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In 2009, ChipMOS Technologies (Bermuda) imos 0.1141552511415525% ChipMOS TECHNOLOGIES Bermuda Ltd. U.S.: Nasdaq USD17.54 0.02 0.1141552511415525% /Date(1469653200300-0500)/ Volume (Delayed 15m) : 194344 P/E Ratio 23.7027027027027 Market Cap 479469862.68631 Dividend Yield 0.798175598631699% Rev. per Employee N/A More quote details and news » almost collapsed after two of its top customers, which together accounted for 40% of its revenue, went belly up. Today, it is positioned for growth that could boost its shares by 30% from current levels. And they have already doubled this year.
The small semiconductor assembly and testing outfit's remarkable comeback is being fueled by some of the hottest markets around, including smartphones, tablets, and vehicle infotainment systems.
Established in 2000, ChipMOS bases its operations in Taiwan. (Its holding company, however, is located in Bermuda; hence the name.) ChipMOS (ticker: IMOS), along with Chipbond Technology (6147.Taiwan), are the main players in the global test-and-assembly industry. The company, which has a stock-market value below $500 million and annual sales of around $600 million, processes, checks, tests, and modifies silicon wafers produced by Taiwan Semiconductor Manufacturing (TSM), Intel INTC -0.7409518381305216% Intel Corp. U.S.: Nasdaq USD34.83 -0.26 -0.7409518381305216% /Date(1469653200374-0500)/ Volume (Delayed 15m) : 22470852 AFTER HOURS USD34.83 % Volume (Delayed 15m) : P/E Ratio 16.82608695652174 Market Cap 165694980720.52 Dividend Yield 2.985931668102211% Rev. per Employee 527624 More quote details and news » (INTC), Fujitsu 6702.TO 2.405130946018172% Fujitsu Ltd. ADR U.S.: OTC USD19.16 0.45 2.405130946018172% /Date(1469657999000-0500)/ Volume (Delayed 15m) : 1292 P/E Ratio 10.467085495766185 Market Cap 7744393940.68335 Dividend Yield N/A Rev. per Employee 252233 More quote details and news » (6702.Japan, Texas Instruments TXN -0.21002520302436292% Texas Instruments Inc. U.S.: Nasdaq USD71.27 -0.15 -0.21002520302436292% /Date(1469653200427-0500)/ Volume (Delayed 15m) : 13740067 AFTER HOURS USD71.33 0.0600000000000023 0.08418689490669286% Volume (Delayed 15m) : P/E Ratio 23.996632996632997 Market Cap 71721889768.8715 Dividend Yield 2.1327346709695525% Rev. per Employee 430297 More quote details and news » (TXN), Himax HIMX -0.6644518272425249% Himax Technologies Inc. ADR U.S.: Nasdaq USD8.97 -0.06 -0.6644518272425249% /Date(1469653200098-0500)/ Volume (Delayed 15m) : 1604851 AFTER HOURS USD8.9 -0.0700000000000003 -0.7803790412486065% Volume (Delayed 15m) : P/E Ratio 62.421711899791234 Market Cap 1552326593.45569 Dividend Yield 1.4492753623188406% Rev. per Employee 366822 More quote details and news » (HIMX), Micron Technology MU -3.2719836400817996% Micron Technology Inc. U.S.: Nasdaq USD14.19 -0.48 -3.2719836400817996% /Date(1469653200274-0500)/ Volume (Delayed 15m) : 34607730 AFTER HOURS USD14.28 0.0899999999999999 0.6342494714587738% Volume (Delayed 15m) : P/E Ratio 45.774193548387096 Market Cap 15233195920.2874 Dividend Yield N/A Rev. per Employee 401950 More quote details and news » (MU) and other customers, and assembles them into components for use in electronic devices.
THE COMPANY'S WOES stemmed from an expansion spree that left it heavily in debt, just as the 2008-2009 financial crisis shook the global economy. Its stock, in the mid-$20s before the downturn, sank to a low of 18 cents in December 2008. "It was a very difficult time," Chief Financial Officer Shou-Kang Chen recalls in a telephone interview from the company's headquarters in Hsinchu. "Our expansion was predicated on contracts with our customers who were hurt badly by the recession, which was out of our control. But we were able to renegotiate our debt, spread out payments, freeze our capital spending, and generally weather the storm."
It also didn't hurt that 2010 saw the start of a turnaround for the semiconductor industry. Or that ChipMOS was able to collect $100 million owed by its biggest customer, Spansion (CODE), which had gone into receivership.
"Because ChipMOS wasn't well known, even though it's listed in the U.S., many investors expected it to go bankrupt, as well," says analyst Richard Shannon with Craig-Hallum Capital in Minneapolis. "But because its business was basically stable, and it was only one of two players in its particular business niche, they were able to recover relatively quickly, moving from a negative 29 cents a share of free cash flow in 2010 to $4.24 in 2011, and toward an expected $3.60 in 2012 and $4.11 in 2013."
At a recent price of $12.63, ChipMOS stock was trading at less than four times this year's expected free cash flow, the metric "that really tells the story of how cheap the stock is, and is the best way to judge the true value of a stock like this," says Shannon. He rates the stock a Buy, with a 12-month price target of $26.
Comments Taz Turner, who runs the New York-based South Shore Capital Partners hedge fund: "Four dollars a share in cash flow this year and probably $5 next year is pretty hard to ignore. And earnings should start to rise in earnest this year, as the company works out from under heavy depreciation and debt left over from its overexpansion in 2006-2007. It's been kind of a Lazarus stock—back from the dead."
Management has focused on the strong demand for liquid-crystal displays for smartphones and tablet computers from customers such as Apple aapl 6.4963277128374886% Apple Inc. U.S.: Nasdaq USD102.95 6.28 6.4963277128374886% /Date(1469653200096-0500)/ Volume (Delayed 15m) : 90512694 AFTER HOURS USD103.45 0.480000000000004 0.48567265662943176% Volume (Delayed 15m) : P/E Ratio 12.026869158878505 Market Cap 529502645839.676 Dividend Yield 2.214667314230209% Rev. per Employee 2050050 More quote details and news » (AAPL), Hewlett-Packard hpq -1.3399153737658673% HP Inc. U.S.: NYSE USD13.99 -0.19 -1.3399153737658673% /Date(1469653289842-0500)/ Volume (Delayed 15m) : 17536777 AFTER HOURS USD13.87 -0.8577555396711937% Volume (Delayed 15m) : P/E Ratio 7.402116402116402 Market Cap 24256408571.3523 Dividend Yield 3.5453895639742674% Rev. per Employee 259770 More quote details and news » (HPQ), Toshiba 6502.TO 0.5194805194805194% Toshiba Corp. ADR U.S.: OTC USD15.48 0.08 0.5194805194805194% /Date(1469658001000-0500)/ Volume (Delayed 15m) : 6098 P/E Ratio N/A Market Cap 10889112362.4023 Dividend Yield N/A Rev. per Employee 251427 More quote details and news » (6502.Japan), and Dell (DELL). The LCD business produced about 35% of ChipMOS' revenue last year, versus 22% in 2009.
Turner adds that "2012 could shape up to be a terrific year for this segment of the semiconductor business, and assembly and test capacity could become tight," given the demand created by Apple's iPad and iPhone, Amazon.com's amzn 0.14682091926208893% Amazon.com Inc. U.S.: Nasdaq USD736.67 1.08 0.14682091926208893% /Date(1469653200391-0500)/ Volume (Delayed 15m) : 2730735 AFTER HOURS USD742.45 5.83000000000004 0.7846118343355912% Volume (Delayed 15m) : P/E Ratio 303.156378600823 Market Cap 347071973346.211 Dividend Yield N/A Rev. per Employee 491412 More quote details and news » (AMZN) Kindle e-reader, smartphones using Google's (GOOG) Android operating system, and lightweight ultrabook laptops from a host of manufacturers.
ChipMOS marketers have also won new customers, such as Asahi Kasei Microdevices 3407.to 0.9268795056642637% Asahi Kasei Corp. ADR U.S.: OTC USD14.7 0.135 0.9268795056642637% /Date(1469658000000-0500)/ Volume (Delayed 15m) : 1252 P/E Ratio 13.449222323879232 Market Cap 10252389603.4439 Dividend Yield N/A Rev. per Employee 492606 More quote details and news » (3407.Japan), which is aggressively expanding outside Japan and could be generating up to 5% of ChipMOS' sales by 2013.
With growing cash flow, the company is likely to be nearly debt-free by year end. Instead, it will have seven cents a share of net cash, versus a negative $2.86 for 2011, estimates Shannon. He sees net cash reaching $4.15 a share in 2013 and $7.22 in 2014.
At the same time, earnings are climbing. Shannon estimates that profits will be $1.85 a share this year and $3.00 in 2013, versus a pro forma 13 cents last year. The company reports first-quarter results on May 18.
Brian Grad, an analyst and portfolio manager with ChipMOS' top institutional shareholder, Bannockburn, Ill.-based DLS Capital, calls the company "massively undervalued." DLS has owned the stock for three years and holds 2.25 million shares, about 7% of the total outstanding. "You can make an argument that ChipMOS is a $30-plus stock…. The industry trades at a multiple of five times to six times and seven times at peaks. That would translate into a $31 stock" by year-end 2013, based on his cash-flow estimates.
THE STOCK ALSO LOOKS cheap on the basis of its price/earnings ratio—seven times expected 2012 net, in an industry that typically fetches 10 times forward earnings. On the same basis, its price-to-earnings growth (PEG) ratio is a modest 0.45.
Some shareholders expect ChipMOS to initiate a dividend eventually. The company will say only that it expects to have sufficient cash flow if its board ever wants to. ChipMOS already has authorization to buy back $10 million worth of its shares, but has difficulty doing so because of Nasdaq regulations.
A boon for shareholders could come if the company's main subsidiary, ChipMOS Taiwan, is listed in Taipei, as bulls believe it will be. ChipMOS Technologies (Bermuda) common, now listed on Nasdaq, would be exchanged for the Taiwan stock, which, in turn, would list American depositary receipts in New York on Nasdaq. The company says it "wouldn't rule out the option," but is noncommital.
Observes Scott Bishins, a Boca Raton, Fla., investor who owns about 1%, or 320,000 shares, of ChipMOS: "If ChipMOS were trading at the same valuation in Taipei as Chipbond currently is, it would be changing hands somewhere between $35 and $40."
Finally, ChipMOS's low price and good prospects could tempt an acquirer, although there's no indication that they have. But deal or no deal, investors who own the stock should eventually be in the chips.
E-mail: firstname.lastname@example.com


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Local College Rejects Request To Allow Students To Carry Guns on CampusFormer Marine says he and others could provide additional security at no additional cost.
Nixon Vows to Veto Sweeping Missouri Gun Rights BillNixon had received more than 4,000 emails, faxes, letters, mail-ins and electronic petitions concerning the bill.
Missouri Senator Roy Blunt Reacts to 'Terrorist Watch List'Missouri Senator Roy Blunt is reacting to calls for a "terrorist watch list" that would prevent some people from buying guns.
All Bodies Removed from Club in Worst US Mass ShootingThe latest information Monday morning, from the attack on an Orlando nightclub early Sunday morning.
Guns at Zoo Case Won't Be Decided This YearCincinnati man wants temporary order upholding ban overturned.
Missouri House Passes Bill to Allow Guns at College CampusesThe deadline to pass legislation is May 13.
Majority of STL Murders Unsolved, Guns Used in All But 4Vast majority of victims and suspects are black men.
Missouri House Advances Bill to Expand Castle Doctrine LawDemocratic opponents say the legislation encourages use of deadly force.
St. Louis Police Stress a No Gun Policy to Cards FansChief Dotson says fans will notice a larger police presence, near the ballpark and surrounding areas for opening day.
Missouri Supreme Court Rules for Suits Against Gun DealersAttorney Alla Lefkowitz of the Brady Center to Prevent Gun Violence says the ruling means Missouri dealers can be held accountable for selling firearms irresponsibly.
Missouri House Committee Votes to Reverse Guns-on-Campus BanThe Select Committee on General Laws will review the bill next.
Missouri Panel Considers More Gun Access on College CampusesThe bill would only apply to public colleges and universities and includes exceptions for areas on campus with grade school children, some sporting events and hospitals.

subset: commoncrawl


text:
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text:
Make sure your girl is top of the class with the new Little Joule collection. Perfect for heading back to school in style, pick up pencil cases, lunchboxes, bags, vests, coats and much more.
RAINDANCE Waterproof Coat
RAINDROP Waterproof Coat
Printed Printed Rain Boots
KINNAIRD Pack Away Jacket
MARCOTTE Quilted Coat
PATCH Rucksack
MUNCH Lunch Box
ACTIVE Drawstring Bag
ZIPPY Rucksack
TODDLER KINNAIRD Padded Jacket
WYNTER Parka-Style Coat


text:
Top Definition
A medical definition used by doctors to refer to any really embarrassing condition. Can also be used in the case of any accident involving damage to the genitalia.
Doctor! Oh my god you have to come see this! This kids has his penis caught in his zipper!
by Laura-Leigh January 16, 2006
Trending Now


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Introduction to Audiology (with CD-ROM) / Edition 9by Frederick N. Martin, John Greer N. Clark
Pub. Date: 06/17/2005
Publisher: Allyn & Bacon, Inc.
"This text does a wonderful job of covering a LOT of topic areas in a relatively short, easy-to-read format."
Alison M. Grimes, California State University, San Bernardino and Fullerton
The leading text for the introduction to hearing and hearing disorders course is now available in a new edition with a valuable new learning CD-ROM!
"This text does a wonderful job of covering a LOT of topic areas in a relatively short, easy-to-read format."
Alison M. Grimes, California State University, San Bernardino and Fullerton
"I would like to compliment the authors on developing, and continuing to refine, a classic book in audiology."
Dr. Carl Crandell, University of Florida
"Introduction to Audiology is exceptionally detailed and complete but can be used to cover any topic an instructor wishes by careful picking and choosing."
Dr. Margaret F. Carlin, University of Southern Mississippi
Highlights of the Ninth Edition:
- Placement of behavioral site-of-lesson testing into a historical note allows room for more detailed discussions of recent objective measures and for new material on licensing/certification, outcome measures, and evidence-based practice.
- Updated material throughout the text, including a thoroughly revised discussion of the rapidly evolving measures of auditory evoked potentials.
- Separate discussions of pediatric and adult hearing aid selection/verification and hearing loss management.
- TECHNOLOGY ADVANTAGE! CD-ROM provides expanded coverage of many topics, illustrative movies, and much more.
Research Navigator for Education
Research Navigator can be your best friend when you'refacing a large research project. Especially helpful with the toughest challengegetting startedResearch Navigator offers a comprehensive, step-by-step walk-through of the research process, along with access to some of the most respected source databases available. Access to Research Navigatora $15 valueis FREE when packaged with any new A&B textbook! If your text did not come packaged with Research Navigator, look for it in your bookstore or visit researchnavigator.com today to purchase immediate access.
The Career Center
Do your students need help transitioning from being a student to becoming a professional? With The Career Center, they can register to receive eight 30-minute career counseling sessionsa total of four hours of career consultant time! The Career Center is designed to address the wide range of preparation and life stages of individuals who are attempting to develop their careers. Qualified career specialists advise students as they establish, or reestablish, themselves in today's competitive global economy. The Career Centera $25 valueis FREE to your students when you order it packaged with any new Allyn & Bacon textbook. Visit ablongman.com/careercenter for more information.
Contact your local Allyn & Bacon representative and request special packaging codes to take advantage of these great offers.
Product Details
- 9780205453306
- Publisher:
- Allyn & Bacon, Inc.
- Publication date:
- 06/17/2005
- Edition description:
- Older Edition
- Pages:
- 504
- Product dimensions:
- 7.50(w) x 9.18(h) x 1.01(d)
Table of Contents
Each chapter begins with "Learning Objectives" and concludes with "Summary," "Study Questions," "References," and "Suggested Readings."
How to Use This Book.
How to Use the CD-ROM.
About the Authors.
1. The Profession of Audiology.
The Evolution of Audiology
Licensing and Certification
Prevalence and Impact of Hearing Loss
A Blending of Art and Science
Audiology Specialties
Employment SettingsProfessional Societies
2. The Human Ear and Simple Tests of Hearing.
Anatomy and Physiology of the Ear
Pathways of Sound
Types of Hearing Loss
Hearing Tests
Tuning Fork Tests
3. Sound and Its Measurement.
Sound Velocity
Complex Sounds
The Decibel
Environmental Sounds
Sound Measurement
4. Pure-Tone Audiometry.
The Pure-Tone Audiometer
Test Environment
The Patient's Role in Manual Pure-Tone Audiometry
The Clinician's Role in Manual Pure-Tone Audiometry
Air-Conduction Audiometry
Bone-Conduction Audiometry
Audiogram Interpretation
The Audiometric Weber Test
Automatic Audiometry
Computerized Audiometry
5. Speech Audiometry.
The Diagnostic Audiometer
Test Environment
The Patient's Role in Speech Audiometry
The Clinician's Role in Speech Audiometry
Speech-Threshold Testing
Masking for SRT
Bone-Conduction SRT
Most Comfortable Loudness Level
Uncomfortable Loudness Level
Range of Comfortable Loudness
Speech-Recognition Testing
Computerized Speech Audiometry
6. Diagnostic Hearing Tests.
Acoustic Immittance
Acoustic Reflexes
Otoacoustic Emissions (OAE)
Auditory Evoked Potentials
An Historical Note
7. Hearing Tests for Children.
Auditory Responses
Identifying Hearing Loss in Infants under 3 Months of Age
Objective Testing in Routine Pediatric Hearing Evaluation
Behavioral Testing of Children from Birth to Approximately 2 years of Age
Behavioral Testing of Children Approximately 2 to 5 Years of Age
Language Disorders
Auditory Processing Disorders
Psychological Disorders
Developmental Disabilities
Identifying Hearing Loss in the Schools
Nonorganic Hearing Loss in Children
8. The Outer Ear.
Anatomy and Physiology of the Outer Ear
Development of the Outer Ear
Hearing Loss and the Outer Ear
Disorders of the Outer Ear and Their Treatments
9. The Middle Ear.
Anatomy and Physiology of the Middle Ear
Development of the Middle Ear
Hearing Loss and the Middle Ear
Disorders of the Middle Ear and Their Treatments
Other Causes of Middle Ear Hearing Loss
10. The Inner Ear.
Anatomy and Physiology of the Inner Ear
Development of the Inner Ear
Hearing Loss and Disorders of the Inner Ear
Causes of Inner-Ear Disorders
11. The Auditory Nerve and Central Auditory Pathways.
Anatomy and Physiology of the Auditory Nerve and Ascending Auditory Pathways
The Descending Auditory Pathways
Development of the Auditory Nerve and Central Auditory Nervous System
Summary of the Auditory Pathways
Hearing Loss and the Auditory Nerve and Central Auditory Pathways
Disorders of the Auditory Nerve
Disorders of the Cochlear Nuclei
Disorders of the Higher Auditory Pathways
Tests of the Higher Auditory Pathways
Tests for Auditory Processing Disorders
12. Nonorganic Hearing Loss.
Patients with Nonorganic Hearing Loss
Indications of Nonorganic Hearing Loss
Performance on Routine Hearing Tests
Tests for Nonorganic Hearing Loss
Management of Patients with Nonorganic Hearing Loss
13. Amplification/Sensory Systems.
Hearing Aid Development
Hearing Aid Circuit Overview
Characteristics of Hearing Aids
Binaural Amplification
Types of Hearing Aids
Selecting Hearing Aids for Adults
Selecting Hearing Aids for Children
Hearing Aid Acceptance and Orientation
Dispensing Hearing Aids
Hearing Assistance Technologies
14. Audiologic Treatment.
Patient Histories
Referral to Other Specialists
Audiologic Counseling
Management of Adult Hearing Impairment
Management of Childhood Hearing Impairment
The Deaf Community
Management of Auditory Processing Disorders
Management of Tinnitus
Vestibular Rehabilitation
Multicultural Considerations
Evidence-Based Practice
Outcome Measures
Author Index.
Subject Index.
Customer Reviews
Average Review:
and post it to your social network
Most Helpful Customer Reviews
See all customer reviews >


text:
Nancy Cerny, co-founder and chef of CVC Catering, made a variety of Super Bowl snacks that will keep you out of the kitchen and in front of your TV during the big game.
Photos: CVC Catering demonstrates easy Super Bowl grubPublished 8:18 AM EST Feb 03, 2013
Slideshow Central
CommentsThe views expressed are not those of this site, this station or its affiliated companies. By posting your comments you agree to accept our terms of use.blog comments powered by Disqus


text:
ORR Innovation Awards 2011: Initiative of the Year
Angelos Deftereos, Oric
As head of the Marsh operational risk practice in New York, Angelos Deftereos has worked hard to bring operational risk management and insurance closer together. To facilitate this goal, he has been instrumental in the formation the Operational Risk Industry Consortium, or Oric. Oric is a working group comprised of large financial institutions set up in 2008. The goals of the group are to enable banks to share best practices regarding the transfer of operational risk, to work with regulators to create...
More on Operational Risk
7 days in 60 seconds
Repo, MVA and securitisation
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Can I get an amen?
It's a gospel hymn for the digital age: "Keep Yo Business Off of Facebook."
That's the church choir's message in what has been called "the greatest song since 'Amazing Grace.'"
"Sunday you actin' like a saint, but yo Facebook status say you ain't," the social media-savvy chorus sang.
The five-week old video is going viral on—of all places—Facebook, so maybe we'll finally have a little less noise on our feeds.
Once you put this on Facebook where it belongs.
H/T Gawker | Photo via Elvert Barnes/Flickr
Promoted Stories Powered by Sharethrough
Japanese teen pop meets death metal in an explosion of awesome
In an age when nearly every song ever recorded is available at a moment's notice, it's easy to get cynical about music. Everything's been done before and we have a never-ending Spotify playlist to prove it.
The great defriending of Facebook
Facebook is changing. Surely you've noticed. Your best friends are getting buried beneath memes; your mom is getting pushed aside by image spam. Your social graph is becoming secondary to your interest graph.
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PHILADELPHIA - The last time the Eagles faced the Baltimore Ravens four years ago, Eagles coach Andy Reid made the shocking decision to bench struggling starting quarterback Donovan McNabb at halftime in favor of Kevin Kolb.
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Sleepy Eye Public School will be hosting a Family Science Night on Thursday, Jan. 30, 5-7 p.m. in the cafeteria.
Family Science Night provides an evening of hands-on science activities where students and parents will work together to conduct simple inquiry-based science activities.
Students and parents can expect to see flaming money, glow flubber and fizzy potion, plus more. Free refreshments will be offered.
Location, ST | website.com


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plant quick find clear
Nemesia is a charming cool-season annual with pretty little snapdragon-shape flowers -- often fragrant -- that bloom in a wide range of colors. It does best in spring and fall (winter in mild-winter climates), though some varieties have better heat-tolerance than others. In cool-summer areas, such as the Pacific Northwest, nemesia will continue to bloom right through the summer into fall. Nemesia prefers moist, well-drained soil that's rich in organic matter.
Part Sun, Sun
Under 6 inches to 3 feet
To 1 foot wide
Foliage Color:
Seasonal Features:
Special Features:
how to grow Nemesia
more varieties for Nemesia
'Aromatica True Blue' nemesia
Nemesia 'Aromatica True Blue' bears fragrant soft-blue flowers on 14-inch-tall plants.
'Candy Girl' nemesia
Nemesia 'Candy Girl' bears soft-pink flowers on compact, 12-inch-tall plants.
'Lemon Mist' nemesia
Nemesia 'Lemon Mist' is a recent selection with purple-and-white flowers blotched in yellow. It blooms profusely in spring and fall, and it grows 7 inches tall and wide.
'Opal Innocence' nemesia
Nemesia 'Opal Innocence' offers fragrant lavender-gray flowers during the cool seasons of spring and fall. It grows 16 inches tall and 8 inches wide.
'Safari Violet Rose' nemesia
Nemesia 'Safari Violet Rose' bears violet-pink flowers on 14-inch-tall plants.
'Serengeti Red' nemesia
Nemesia 'Serengeti Red' is an especially eye-catching selection with deep-red flowers. It grows 10 inches tall.
'Serengeti Sunset' nemesia
Nemesia 'Serengeti Sunset' shows off red flowers streaked in yellow, orange, and pink. It grows 14 inches tall.
'Serengeti Upright Purple' nemesia
Nemesia 'Serengeti Upright Purple' offers lovely purple flowers. It grows 14 inches tall.
'Serengeti Upright Violet + White' nemesia
Nemesia 'Serengeti Upright Violet + White' offers lovely violet-purple flowers marked with white. It grows 14 inches tall.
'Sunsatia Cranberry' nemesia
Nemesia 'Sunsatia Cranberry' bears bold red flowers on plants that trail to 36 inches over the side of a container or basket.
'Sunsatia Pear' nemesia
Nemesia Sunsatia Pear is a frost-tolerant selection that bears white flowers marked with orange. It grows 18 inches tall.
plant Nemesia with
The quintessential cottage flower, pinks are treasured for their grasslike blue-green foliage and abundant starry flowers, which are often spicily fragrant. Depending on the type of pink, flowers appear in spring or summer and tend to be pink, red, white, rose, or lavender, but come in nearly all shades except true blue. Plants range from tiny creeping groundcovers to 30-inch-tall cut flowers, which are a favorite with florists. Foliage is blue-green.Shown above: 'Firewitch' dianthus
Few gardens should be without the easy charm of snapdragons. They get their name from the fact that you can gently squeeze the sides of the intricately shaped flower and see the jaws of a dragon head snap closed. The blooms come in gorgeous colors, including some with beautiful color variations on each flower. Plus, snapdragons are an outstanding cut flower. Gather a dozen or more in a small vase and you'll have one of the prettiest bouquets around.Snapdragons are especially useful because they're a cool-season annual, coming into their own in early spring when the warm-season annuals, such as marigolds and impatiens, are just being planted. They're also great for fall color.Plant snapdragon in early spring, a few weeks before your region's last frost date. Deadhead regularly for best bloom and fertilize regularly. Snapdragons often self-seed in the landscape if not deadheaded, so they come back year after year, though the colors from hybrid plants will often will be muddy looking. In mild regions, the entire plant may overwinter if covered with mulch.Shown above: 'Rocket Red' snapdragon
From tiny, cheerful Johnny jump-ups to the stunning 3-inch blooms of Majestic Giant pansies, the genus Viola has a spectacular array of delightful plants for the spring garden. They're must-haves to celebrate the first days of spring since they don't mind cold weather and can even take a little snow and ice!They're pretty planted in masses in the ground, but also cherished for the early color they bring to pots, window boxes, and other containers. By summer, pansies bloom less and their foliage starts to brown. It's at this time that you'll have to be tough and tear them out and replant with warm-season annuals, such as marigolds or petunias. But that's part of their charm -- they are an ephemeral celebration of spring!


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Jody Geisler | Illinois, United States | Birth Record | 351625958
Jody Geisler is a person located in Illinois, United States. January 11, 1962
JODY D GEISLER - SALON D' AMIS INCORPORATED - Business Profiles
JODY D GEISLER is the Registered Agent and Incorporator of SALON D' AMIS INCORPORATED, registered in Ohio.
classmates: Jody (Hall) Geisler
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Jody Micheal Geisler II, 24, of Bourbonnais, died at 4:15 p.m. Wednesday, Jan. 13, 2010, at Provena St. Mary's Hospital in Kankakee. He was born June 11, 1985, in Watseka, the
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Jody Geisler - Kasota, Minnesota
Jody Geisler. Kayla Geisler, 22, Jun 1992. Megan J Geisler. Thomas J Geisler, 47, Jul 1967. Thomas M Geisler, 27, Nov 1987. Lee And Tia Langevin, 41 ...
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Hardin County, Illinois Obituaries and Death Notices. Jody Geisler, Sr. Graveside services for Jody Michael Geisler, Sr., 44, of Rosiclare will be at 11:00 a.m. ...
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Name: Jody M. Geisler. Birth: date. Death: dd mm 2010 - city, Iroquois, Illinois. Civil: Illinois. Other: city, Hardin, Illinois. U.S., Find A Grave Index, 1600s-Current
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Reducing Risks for Mental Disorders: Frontiers for Preventive...
The understanding of how to reduce risk factors for mental disorders has expanded remarkably as a result of recent scientific advances. This study, mandated by...
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Jody Geisler - 13 January 2010
http://www.myspace.com/466626974 Jody Micheal Geisler II, 24 of Bourbonnais, IL passed away on Wednesday, Jan. 13, 2010 at Provena St. Maryâs Hospital in...
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Jody Geisler 513-988-1933 | 512 Sudbury Dr Trenton Ohio
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Jody M. Geisler, 25, of 544 S. Schuyler Ave., Apt. 3, was arrested by Kankakee police Sunday at that address for domestic battery, according to ...
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Producer, Randy Gosselin, Jody Geisler, Shawn Campbell. Contact Info, 403-813 -8962 or 403-601-4257 or 403-830-1244. Summary, August 24, Enter 8 AM, ...
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|Publication number
|Publication type
|Application number
|Publication date
|Oct 28, 2003
|Filing date
|Jun 19, 1998
|Priority date
|Sep 29, 1997
|Fee status
|Publication number
|Christopher R. Bjornson, Rod L. Rietze, Brent A. Reynolds, Angelo L. Vescovi
|Original Assignee
|Neurospheres Holdings Ltd.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (5), Non-Patent Citations (23), Referenced by (26), Classifications (9), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
The present application is related to U.S. application Ser. No. 09/100,679, now U.S. Pat. No. 6,093,531, entitled "Generation of Hematopoietic Cells from Multipotent Neural Stem Cells", which was filed on Jun. 19, 1998, which claims the benefit of U.S. Provisional Application Ser. No. 60/060,289.
Cell transplantation is increasingly becoming a therapy of choice for a variety of cell-based disorders ranging from sickle cell anemia and diabetes to Parkinson's disease. For example, cell lines may be transplanted to deliver a biologically active agent such as insulin, for the treatment of diabetes; parathyroid hormone, for treatment of hypoparathyroidism; erythropoietin, for treatment of anemia; and gamma-amino-butyric acid, for treatment of epilepsy. The cells may naturally secrete the biologically active molecule, or be genetically modified to do so. There are several obstacles that prevent cell transplantation therapy from realizing its full potential. For example, obtaining quantities of cells suitable for transplantation is often a problem. Cell lines transformed with oncogenes can pose a risk of unwanted cell migration, unrestricted proliferation, and possibly tumor formation. Transplant rejection is also a potential problem. These problems have been addressed by encapsulating the transplanted cells in immunoisolatory vehicles which retain the cells at a desired location within the transplant recipient, where the cells secrete the biologically active substances. The immunoisolatory vehicle prevents unwanted cell migration, possible tumor formation, and reduces the possibility of transplant rejection. Methods of transplanting encapsulated cells are disclosed in U.S. Pat. No. 5,550,050.
For some cell-based disorders, it is necessary for the transplanted cells to become integrated with the host tissue being treated. In these cases, encapsulation methods cannot be used. Thus, it is important that the transplanted cells are human leukocyte antigen (HLA) matched to the patient's tissue to reduce the likelihood of transplant rejection. Hematopoietic stem cell transplantation, is an example of a therapy where donor cells become integrated with the patient's own tissue. It is an effective therapy for a number of diseases, such as sickle cell anemia, aplastic anemia, and a variety of immunodeficiency disorders, including those which result from treatments for other disorders such as chemo- and radiotherapy treatment for cancer (reviewed in Amos and Gordon, Cell Transplantation 4(6):547-569 (1995)). Hematopoietic stem cells, are present in adult bone marrow and blood (in smaller numbers), and are capable of giving rise to all of the cells of the hematopoietic cell lineage. Fetal sources of hematopoietic stem cells in umbilical cord blood and liver, have also been reported. Lu et al., Critical Rev. in Oncol./Hemataol. 22:61-78 (1996).
Certain neurological disorders treated by cell transplantation, also require that the cells become integrated with the host tissue. For example, in the treatment of myelin deficiencies, it is necessary for the transplanted cells to reform the insulating cellular sheaths around the axons of demyelinated neurons. Animal models of myelin deficiencies have shown promising results from the transplantation of undifferentiated neural stem cell progeny into demyelinated regions of the central nervous system. Hammang et al., Experimental Neurology 147:84-95 (1997).
Several tissues in the body contain stem cells. The primary role of stem cells in adults is to replace cells which have been lost by natural cell death, injury or disease. Stem cells have been defined as "undifferentiated cells capable of a) proliferation, b) self-maintenance, c) the production of a large number of differentiated, functional progeny, d) regenerating tissue after injury, and e) a flexibility in the use of these options". Potten and Loeffler, Development, Vol. 110, �. 1001-1020 (1990). Stem cells isolated from the early embryonic blastula, i.e. prior to gastrulation, can produce cell types of all different lineages (for review see Keller, G. M. Curr. Opin. Cell Biol. 7:862-869 (1995)). More recently, it has been hypothesized that neural tissue is likely to be the default state for all cells during early embryonic development. Green, Cell 77:317-320 (1994); Hemmati-Brivanlou & Melton, Cell 88:13-17 (1997). However, in the adult, it is generally believed stem cells present in a specific tissue are restricted to produce cell types of that tissue. For example, hematopoietic stem cells derived from adult bone marrow give rise to progeny of the blood, immune system, and myogenic precursors, but have not been reported to give rise to other tissue types. Ferrari et al. Science 279:1528-1530 (1998). Similarly, adult neural stem cells obtained from neural tissue have only been reported to give rise to neural specific cell types.
In addition to the treatment of various cell-based diseases and disorders, cell transplantation could also be potentially useful for treating injuries and/or strengthening, or otherwise, augmenting various tissues such as, skin, heart muscle, and bone. However, lack of availability of sufficient quantities of compatible, healthy cells of the required phenotype, which can become integrated with the desired tissue, prevents cell transplantation therapies from reaching their full potential. For example, in the treatment of bone marrow diseases, it is difficult to find well-matched donors who are willing to be subjected to the painful and time-consuming bone marrow donation process.
A reliable source of cells that can be used for transplantation, with reduced risk of rejection, to replace or augment cells in a variety of tissues is needed.
It is an object of the invention to provide a source of stem cells that can be used to augment any type of mammalian tissue including, but not limited to, bone marrow, liver, thymus, spleen, pancreas, heart muscle, lung, skin, skeletal muscle, smooth muscle, gonadal, intestinal, central nervous system (CNS), and lymph tissue. It is also an object of the invention that the stem cells be obtainable from autologous, allogeneic, or xenogeneic tissue, and readily proliferated ex vivo to generate a sufficient number of cells for tissue augmentation.
These objects are achieved by providing methods for augmenting one or more tissues of a mammal by administering multipotent neural stem cell (MNSC) progeny to the mammal and allowing the MNSC progeny to integrate with the tissue. The MNSC progeny can be administered to the mammal by any suitable method. For example, the cells can be administered systemically, where they migrate to tissues requiring augmentation, they can be applied close to the periphery of the tissue to be augmented, or injected or applied directly to the tissue to be augmented. In the treatment or augmentation of CNS tissue, MNSC progeny can be administered outside the CNS, and migrate to the CNS and differentiate into CNS cells.
Methods for generating differentiated non-neural mammalian cells from MNSC progeny are also provided which comprise placing the multipotent neural stem cell progeny in an environment that induces them to produce the differentiated non-neural cells.
The file of this patent contains at least one drawing executed in color. Copies of this patent with color drawings will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.
FIGS. 1A-1C show tissue sections (10 μm) of mouse spleens which were assayed for the presence of beta-galactosidase (β-gal) labeled cells using X-gal histochemistry (Mag. 63�). The few Balb/C mice which had been irradiated and survived after being administered only Earl's Buffered Saline Solution systemically, were used as negative controls (hereinafter referred to as "EBSS negative control") (FIG. 1A). Non-irradiated ROSA mice, which are genetically labeled to express β-gal, were used as positive controls (hereinafter referred to as "ROSA positive control") (FIG. 1B). The experimental animals were Balb/c mice that survived at least 6 months following irradiation and systemic injection of β-Gal labeled MNSC progeny. These mice are referred to herein as "test mice"). FIG. 1C shows a tissue section of a spleen harvested from a test mouse. The presence of β-gal expressing cells, and demonstrates that some of the administered MNSC progeny integrated with the tissue of the spleen.
FIGS. 1D-1F show tissue sections (10 μm) of mouse thymus which were assayed for the presence of β-gal (Mag. 63�). EBSS negative and ROSA positive controls are shown in FIGS. 1D and 1E, respectively. FIG. 1F shows tissue from a test mouse following X-gal histochemistry and indicates that some of the administered MNSC progeny integrated with the tissue of the thymus.
FIGS. 2A-2C show tissue sections (10 μm) of mice small intestine which were assayed for the presence of β-gal. FIG. 2A (Mag. 20�) shows tissue from an EBSS negative control. FIG. 2B shows a tissue section of a portion of the small intestine harvested from a test mouse (Mag. 20�) following X-Gal histochemistry and indicates that some of the administered MNSC progeny integrated with the small intestine tissue. FIG. 2C shows a higher magnification (63�) of another region of the small intestine tissue of the same test mouse as shown in FIG. 2B.
FIGS. 2D and 2E show sections (10 μm) of mouse lymphatic tissue which were assayed for the presence of β-gal (Mag. 63�). An EBSS negative control is shown in FIG. 2D. FIG. 2E shows tissue from a test mouse following X-gal histochemistry and indicates that some of the administered MNSC progeny integrated with the lymphatic tissue.
FIGS. 3A-3D show tissue sections (10 μm) of mouse testes which were assayed for the presence of β-gal. ROSA positive and EBSS negative controls are shown in FIGS. 3A and 3B, respectively (Mag. 20�). FIGS. 3C and 3D show tissue sections of different regions of testes harvested from a test mouse (Mag. 63�) following X-gal histochemistry and indicates that some of the administered MNSC progeny integrated with the tissue of the testes.
FIGS. 3E-3H show tissue sections (10 μm) of mouse central nervous tissue (brain) which were assayed for the presence of β-gal. ROSA positive and EBSS negative controls are shown in FIGS. 3E and 3F, respectively. FIG. 3G shows a tissue section of a portion of brain harvested from a test mouse (Mag. 20�) following X-gal histochemistry and indicates that some of the administered MNSC progeny integrated with the tissue of the brain. FIG. 3H is a higher magnification (63�) of the same brain region shown in FIG. 3G.
FIGS. 4A-4L show tissue sections (10 μm) of mouse central nervous tissue (brain) which were assayed for the presence of β-gal. FIGS. 4B, 4D, 4F, 4H, 4J, and 4L are higher magnification photos (63�) of the same region of tissue as shown in FIGS. 4A, 4C, 4E, 4G, 4I, and 4K, respectively. Positive controls are shown in FIGS. 4A and 4B. Negative controls are shown in FIGS. 4C and 4D. Tissue sections from various regions of the brain harvested from test mice are shown in FIGS. 4E, 4G, 4I, and 4K (Mag. 20�), and FIGS. 4F, 4H, 4J, and 4L (Mag. 63�). The arrows point to cells which indicate that some of the peripherally administered MNSC progeny integrated with tissue of the central nervous system following X-gal histochemistry.
The contents of U.S. application Ser. No. 09/100,679, now U.S. Pat. No. 6,093,531, entitled "Generation of Hematopoietic Cells from Multipotent Neural Stem Cells, which was filed on Jun. 19, 1998, and which is a continuation-in-part of provisional application no. 60/060,289, filed Sep. 29, 1997, are incorporated herein by reference. That application discloses the significant discovery that multipotent neural stem cells (MNSCs) which can be obtained from non-tumorous embryonic and adult neural tissue, and continuously proliferated ex vivo (as described in WO 93/01275 and in U.S. Pat. No. 5,750,376) without being transformed with oncogenes, are capable of producing progeny that differentiate into cells of the hematopoietic system. Specifically, that application discloses that labeled, undifferentiated MNSC progeny were systemically administered to animals that had their hematopoietic systems severely compromised by irradiation. The majority of irradiated animals that were administered the MNSC cell progeny survived for prolonged periods (greater than six months). The injected MNSC cell progeny gave rise to cells that were capable of repopulating the hematopoietic system back to levels seen before irradiation. These newly-generated cell types included, but were not limited to, CD3e, CD4, CD8, CD11b and CD19 cells. In sharp contrast, the majority of control animals that were irradiated, but did not receive an injection of MNSCs, died within a short time period (within approximately one month).
The present application concerns the further discovery that MNSC progeny can be influenced by environmental signals to produce progeny that differentiate into tissue-appropriate cells, which are not restricted to neural and blood lineages. A multipotent neural stem cell is an undifferentiated cell that can be found in neural tissue of embryonic, fetal, neonatal, juvenile and adult mammals, and may exist in non-neural tissues as well. It can be induced to proliferate ex vivo by the presence of one or more growth factors, including epidermal and/or fibroblast growth factors, to give rise to undifferentiated progeny which includes daughter MNSCs and progenitor cells. The progenitor cells can be induced to differentiate ex vivo or in vivo into neurons, astrocytes, and oligodendrocytes. Methods of continuously proliferating MNSCs ex vivo and inducing the neural differentiation of MNSC progeny are disclosed in U.S. Pat. No. 5,750,376.
Applicants have discovered that by selecting or altering the environment in which MNSCs and their undifferentiated progeny are placed, the ultimate fate of the neural stem cell progeny into either neural (ectodermal) or non-neural (ectodermal, endodermal and mesodermal) cells can be directed. When administered systemically, MNSC progeny relocate to numerous regions where non-neural stem cells are normally found including, for example, tissues where there is normally high cell turnover. Thus, it is believed that the multipotent neural stem cell is a pluripotent stem cell, and perhaps even an omnipotent stem cell, that, depending on the environment in which it is placed, can give rise to differentiated cells of any tissue type, in addition to neural and blood tissue.
When reference is made herein to the environment in which MNSC progeny are placed, the common meaning of the term "environment" is intended. Thus, the term refers to the combination of external or extrinsic physical conditions that affect and influence the growth and development of multipotent neural stem cells and/or their progeny. The environment can be ex vivo or in vivo. For example, Example 7 of U.S. Pat. No. 5,750,376, describes various culture conditions that induce multipotent neural stem cell progeny to give rise to neurons, astrocytes and oligodendrocytes. Hence, these culture conditions are ex vivo environments that induce multipotent neural stem cells and/or their progeny to give rise to differentiated neural cells. An example of an in vivo environment that affects and influences the growth and development of multipotent neural stem cells and/or their progeny is provided in Example 15 of U.S. Pat. No. 5,750,376, where MNSC progeny placed near an axon of a myelin-deficient rat gave rise to myelin (i.e. oligodendrocytes were generated).
Because of the universal potential of MNSCs, MNSCs and their progeny can be administered to a recipient mammal to augment one or more selected tissues of the mammal. By the term "augmented", it is meant that the transplanted neural stem cells and/or neural stem cell progeny provide a needed or added function to recipient tissue. Usually, it is preferred that the augmentation includes integration of the transplanted cells or their progeny with the recipient tissue. One type of tissue augmentation that the MNSC progeny may achieve, is a strengthening of, or otherwise increase in, the mass of a particular tissue. Another way in which neural stem cell progeny can augment tissue is by secreting biologically active agents the tissue needs for normal functioning or for treatment of disease. Transplantation of MNSC progeny may also be used to repair damaged tissues. It can also be used to augment normal tissue whereby the transplanted MNSC progeny provide an added function to the treated tissue to render it supra-normal, for example by endowing the tissue with an ability that is not normally present in the tissue. Undifferentiated transplanted MNSC progeny can augment tissue by serving as a reserve source of cells, which proliferate and/or differentiate as needed in response to environmental signals that may be triggered by injury, aging, or other stimulus. Thus, the cells that augment the transplanted tissue may be undifferentiated and/or differentiated cells. They may comprise the cells that were initially transplanted to the recipient mammal, and/or may comprise the differentiated or undifferentiated progeny of the cells that were initially transplanted.
When reference is made to administering or transplanting MNSC progeny to augment a selected tissue, the terms "administer", "administering", "transplant" and "transplanting" are intended to encompass any suitable method of causing the MNSC progeny to come in contact with the selected tissue. The MNSC progeny can be administered directly to the tissue being augmented or near the tissue being augmented (where the transplanted cells may migrate to and become integrated with the selected tissue). MNSC progeny can also be administered to one or more sites distant from the tissue being augmented, for example, by systemic, subcutaneous, or intraperitoneal administration. As shown in the Figures, systemic administration of MNSC progeny allows the transplanted cells to integrate with a variety of tissues.
Any mammalian tissue can be augmented using MNSC progeny including, but not limited to blood, bone marrow, liver, thymus, spleen, pancreas, heart muscle, lung, skin (pilated and nonpilated), skeletal muscle, smooth muscle, gonadal, intestinal, central nervous system, bone, peripheral nervous system and lymph tissue. For example, systemically administered MNSC progeny can migrate to various regions of the brain, demonstrating the ability to bypass the blood-brain barrier (see Example 1, and FIGS. 4E-4L) and incorporate with the CNS. Therefore, in addition to providing a method for augmenting non-neural tissues, the present invention also provides a method for augmenting the central nervous system of a mammal by administering MNSC progeny to a site or sites outside the CNS.
Whether the MNSC progeny have augmented a particular tissue can be ascertained by labeling the MNSC progeny prior to transplantation and looking for the presence of the label in the tissue of interest. For example, X-Gal histochemistry is used to detect cells that have been genetically modified to express β-galactosidase prior to transplantation. Lund-Hansen et al., Histochem. 81(4): 321-330 (1984). Fluorescent or luminescent markers can be also be used, such as green fluorescent protein (GFP). Chalfie et al., Science 263:802-805 (1994). Certain luminescent markers described in U.S. Pat. No. 5,650,135, can be used and subsequently detected using non-invasive measures. BrdU labeling can also be used but may not be preferred as the label dilutes as the cells divide. Microspheres, and any other type of label suitable for tracking cells can be used. Non-autologous transplanted cells may be detectable without prior labeling, for example, by detecting the presence of foreign major histocompatibility complex (MHC) molecules or other identifying antigens that may be present on the cell surface once the cells have differentiated.
MNSCs may be induced to proliferate ex vivo and the progeny transplanted in the undifferentiated state without further modification or manipulation ex vivo, as the stem cell progeny automatically repopulate the lost or malfunctioning cell type in response to intrinsic environmental signals. Methods for generating large numbers of enriched populations of MNSCs for transplantation purposes are disclosed in U.S. Pat. No. 5,750,376. As used herein, the phrase "enriched population of multipotent neural stem cells" means a population of cells that contains a higher percentage of MNSCs than are present in the tissue from which the MNSCs originated. Typically, less than about 0.1% of cells obtained from mammalian neural tissue are MNSCs. Therefore, an enriched population of MNSCs that contains about 1% MNSCs typically contains at least 10 times more MNSCs than that present in the neural tissue from which the MNSCs are derived. Secondary and subsequent MNSC cultures prepared according to the methods disclosed in the patent and publications referenced above, generally provide a suitably enriched population of MNSCs. When undifferentiated MNSC progeny are used for augmenting a selected tissue, the enriched population of MNSCs, preferably comprises at least 1% MNSCs. More preferably, at least about 5% of the cells will be MNSCs. Still more preferred is the use of enriched population of MNSCs comprising at least 10% MNSCs. It is possible to obtain enriched populations of MNSCs comprising at least about 20% MNSCs. The use of highly enriched populations of MNSCs, containing at least 15%, or in some cases 20%, MNSCs may be desirable in that it may reduce the total number of cells needed for transplantation.
The percentage of MNSCs present in a culture can be estimated by passaging a known number of cells from the culture to fresh culture medium containing one or more growth factors that induces multipotent neural stem cell proliferation, such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). The percentage of cells that form neurospheres indicates the approximate percentage of stem cells present in the culture. The term "neurosphere" refers to a cluster of precursor cells that forms when a MNSC is induced to proliferate in vitro. A neurosphere comprises the progeny of a single MNSC which includes daughter MNSCs and undifferentiated progenitor cells. U.S. Pat. No. 5,750,376 describes neurospheres in detail and provides photographs of neurospheres. Cell sorting techniques could be used to further enrich the cultures for MNSCs, by separating committed progenitor cells from MNSCs.
Once an enriched population of MNSCs is obtained, the cells may be transplanted in the undifferentiated state without further modification or manipulation in vitro, as the neural stem cells automatically repopulate lost or malfunctioning cell types in response to intrinsic environmental signals.
Alternatively, undifferentiated MNSC progeny may be pretreated prior to transplantation, with one or more factors, such as cytokines, growth factors, or other signals that increase the efficiency of the cells to produce progeny that differentiate into a specific cell type. Examples of differentiation-inducing factors that can be used in MNSC progeny include members of the fibroblast growth factor family (FGFs 1-9); neurotrophins such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), NT-3, NT-4/5; interleukins (IL-1 to IL-18); stem cell factors; erythropoietin; colony stimulating factors such as macrophage colony stimulating factor (MCSF) and granulocyte-macrophage colony stimulating factor (GMCSF); hepatocyte growth factor (HGF); insulin and insulin-like growth factors (e.g. IGF-1 & IGF-2); members of the transforming growth factor beta (TGF-β) including basic myelin proteins (BMP-2, BMP-4, BMP-5, BMP-6, BMP-7), activins A & B, decapentaplegic (dpp), 60A, OP-2, dorsalin, GDFs (1, 3, and 9), GDNF, nodal, MIS, inhibin-α, and transforming growth factors betas (TGF-β1, TGF-β2, TGF-β3, TGF-β5); vitamin and vitamin derivatives such as retinoic acid, and vitamin D; hormones such as progesterone, estrogen, adrenocorticotrophic hormone (ACTH), thyrotropic-releasing hormone (TRH), luteinizing hormone releasing hormone (TRH); neurotransmitters; peptides such as substance P, vasoactive intestinal peptide (VIP), carnosine, cholecystokinin (CCK) and CCK-like peptide; endorphins and enkephalins; solubilized proteoglycans (e.g. heparan); members of the eph family; prostaglandins; amino acids such as gamma-aminobutyric acid (GABA), glycine, glutamate, cysteine, taurine and aspartate; serum; and cell-conditioned culture medium.
As an alternative to transplanting undifferentiated MNSC progeny, the cells can be either in the process of differentiating or have differentiated ex vivo into specific cell types before transplantation by placing the cells in an environment that induces the stem cells to produce progeny that differentiate into the desired lineage. Depending on the desired phenotype, neural stem cell progeny can be induced to differentiate along a particular lineage by modification of the culture environment for example, by the addition of one or more growth factor or cytokines, and/or coculture of the neural stem cell progeny with cells from selected cell lines or feeder cells that provide a substratum and/or release extrinsic factors into the culture medium that influence the differentiative pathway of the MNSC progeny. In addition, manipulation of the substrate on which the cells are grown can influence the phenotypic outcome of a population of cells, either prior to transplantation or once transplanted. Current culture techniques can be used to influence the differentiative pathway of the MNSC progeny. For example, culture conditions known to influence the differentiative fate of the progeny of early embryonic blastula stem cells can be used. (see Keller, supra). Thus, ex vivo techniques can be used to provide a population of cells for transplantation that is enriched for the presence of newly generated, undifferentiated or selectively differentiated progeny of the neural stem cells.
MNSC progeny that have been cultured ex vivo can be subjected to "xenoincubation" prior to transplantation. Xenoincubation involves an initial transplantation of the MNSC progeny into a host animal such as a monkey, or pig to induce differentiation of the MNSC progeny. For example, neural tissue is removed from a patient requiring tissue or organ transplantation (e.g. blood, kidney, liver, skin, pancreas etc). Alternatively, the neural tissue is obtained from an allogeneic donor. MNSCs from the neural tissue are proliferated ex vivo using known proliferation methods to produce MNSC progeny which are then administered to a xenogeneic host, such as a monkey or pig, which will subsequently be used as an organ or tissue donor. Optionally, the organ or tissue of interest may have been compromised to increase the efficiency by which the transplanted MNSC progeny to augment the tissue, for example, by integrating with and/or appropriately differentiating into cells of the tissue or organ. After the donor organ or tissue of interest has been sufficiently augmented by the transplanted MNSC progeny, it is harvested and transplanted into the recipient using procedures known in the art. This method can be used to reduce the risk of rejection of transplants from xenogeneic donors, because allogeneic or autologous cells are incorporated with the organ or tissue of interest. This method can also be used to provide a supply of animal donors that can serve as living blood banks. These animals will have their endogenous hematopoietic systems destroyed or compromised and then reconstituted with human cells. This provides an immediately available source of fresh human blood for transfusion purposes.
In addition to the above possible ex vivo modifications, MNSC progeny can also be genetically modified so that upon transplantation, they produce a desired expression product, for example, one that alleviates the symptoms of a specific disorder. The genetically modified cells could contain a desired gene, such as a gene capable of expressing a missing peptide, a disease-resistant protein or other beneficial protein. In contrast to the other stem cell systems, such as the hematopoietic stem cell system, methods are known which allow MNSCs to be induced to continuously divide under appropriate ex vivo culture conditions, making them excellent targets for genetic modification. MNSC progeny can also be genetically modified to "knock-out" or remove undesired genes. The term "genetic modification" as used herein refers to the stable or transient alteration of the genotype of a precursor cell by intentional introduction of exogenous DNA, or by knocking-out or otherwise altering existing genes. Exogenous DNA that is introduced may be synthetic, or naturally derived, and may contain genes, portions of genes, or other useful DNA sequences. Methods for genetic modification of cells are well-known in the art. Methods for introducing exogenous DNA into MNSC progeny are disclosed in U.S. Pat. No. 5,750,376. It may be desirable to genetically modify the MNSC progeny if they are to be used for transplantation into a patient to alleviate the present or future symptoms of a specific disease with a genetic basis. The cells can be genetically modified before transplantation using an appropriate technique such as homologous recombination. The cells are then transplanted to the desired location where they receive extrinsic signals from the surrounding environment to produce progeny that differentiate into the desired cell type.
Undifferentiated and/or differentiated neural stem cell progeny are transplanted into a patient using any suitable treatment regime known in the art. For example, the cells can be administered directly to a site requiring augmentation using an injection cannula, or other suitable delivery device. Micro- or macroencapsulated cells can be administered to sites requiring augmentation when it is not necessary for the cells to become integrated with the host tissue. The cells can also be administered systemically so that they circulate throughout the host and migrate to and incorporate with various tissues requiring augmentation. The cells can also be administered orally, peritoneally, subcutaneously, topically or by any other method that allows them to incorporate with host tissue requiring augmentation. For example, intravenous injection of pancreatic progenitor cells into diabetic baboons and beagles with diabetes related to an autoimmune disorder have had promising results (Kenyon, N. S. Emerging applications of hematopoietic stem cell transplantation in the treatment of insulin dependent diabetes, IBC on Hematopoietic Stem Cells (1997)). However, as noted, MNSCs automatically proliferate in vivo in response to environmental signals. Therefore, the number of MNSCs needed for transplantation may be fewer than required for traditional cell transplantation therapies. The approximate number of MNSC progeny that are needed for a particular purpose can be determined using routine experimentation, for example using animal models.
The optimum number of cells can be determined using routine clinical trials. For systemic administration of MNSC progeny, procedures presently used for the transplantation of hematopoietic stem cells for the treatment of various disorders can be followed (see Bensinger et al. J. of. Clin. Oncology, 13(10):2547-2555 (1995); Tricott et al., Blood 85(2):588-596). For systemic administration of MNSC progeny, approximately 102 to 107, and more typically, about 103 to 106 neural precursor cells/kg body weight should be sufficient. In many instances, transplanted MNSCs continue to proliferate in vivo in appropriate response to extrinsic signals to produce the necessary amount of new cells to augment a particular tissue. Tumor formation of transplanted MNSC progeny has not been observed. It is believed that this is because transplanted neural stem cells respond appropriately to environmental cues and cease proliferation after the treated tissue has been sufficiently augmented.
Xenogeneic and allogeneic transplantation using MNSCs and stem cell progeny can be carried out without transplant rejection. For example, no signs of transplant rejection were observed in studies where the hematopoietic system of mice were severely depleted and reconstituted using human MNSC progeny. This could be due to a reduced level of or missing MHC molecules on the surface of MNSCs. MHC molecules have been found to be absent from the surface of mouse MNSCs, and may be absent from the surface of MNSCs of other species as well. (see Motluk, A., New Scientist. p. 40 (1998)). In any event, because MNSCs can be obtained from all mammals, and proliferated ex vivo to achieve suitable numbers of cells for transplantation, in most cases autologous or allogeneic transplantation will probably be preferred. When the transplantation is not for the treatment of a genetic disorder that also affects MNSCs, the use of autologous cells may be most preferred. However, certain genetic defects may be correctable by genetic modification of a patient's MNSCs ex vivo and transplantation of the cells back into the patient.
When undifferentiated neural stem cell progeny are transplanted, they may, in response to environmental signals, subsequently differentiate into cells normally found in the tissue that is being augmented. For example, undifferentiated MNSC progeny, when injected systemically into a mammal with a depleted hematopoietic system, generate new blood cells. As another example, MNSC progeny, when injected into a myelin-deficient CNS, generate oligodendrocytes which form the needed myelin (See Hammang et al., supra; U.S. application Ser. No. 08/479,796). Neural stem cell progeny can also augment tissue while remaining in the undifferentiated state. For example, undifferentiated neural stem cell progeny that have been genetically modified to secrete a needed biological factor may be administered to a tissue in need of that biological factor. Undifferentiated neural stem cell progeny can also augment tissue simply by serving as a reserve source of new cells. As existing cells in the tissue die or become non-functional, as a result of injury, disease, apoptosis, or aging, the undifferentiated neural stem cell progeny, in response to environment signals, generate new cells to replenish injured, dead, or non-functional cells.
MNSC progeny transplantation can be used to augment normal, healthy tissues, or any tissue in need of augmentation as a result of disease, disorder, injury or aging. Injuries such as wounds, muscle or ligament tears, weakened heart muscle due to myocardial infarction, and burns can benefit from MNSC transplantation. For example, MNSC progeny can be administered directly to a wound, where, in response to the surrounding environment, they differentiate into fibroblast and other appropriate cell types. Alternatively, the MNSC progeny can be administered away from the site of injury, and the cells migrate to the area(s) in need of cell replenishment.
MNSC progeny can also be administered to a patient at risk for a certain disease or condition, or after the onset of the disease or condition. For example, MNSC progeny can be administered before or immediately after a myocardial infarction. Death is more likely to occur after a myocardial infarction, not during, due to the cellular death that occurs in the heart wall after the ischemic event. When these cells die, the heart is weakened and may rupture if it beats too strongly. Until fibroblasts fill in the lesion with scar tissue (˜10 days), the patient is most susceptible to dying as the result of a ruptured heart wall. MNSC progeny administered systemically or directly to, or nearby, the heart muscle prior to or immediately after the myocardial infarction episode, incorporate with the heart muscle and differentiate into appropriate cell types, thereby speeding up the healing process and reducing the likelihood of complications occurring after the myocardial infarction.
MNSC progeny can also be administered to aging tissue to provide structural support, serve as a reserve to replace aging or dying cells, and/or provide other augmentation functions. Newly generated neural stem cell progeny can also be transplanted prophylactically into a recipient to provide an order of protection from anticipated senescence-related, naturally-occurring conditions.
Additionally, the neural stem cell progeny can be used for the prevention or treatment of other naturally-occurring disorders for example bone injuries, as well as disorders that occur more commonly with age, such as osteoporosis, and stress fractures. Administration of MNSC progeny may prevent or treat other bone disorders as well.
MNSC progeny can also be used to augment normal tissue. For instance, it may be desired for body builders or laborers to have neural stem cell progeny differentiate into new muscle tissue to add additional tissue size and muscle strength. It may also be desirable to differentiate MNSC progeny into fat tissue to be used to enlarge specific parts of the body or increase body weight. Similar approaches are useful for developing supra-normal efficacy in all normal tissues.
In addition to the above transplantation uses of MNSC progeny, differentiating or differentiated MNSC progeny that have been subjected to ex vivo environments that induce MNSC progeny to differentiate into non-neural cell types can be used to generate large quantities of cells of a variety of neural and non-neural phenotypes. The different cell types can be used for drug-screening, preparation of cDNA libraries, and as models for discovering mechanisms of tissue development.
All cited references, including patents and patent applications, are incorporated herein by reference in their entireties.
The following examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any manner.
U.S. application Ser. No. 09/100,679, now U.S. Pat. No. 6,093,531, entitled "Generation of Hematopoietic Cells from Multipotent Neural Stem Cells, which was filed on Jun. 19, 1998, and which is a continuation-in-part of U.S. application Ser. No. 60/060,289, describes experiments that show that systemic administration of β-gal labeled MNSC progeny will give rise to complete reconstitution of all major hematolymphatic lineages in animals that have had their hematopoietic systems severely compromised by radiation. The majority of animals treated with embryonic mouse, embryonic human, or adult mouse MNSC progeny survived prolonged periods (6-15 months). In contrast, the majority of negative control animals, irradiated mice that received systemic administration of saline, died within one month. Further X-Gal histochemical analysis, used to detect β-galactosidase activity, was used on the animals that received the MNSCs and revealed the presence of donor cells incorporated into ectodermally-derived tissue (the grain), mesoderm-derived tissue (gonads (testes), lymph nodes, spleen, and heart) and endodermally-derived tissue (small intestines and thymus). Thus, MNSCs which have been systemically administered to mammals will migrate to and augment tissues originating from all 3 embryonic germ layers. The results of these studies are shown in the FIGS. 1A through 4J.
Muscle damage is chemically induced in either a tibialis anterior, gastrocnemius or soleus muscle of each of a number of anaesthetized mice by administering 25 μl of 1 mM cardiotoxin (Latoxan) in 0.9% saline into the muscle, essentially as described in Ferrari et al., supra.
β-gal labeled MNSC progeny, obtained from embryonic or adult ROSA mouse neural tissue or embryonic human neural tissue, using the methods outlined in US. Pat. No. 5,750,376, are administered into the damaged muscle sites essentially as described in Ferrari et al., supra, or administered systemically by tail vein injections to the experimental animals as outlined in U.S. application Ser. No. 09/100,679, now U.S. Pat. No. 6,093,531, filed Jun. 19, 1998, which is a continuation of U.S. application Ser. No. 60/060,289. The stem cell progeny are administered to individual animals at different time intervals during the necrotic period following the cardiotoxic insult.
The injured muscles and contralateral control muscles are examined at various times after injection (5 days to 5 weeks). Whole mount histochemical staining of the injured muscles which received mouse cells reveal fibers containing β-gal+, centrally aligned nuclei occupying the injury site. Similarly, the appropriate detection methods (see Ferrari, et al., supra) reveal the presence of human neural stem cell-derived muscle fibers in the lesioned region of animals which received human embryonic neural stem cell progeny.
The 6-OHDA lesion rat model of Parkinson's disease is used to measure the effects of systemic administration of labeled MNSC progeny on rotation behavior. MNSC progeny, are prepared and administered into the tail vein of the 6-OHDA lesioned rat using the methods referenced in Example 2. The ability of systemically administered MNSC progeny to augment the lesioned areas of the brain and overcome the rotational bias produced by the unilateral 6-OHDA lesions is observed using histochemical and behavioral analysis.
A. Cardiac Muscle
Cardiac muscle is generated ex vivo from MNSC progeny using the culture methods described by Wobus et al. Differentiation 48:173-182 (1991).
B. Lymphohematopoietic cells
The method of Nakana, et al. (Science 265:1098-1101 (1994)) is used to generate lymphohematopoietic cells from MNSC progeny. The undifferentiated neural stem cell progeny are cocultured with OP9 stromal cell line (the cells of which lack the ability to produce functional macrophage colony stimulating factor). Neutrophils, macrophages, erythroid cells, mast cells, megakaryocytes and lymphoid cells are obtained.
The newly generated cells produced by the methods described in Examples 4A and 4B are used for transplantation, preparation of cDNA libraries, drug screening, and other purposes.
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|U.S. Classification
|424/93.1, 424/93.21, 435/1.1, 424/93.7
|International Classification
|Cooperative Classification
|European Classification
|Mar 17, 1999
Owner name: NEUROSPHERES HOLDINGS LTD., ALBERTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BJORNSON, CHRISTOPHER R.;RIETZE, ROD L.;REYNOLDS, BRENT A.;AND OTHERS;REEL/FRAME:009821/0485;SIGNING DATES FROM 19980828 TO 19990205
|Apr 30, 2007
|Fee payment
Year of fee payment: 4
|Jun 6, 2011
|Maintenance fee reminder mailed
|Oct 28, 2011
|Lapse for failure to pay maintenance fees
|Dec 20, 2011
|Expired due to failure to pay maintenance fee
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text:
Pornfolk at the AVN Awards by Nate 'Igor' Smith for LA Weekly.
The porn industry has had a rough five years, from an online migration of content that has pirated its products to a drive in its hometown of L.A. to require condoms on-set.
Now a conservative group wants to cut off one of adult media's key constituencies -- the military:
The organization, Morality in Media, says it applauds the Navy's move last week to ban porn from its workplaces and even its on-base convenience stores, known as exchanges.
The wing of the military was reacting to its record of excessive sexual assaults.
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Now Morality in Media says its time for the rest of the United States Armed Forces to follow suit.
In a statement sent out over the weekend it says:
Inside porn's AVN Awards with Nate 'Igor' Smith.
... We have called on Secretary of Defense Chuck Hagel to stop the sale of pornography in military exchanges. Pornography is exploitative and demeaning and has no place in the U. S. Military, especially in light of our military's current sexual exploitation crisis.
The group suggests there's a link between horny guys and sexual assaults.
It also wants the entire military to ban porn at exchanges and even to "prohibit access to pornography by electronic devices on military bases worldwide."
The organization is lobbying congress to put pressure on Hagel.
This is a huge demographic for the L.A.-based smut industry. We wonder how it will respond.
Send feedback and tips to the author. Follow Dennis Romero on Twitter at @dennisjromero. Follow LA Weekly News on Twitter at @laweeklynews.
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|Book Details
|Green Books Pvt Ltd
|Number of Pages
|232 Pages
|Publication Year
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Neha Jose
Feb 21, 2014
Super awesome book
Ranjith k v
Feb 19, 2014
Be prepared.....
Prashant Sahare
Dec 30, 2013
Muhammed Rafi
Dec 26, 2013
Be thankful for what you have...
Nikhil VT
Nov 18, 2013
'Top Reviews' lists the most relevant product reviews only. Show ALL instead?Expand all Reviews
Jul 2, 2012
Great workThis is one of the best work of fiction I have ever read in Malayalam. A land mark book. We can feel the pain and emotions that the author would have undergone while writing this book. The book is as raw as life could be and as beautiful as life should be. Being an author myself, I could associate with the afterword in which the author describes the process of writing. Writing itself is a tough task, writing so beautifully, so lyrically is nearly impossible. Benyamin has achieved the near impossible- writing a great piece of fiction, while keeping the reader engrossed like he is reading a pot … (Expand)
Abdul Kareem Tharayil
Feb 1, 2012
Think twice before accepting a Gulf Gift!As a person in my sixties and have spent the middle piece of my life in the Desert, surely the best of it except for few initial teething years, I'm convinced the narratives are factual, accurate and justly honest. The author has dispensed optimum effort to research on Najibâ??s zig-zag turns in his expatriate life as well as the curves, wrinkles, climatic and geographical aspects etc., of the Desert. At the conclusion the reader is in pain to point a finger towards the actual culprit. Was it the â??Arbabâ? who faked as sponsor to fetch an unclaimed slave from the Airport Lounge. Or th… (Expand)
Dec 30, 2011
Excellent NarrationMy First try with flipkart - Fast response to the order.
Akhil Ramesh
Sep 28, 2011
Excellent WorkIt inspires a lot a must read book. A good Work by Benyamin and I had first read it via the internet and then bought the book for futher reading as I felt it a good one. Go get it now
Sep 22, 2012
You are lucky : You never endured that lifeA must read book , which is written in a simple language by Benyammin.
Lakshmi M
Jul 31, 2012
A touching storyOne of my friends recommended me to read this book. I browsed through flipkart and was very happy to find it here. Immediately I placed the order and got the book in my hand in 2 or 3 days time. It is a wonderful book touching any human mind. One will wonder this type of life is also there in the world. It is a lesson for the people who are eager to go abroad and make money, with no proper visa. Though it is a fiction, I could feel the pain and trauma the author must have gone through while writing this book. It is a must read book, and hope an English version of this book will come out soon, … (Expand)
Neha Jose
Feb 21, 2014
Super awesome bookDon't think twice in getting this book. This book is really one of the best.Hats off to the author for writing such a great book.
Ranjith k v
Feb 19, 2014
Be prepared.....let's take preparations to live like a goat dude..when that phase come with unexpected pace... thanks
Prashant Sahare
Dec 30, 2013
ExcellentThis is very nice book & very good for improvement....I think everybody should read this book........
Muhammed Rafi
Dec 26, 2013
Be thankful for what you have...Very touching.....it will teach you be happy & thankful for what God has given to you....the hero did not leave faith in God at any point of his hardships and never does he curses himself for his fate.....The book will hopefully give a new insight to life...good wishes for the writer & for you...the new reader


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Is webstreaming public meetings worth the effort?
In 2007, the Port of Tacoma discussed the idea of televising and webstreaming its public Commission meetings. I had the staff lead in researching the issue, and developing options and recommendations.
In December 2007, the Port Commission approved the project. The Port started webstreaming its meetings on March 20, 2008.
This presentation highlights some of the issues, and lessons learned.