker as the school followed us. The next step is put out the trolling lures again and search for the next school.
The trolling/spooning technique located about 5 or 6 separate schools. The floating markers showed the most common school location to be at the breaking edge of the 35 foot terrace before it dropped into deep water. Later in the day and further back in the canyon where depth was commonly 18 feet, we found a 50 yard long basin that was 30 feet deep. Sure enough schools that had been holding on the shallow bench now dropped into the deep little basin. They could still be activated with spoons and catching continued.
At midday fishing success slowed. We had a cooler full of fish from 2.5 to 4 pounds. There were no yearling fish and only two that might have been 5 pounds. Back at the Wahweap fish cleaning station we counted 33 stripers. What a great day for fishing in December!


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Unprofessional Fridays: 01/30/2015
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The chaos and fun of Saints Row is fully intact in the underworld, but a new setting can only go so far.
Dimensions recaptures enough of Geometry Wars' thrills to stand as the best new dual-joystick shooter in quite a while.
The little mushroom man finally gets his name on the marquee, and the result is a charming, unique, and puzzle-heavy adventure.
Object »
Aglthin Dasmore is an elderly Erudite who has denounced his former life as a necromancer and now lives peacefully as a fisherman in Toxxulia Forest. The guildmaster of Paineel's necromancer guild wishes him dead.
Bait Masterson is a reclusive fisherman who spends his days on the shores East Freeport.
A close associate of Sonic the Hedgehog, Big the Cat is a fisherman who lives at the Mystic Ruins. Big debuted in the Sonic Adventure game for the SEGA Dreamcast, along with his sidekick; Froggy.
Brunar Rankin is a barbarian fisherman and thief that hangs out in East Freeport.
The female main character of Harvest Moon: Island of Happiness and Harvest Moon: Sunshine Islands.
Dok is the proprietor of Dok's Cigars in Halas.
Fiddy Bobick owns Bobick's Boats, which is a bait & tackle shop located at the small dock in Rivervale.
"FBI Special Agent Francis York Morgan. Please, call me York. That's what everyone calls me."
A powerful Hollow that has escaped the Shinigami's radar for over 50 years due to the fact his ability to transport himself inbetween Hueco Mundo and Earth without trouble. It and Ichigo Kurosaki have a painful history together.
Greenvale Forest Park's Warden. He found Anna's body along with the twins.
Lakitu has appeared in a variety of Mario games; from Super Mario Bros on the NES right up to Mario Kart 7. He is responsible for dropping Spinies onto the levels below, holding up signs and his very own start signal from all nine Mario Kart games.
Link is the iconic protagonist of The Legend of Zelda franchise.
The male main character from Harvest Moon: Island of Happiness and Harvest Moon: Sunshine Islands.
Head of the wealthy Kashiwara family. Dotes on Sarina and is over-protective of her.
Serving as the narrator of Final Fantasy XIII and one of the playable characters, Vanille is a remarkably upbeat person, yet prefers to hide her past from those whom she grows to love.
The Senator is a secret character in Eternal Champions: Challenge from the Dark Side. He is a satirical take on US Politicians protesting violent video games in the early 1990s.
Smaka is an ogre who sells her wares in Neriak's Foreign Quarter. Her cough medicine is quite expensive, but for good reason.
The Gobbler is an ogre that owns a supply shop in Neriak's Foreign Quarter called Bites n' Pieces.
The Muglwump is a giant tadpole residing in The Warrens. He is somewhat of a raid encounter for lower level adventurers on Odus.
The player-character in the Animal Crossing series.
This enormous frog is a living vault that stores your weapons in it's stomach.
The silent protagonist of Persona 4. As the leader of the Investigation Team, Yu Narukami becomes deeply involved in the serial murder cases in the Inaba region shortly after arriving in town to live with his uncle.
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More relatives of Philippine boxer Pacquiao get into politics
GENERAL SANTOS, PHILIPPINES (AFP) - Philippine boxing hero-turned-congressman Manny Pacquiao had three more relatives elected to public office on Tuesday, but a representative for the star downplayed suggestions he was creating his own "political dynasty".
The Commission on Elections said two of the boxing superstar's brothers, along with a sister-in-law, won village council seats in their home city of General Santos in the country's south. Messrs Rogelio and Bobby Pacquiao were elected councillors in separate districts of the city in polls held Monday, while Bobby's wife, Lorelei, won re-election as village chief.
Although villages are the smallest government units, seats are hotly contested and considered the first step in building a crucial grass-roots network for politicians aspiring to higher office. It is common practice among Filipino politicians to have their relatives also run for office to put a "dynasty" in place in the hope of expanding their influence and keeping them in power.
The 34-year-old Mr Pacquiao, who recently expressed hopes of becoming president, has used the fame and riches generated from his boxing to launch a successful political career.


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American Income Life
American Income Life Reviews in Covina, CA
American Income Life 638Review Highlights
You have the opportunity to make a lot of money if you have what it takes to make the sale (in 20 reviews)
If you are a shark you will do well and make a lot of money off the backs of others (in 14 reviews)
There are not any cons that I can think of other than the long hours (in 67 reviews)
The only way to make a lot of money is to be dishonest (in 10 reviews)
"Extraordinary! "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at American Income Life full-time (less than a year)
ProsThe compensation is unmatched by any other company I know. The systems put in place for employees guarantee success. The company is an honest, ethical company that has working class families' best interests in mind. We are in the business of protecting the futures of families and providing them financial security. The leadership truly cares about our success.
ConsIt is hard to think of cons to working at AIL. You are your own boss, you create your own destiny, some may see that as a con, but I don't.
Advice to ManagementAdviceContinue to create training and learning opportunities employees in all positions.
RecommendsPositive OutlookApproves of CEO -
2 people found this helpful
"Good while it lasted, Management guidance was not adequate "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I worked at American Income Life full-time (less than a year)
ProsThe company really does have plenty of clients to meet with and the sales job part of it is fairly easy.
ConsI was not able to grow because I did not have enough backup when I needed it while I was in the field. I would call managers and sometimes they would not be available to answer questions. After not generating any sales in a month, my manager did not even step in to help get back on track. He was to busy with other things. Driving around for 8 hours on my own funds did not work out.
Advice to ManagementAdviceBalance out time with new recruits. Be available while agent is in the field.
Doesn't RecommendNeutral Outlook -
4 people found this helpful
"scam "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I have been working at American Income Life as a contractor (less than a year)
ProsI am looking for a job and these insurance pigs keep hounding me.
Consthey are liars. it is a scam
Advice to ManagementAdviceabuse yourself leave others alone
Doesn't RecommendNegative OutlookDisapproves of CEO -
3 people found this helpful
"phenomenal upper-managment. toughest job if u make it u will succeed! "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Career Opportunities
I worked at American Income Life
sales development
leadership development
honesty/integrity ( this is true under the person who hired me)
confidence builder
team work
fast paced career track(i chose not to peruse due to commitment level)ConsTime Commitment( no previous experience)
drive time (wish i lived in the valley)
down time when managers are doing other things
crowded phone rooms
rejection from clients was new to me but this changed after 30 daysAdvice to ManagementAdviceThe State Director and Regional Manager are some of the best leaders i know i wasn't able to work on the team i wanted because i was recruited by another manger however they helped me with anything i needed. the unfortunate part was they also run 2 other offices and they spend majority of their time working with management and top producers. i received an scholarship to go back to school (they do not allow part-time). this office has rare leaders that care about you as long as you care about your future. i noticed that they are serious about their business so if your not committed to give up leisure you best stay away. i witnessed 9 promotions in the first month and over 20 in the 4 months i was there. pros and cons i still respect training i was given by my trainer. and to this day I'm an active recruiter for this company.
Approves of CEO -
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Proposition 8 passes
Photo gallery: Ted Rall cartoons
Gay marriage: Scalia knew this day would come
Little Hoover's dim view of California's energy future
Follow Ted Rall on Twitter @TedRall
Copyright © 2015, Los Angeles TimesALSO:
Photo gallery: Ted Rall cartoons
Gay marriage: Scalia knew this day would come
Little Hoover's dim view of California's energy future
Follow Ted Rall on Twitter @TedRall
Copyright © 2015, Los Angeles TimesCartoonist Ted Rall on local and state politics.
The Super Bowl is here, and those of us who have been watching the NFL from day one of the season are looking forward to a good game. We're also facing truckloads of criticism for being fans. We'll be called brutes and bullies and layabouts and plenty of worse things. Can we answer these...
Physician-assisted suicide is back on California's political agenda. Indeed, anyone who read the newspaper or watched TV coverage when the End of Life Option Act (SB 128) was introduced Jan. 21 might think it's a done deal, though the bill hasn't even cleared committee. The message from...
Collapsing oil prices are dealing a crippling blow to Africa's economic giant, Nigeria, which is simultaneously absorbing a second shock: U.S. refineries once purchased as much as 40% of its production; now they're no longer buying.
Benjamin Franklin was in his early 20s when he embarked on what he called his "bold and arduous project of arriving at moral perfection." He set out 13 virtues including order, industry, sincerity and humility, and made a chart in which he tracked each virtue for a week at a time...
The news from U.S. negotiators who are trying to persuade Iran to accept binding limits on its nuclear technology was not good last week.
The Los Angeles Unified school board has enough divisions over educational philosophy to fill a thousand school-board campaigns. The last thing we need is the introduction of phony racial divisions and shameful accusations that strongly and wrongly imply a candidate is racist.
The government's approach to policing corporations doesn't make much sense. Individual managers or employees acting alone or in collusion commit crimes in the name of the corporation -- bribery, say, or a little book-cooking to cover up some financial problem. An investigation ensues...


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Rachel Bilson Bikini Pictures in Barbados With Boyfriend
Rachel Bilson Rocks a Bikini For Beach PDA and Fun With Shirtless Hayden
Rachel Bilson slipped into a printed M Missoni bikini for a day in the Barbados sun on Saturday. She was joined by her shirtless boyfriend, Hayden Christensen, and a bunch of friends to hit the beach. The group splashed around in the waves and even hopped on a raft for a ride in the water, though Rachel and Hayden got away from the crowd to share a sweet kiss in the sand. It looks like the getaway is becoming a tradition since Rachel and Hayden took a tropical trip to the same destination this time last year.
Rachel is vacationing during time off from filming Hart of Dixie, which returned to the air last month after a midseason break and will debut a new episode tomorrow. Despite her time off, she's been busy promoting the show, and she landed on the cover of Cosmopolitan's May issue.
Celebrity Couples
Hayden Christensen
Rachel Bilson
- Eli Manning's wife, Abby, gives birth to a baby girl — Us Weekly
- Kim Kardashian has really mastered one kind of selfie — HuffPost Celebrity
- Who is Rachel McAdams's mystery dinner date? — Lainey Gossip
- Iggy Azalea backtracks after a social media rant — Dlisted
- Rihanna strips down for a sexy spread — ET
- Why Reese Witherspoon dressed up as a guy — JustJared
- Hilary Duff is one hot mom — Hollywood Tuna
- Eddie Murphy shares exciting SNL news — Pink Is the New Blog
- Why Suge Knight is under arrest — The Superficial


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"I love this bread, it really was easy to make which is necessary for me because I'm not good at bread making. Due to the rising time, I prepared it before I went to bed so it would be done in time for dinner the next day. I served it with homemade Olive Garden Minestrone Soup."
"These burgers are really good. I didn't have enough spinach so I added some kale. I also used fresh garlic and onions instead of garlic and onion powder, and decreased the amount of Italian seasoning."
"This dip is really good. I couldn't find monterey jack cheese so I used a spicy taco cheese mix instead."


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Alberto Mechoso and his sister Beatriz carry the urn with the remains... News Photo 158782679Alberto Mechoso,Argentina,Beatriz,Buenos Aires,Carrying,Civil Rights,Dead,Decorative Urn,Disappear,Domination,Father,Females,Funeral,Horizontal,Last Occurrence,Military,Montevideo,Politics,Rebellion,Sister,UruguayPhotographer PABLO PORCIUNCULACollection: AFP 2012 AFPAlberto Mechoso (L) and his sister Beatriz carry the urn with the remains of their father, Uruguayan anarchist Alberto Mechoso --disappeared in Buenos Aires in 1976 during Argentina's military dictatorship-- during his funeral in Montevideo on December 28, 2012. The Uruguayan Government gave the remains of Mechoso to his relatives after being identified in Argentina. Mechoso was detained in September 26, 1976 and he was seen for the last time at the clandestine detention centre Automotoras Orletti on that year. AFP PHOTO/Pablo PORCIUNCULA (Photo credit should read PABLO PORCIUNCULA/AFP/Getty Images)


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The Hiawatha ChapterMeeting has been rescheduled for Monday, Oct. 6!For more information,contact Terry Fieldsof Mayo Employees Federal Credit Union.
Monday, October 6, 2014
Social -- 5:30 p.m.
Dinner -- 6:15 p.m.
Program -- 7:00 p.m.
Willow Creek Country Club
1700 48th Street SW
Rochester MN 55902
Willow Grand Buffet - (Sirloin of Beef, Roasted Turkey Breast, Pasta Salad, Parsley Buttered Potatoes, Honey-glazed Carrots, Apple Cobbler and Coffee).
Meet & Greet Your Area Legislative Candidates
$21 per person
Please make checks payable to the Hiawatha Chapter of Credit Unions - please make your check payable for the number of reservations made, even if some don't show.
Prize donations for CUVOL drawing are greatly appreciated.
Hosted By:
First Alliance Credit Union and
Mayo Employees Federal Credit Union
R.S.V.P By:
Wednesday, September 24, 2014
R.S.V.P. To:
Terry Fields


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Featured Events
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text: POPSUGAR Fashion Burberry Burberry Prorsum Spring 09 Menswear by coutorture 1/06/09 0 Shares Print 0 0 0 0 0 Previous Photo 1 of 31 View on One Page ADVERTISEMENT ( more slides) Next What's Your Reaction? Thanks for your reaction Don't forget to share this with your friends! 0 0 0 0 0 0 1 Burberry Prorsum Spring 09 Menswear Photos by Venturell. Previous Photo 1 of 31 View on One Page ADVERTISEMENT ( more slides) Next 0 0 0 0 0 Read More Spring 09RunwayMenswearBurberry Burberry McQ's Artsy Spring Campaign, Ralph Lauren Goes to 'Downton Abbey' 5 days ago This Week's Best Dressed Prove There's More to Killer Style Than Award Show Gowns 1 week ago Winter Accessories So Cute, You Won't Mind Bundling Up a Bit 3 weeks ago There's a Perfect Statement Necklace For Every Sweater in Your Closet 12/24/14 70 Perfect Fashion Gifts For Every Type of Girl on Your List 12/15/14 Classic Gifts For Any True Fashion Fan 12/15/14 Stars Celebrated the Best of British at the Evening Standard Theatre Awards 12/01/14 Get chic with our daily newsletter Enjoy street style trends, runway looks, and the best in celeb beauty in your inbox. Fashion & Beauty News Celebrity Style Beauty Tips Street Style Sign up with What's Your Reaction? Thanks for your reaction Don't forget to share this with your friends! 0 0 0 0 0 0 0 0 0 0 0 0Reactions Link Love Emma Watson just snagged the role of a lifetime — InStyle Is your outfit missing a little something? Just add leather — HuffPost Style Get 'em while they're hot: Birkenstocks are back (again) for Spring — SHEFinds These fashion bloggers visited a sweatshop and it got intense — Who What Wear Can you believe these shoes cost less than $100?! — StyleList There's a new vintage site in town — and it's pretty chic, too — Style.com Girls keeps getting more and more stylish with each episode — Fashionista That sexy Victoria's Secret Super Bowl ad is finally here! — Racked There were so many ear cuffs at the SAG Awards last night — Lucky Latest Fashion


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Find the Elise Manning you are looking for with our people search tools. Gain access to an information database to help you find a person based on age, past residences, relatives, aliases, and more at PeopleFinders.com. Elise Manning was born in 1946 and is 69 years old. Known relatives include William T Manning, Chad Edward Marston, William Edward Mullen, Renee A Marston, John E Marston, Valerie Mullencobb, Ewell M Marston, Elsie Mullenmanning, Linda W Mullen.
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Great food, good value. Very friendly staff. Always busy so good idea to go early or reserve a table!
Great food, good value. Very friendly staff. Always busy so good idea to go early or reserve a table!
We were two families traveling together, staying for a week just outside Lardos. Valantina's had the best food we came across and also some of the nicest staff. My only regret is that we didn't come back a second time.
Decided to take a taxi from pefkos to lardos one evening on a reco. Lardos is so Greek with a bit of Neon thrown in. In our opinion, Valantinas was the best meal/experience we had over the two weeks in Rhodes and we had alot of very good meals in Pefkos. Great setting, great food and service. We were at... More
The reviews were right both in presentation and value for money.All the staff including owner made us feel very welcome,we in particular enjoyed the Lamb Shanks,Duck and Fish dishes.If you are visiting Lardos then this restaurant is well worth visiting you will not be disappointed.
Another great restaurant. Typical Greek food, plus other dishes such as Amazing Ribs, as good as we had in America. Good prices and lovely staff.
Valantinas was an absolute highlight to our holiday in the first 2 weeks in September! Although the hotel we were staying at was all inclusive, we ended up eating out at Valantinas 5 times in 2 weeks, it was just that good! I definitely recommend booking to avoid disappointment, however, if you get there early enough they can usually find... More
Just had another fantastic meal at Valantina's. The food is delicious, cooked to perfection. We had the liver which was beautiful and the pork medallions with plums and pine nuts. Oooo it was perfection. Then, just when we thought it couldn't get any better we had chocolate soufflé with ice cream - wow it was amazing. The staff - Petros,... More
Good is great,waiters really good looking and attentive.romantic atmosphere in a tiny Greek working town.
Always made Welcome, although we only visit a few times a summer. Food always good quality and tasty
Fantastic restaurant. Staff very friendly. WE had only been to the restaurant once and they recognised us when we back a few days later. Food fantastic. Highly recommend.
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For an independent band, inking with a brand-name outfit like K-Tel had exciting implications: For one, the label could get the band's material into large record chains such as Musicland and Sam Goody, which don't normally stock one-off recordings from unaffiliated acts. Yet as Cuts began working its way up radio charts -- the disc's first single, "Is My Love Enough?," hit number five on the New Music Weekly chart, ahead of tracks from Stevie Nicks and matchbox twenty -- Daniels sensed that all was not well in the K-Tel world.
"I started getting calls from distributors and stores who said that people had been coming in asking about songs of ours they were hearing on the radio," Daniels says. "And then they'd go to the section where Choice Cuts should have been, and it wasn't there. Our older stuff, our Rounder record, would be there, but not the one that was being spun around the country. I calculated it was maybe fifty to a hundred records we could have been moving a week. That's a lot of dough. And it hurts not to get it."
So in February, after tracking reports of K-Tel's failure to keep up with the demand for Choice Cuts for five months, Daniels and his manager decided to file a cease-and-desist order against K-Tel, requiring the company to relinquish the rights to the Kings material. Their timing turned out to be fortuitous: In early March, the company fired most of its staff and headed to bankruptcy court, reportedly with the intent of emerging as a very different K-Tel, one with an emphasis on producing compilation recordings for businesses and distributing DVDs. (K-Tel management could not be reached for comment.) Had the Kings not reclaimed the rights to their own music, it could have been tied up in legal rigmarole for several years.
"We are just grateful and relieved that we got our stuff back," Daniels says. "And we are still planning to go into the studio in the fall to record the album we were going to do for them. It just set us back a bit."
The sour K-Tel experience strengthened Daniels's belief that artists must continually lubricate their "industry" deals with their own elbow grease. So he and a small staff are currently working to fill orders through Daniels's Moon Voyage label (which has re-released Choice Cuts) and independent distribution companies such as Denver's USA 1 Stop. And despite the current lack of a familiar imprint on the album, Choice Cuts is continuing to do well on the radio: Its second single, "An American Tragedy," is currently at number 58 in radio-tracker FMQB's Top 200 chart.
"I feel a little bit like I'm taking my cue from Ani DiFranco," says Daniels. "She's a brilliant businesswoman who has the right idea about managing her affairs. We've had, over the years, different deals with different companies: BMG, Virgin/France, Flying Fish, Rounder. And what I've seen with every single one of those deals is that we never got accurate returns on how the record was selling. We never got good information, and we always seemed to manage to be in debt to the record company.
"This experience in particular has taught me that you really make your own success in this business," he adds. "Major record labels can do an incredible service, but only if every single thing falls into place. You've got to know that it's got to be up to you. If the label starts to drop the ball, you are there to catch it."
Choice words from one who's been there.
Jeffrey-Paul Norlander's decision to bring back the Denver Gentlemen (see "Revival of the Fittest," page 89) is not the only wise artistic choice he's made recently: Earlier this year, Norlander hooked up with Absalom Recordings, the Canadian indie, for the long-awaited release of Introducing the Denver Gentlemen, a live album recorded at the Bug Theatre in 1996. Absalom has proved itself to be a label full of good ideas, as evidenced by its current series of limited-edition CD EPs. Though the releases (available by subscription only) branch off into two camps distinguished by instrumentation, both feature wonderfully diverse rosters: The acoustic set includes music from Songs: Ohio, the Czars, the Baptist Generals, Howe Gelb, Calexico and Johnny Dowd, while the eclectic set enlists the Autumns, Soul Junk, the Roman Candles, Unwed Sailor, Simon Raymonde and Paul Mumaw. Aside from quality, the most pleasing common denominator is the presentation: Each EP is packaged in hand-stamped cardboard and is teeny-tiny, measuring only three inches across. They're so...cute -- just the thing for the rare-CD collector (or miniature fetishist) in your life. Check out absalomrecordings.com.


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Deputy director for management Jeffrey Zients hires Shelley Metzenbaum to help lead the performance management effort. OMB to lean on the Performance Improvement Council to develop and advocate for new approach.
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God's Blessings for Mothers
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US 5516785 A Abstract Method of using anabaseine, and DMAB-anabaseine for stimulating brain cholinergic transmission and a method of making anabaseine.
Claims(9) 1. A method of treating degenerative memory dysfunction in an animal comprising administering to the animal a therapeutically effective amount of a nicotinic receptor agent, wherein the agent is selected from the group consisting of anabaseine, and DMAB-anabaseine.
2. The method of claim 1, wherein the administration is parenteral.
3. The method of claim 2, wherein the parenteral administration is by subcutaneous, intramuscular, intraperitoneal, intracavity, transdermal, or intravenous injection.
4. The method of claim 1, wherein the administration is enteral.
5. The method of claim 1, wherein the administration is at a dosage of about 1 μg/kg/dose to about 1000 μg/kg/dose.
6. The method of claim 1, wherein the administration is at a dosage of about 10 μg/kg/dose to about 500 μg/kg/dose.
7. The method of claim 1, wherein the administration is at a dosage of about 30 μg/kg/dose to about 100 μg/kg/dose.
8. The method of claim 1, wherein the animal is human.
9. The method of claim 1, wherein the memory dysfunction is dementia.
Description This application is a 371 of PCT/US92/01451 filed Feb. 27, 1992. This invention relates to anabaseine, DMAB-anabaseine, and anabasine and their use to treat degenerative diseases of the nervous system. It has long been customary in classifying diseases of the nervous system to group them as degenerative, thereby indicating they are characterized by a gradually evolving, relentlessly progressive, neuronal death. Science has shown that a considerable portion of disorders that are classed as degenerative are associated with genetic predisposition which results in a pattern of dominant or recessive inheritance. However, others, although they do not differ in a fundamental way from the hereditary disorders, may occur only sporadically as isolated instances within a given family. As a consequence, since by definition, classification of degenerative diseases cannot be based upon exact knowledge of their cause or pathogenesis, subdivision of these diseases into individual syndromes rests upon descriptive criteria based largely upon pathologic anatomy and consideration of clinical aspects. As a result, this group of diseases presents itself in the form of several clinical syndromes. However, apart from the general differences that allows the distinction of one syndrome from another, there are certain general attributes which typify this entire class of disorders. The degenerative diseases of the nervous system can typically be divided into disorders characterized by progressive dementia in the absence of other prominent neurologic signs (e.g., Alzheimer's disease, senile dementia, and Pick's disease); syndromes which combine progressive dementia with other prominent neurologic abnormalities (e.g., Huntington's disease, Hallervorden-Spatz, and progressive familial myoclonic epilepsy); syndromes of gradually developing abnormalities of posture and movement (e.g., Parkinson's disease, striatonigral degeneration, torsion dystonia, and Gilles de la Tourette syndrome); syndromes of progressive ataxia (e.g., cerebellar cortical degeneration, olivopontocerebellar atrophy, and Friedgreich's ataxia); and syndromes of muscular weakness and wasting without motor neuron disease (e.g., amyotrophic lateral sclerosis, spinal muscular atrophy, and hereditary spastic paraplegia), to name but a few. Among those diseases listed above, perhaps those most familiar are Alzheimer's and Parkinson's diseases. These diseases are progressive neurological disorders characteristically associated with aging. Alzheimer's disease is characterized by a profound loss of memory and other cognitive functions, while Parkinson's disease is an extrapyramidal movement disorder. Both are invariably fatal. Although there is no effective treatment for Alzheimer's disease, clinical trials are underway with several drugs that increase brain cholinergic transmission. In Parkinson's disease, several treatments are temporarily useful, notably L-DOPA related therapies that replace dopamine in the nigrostriatal pathway. However, in Parkinson's disease the therapeutic efficacy of even the best drugs is temporary at best. Although the loss of neurons in the late stages of Alzheimer's disease is profound, only a few neuronal pathways appear to be affected in its earliest stages. These include cholinergic projections from the nucleus basalis to the cerebral cortex and from the septum to the hippocampus, noradrenergic projections from the locus cerululus to the cerebral cortex, and several peptidergic neurons that are probably intrinsic to the cerebral cortex. The loss of the aforementioned cholinergic pathways in particular is believed to underlie the early memory loss, since these pathways are known to be important for memory and cognition. This association accounts for the major emphasis in novel cholinergic treatments for Alzheimer's disease, at least in its early stages. A recent study on Alzheimer's disease demonstrated that loss of cholinergic projections from the nucleus basalis to the cerebral cortex was sufficient, after extended intervals, to cause trans-synaptic neuron loss in the rat. Thus, it is conceivable that the early loss of analogous cholinergic neurons in Alzheimer's disease could cause a profound cascade phenomenon resulting in the loss of many neurons over a period of years. If so, then replacement therapy might not only improve survival of these neurons, but perhaps more important, keep other brain cells from dying. Given the possibility of such therapy, it is of primary importance to determine the type of cholinergic agent most likely to improve memory and/or keep brain neurons from dying after the loss of cholinergic neurons. To address this issue, it is necessary to consider the two general types of cholinergic transmission in the brain. One is termed muscarinic, the other nicotinic. These terms are based on the type of receptor to which acetylcholine binds to in order to elicit its neurotransmitter effect. In brain regions associated with memory, the muscarinic receptors predominate quantitatively over the nicotinic receptors, although both types coexist. For this reason, most investigators traditionally focused on the development of muscarinic agonists to improve memory-related behaviors. These agents have been found to have moderate effects in rats with lesions of the nucleus basalis, but have little effect in patients with pronounced Alzheimer's disease. There is reason to believe, however, that nicotinic transmission may also be important for treating Alzheimer's disease. This is supported by the fact that cerebral cortical nicotinic receptors decrease significantly during the disease, while post-synaptic muscarinic receptor levels are often unchanged. These observations are consistent with the hypothesis that neurons expressing nicotinic receptors are lost in the disease. When these observations are combined with those of the present inventors, that lesions of ascending cholinergic neurons from the nucleus basalis cause a trans-synaptic neuron loss in the cortex, it is hypothesized that the neurons in the cortex that die trans-synaptically (and in Alzheimer's disease) do so because they do not receive enough nicotinic stimulation. For this reason, the inventors believe nicotinic agents may be useful as replacement therapy for keeping brain neurons alive in Alzheimer's disease that would otherwise die from lack of nicotinic transmission. An analogous situation exists in several other systems such as: (a) muscle cells, which atrophy in the absence of nicotinic activation; (b) sympathetic ganglia, which require either nerve growth factor or nicotinic transmission (in the presence of calcium ions) in order to survive in culture; and (c) nigrostriatal dopamine neurons, which appear to be partially spared by nicotine following lesions of the substantial nigra. Also, it is important to note that there exist several types of nicotinic receptors in the brain, which allows considerable potential selectivity in targeting drugs for certain nicotinic sites. The observation that nicotine treatment can preserve nigrostriatal dopamine neurons in an animal model for Parkinson's disease is consistent with epidemiological evidence that there is a lower incidence of this disease in cigarette smokers (even after adjusting for the smoking-induced increase in mortality). The mechanism whereby nicotine can preserve these neurons is not known, but it does appear to involve effects of nicotinic transmission on dopamine neurons themselves, since these neurons possess this type of cholinergic receptor. While the remainder of this patent application focuses on the potential treatment of Alzheimer's disease with nicotinic receptor agents, it should be noted that these drugs may be just as effective, or more so, on dopaminergic neurons that are lost in Parkinson's disease. Nicotine has been used in several clinical trials for the treatment of Alzheimer's disease, primarily over rather short intervals for its potential memory enhancing effect (not for its ability to block long term trans-synaptic cell loss). In one recent study, nicotine had a marginally positive effect on memory and an even greater one of improving the mood of the patients. These positive results have not been followed up with longer term ones, however. Unfortunately, while nicotine has a history of improving memory related behaviors in humans and animals, its potent toxicity, low effective dose range, and peripheral side effects, have basically rendered it unacceptable for treating Alzheimer's disease. Thus, considerable need exists for agents which stimulate cholinergic transmission, but, unlike nicotine, are relatively non-toxic. The present invention provides a method of using agents which have this capability. The present invention arose out of the discovery that anabaseine, DMAB-anabaseine, and anabasine could be used to improve overall brain neurocortical cholinergic activity. The interaction of these agents with nicotinic receptors has decreased levels of toxicity as compared to nicotine. In the absence of long term studies for the clinical effectiveness of nicotine or its analogs for degenerative neural diseases, such as Alzheimer's or Parkinson's disease, the present invention has developed the nucleus basalis lesioned rat as a model for trans-synaptic neuronal degeneration caused by the loss of ascending neurons. Bilateral lesions of cholinergic neurons in the nucleus basalis were induced with ibotenic acid to cause long-term, essentially irreversible deficits in neocortical choline acetyltransferase activity, an enzyme selective for cholinergic neurons. However, passive avoidance behavior, a learning and memory paradigm particularly sensitive to nucleus basalis-lesions, reportedly recovers to normal levels sometime between 2-8 months post-lesioning. Various other aspects and attendant advantages of the present invention will be more fully appreciated from an understanding of the following detailed description in combination with the accompanying examples. FIG. 1 Effects of NBM lesions on anabaseine-induced improvement in passive avoidance behavior. FIG. 2 Effects of NBM lesions on DMAB-anabaseine-induced improvement in passive avoidance behavior. FIG. 3 Effects of anabasine on passive avoidance behavior. FIG. 4 Effect of DMAB-anabaseine on performance of aged rats in the 17-arm radial maze. FIG. 5 Effect of DMAB-anabaseine on performance of aged rats in the Lashley III maze. FIG. 6 Aspartate release from brain tissue exposed to anabaseine. FIG. 7 Aspartate release from brain tissue exposed to DMAB-anabaseine. Anabaseine, 2-(3-pyridyl)-3,4,5,6- tetrahydropyridine, occurs in certain marine worms, which use the substance to paralyze prey and deter predators (Kem, et al., Toxicon, 9:23, 1971). Anabaseine is a potent activator of vertebrate neuromuscular nicotinic acetylcholine receptors (Kem, Amer. Zoologist, 25:99, 1985). Both nicotine and anabaseine possess a non-aromatic ring attached to the 3-position of a pyridyl ring. Anabaseine's non-aromatic tetrahydropyridine ring imine double bond is conjugated with π-electrons of the 3-pyridyl ring. The imine nitrogen is a much weaker base than the pyrrolidinyl nitrogen of nicotine (Yamamoto, et al., Agr. Biol. Chem., 26:709, 1962). Considerable evidence (Barlow and Hamilton, Brit. J. Pharmacol., 18:543, 1962) exists that the non-aromatic ring nitrogen of nicotine must be protonated (cationic) in order to avidly bind to the skeletal muscle nicotinic receptor and activate the opening of its channel. At physiological pH, anabaseine also exists in a hydrolyzed ammonium-ketone form as well as the cyclic imine (unionized) and cyclic iminium (monocationic) forms. The inventors have determined that anabaseine acts as a central nicotinic receptor agonist primarily through its cyclic iminium form. The synthesis of anabaseine was first reported in 1936 (Spath, et al., Chem. Ber., 69:1082, 1936). Unfortunately, this technique utilized an elaborate isolation scheme involving a distillation and preparation of a picrate. Medicinally, the picrate is of no useful value, in fact, since picrate is toxic and potentially explosive, its presence precludes the direct use of anabaseine in physiological systems when produced by this technique. The first analog of anabaseine to be synthesized was 3-[p-(dimethylamino) benzylidene]-3,4,5,6-tetrahydro-2,3'-bipyridine, also termed DMAB-anabaseine (Kem, et al., Toxicon, 9:23, 1971). This compound, resulting from the electrophilic attack of Ehrlich's reagent upon anabaseine, is a stable orange-colored compound. The present invention provides an improved method for synthesizing anabaseine which overcomes the problems associated with prior disclosed techniques for its synthesis. The first part of the improved synthesis of anabaseine, the joining of an activated derivative of nicotinic acid and a modified 2-piperidone, is performed using a mixed Claisen condensation. The second part of the synthesis involves the hydrolysis and decarboxylation of the condensed product. The overall reaction sequence is shown below. ##STR1## In the scheme presented herein, certain protecting and activating groups are specifically illustrated. However, one skilled in the art will recognize that other protecting and activating groups could have been used. For example, a variety of amino protecting group can be used to protect the nitrogen of 2-piperidone (1). Representative amino protecting groups are C1 -C4 alkanoyl, benzyl, and trialkylsilyl derivatives such as trimethylsilyl and butyldimethylsilyl. The preferred amino protecting group is trimethylsilyl (TMS). The TMS-protected 2-piperidone (2) is prepared by deprotonation and subsequent reaction with trimethylchlorosilane. Typical silylation conditions are the use of lithium diisopropylamide (LDA) in an inert solvent such as tetrahedrofuran (THF) at -70� C. For each one mole of 2-piperidone, at least one mole of LDA, preferably 11/2 moles, should be used to ensure complete silylation. While maintaining the temperature at -70� C., at least one molar equivalent of TMS is combined with the LDA-added reaction mixture. Normally, silylation is complete within a few hours by raising the reaction temperature to ambient temperature. The protected 2-piperidone (2) is next enolyzed to an enolate by base. Conveniently, this enolization can be conducted by simply adding additional LDA to the reaction mixture containing compound (2). Although this is a preferred process, other suitable bases which can be employed include metal amides such as NaNH2 or KNH2, metal hydrides such as NaH or KH, and metals such as Na or K. In practice, the reaction mixture is cooled to -70� C., at which point at least one molar equivalent of LDA is added. Enolization is usually complete within an hour, and the resultant amide enolate (3) can be directly used in the next condensation reaction. The key Claisen condensation between a 2-piperidone enolate and a nicotinic acid derivative can be carried out, e.g., by combining the lithium amide enolate (3) in an inert solvent such as THF with about one molar equivalent of ethyl nicotinate. Reaction temperature can be varied, but it is preferred to start the condensation at -70� C. and to allow the temperature to warm up to ambient temperature. Reaction requires a few hours to 24 hours until its completion. Although an ethyl ester form of nicotinic acid (4) has been illustrated hereinabove, activation of the carboxylic group to expedite condensation can be achieved by other activating groups known in the art. Especially useful in the herein described condensation are anhydrides, particularly cyclic anhydrides, acid halides, and activated esters such as those derived from N-hydroxysuccimide and N-hydroxypthalimide. Alkyl esters of up to C5 other than ethyl ester can also be used. The condensed product (5) is isolated after removal of TMS group by hydrolysis. The product (5) is normally subjected to hydrolysis and decarboxylation without further purification. Conversion of compound (5) to the final anabaseine (6) is accomplished by first hydrolyzing compound (5) with a strong acid such as concentrated hydrochloric acid; and by second decarboxylating the intermediate β-keto acid (not shown in the above scheme). Both hydrolysis and decarboxylation steps are conveniently conducted in one-pot in the presence of concentrated hydrochloric acid at an elevated temperature, e.g., under reflux. Anabaseine (6) is thus obtained as its dihydrochloride. Anabasine is commercially available from Aldrich Chemical Co. Alternative sources of anabasine are reduction of anabaseine. Reduction of anabaseine to anabasine can be achieved by several ways: (1) Hydrogeneration with hydrogen over Pd/C, as described in E. Spath et al., Chem. Ber. 69, 1082 (1936); (2) Borohydride reduction with either NaBH3 CN or with NaBh4, as described in E. Leate, J. Org. Chem. 44, 165 (1979); and (3) Reduction with hot formic acid. Anabasine having the following formula contains an asymmetric center at the 2-carbon of the piperidine ring. ##STR2## Thus, anabasine can exist as an optically active form. The present invention embraces such optically pure anabasine, the pure enantiomers thereof, and the racemate thereof. Anabaseine and anabasine in their free base form will form acid addition salts, and these acid addition salts are non-toxic and pharmaceutically acceptable for therapeutic use. The acid addition salts are prepared by standard methods, for example by combining a solution of anabaseine or anabasine (base) in a suitable solvent (e.g., water, ethyl acetate, acetone, methanol, ethanol or butanol) with a solution containing a stoichiometric equivalent of the appropriate acid. If the salt precipitates, it is recovered by filtration. Alternatively, it can be recovered by evaporation of the solvent or, in the case of aqueous solutions, by dyophilization. Of particular value are the sulfate, hydrochloride, hydrobromide, nitrate, phosphate, citrate, tartrate, pamoate, perchlorate, sulfosalicylate, benzene sulfonate, 4-toluene sulfonate and 2-naphthalene sulfonate slats. These acid addition salts are considered to be within the scope and purview of this invention. As a result of using the above method for the synthesis of anabaseine: (1) the chemistry is cleaner and simpler; (2) higher yields of anabaseine are obtained; and (3) picric acid is not present, such that a more directly pharmacologically useful form of anabaseine is produced. The term "therapeutically effective" means that the amount of nicotinic receptor agent used is of sufficient quantity to increase brain cholinergic transmission. The dosage ranges for the administration of the agent of the invention are those large enough to produce the desired effect in which the nicotinic receptors show some degree of stimulation. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary from about 1 μg/kg/dose to about 1000 μg/kg/dose, preferably from about 10 μg/kg/dose to about 500 μg/kg/dose, most preferably from about 30 μg/kg/dose to about 100 μg/kg/dose in one or more dose administrations daily, for one or several days. Alternatively, the dosage can be administered indefinitely in order to prevent a recurrence of cognitive function loss, for example, by administration of the agent in a slow-release form. The nicotinic receptor agent of the invention can be administered enterally, parenterally, or by gradual perfusion over time. The nicotinic receptor agent of the invention can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally, or orally. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. In order to form a pharmaceutically acceptable composition suitable for effective administration, such compositions will contain an effective amount of the nicotinic receptor agent, together with a suitable amount of a carrier vehicle. Additional pharmaceutical methods may be employed to control the duration of action. Controlled release preparations may be achieved by the use of polymers to complex or adsorb the nicotinic receptor agent. The controlled delivery may be exercised by selecting appropriate macromolecules (for example, polyesters, polyamino acids, polyvinyl pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, and protamine sulfate) and the concentration of macromolecules as well as the methods of incorporation in order to control release. Another possible method to control the duration of action by controlled release preparations is to incorporate the nicotinic receptor agent into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly (lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating the nicotinic receptor agent into these polymeric particles, it is possible to entrap the nicotinic receptor agent in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacrylate) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions. Such teachings are disclosed in Remington's Pharmaceutical Sciences (17th Ed., A. Oslo, ed., Mack, Easton, Pa. 1985). The invention also relates to a method for preparing a medicament or pharmaceutical composition comprising the nicotinic receptor agent of the invention, the medicament being used for therapy to stimulate brain cholinergic transmission. The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention. A dihydrochloride crystalline form of anabaseine was prepared via the initial synthesis of 3-nicotinoyl-2- piperidine enolate which was then hydrolyzed and decarboxylated to yield anabaseine. 1) Preparation of 3-Nicotinoyl-2-piperidine Enolate ##STR3## a) Reaction A 250 mL flask equipped with a nitrogen inlet was flame dried and charged with nitrogen. Dry THF (40 mL) was added to this flask and cooled to -70� C. in a dry ice/acetone bath before 38 mL (57 mmol, 1.5 eq) of 1.5M LDA in cyclohexanes (from Aldrich) was added. A solution of 5.68 g (57.3 mmol, 1.5 eq) of 2-piperidone (previously dried) in 15-20 mL of THF (distilled from sodium and benzophenone to dry) was added through a cannula over a period of 20 min to the stirring LDA solution at -70� C. to form the deprotonated amide. While stirring the reaction mixture at -70� C., 7.2 mL (56.7 mmol, 1.5 eq) of trimethylsilyl chloride was added through an oven-dried syringe all at once. The resulting solution was stirred at -70� C. for 15 min and at room temperature or 2 hrs to form the TMS protected piperidone. The solution turned milky colored and a solid precipitate (thought to be LiCl) formed after a few minutes at -70� C. The precipitate dissolved and the solution was clear yellow at room temperature. The reaction mixture was cooled back down to -70� C., before another 38 mL (57 mmol, 1.5 eq) of 1.5M LDA was added with stirring to form the amide enolate. After stirring the reaction mixture at -70� C. for 20 min, 5.2 mL (38 mmol, 1 eq) of ethyl nicotinate was added. The reaction mixture was stirred vigorously at -70� C. for 20 min and at room temperature for 17 hrs. After stirring at room temperature for 30 min the reaction mixture was cloudy and after 90 min the reaction mixture contained a precipitate. The yield can be increased if 2 equivalents of the protected 2-piperidone enolate are used instead of 1.5 equivalents. After stirring for 17 hrs at room temperature, the reaction mixture was thick with cream colored precipitate (product). Water (50 mL) was added and the reaction mixture was stirred for 15 min to hydrolyze the TMS protecting group. The thick pasty precipitate was filtered out of the reaction mixture. The precipitate appeared to pick up water on standing but then formed a stable pale yellow solid. The solid was dried in a drying pistol to yield 8.060 g of pale yellow powdery solid product (mp>250� C.). This solid was used without further purification. The remaining phases (water and organic) from the reaction mixture can be checked for product using ferric nitrate (Fe(NO3)3). An aqueous solution of ferric nitrate turns dark blue or purple in the presence of a compound. Add a couple drops of ferric nitrate solution to a neutralized sample of the aqueous or organic phases from the reaction mixture to check for additional product. 2) Hydrolysis/Decarboxylation of 3-Nicotinoyl-2-piperidone Enolate to Anabaseine ##STR4## a) Reaction The lithium enolate of 3-nicotinoyl-2-piperidone (4.94 g) of step 1 was added slowly to a round bottom flask containing 30 mL of concentrated HCl which was chilled in an ice bath and stirred. The enolate was not readily soluble. The reaction mixture was heated at reflux under nitrogen overnight to effect the hydrolysis and decarboxylation. The product, anabaseine dihydrochloride, was very water soluble. The reaction should not be diluted with too much aqueous acid or the product will not crystallize during the work up. Next, the reaction mixture was cooled to room temperature and diluted slowly with isopropyl alcohol to a volume of about 350 mL. The isopropyl alcohol solution was cooled in the refrigerator and the product slowly crystallized. The solution was allowed to warm to room temperature before filtering the 3.88 g of white needle-like crystalline solid (mp 173�-178� C., decomp). The filtrate was cooled in the refrigerator to yield 0.209 g of a second crop of product. The first crop of solid was recrystallized by adding it to about 200 mL of hot isopropyl alcohol and adding 6M HCl slowly to the boiling mixture until all of the solid dissolved (about 5 mL of HCl was added). After cooling the solution in the refrigerator, 3.26 g of anabaseine dihydrochloride was collected (mp 175�-180� C., decomp). Anabaseine dihydrochloride was prepared in 56% overall yield based on the moles of ethyl nicotinate used Since the dry crystalline solid product is not hygroscopic, but the wet solid may pick up water after filtration, filtration should be performed, for example, under nitrogen atmosphere. A. Passive Avoidance Behavior Male Sprague Dawley albino rats were used for all studies and were maintained in departmental animal facilities, using NIH guidelines for care of animals. Where lesioned animals were tested, lesions were induced in anesthetized animals by bilateral infusion of ibotenic acid (5 μg in 1 μl) or phosphate buffered saline (PBS) into the nucleus basalis region. For passive avoidance behavior, animals received a moderately strong shock (0.8 m Amp) for 1 second after entering a dark room. After 24 hours, the animals were again tested to determine if they could remember to stay out of the dark room. Animals were only allowed 5 minutes to make their choice, when they were removed from the lighted chamber. For testing the effects of drugs in animals that were not lesioned, shocks were only 0.5 m Amp in intensity, and in the animals were allowed 72 hours until they were tested after training. In all drug-treatment studies, the drugs were injected intraperitoneally in saline diluent 5 minutes before the trial and 5 minutes before the testing period. As shown in FIGS. 1 and 2, anabaseine and DMAB-anabaseine, respectively, were more potent in lesioned then in unlesioned animals. For nicotine, 0.05 mg/kg was effective in unlesioned animals, while 0.02 mg/kg was effective in lesioned animals. For anabaseine, a similar 2.5 fold shift was observed. For both of these drugs, the animals were also more sensitive after lesioning in that 0.2 mg/kg doses interfered with training or behavior. For DMAB-anabaseine, potency was increased between 2-2.5 fold by lesioning. The effect of (-)anabasine on passive avoidance was also determined using unlesioned animals (FIG. 3). In these experiments (-)anabasine was injected intraperitoneally 5 min. before training and testing in the passive avoidance apparatus. Only animals that trained within 300 sec the first time were used (i.e., those animals that entered the dark compartment and received a mild foot shock). These results indicate that anabaseine, DMAB-anabaseine, and anabasine can improve this type of memory-related behavior, apparently by binding to and activating nicotine transmission, even in animals with reduced neocortical cholinergic activity. This latter state mimics that seen in Alzheimer's disease. B. Radial Maze Testing The 17 arm radial maze requires animals to remember a baited set of 8 arms out of the 17 total arms. At the start of each daily trial, rats are placed in the center of the maze and permitted to choose among the 17 arms until all 8 food rewards are taken or until fifteen minutes elapse. Those animals that reach a performance criteria of 17 arm choices on two consecutive days of testing during the first 14 days of testing are continued in testing for an additional 30 days. For such animals, only data collected after day 14 are used in the statistical analyses. Statistical analyses are done on 3 sets of data. The first is a measure of general learning: the percent correct choices (entries into baited arms) over the first 8 arm choices. The second is a measure of short term memory (working memory) calculated from the first 12 arm choices: the percent of choices into baited arms (containing food) over the total number of choices within the baited set. Working memory, an interatrial measure of short term memory, measured the rat's ability to remember which of the arms in the baited set were previously entered and the food reward taken. The third set of data measured long-term or reference memory and also was calculated from the first 12 arm choices. Reference memory, defined as an inter-trial measure, is the percent correct choices in the baited set over the total number of arm choices. Two groups of aged rats were tested in the 17-arm radial maze. One group as given 0.2 mg/kg nicotine (n=5) and the other 2 mg/kg DMAB-anabaseine (n=5) at 15 minutes prior to each daily trial. The purpose of these injections was to determine if activation of nicotinic receptors (by nicotine or DMAB-anabaseine) can enhance the poor learning ability and long term memory of aged rats in this task. As shown in FIG. 4, DMAB improved a measure of long term memory without affecting the short term memory of the animals. This selective effect is sometimes typical of nicotine and other memory/learning paradigms. C. Lashley III Maze Testing The Lashley III maze tests an animal's ability to learn a series of left-right alternation turns. Six alternation errors are possible for any given daily trial; chance performance level is 3 errors per trial. Previous studies have shown that young adult sham operated animals quickly learn to reduce their number of alternation errors to near zero by the end of the test period. By contrast, 23 months old (Aged) sham operated animals made substantially more errors over the 25 days of testing. Moreover, bilateral nucleus basalis lesioning of aged rats resulted in an even greater learning deficit compared to aged, sham-lesioned animals. Therefore, both age- and lesion-induced learning deficits were observed. Nonetheless, all groups did improve their performance over time. Aged animals injected with saline or DMAB-anabaseine were evaluated in the Lashley III maze (FIG. 5). When injected at a 2 mg/kg dose before training, DMAB reduced the number of errors that the aged animals made in this maze over the first two blocks of tests. This reflected an improvement in another memory-related behavior with this nicotine agonist. Neurotransmitter release from synaptosomes provides a potential marker for receptor-activity at different types of nerve terminals. Neurotransmitter release from intact slices or minces provides a marker for receptor activity at many sites on the neuron. A comparison of the effects of nicotine and other drugs on synaptosomes versus slices provides some idea as to the location of nicotinic receptors on different types of cerebral cortical neurons, as well as their cellular location. These different types of cerebral cortical transmitter systems have been tested. The first is the cholinergic; the procedures used to load cholinergic neurons or slices with newly synthesized [3H]ACh were described previously (Meyer, et al., 1987). The second is aspartate, an excitatory amino acid which, like glutamate, is associated with memory (long term potentiation) and neuropathology (e.g., stroke). The third type of neurotransmitter is GABA, which is the predominant transmitter in the cerebral cortex and is therefore very likely to receive cholinergic innervation. In order to measure aspartate or GABA release, tissues were incubated with 100 nM [3H] aspartate or 250 nM [3h] GABA in Krebs Ringer buffer at 37� C. for 30 minutes, then washed them in ice cold buffer. All release-incubations were at 37� C. for 15 minutes in the presence or absence of 50 mM KCl (depolarization). Radiation accumulation was also measured in slices in order to express the released levels of transmitter as % of total transmitter, since slices were somewhat variable with respect to accumulation of label. K+ induced release of transmitter was determined by subtracting the basal release from that in the presence of the elevated K+, such that only the incremental release was determined. Neurotransmitter levels (aspartate, glutamate) and enzyme levels were assayed as described by Arendash, et al., Science, 238:952, 1987. Nicotine, anabaseine, and DMAB-anabaseine were found to have no effect on the basal or 50 mM KCl induced release of newly synthesized [3H]ACh form synaptosomes. Also, no effect was seen on the release of [3H] aspartate from isolated terminals. Consequently, there do not appear to be nicotine receptors or aspartate terminals (or glutamate terminals, since aspartate may be taken and released from glutamate terminals) in the cerebral cortex. In studies on brain tissue slices, nicotine (100 nM) increased the K+ induced release of aspartate from slices without affecting the spontaneous release of transmitter (FIG. 6). The fact that nicotine can directly depolarize aspartate neurons without increasing basal release as well as K+ induced release is surprising. One hypothesis is that nicotine stimulates another type of neuron (presumably excitatory) to dis-inhibit the release of aspartate; this dis-inhibition would not be seen except when the aspartate neuron itself was activated by depolarization. Interestingly, anabaseine and DMAB-anabaseine (except at one low concentration) did not increase aspartate release in a dose-related manner (FIGS. 6 and 7). Thus, the effect on depolarization-induced aspartate release was correlated with inhibition of high affinity [3H] nicotine binding, not the inhibition of [3H]ACh or [3H]methcarbachol binding This pattern was also observed with [3H]ACh release and [3H]GABA release from cortical slices. Nicotine (100 nM) increased the K+ induced release of ACh but reduced the K+ induced GABA release from slices, while anabaseine (1 μM) had no effect on either process. Nicotine also increased basal ACh release, suggesting a direct excitatory effect on intrinsic cholinergic cell bodies (not terminals, from synaptosome studies described above). Thus, it appears that the ability of nicotinic types of compounds to modulate neurotransmitter release is not mediated through one of the receptors with high affinity for anabaseine, or DMAB-anabaseine. The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made without departing from the spirit or scope of the invention. Patent Citations
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Isle Royale
Syllabification: Isle Roy·alePronunciation: /ˌīl ˈroiəl
Definition of Isle Royale in English:
An island in Michigan, in western Lake Superior, near Grand Portage in Minnesota. Part of a national park, it is noted for its wildlife.
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Winnipeg Free Press - PRINT EDITION
We uncover naked people making the news
Now that another snowstorm has left our city looking like Antarctica -- which is appropriate considering the zoo will soon be home to a "waddle" of penguins -- it seems like the perfect time for another instalment of our semi-recurring feature Naked People in the News.
Normally, this is a journalistic topic we only confront when the weather turns warm, but we are willing to make an exception today because we have become aware of a dangerous trend involving people making headlines via the technique of doing incredibly stupid things without the benefit of clothing.
As a crusading investigative journalist, we have also become aware of the fact that, if you repeatedly type the word NAKED in big block letters, you will get kajillions of Internet hits from bored office workers who are trapped in tiny cubicles and have way too much time on their hands.
Our new journalistic motto is: "If you are NAKED, we will cover you." NAKED! NAKED! NAKED! Please don't thank us. We are just doing our job.
Which, not surprisingly, brings us to our first nude newsmaker, a 24-year-old Iowa man named José Angel Perales Jr., who was arrested after being captured on surveillance video breaking into a lingerie store after hours and stealing goods.
According to news reports, the security footage reveals the burly suspect wandering around the boutique for several hours and trying on various lingerie items before leaving in (why not?) a red dress and a blond wig.
The stories state police did not have a lot of trouble tracking down their suspect. This was partly due to good old-fashioned policing, but we suspect it didn't hurt that, when they examined the security video of Perales wandering around NAKED, they noticed he had his last name tattooed on his back.
We know what you are thinking here. You are thinking: "Do not rush to judgment, Doug. This is the kind of unfortunate incident that could happen to anyone."
Well, you are correct, but if we have said it once, we have said it a million times: "If you are going to rob a lingerie store, at minimum you should take the standard precaution of wearing a camisole, a negligee and several brassieres, especially if you are a full-figured bandit."
But we don't have time to ponder the implications of this groundbreaking case, because we need to devote our mental energy to our next naked newsmaker, whose unclad antics have gone viral.
If you want to check this one out for yourself, just go to the video-sharing site and search for "naked man in hotel hallway." Here's a helpful research tip: Try to do this when your wife is not home if you want to avoid embarrassing conversations such as this:
My wife: "What the (bad word) are you doing?"
Me: "Just researching a column, honey."
My wife: "You're not the man I married."
Getting back to our story, according to several hard-hitting online news reports, what happened is a man at an unidentified hotel managed to lock himself out of his room when he stepped into the hallway to leave some dirty room-service dishes for hotel staff to pick up.
When the door to his room closed behind him, the man realized he was locked out because he didn't have his key with him. This is probably because he was wearing nothing but his birthday suit at the time.
Closed-circuit security footage uploaded to YouTube shows him wandering naked through the hallways, past other guests and into an elevator, using two plate covers to shield his modesty, as he casually makes his way to the front desk.
"I locked myself out of my hotel room," the naked man can be heard explaining on the video clip.
"Do you have any ID?" the front desk clerk responds. "I just need to see your driver's licence."
The naked man is indignant. "How can I have a driver's licence if I'm naked, man?" he snorts.
So far, thousands and thousands of people around the globe have watched this clip and more than a few viewers have suggested it might be a stunt, which is entirely possible. I mean, who among us has NOT strolled with no visible means of support through a major hotel simply for comic hijinks?
Regardless, the bottom line (if you catch our subtle drift) is this tragedy could happen to anyone, so if you plan to stay at a posh hotel in the near future, please remember this important safety tip -- Never EVER order room service!
Republished from the Winnipeg Free Press print edition March 6, 2013 A2
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Gwen Stefani showed up in London today wearing this jumpsuit, and while I think she looks totally fierce, it's such a utilitarian garment that I couldn't help but do a side-by-side comparison with this beaming stock photo model who is pretending to be a mechanic. So, whose look do you prefer?
Zergnet: Simply Irresistible
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