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To better understand the meaning of GIRLFRIEND, certain examples of its usage are presented.Examples from famous English prose on the use of the word GIRLFRIEND
"Potter, you've got yourself a girlfriend! drawled malfoy"
"Well - percy's got a girlfriend"
"You know, ron grimaced, his girlfriend"
Colin farrell quietly breaks up with girlfriend timesofindia.indiatimes.com
Colin farrell and girlfriend breakup timesofindia.indiatimes.com
House and cuddy go on a double date with wilson and his girlfriend, sam (cynthia watros) timesofindia.indiatimes.com
"As girlfriend will not stay forever" - This term girlfriend was used by ankur mudgal in the Poem Law, me and my girlfriend - poem.
"But i was concentrating upon my girlfriend miss" - This term girlfriend was used by ankur mudgal in the Poem Law, me and my girlfriend - poem.
"Cricket in field and girlfriend in dreams" - This term girlfriend was used by ankur mudgal in the Poem Pains will lead to victory - poem.
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Words related to GIRLFRIEND
from the English Thesaurus.
Information about GIRLFRIEND: Answer of: what is meaning of GIRLFRIEND in Hindi? Definition, usage and meaning of GIRLFRIEND in Hindi. Synonyms, antonyms, and words related to GIRLFRIEND.
Tags: Meaning of GIRLFRIEND in Hindi, GIRLFRIEND meaning in Hindi
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Photo Credit: Gary Gershoff/WireImage/Getty Images
News flash: Teresa Giudice likes to stir the pot.
Oh, fine. Have it your way. That's not so much a news flash as an underlying plot point of The Real Housewives of New Jersey (Bravo, Sunday, 10 p.m. ET).
Their angry exchange truly reached its boiling point with the arrival of the show's formidable queen of confrontation, Caroline Manzo. "What's all the screaming about?" she asked casually as she joined the feuding pair. The horrified look on Giudice's face was telling: She knew she was being ambushed.
The blowout led Giudice to this conclusion: "I'm not a therapist, but Jacqueline's's crazy -- she's lost her mind," Teresa snapped. "She's like Heckle and Jive."
Laurita was just as displeased, and vowed to end her friendship with Giudice "for her health."
For the uninitiated, it may be confusing to witness these women in heated dialogue. There isn't always an explanation provided amidst the protracted string of accusations, defensive remarks and declarations of indifference and/or hatred.
Gorga took to her blog to vehemently deny the charge. The ill will continues to this day: Just last week, the feuding sisters-in-law had to be interviewed separately on The View.
Then again, stirring the pot is just what Housewives producers want from her. So... right on, Teresa!
WATCH: How Well Do The Real Housewives of New Jersey Ladies Know Their Show?

subset: commoncrawl


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State and federal legislation filed to further protect children
Attorney General Abbott, Senator Cornyn, Congressman Smith
AUSTIN – Texas Attorney General Greg Abbott, U.S. Sen. John Cornyn and U.S. Congressman Lamar Smith today joined forces to advance state and federal legislative efforts that will help protect young Texans from child predators.
"With sexual predators increasingly using new technology to prey upon children, it is critical that law enforcement stay ahead of the criminals," said Attorney General Abbott. "Innovative legislative responses to high tech crimes are vital to the ongoing success of our crackdown on cyber predators and online child pornographers. Thanks to creative legislative initiatives at both the state and federal levels, law enforcement will have the legal tools we need to help protect Texas children."
Citing recent developments in the Texas Legislature, Attorney General Abbott expressed his support for legislation by state Sen. Florence Shapiro and Rep. Aaron Peña that would update state sex offender registration laws. If enacted, Senate Bill 689 and House Bill 1239, would upgrade state sex offender registration laws to reflect modern technological innovations and communications platforms.
Specifically, the bills would require that convicted sex offenders provide their e-mail addresses, mobile telephone numbers, social networking aliases and other electronic identification information to the Department of Public Safety's sex offender registry. In October 2008, Attorney General Abbott recommended that the Legislature act to increase law enforcement's access to sex offender's electronic identities. The Shapiro-Peña legislation reflects both legislators' efforts to protect children by enacting the Attorney General's recommendations.
At the federal level, Sen. Cornyn, a former Texas Attorney General, sponsored the Internet Stopping Adults Facilitating the Exploitation of Today's Youth (SAFETY) Act of 2009 in the U.S. Senate. Congressman Smith, a former Texas legislator, sponsored companion legislation in the U.S. House of Representatives.
"I'm proud to join my colleague Lamar Smith from the House of Representatives in announcing our legislation, the Internet SAFETY Act, to combat Internet predators and create a safer environment for Texas children. It is our hope that we can garner the support of all our colleagues and pass this bill to strengthen penalties for child sex offenders and Internet predators," Sen. Cornyn said. "Our legislation complements the hard work of Attorney General Abbott, who has been relentless in his efforts to crack down on violence against children. He is realistic about the dangers that exist on the Internet and makes every attempt to keep Texas families informed and equipped with the resources to protect their children."
Rep. Smith added: "Of the nearly 600,000 images of graphic child pornography found online and reported to law enforcement officials, only 2,100 of these children have been identified and rescued. Federal, state and local law enforcement officials have reached a digital dead end in their battle against the online sexual exploitation of children. Investigators need the assistance of Internet Service Providers to identify users and distributors of online child pornography. The Internet SAFETY Act requires ISPs to retain subscriber records, similar to records retained by telephone companies, to aid law enforcement officials in their fight against child pornography."
If enacted, the Internet SAFETY Act would:
• Create a new federal offense for the financial facilitation of child pornography;
• Create a new federal offense for facilitation of child pornography or child exploitation by an Internet content hosting provider or e-mail service provider;
• Require the U.S. Attorney General to promulgate regulations regarding the record retention of subscribers' Internet Protocol addresses or user information by Internet Service Providers;
• Increase penalties for sexual exploitation of children;
• Increase penalties for activities relating to material involving the sexual exploitation of children, and those constituting child pornography; and,
• Provide $30 million a year over five years for the Innocent Images National Initiative.
Since its establishment in 2003, the Office of the Attorney General's (OAG) Cyber Crimes Unit has arrested more than 100 sexual predators for using the Internet to prey upon children. Together, the Cyber Crimes and Fugitive Units have arrested 28 convicted sex offenders who used MySpace in violation of their parole conditions. Four additional subjects were arrested for using MySpace to meet and sexually proposition users whose online profiles indicated they were between the ages of 12 to 14 years old. In all four of those cases, the profile actually belonged to an undercover Cyber Crimes Unit investigator.
Since taking office, Attorney General Abbott has earned a national reputation for aggressively arresting and prosecuting online child predators. The Fugitive Unit and the Cyber Crimes Unit, which protects children from online sexual exploitation, have combined to arrest more than 900 sex offenders since 2003. Cyber Crimes Unit investigators also have traveled to schools and communities statewide to offer educational cyber safety programs.


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This is a cute–if not hard to watch–reminder that this Rosh Hashanah, you don't actually have to dip all your Apples into honey. Unless your resolution is to cut back on technology.
Hat tip to Jordana Horn for finding the video below which is by far the craziest bar mitzvah video I, and likely you, have ever, ever seen. I'll skip the obvious jokes about everything being bigger in Texas and just let you watch and decide for yourself.
Like this post? Get the best of Kveller delivered straight to your inbox.
Catch the latest episode of Saturday Night Live? In an actually funny sketch, "The Quirky Girls Club" featuring Zooey Deschanel and Mary Kate Olsen offer their praise for the original quirky girl, Blossom star Mayim Bialik. Check out the clip below, and skip ahead to the 3:00 minute mark if you're in a hurry. Thanks to The Shmooze for writing it up!


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Phone: (717) 477-1256orFAX: 717- 477- 4014
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Shippensburg University offers a variety of summer camps designed to improve athletic skills, provide academic enrichment, and to explore new and exciting activities. Camps in a variety of sports and academic disciplines are available to boys and girls ages 8 - 17 years in both residential and commuter plans.
Thanks for visiting SU Camps! We are looking forward to a great 2015 camp season with our traditional camps and also some new offerings. We hope that you will return to our site in Spring 2015 to explore what we have to offer.
Air conditioned suite style residence halls will be used for our campers!!!!
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Shippensburg University - 1871 Old Main Drive - Shippensburg, PA 17257 - (717) 477-7447
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Email Address
Placements are, however, only available to countries with a National International Association for the Exchange of Students for Technical Experience (IAESTE) Committee.
Duration: Usually, traineeships are two to three months in duration with various firms, institutions of higher education and research institutes.
In individual cases, traineeships of extended duration can be arranged.
Value: Trainees are usually paid 650,-- euros per month; the DAAD, however, is not able to grant additional funds to cover travel costs.
Placement Requirements:
Country-specific information, dates and deadlines, application address and advice
Follow the links below for more information and application contacts.
For more information and application see; Worldwide Work Experience Placements
More: International Placements » Work Placements » Training Placements
Ebook - CHOICE: The Power to Change Your World


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China's VP Xi Jinping Meets With Obama, Biden
EIN News Covers All Aspects of Xi Jinping's U.S. Visit
WASHINGTON, Feb. 15, 2012 /PRNewswire-USNewswire/ -- EIN News has announced the launch of Xi Jinping News Today, a media monitoring website that covers all details of the Chinese vice president's visit to the United States.
Xi Jinping, China's leader-in-waiting, has met with Barack Obama, who criticized the PRC's human rights record. See:
- Xi Jinping Barack Obama News - http://xijinping.einnews.com/news/xi-jinping-barack-obama
At the Pentagon, Xi Jinping discussed military affairs with Defense Secretary Leon Panetta and the chairman of the Joint Chiefs of Staff, Gen. Martin Dempsey. See:
- Xi Jinping Pentagon News - http://xijinping.einnews.com/news/xi-jinping-pentagon
The Chinese leader also insisted on visiting Iowa because he spent some time in the state in 1985, looking for new ideas in agriculture. See:
- Iowa Xi Jinping News - http://xijinping.einnews.com/state/iowa
For the full list of the website's news sections visit:
- All Xi Jinping News Topics - http://xijinping.einnews.com/sections
- Xi Jinping News by Country - http://xijinping.einnews.com/all_countries
About the publisher of Xi Jinping News Today, EIN News (http://www.einnews.com/)
EIN News has developed one of the world's leading real time news indexing services. Its systems continuously scan the web, indexing news from thousands of worldwide sources. The data is then filtered according to specific needs, and the processes are supervised by a team of professional news editors.
Thousands of industry, government and private institutions rely on EIN News for their media monitoring needs. Combining both intelligent search technologies and the human element, EIN News delivers the most efficient, yet personalized media monitoring, news aggregation and syndication services on the market.
EIN News is positioned as the leading news index on the planet.
SOURCE EIN NewsBack to top


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DIS Veteran
Join Date: Feb 2007
Location: Eastern Massachusetts
Posts: 5,051
Just wanted to throw out there that many children do very well with 504 plans: For example, one first grade student at my school has ADHD, anxiety, bi-polar. He takes medication and it works wonders for him. He does require some accommodations in the classroom. Some examples: he is allowed to stand, instead of sit in his chair; he is allowed to chew gum on an as needed basis (if he feels anxious he will start chewing his clothes). He does not need the curriculum changed or modified at all and his accommodations can easily be met by the classroom teacher. He does not need the help of a Special Education teacher at all.
Not that I am saying that the OP's son doesn't need an IEP. But, sometimes I know that 504 plans can get a bad rap and are seen as some sort of consolation prize. They are great for some children; but not nearly enough for others.
The whole tag thing, so 1990's internet *****. Why can't you say "f o r u m"?
Join Date: Dec 2008
Location: GreatWoods parking lot.
Posts: 3,131
My son has had a 504 since K (he's in 6th grade now) due to medical though we do have certain educational items in there regarding test taking modifications (like he can leave the room if needed). We've really only had one grade where I REALLY had to shove that 504 in a teacher's face because she 1) refused to even look at it 2) decided on her own that my son (who never makes a peep out of turn in class and from every other teacher I always get "I wish I had a classroom of him" ) was somehow using his medical needs to scam the system and get out of doing work and/or taking tests. Because it wasn't an IEP she felt she didn't need to follow it (and frankly, I think her attitude would have been the same with an IEP)
But, yes, we've had some accommodations added that are educational in nature and similar to what you've said, his accommodations are easily met in the classroom with no special ed services.
DIS Veteran
Join Date: Jul 2010
Location: Connecticut
Posts: 999
OP, I hope you are able to have success getting a 504 plan. My ds, 15 yo with ADHD, was just denied one last month because it was decided that his disability 'moderately' impaired him rather than 'substantially' impairs him in school
In our case, the school is doing the accomodations we felt he needed, just not on a plan
OP, do your ds' teachers have email addresses you can use for them directly? In our city, they are published on the website and I have had good success communicating directly with them-they have been positive about it.
I let my mind wander and it didn't come back!
Join Date: Jan 2012
Location: Near Buffalo, NY
Posts: 919
My daughter has had an IEP since she was 4 in Preschool (she is currently almost 16). She had a sensory processing delay, ADHD, ODD and was classified as severly emotionally disturbed. All of her issues were behavioral except for a few organizational problems(which we are STILL trying to resolve).
I am not sure of your plans for higher education but an IEP diploma in NY is practically worthless. My daughter is planning on attending college and is in the ACT program in high school. It is designed for kids on IEP's to attain a Regents diploma, its kind of like the 1:12:1 contained classrooms in lower grades. If you are getting to much of a run around from your school's committee for special education check around your area for groups to help you. There are some that will even send an advocate with you to the meetings that better understands the CSE guidelines and can make sure the committee is not just brushing you off.
Good luck with everything, dealing with CSE can be difficult, just don't feel that you have to settle for what they recommend.
DIS Veteran
Join Date: Jan 2003
Location: Northern CA
Posts: 1,093
My DD (18) has asperger's with ADD. She wasn't diagnosis until she was 13.
The public school drives me crazy. My DD doesn't qualify for an IEP with her AS diagnosis. She also doesn't qualify for and IEP with her ADD... because she is on daily medication.
In 9th grade we sat down with the High School and put together a 504. We ask for things like: tests taking in the office, no calling on her in class, no note taking--notes to be given to her by teachers, no copying from the board, can turn in late assignments.
I think the best thing you can do for your child is to educate yourself! You have to know EXACTLY WHAT TO ASK FOR. The schools are not going to willingly help you. You have to be able to go in and fight for what is needed. But, you can not do this if you do not understand how the laws work and what rights you have. If you can afford it-- I would hire a special education Attorney, that can help you with the process. [/I]
DH DW DD (20) DS (18) DS (16) DD (14) Leo Teddy
May 2002 ~ 4 day Wonder Feb 2003 ~ 7 day Magic/ Eastern May 2004 ~ 7 day Magic/ Western Nov 2004 ~ Thanksgiving on the Magic /Western Double Dip May 2005 ~ 14 day Panama Canal Cruise: "Bringing the Magic to CA" Nov 2005 ~ Thanksgiving on the Magic/ Western Double Dip Apr 2006 ~ Easter on the Magic/ Eastern,Feb 2007 ~ Valentines on the Wonder May 2007~ Transatlantic: Taking the Magic to the Med Oct 2008~ Celebrating Halloween & my birthday with Mickey on the Magic Dec 2009 ~ Christmas in the Parks & New Years on the Wonder Feb 2010 ~ Disneyland & DCA Dec 2010 ~ Jan 2011~ "Surprise" Christmas & New Years on the Magic Mar ~'Mother & Son' do ESPN-the-Weekend April ~'Mom & daughter' Spring Break May ~ Eastbound TransAtlantic Oct ~'Mother & Daughter Cruise' MR Dec 2011 ~ Christmas WDW & New Years on the DreamDec 2012~ Christmas & New Years on the Fantasy Mar 2013~Mom & Daughter Cruise Celebrating DD's HS Graduation Aug 2013~ Trip to WDW to visit our DD in the DCP Dec 2013~ Christmas on the Magic Nov 2014 ~ GIRLS TRIP TO WDW Dec 2014~ CHRISTMAS IN THE PARKS
Join Date: Mar 2012
Posts: 163
Heading out now, another adventure
Have a good time, WDW is a magical place
Join Date: Mar 2008
Posts: 5,570
I have to disagree, I have never met a single person who is aspergers who did not have significant educational needs, no mater how well self adapted they are. At a minimum improving social fluency to reduce the effort it takes navigate the NT world and manage associated anxiety.
The big confusion is differentiating acedemic need from functional curricular needs and realizing that that they are equally covered under IDEA.
Aspergers or other ASD does not have to be "severe" or even moderate to create significant educational needs, it is all about the impact which is virtually always significant.
Join Date: Mar 2012
Posts: 163
Hi, I'm Taryn. Now you've met someone. There are a lot of aspies that don't have challenges severe enough to need accommodations, but they're not the ones you notice. It is entirely possible you've met someone like that before and just didn't know. Mostly we just exist and people never know.
Heading out now, another adventure
Have a good time, WDW is a magical place
Join Date: Mar 2008
Posts: 5,570
Yes lots of us aspies out there, but if you manefest significantly enought to meet the diagnostic criteria, then you have significant educational needs in the functional curricular areas
Utterrandomness, Welcome to our forum, great to have another aspie on board.
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Tag: parallels desktop 9
Daily Update for September 9, 2013
It's the TUAW Daily Update, your source for Apple news in a convenient audio format. You'll get all the top Apple stories of the day in three to five minutes for a quick review of what's happening in the Apple world. You can listen to today's Apple stories by clicking the inline player (requires Fl...
Parallels responds to Slashdot user concerns over Desktop 9 installing Access without permission
Over the past few weeks, Parallels announced both Parallels Desktop 9 and Parallels Access. While the former is a new version of the venerable virtualization application, Access is a totally new product for Parallels, allowing the "appification" of desktop apps on an iPad. Several Slashdot users e...
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United States Patent: 6,780,413
Issued: August 24, 2004
Inventors: Hott; Jonathan S. (Birmingham, MI); Youle; Richard J. (Bethesda, MD); Hallett; Mark (Bethesda, MD); Dalakas; Marinos C. (Bethesda, MD)
Assignee: The United States of America as represented by the Department of Health and (Washington, DC)
Appl. No.: 005512
Filed: November 7, 2001
Compositions and methods for treatment of focal muscle spasms. Immunotoxin conjugates comprise a toxin conjugated to an antibody reactive to a muscle specific antigen.
In one aspect the present invention is directed to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia. In other embodiments a therapeutically effective amount of the immunotoxin conjugate is administered with a therapeutically effective amount of botulinum toxin, as an immunoconjugate or in unconjugated form.
In another aspect the present invention relates to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a galactose binding moiety and a toxin selected from the group consisting of: ricin-A and abrin-A, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In some embodiments the galactose binding moiety is selected from the group consisting of: ricin-B and abrin-B. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia.
In another aspect the present invention relates to an immunotoxin conjugate, comprising an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, where the antibody is selectively reactive, under immunologically reactive conditions, to a mammalian nicotinic acetylcholine receptor. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin.
Intramuscular injection of botulinum toxin A (BTX) is often considered primary therapy of many disorders characterized by muscular spasms. The utility of BTX, however, is limited by its short duration of action, the possible development of resistance after repeated injections, and cross-reactivity with autonomic neurons. Surprisingly, we have determined an immunotoxin (ITX) engineered to damage skeletal muscle fibers selectively by chemically linking a monoclonal antibody against the nicotinic acetylcholine receptor to the toxin ricin was 20,000-fold more toxic to myotubes than myoblasts, consistent with the degree of acetylcholine receptor expression. In vivo, ITX produced destructive myopathic changes at a dose 300-fold less than the maximum tolerated dose. Assessment of rat muscle strength after unilateral gastrocnemius injections showed ITX was more effective and had a longer duration of action than BTX. Immunotoxins of the present invention have utility as a tissue culture selection agent against cells or tissues expressing nicotinic acetylcholine receptors (nAchR) Immunotoxins of the present invention also have utility in the treatment of involuntary muscle spasms. Patients repeatedly exposed to botulinum toxin for the treatment of muscle spasms frequently become resistant to its use. Consequently, surgical treatment is often indicated. Intramuscular injection of the immunotoxin conjugates of the present invention can delay or prevent the requirement for surgery.
Antibodies to Muscle Specific Antigens
Antibodies of the present invention are selectively reactive, under immunologically reactive conditions, to a muscle specific antigen. The term "muscle specific antigen" includes reference to those antigens whose presence is substantially limited to the membrane of muscle cells at the localized site at which the immunotoxin of the present invention is administered. Thus a muscle specific antigen may be present on non-muscle cells but is substantially inaccessible to the immunotoxins of the present invention due to the mode of administration. Preferably, however, muscle specific antigens are unique to muscle cells.
Muscle specific antigens are known in the art. For example, antibodies reactive to N-CAM (neuronal cell adhesion molecule) can and have been generated and are available commercially (Sigma Chemical Company, St. Louis, Mo.). Anti-N-CAM monoclonals bind to the CD56 differentiation antigen specifically expressed on regenerating or newly denervated muscle fibers (Couvalt and Sanes, Proc. Natl. Acad. Sci. USA (1985) 82:4544-4548; Cashman et al., Ann. Neurol. (1987) 21:481-489; IIIa I, Leon-Monzon M, Dalakas M C., Ann. Neurol. 1992; 31:46-52). Likewise, the muscle-specific antigen Leu-19 (Becton Dickinson) can be used to generate antibodies by standard immunological methods. Antibodies to other muscle specific antigens, such as monoclonal anti-dystrophin, are commercially available (Sigma).
In preferred embodiments the muscle specific antigen is a nicotinic acetylcholine receptor (nAchR). The nAch receptor and antibodies generated thereto are readily available from publicly accessible depositories. Cell line TE671 (equivalent to the RD cell line) expresses AchR for preparation of anti-human nAchR antibodies and is available from the ATCC under deposit number CRL 8805. See, U.S. Pat. Nos. 5,041,389, and 4,789,640, both incorporated herein by reference. Hybridomas producing a human IgG1 monoclonal antibody against nAchR is deposited with the Fermentation Research Institute of Japan under the accession number FERM BP-1798 (U.S. Pat. No. 5,192,684, incorporated herein by reference). Monoclonal antibodies to acetylcholine receptors are produced by hybridomas having accession number ATCC Nos.: HB 8987 (mAb 64), HB 189 (mAb 270), and TIB 175 (mAb 35), all of which are incorporated herein by reference.
Many methods of making antibodies are known to persons of ordinary skill. "Antibody" includes antigen binding forms of antibodies (e.g., Fab, F(ab)2). The term also refers to a polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof which specifically bind and recognize an analyte (antigen). The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
Antibodies exist e.g., as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH -CH 1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology, Third Edition, W. E. Paul, ed., Raven Press, N.Y. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments such as single chain Fv, chimeric antibodies (i.e., comprising constant and variable regions from different species), humanized antibodies (i.e., comprising a complementarity determining region (CDR) from a non-human source) and heteroconjugate antibodies (e.g., bispecific antibodies).
The following discussion is presented as a general overview of the techniques available; however, one of skill will recognize that many variations of the following methods are known.
A. Antibody Production
A number of immunogens are used to produce antibodies specifically reactive with a muscle specific antigen. A recombinant, synthetic, or native muscle specific antigen of 5 contiguous amino acids in length or greater from a muscle specific antigen is the preferred immunogen (antigen) for the production of monoclonal or polyclonal antibodies. The term "recombinant" when used with reference to a cell, or nucleic acid, or vector, includes reference to a cell, or nucleic acid, or vector, that has been modified by the introduction of a heterologous nucleic acid or the alteration of a native nucleic acid to a form not native to that cell, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.
In a typical procedure, the muscle specific antigen is injected into an animal capable of producing antibodies. Methods of producing polyclonal antibodies are known to those of skill in the art. In brief, an immunogen (antigen), preferably a purified muscle specific antigen (e.g., nAchR), an muscle specific antigen coupled to an appropriate carrier (e.g., GST, keyhole limpet hemanocyanin, etc.), or an muscle specific antigen incorporated into an immunization vector such as a recombinant vaccinia virus (see, U.S. Pat. No. 4,722,848) is mixed with an adjuvant and animals are immunized with the mixture. The animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to the muscle specific antigen of interest. When appropriately high titers of antibody to the immunogen are obtained, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the muscle specific antigen is performed where desired (see, e.g., Coligan (1991) Current Protocols in Immunology Wiley/Greene, NY; and Harlow and Lane (1989) Antibodies: A Laboratory Manual Cold Spring Harbor Press, N.Y.).
Antibodies, including binding fragments and single chain recombinant versions thereof, against predetermined fragments of muscle specific antigen are raised by immunizing animals, e.g., with conjugates of the fragments with carrier proteins as described above. Typically, the immunogen of interest is an muscle specific antigen of at least about 5 amino acids, more typically the muscle specific antigen is 10 amino acids in length, preferably, 15 amino acids in length and more preferably the muscle specific antigen is 20 amino acids in length or greater. The peptides are typically coupled to a carrier protein (e.g., as a fusion protein), or are recombinantly expressed in an immunization vector. Antigenic determinants on peptides to which antibodies bind are typically 3 to 10 amino acids in length.
Monoclonal antibodies are prepared from cells secreting the desired antibody. Monoclonals antibodies are screened for binding to an muscle specific antigen from which the immunogen was derived. Specific monoclonal and polyclonal antibodies will usually bind with a KD of at least about 0.1 mM, more usually at least about 50 .mu.M, and most preferably at least about 1 .mu.M or better.
In some instances, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as mice, rodents, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies are found in, e.g., Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, Calif., and references cited therein; Harlow and Lane, Supra; Goding (1986) Monoclonal Antibodies: Principles and Practice (2d ed.) Academic Press, New York, N.Y.; and Kohler and Milstein (1975) Nature 256: 495-497. Summarized briefly, this method proceeds by injecting an animal with an immunogen comprising an muscle specific antigen. The animal is then sacrificed and cells taken from its spleen, which are fused with myeloma cells. The result is a hybrid cell or "hybridoma" that is capable of reproducing in vitro. The population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the immunogen. In this manner, the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance.
Alternative methods of immortalization include transfection with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells is enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate (preferably mammalian) host. The muscle specific antigens and antibodies of the present invention are used with or without modification, and include chimeric antibodies such as humanized murine antibodies.
Other suitable techniques involve selection of libraries of recombinant antibodies in phage or similar vectors (see, e.g., Huse et al. (1989) Science 246: 1275-1281; and Ward, et al. (1989) Nature 341: 544-546; and Vaughan et al. (1996) Nature Biotechnology, 14: 309-314). Alternatively, high avidity human monoclonal antibodies can be obtained from transgenic mice comprising fragments of the unrearranged human heavy and light chain Ig loci (i.e., minilocus transgenic mice). Fishwild et al., Nature Biotech., 14:845-851 (1996).
Also, recombinant immunoglobulins may be produced. See, Cabilly, U.S. Pat. No. 4,816,567; and Queen et al. (1989) Proc. Nat'l Acad. Sci. USA 86: 10029-10033.
B. Human or Humanized (Chimeric) Antibody Production
The anti-muscle specific antigen antibodies of this invention can also be administered to a mammal (e.g., a human patient) for therapeutic purposes (e.g., as targeting molecules when conjugated or fused to effector molecules such as labels, cytotoxins, enzymes, growth factors, drugs, etc.). Antibodies administered to an organism other than the species in which they are raised are often immunogenic. Thus, for example, murine antibodies administered to a human often induce an immunologic response against the antibody (e.g., the human anti-mouse antibody (HAMA) response) on multiple administrations. The immunogenic properties of the antibody are reduced by altering portions, or all, of the antibody into characteristically human sequences thereby producing chimeric or human antibodies, respectively.
i) Humanized (Chimeric) Antibodies
Humanized (chimeric) antibodies are immunoglobulin molecules comprising a human and non-human portion. More specifically, the antigen combining region (or variable region) of a humanized chimeric antibody is derived from a non-human source (e.g., murine) and the constant region of the chimeric antibody (which confers biological effector function to the immunoglobulin) is derived from a human source. The humanized chimeric antibody should have the antigen binding specificity of the non-human antibody molecule and the effector function conferred by the human antibody molecule. A large number of methods of generating chimeric antibodies are well known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,502,167, 5,500,362, 5,491,088, 5,482,856, 5,472,693, 5,354,847, 5,292,867, 5,231,026, 5,204,244, 5,202,238, 5,169,939, 5,081,235, 5,075,431, and 4,975,369). Detailed methods for preparation of chimeric (humanized) antibodies can be found in U.S. Pat. No. 5,482,856.
ii) Human Antibodies
In another embodiment, this invention provides for fully human anti-muscle specific antigen antibodies. Human antibodies consist entirely of characteristically human polypeptide sequences. The human anti-muscle specific antigen antibodies of this invention can be produced in using a wide variety of methods (see, e.g., Larrick et al, U.S. Pat. No. 5,001,065, for review).
In preferred embodiments, the human anti-muscle specific antigen antibodies of the present invention are usually produced initially in trioma cells. Genes encoding the antibodies are then cloned and expressed in other cells, particularly, nonhuman mammalian cells. The general approach for producing human antibodies by trioma technology has been described by Ostberg et al. (1983), Hybridoma 2: 361-367, Ostberg, U.S. Pat. No. 4,634,664, and Engelman et al., U.S. Pat. No. 4,634,666. The antibody-producing cell lines obtained by this method are called triomas because they are descended from three cells; two human and one mouse. Triomas have been found to produce antibody more stably than ordinary hybridomas made from human cells.
The genes encoding the heavy and light chains of immunoglobulins secreted by trioma cell lines are cloned according to methods, including the polymerase chain reaction, known in the art (see, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor, N.Y., 1989; Berger & Kimmel, Methods in Enzymology, Vol. 152: Guide to Molecular Cloning Techniques, Academic Press, Inc., San Diego, Calif., 1987; Co et al. (1992) J. Immunol., 148: 1149). For example, genes encoding heavy and light chains are cloned from a trioma's genomic DNA or cDNA produced by reverse transcription of the trioma's RNA. Cloning is accomplished by conventional techniques including the use of PCR primers that hybridize to the sequences flanking or overlapping the genes, or segments of genes, to be cloned.
Formation of Immunotoxic Conjugates
Antibodies specifically reactive to muscle specific antigens are joined via covalent or non-covalent bond to a toxin selected from the group comprising: ricin, abrin, ricin-a, abrin-a, and botulinum toxin. Ricin, abrin, and subunits thereof as well as botulinum toxin A through F, are readily available from commercial sources (e.g, Sigma Chemical Company, St. Louis, Mo.). Methods of isolating ricin and abrin are also well known to those of ordinary skill in the art. See, e.g., Nicholson and Blaustein, J. Biochim. Biophys. Acta, 266:543 (1972); Tomita et al., Experientia, 28:84 (1972); Wei et al., J. Biol. Chem., 249:3061 (1974); Lin et al. Toxicon., 19:41 (1981); Olsnes et al. J. Biol. Chem. 249:803 (1974); Wei et al., J. Mol. Biol., 123:707 (1978); Lin and Li, Eur. J. Biochem., 105:453 (1980); Nicolson et al. Biochemistry, 13:196 (1974); and, Olsnes, Methods Enzymol. 50:330-335 (1978), all of which are incorporated herein by reference. The molecules may be attached by any of a number of means well-known to those of skill in the art. In some embodiments, the immunotoxic conjugates of the present invention are recombinantly expressed as single-chain fusion protein comprising both antibody and toxin. Typically the toxin will be conjugated, either directly or through a linker (spacer), to the ligand.
A "linker", as used herein, is a molecule that is used to join two molecules. The linker is capable of forming covalent bonds or high-affinity non-covalent bonds to both molecules. Suitable linkers are well known to those of ordinary skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers. The linkers may be joined to the constituent amino acids through their side groups (e.g., through a disulfide linkage to cysteine).
The procedure for attaching a toxin to an antibody or other polypeptide targeting molecule will vary according to the chemical structure of the toxin. Antibodies contain a variety of functional groups; e.g., sulfhydryl (--S), carboxylic acid (COOH) or free amine (--NH2) groups, which are available for reaction with a suitable functional group on a toxin. Additionally, or alternatively, the antibody or toxin can be derivatized to expose or attach additional reactive functional groups. The derivatization may involve attachment of any of a number of linker molecules such as those available from Pierce Chemical Company, Rockford Ill.
A bifunctional linker having one functional group reactive with a group on the toxin, and another group reactive with an antibody, can be used to form a desired immunoconjugate. Alternatively, derivatization may involve chemical treatment of the toxin or antibody, e.g., glycol cleavage of the sugar moiety of a glycoprotein antibody with periodate to generate free aldehyde groups. The free aldehyde groups on the antibody may be reacted with free amine or hydrazine groups on the toxin to bind the toxin thereto. (See U.S. Pat. No. 4,671,958). Procedures for generation of free sulfhydryl groups on antibodies or antibody fragments, are also known (See U.S. Pat. No. 4,659,839).
Many procedures and linker molecules for attachment of various compounds including toxins are known. See, for example, European Patent Application No. 188,256; U.S. Pat. Nos. 4,671,958, 4,659,839, 4,414,148, 4,699,784; 4,680,338; 4,569,789; 4,589,071; and Borlinghaus et al. Cancer Res. 47: 4071-4075 (1987), which are incorporated herein by reference. In particular, production of various immunotoxin conjugates is well-known within the art and can be found, for example in "Monoclonal Antibody-Toxin Conjugates: Aiming the Magic Bullet," Thorpe et al., Monoclonal Antibodies in Clinical Medicine, Academic Press, pp. 168-190 (1982), Waldmann, Science, 252: 1657 (1991), U.S. Pat. Nos. 4,545,985 and 4,894,443 which are incorporated herein by reference. See also, e.g., Birch and Lennox, Monoclonal Antibodies: Principles and Applications, Chapter 4, Wiley-Liss, New York, N.Y. (1995); U.S. Pat. Nos. 5,218,112, 5,090,914; Hermanson, Bioconjugate Techniques, Academic Press, San Diego, Calif. (1996). In preferred embodiments, the linker molecule is m-Malimidobenzoyl-N-hydroxysuccinimideester (MBS) which can be used to prepare immunotoxin conjugates as described, for example, in Youle and Nevelle, Proc. Natl. Acad. Sci., 77(9):5483-5486 (1980).
In some circumstances, it is desirable to free the toxin from the antibody when the immunotoxic conjugate has reached its target site. Therefore, immunotoxic conjugates comprising linkages which are cleavable in the vicinity or within the target site may be used when the toxin is to be released at the target site. Cleaving of the linkage to release the agent from the ligand may be prompted by enzymatic activity or conditions to which the immunoconjugate is subjected either inside the target cell or in the vicinity of the target site. A number of different cleavable linkers are known to those of skill in the art. See U.S. Pat. Nos. 4,618,492; 4,542,225, and 4,625,014. SPDP is a reversible NHS-ester, pyridyl disulfide cross-linker used to conjugate amine-containing molecules to sulfhydryls. Another chemical modification reagent is 2-iminothiolane which reacts with amines and yields a sulfhydryl. Water soluble SPDP analogs, such as Sulfo-LC-SPDP (Pierce, Rockford, Ill.) are also available. SMPT is a reversible NHS-ester, pyridyl disulfide cross-linker developed to avoid cleavage in vivo prior to reaching the antigenic target. Additionally, the NHS-ester of SMPT is relatively stable in aqueous solutions.
Pharmaceutical Compositions and Method of Administration
Immunotoxic conjugates of the present invention are useful for the treatment of focal muscle spasms such as, but not limited to, blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia. In preferred embodiments, the immunotoxin conjugate comprises ricin (RCA60). While not bound by theory, it is believed that the use of the galactose binding ricin B-chain helps prevent diffusion of the immunotoxin from the site of administration. Additionally, the B-chain increases the potency of the ricin A-chain toxin.
The formulations containing therapeutically effective amounts of the immunotoxin conjugates of the present invention are either sterile liquid solutions, liquid suspensions or lyophilized versions and optionally contain stabilizers or excipients. Lyophilized compositions are reconstituted with suitable diluents, e.g., water for injection, saline, 0.3% glycine and the like. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, and the like. Actual methods for preparing administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa. (1995).
The compositions for administration will commonly comprise a solution of the immunotoxin conjugate of the present invention dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques.
As will be readily understood by the clinician of ordinary skill in the art, the dose will be dependent upon the properties of the particular immunotoxin conjugate employed, e.g., its activity and biological half-life, the concentration of immunotoxin conjugate in the formulation, the site and rate of dosage, the clinical tolerance of the patient involved, the disease afflicting the patient, the severity of the disease, and the like.
Preferably, the pharmaceutical compositions containing the immunotoxin conjugates will be administered by intramuscular injection in a therapeutically effective dose ranging from about 1 ng to 200 ng depending upon the size of the muscle, the severity of the focal muscle spasm, and the specificity and toxicity of the conjugate. For example, for a ricin-anti-nAchR immunotoxin conjugate, an eye muscle will typically require between 5 and 20 ng of conjugate, and a vocal chord will generally require 1 to 2 ng. Preferably, the dose is administered at the site of the neuromuscular junctions of the muscle which is being treated. Those of skill will understand that the dose may be administered to the various neuromuscular junctions of the muscle whose activity one wishes to diminish, this being particularly preferred for muscles whose size allows for such a mode of administration. Therapeutically effective amounts of immunotoxin conjugates of the present invention can be administered alone, in combination, or in conjunction with therapeutically effective amounts of the unconjugated forms of the toxins (e.g., botulinum toxin).
Preferably, the dosage is administered once but may be applied periodically until either a therapeutic result is achieved or until side effects warrant discontinuation of therapy. Generally, the dose should be sufficient to treat or ameliorate symptoms or signs of focal muscle spasm without producing unacceptable toxicity to the patient. An effective amount of the compound is that which provides either subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer.
Solutions comprising immunotoxin conjugates of the present invention will typically have a pH in the range of pH 5 to 9.5, preferably pH 6.5 to 7.5. The immunotoxin conjugates should be in a solution having a suitable pharmaceutically acceptable buffer such as phosphate, tris (hydroxymethyl) aminomethane-HCl, saline, or citrate and the like. Buffer concentrations should be in the range of 1 to 100 mM. The solution of antibody may also contain a salt, such as sodium chloride or potassium chloride in a concentration of 50 to 150 mM. An effective amount of a stabilizing agent such as an albumin, a globulin, a gelatin, a protamine or a salt of protamine can also be included to a solution comprising the immunotoxin conjugate of the present invention. In preferred embodiments the buffer is a saline solution of 0.9% comprising human serum albumin of 1 mg/ml.
Antibody or immunotoxin may also be administered via microspheres, liposomes or other microparticulate delivery systems placed in certain tissues including blood.
Claim 1 of 11 Claims
What is claimed is:
1. A method of treating a focal muscle spasm, comprising administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of said focal muscle spasm, wherein said immunotoxin conjugate comprises an antibody conjugated to a cellular toxin selected from the group consisting of: ricin and abrin, wherein said antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor;
wherein said antibody of said immunotoxin conjugate binds to a nicotinic acetylcholine receptor of a muscle cell of said muscle, and said cellular toxin of said immunotoxin conjugate mediates the death of said muscle cell.


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Items where Salford Author is "Heritage, G"
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Number of items: 6.
|Milan, DJ, Heritage, GL, Large, ARG and Entwistle, NS 2010, 'Mapping hydraulic biotopes using terrestrial laser scan data of water surface properties' , Earth Surface Processes and Landforms, 35 (8) , pp. 918-931.
|Heritage, GL, Large, ARG, Moon, BP and Jewitt, G 2004, 'Channel hydraulics and geomorphic effects of an extreme flood event on the Sabie River, South Africa.' , CATENA, 58 (2) , pp. 151-181. Item not available from this repository.
|Fuller, IC, Large, ARG, Charlton, ME, Heritage, GL and Milan, DJ 2003, 'Reach-scale sediment transfers: An evaluation of two morphological budgeting approaches.' , Earth Surface Processes and Landforms, 28 (8) , pp. 889-903. Item not available from this repository.
|Heritage, GL, Broadhurst, LJ and Birkhead, AL 2001, 'The influence of contemporary flow regime on the geomorphology of the Sabie River, South Africa.' , Geomorphology, 38 (3-4) , pp. 197-211. Item not available from this repository.
|Heritage, GL, Charlton, ME and O'Regan, S 2001, 'Morphological classification of fluvial environments: an investigation of the continuum of channel types' , The Journal of Geology, 109 (1) , pp. 21-33. Item not available from this repository.
Book Section
|Danson, FM, Morsdorf, F and Koetz, B 2009, 'Airborne and terrestrial laser scanning for measuring vegetation canopy structure' , in: Laser Scanning for the Environmental Sciences , Wiley-Blackwell.
This list was generated on Mon Dec 22 16:23:16 2014 GMT.


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Detroit Dining Guide - Detroit Restaurants
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Landmark Detroit restaurants of the well-heeled, manufacturing giant money set like Fox and Hounds, Capital Grille and the Whitney (located in a renovated mansion) still go strong, as do Detroits many soul food standouts, including the infamous Fishbones Rhythm Café located in downtown Detroits Greektown since before Greektown was a trendy dining hotspot. Detroit restaurants overlooking the meandering Detroit River have natural romantic appeal and include Andiamo for picturesque Italian cuisine and the Rattlesnake Club for steaks and views. But for perhaps the most gritty and authentic Detroit restaurant (and ideal for Detroit diners on a budget) is Lafayette Coney Island, a distinctive Detroit Coney Island restaurant located in downtown Detroits Lafayette building that slops some mean chili on a killer dogfor six bucks.
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42° North
Detroit Marriott at the Renaissance Center, Detroit, MI 48243
Dramatic river views accompany every meal at 42 Degrees North restaurant in Detroit. The menu focuses on classic American comfort fare prepared with a contemporary approach, and the restaurant proudly emphasizes local and regionally grown ingredients.
Andiamo Riverfront
400 Renaissance Center, Suite A403, Detroit, MI 48243
Italian .
Andiamo Riverfront restaurant is one of Detroits premier destinations for elegant and romantic dining. Andiamo Riverfront restaurant offers a diverse selection of refined Italian fare including beef, seafood and chicken with great side dishes to match. The restaurant offers dining in four different rooms and sweeping views of the Detroit River.
Atlas Global Bistro
3111 Woodward Ave., Detroit, MI 48201
A trendy bistro in Detroit, Atlas Global Bistro impresses from the first steps with soaring ceilings and a vintage wood bar. This restaurant was awarded three stars from the
Detroit News
, and has been given such titles as Best Restaurant Under $50 and Best Eclectic restaurant. The eclectic menu focuses on approachable international and fusion fare.
Bourbon Steak MGM Grand Detroit
1777 Third St., Detroit, MI 48226
With a sleek design to match its luxury hotel setting, Bourbon Steak is a modern American steakhouse in Detroits MGM Grand Detroit hotel. The celebrated menu is built upon centerpiece ingredients like all-natural Certified Angus Beef and American Kobe cuts deftly cooked over mesquite wood.
Coach Insignia
Renaissance Center, 72nd Floor, Detroit, MI 48243
A top-rated Detroit fine dining restaurant, Coach Insignia offers panoramic views of Detroit, Canada and the Detroit River with every meal. This stylish steakhouse features a well-scripted menu of delicious contemporary cuisine, as well as a world-class wine list with over 800 selections.
670 Lothrop, Detroit, MI 48202
Contemporary French.
For a restaurant with such an ambiguous name, Cuisine certainly boasts an incredibly well-honed culinary point-of-view. Chef/owner Paul Grosz skillfully prepares contemporary French-American cuisine, as well as seasonally changing dishes and an expert focus on vegetarian offerings. Wine pairings from the carefully crafted list are available for all menus.
2901 Grand River Ave., Detroit, MI 48201
Contemporary American.
Iridescence is simply beautiful; hanging orb lights, glowing blue accents and spectacular views of the city skyline make this fine dining restaurant a top choice for classy gatherings and romantic dates. The broadly appealing menu of creative farewhich emphasizes local ingredients and natural flavorspairs brilliantly with the extensive, award-winning wine list.
La Dolce Vita - Detroit
17546 Woodward Ave., Detroit, MI 48203
Serene patios, complete with soothing fountain, make La Dolce Vita a bit of hidden gem in Detroit. Not what youd expect, but everything you could want in a restaurant from the great service to the satisfying food. With imaginative dishes like eggplant lasagna that uses eggplant instead of pasta, the restaurant brings classic Italian to the table with a fresh twist. Dinner is served nightly and lunch is enjoyed Tuesday through Friday while Sunday brunch is also worth a visit to La Dolce Vita. Look past the surrounding neighborhood and come to appreciate the food and ambiance that make this an enjoyable restaurant in Detroit.
501 Monroe St., Detroit, MI 48226
True to its moniker, Mosaic embraces an eclectic, fusion approach to its menu, fusing together varying flavors of world cuisine to create culinary artwork. From waterfalls, granite and copper to a hand-blown blue glass ceiling, Mosaic also impresses with a uniquely stunning setting that is perfect for enjoying the multi-ethnic fare, signature cocktails and entertainment.
Opus One
565 East Larned St., Detroit, MI 48226
Contemporary American.
Excellent, original recipes inspired by French and American cuisines prepared with seasonal spontaneity and the freshest ingredients make Opus One a true destination for foodies. This stylish yet unpretentious Detroit fine dining restaurant features three wine-themed dining rooms and one of the most beautiful bars in the city, and it has earned
Wine Spectator
awards every year since it opened in 1987.
Roast A Michael Symon Restaurant
1128 Washington Blvd., Detroit, MI 48226
Famed restaurateur and Iron Chef Michael Symon strikes gold again with Roast. This fine dining Detroit steakhouse showcases an expert focus on centerpiece ingredients like wood fired, dry aged steaks, rotisserie meats, charcuterie and Heritage meats, and fresh seafood prepared in American style with signature Mediterranean twists.
Saltwater MGM Grand Detroit
1777 Third St., Detroit, MI 48266
Celebrity chef, restaurateur and cookbook author Michael Mina brings style and great flavors to Dallas with Saltwater, one of the great Detroit restaurants at the MGM Grand Hotel. The menu focuses on contemporary seafood preparations and refined American cuisine, including dishes like lobster pot pie, ahi tuna tartare, fresh king crab and oysters from the raw bar. Because this restaurant doubles as a sophisticated nightspot, it is a strictly 21-and-over destination.
Signature Grill
250 Riverfront Dr., Detroit, MI 48226
A casually elegant American restaurant in Detroit, the Signature Grill offers refined preparations of comfort-style fare in a warm and relaxed setting augmented by Detroit River views. This restaurant has earned critical acclaim from
Metro Times Best of Detroit
, and was named Detroits best kept secret by
Hour Detroit Magazine
The Rattlesnake Club
300 River Place, Detroit, MI 48207
Contemporary American.
Located on the picturesque shores of the Detroit River sits the Rattlesnake Club. Winner of numerous culinary and hospitality awards, the restaurant specializes in prime steaks and fresh seafood. The main dining room offers breathtaking views of Detroit, and private rooms are available to accommodate large parties in an intimate setting. Catering is available as well, along with wedding accommodations. Executive Chef Jimmy Smith creates a menu that is plenty of choices and mouth-watering dishes that use locally grown ingredients for the freshest flavors possible. The Rattlesnake club also boasts a full bar for after-dinner entertainment and enjoyment.
Wolfgang Puck Grille MGM Grand Detroit
1777 Third St., Detroit, MI 48226
Contemporary American.
A contemporary version of the classic bar & grill, Wolfgang Puck Grill at the MGM Grand hotel in Detroit offers contemporary American cuisine in a fine dining setting. The menu incorporates fresh, seasonal, all-natural and organic ingredients for both dinner and their locally adored Sunday Brunch.
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Win a New Dodge Dart!
November 30, 2012 | Expired
Love classic cars? Dodge's always been a part that American muscle-car history. Gotta love em! Enter to win yourself a brand new Dodge Dart today! Nothing beats getting a set of brand new wheels, except of course getting them for free. But only one of you can get them so you guys politely sort that out among yourselves…or enter the contest now!


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Genzyme's LEMTRADA™ (alemtuzumab) Application For MS Accepted For Review By The FDA
Genzyme, a Sanofi Company (EURONEXT: SAN and NYSE: SNY), announced that the U.S. Food and Drug Administration (FDA) has accepted for review the company's supplemental Biologics License Application (sBLA) file seeking approval of LEMTRADA (alemtuzumab) for the treatment of relapsing multiple sclerosis (RMS). The company also reported key highlights from the U.S. launch of once-daily, oral AUBAGIO (teriflunomide).
LEMTRADA sBLA Accepted by FDA
The FDA has accepted for standard review the company's sBLA file seeking approval of LEMTRADA. Genzyme expects FDA action on the application in the second half of 2013. Genzyme has already submitted its marketing authorization application for LEMTRADA to the European Medicines Agency (EMA) and the review process is underway. The Committee for Medicinal Products for Human Use (CHMP) opinion for LEMTRADA is expected in Q2 2013.
The LEMTRADA clinical development program includes CARE-MS I and CARE-MS II ( Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis), randomized Phase III studies comparing LEMTRADA to a standard of care MS treatment, Rebif, in patients with relapsing-remitting MS who were naïve to prior treatment or who had relapsed while on prior therapy, respectively. Genzyme announced publication of results of these studies in The Lancet in November 2012.AUBAGIO Early Launch Indicators in the U.S. Since its launch in October, once-daily, oral AUBAGIO has shown very encouraging early launch indicators among U.S. prescribers. 1 Key highlights from the launch include:
- More than 80 percent of MS specialists in the U.S. have prescribed AUBAGIO;
- Approximately 1 in 5 patients prescribed AUBAGIO were treatment-naïve;
- More than 50 percent of AUBAGIO patients were most recently on Copaxone ® or Avonex ®
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At The James we're committed to creating the future of medicine to improve people's lives. That's why all locations – inside and outside – are tobacco-free. Patients and visitors should talk with their physicians about Nicotine Replacement Therapy prior to coming to the hospital.
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text:
We can save you up to 90% off your local dealer on the auto parts you need for your car or truck. We started selling Suzuki Fog Light Bulb parts nearly 30 years ago in Arizona, now we sell worldwide via the internet. Nearly every auto part you could ever need is available on our website. We have been selling Suzuki Fog Light Bulb parts for nearly 30 years. Stop waiting 4-6 weeks for credits for returns, we usually credit your account within days of receiving your return. Don't let your Suzuki Fog Light Bulb break your budget. Get your Suzuki Fog Light Bulb parts from our online store. Please feel free to email our customer service department with any questions or comments you may have about your Suzuki Fog Light Bulb parts order.
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text:
Home Maker: In a last-ditch effort to save the
housing market, Petra Nemcova has branched out into sexy, sexy field
of real-estate development. [NYPost]
Separated at Birth: While Ashley Olsen made the
Maxim "Hot 100 List," Mary-Kate was left off the tally of the
world's hottest tail, thus solidifying her place as the "ugly one."
The Legion of Superheroes: The bright stars of
society and fashion enjoyed the spandex and cowls on display at the
Met Gala. We'll just go ahead and presume our invites got lost in the
mail. [NYMag]
Under the Burka: Islamic fashion designers just can't
win. [Turkish
Daily News]
Vote Thin!: Barack Obama represents a, "shining new
hope for skinny men," and political marginalization for fatties. [ href="http://commentisfree.guardian.co.uk/daniel_nasaw/2008/05/thin_is_in.html">Guardian
Fitting End: Tailor to Sir Roger Moore and Ralph
Lauren, Douglas Howard passes away at 73. [ href="http://www.dnrnews.com/site/article.php?id=1798">DNRNews]
growing numbers, leaving more for the rest of us sloppy Yanks. [ href="http://men.style.com/news/blog/2008/05/no-sex-dear-im.html">Men.Style]


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Frued on Montessori/
Anna Freud was a strong supporter of Maria Montessori, and the Montessori approach to education. Her father also corresponded with Montessori, and professed his respect.
Anna Freud writes, in the preface to Maria Montessori: A Biography, that as a contemporary, she is impressed that "the most important elements of the Montessori method" entered into modern discourse "in one form or another" and became indispensable components in the education of small children...". She lists both sense perception studies and metaphysics as the primary elements that contributed to the success of Maria Montessori.
In a letter of correspondence, Freud himself states, "I am in deep sympathy with your humanitarian and understanding endeavors, and my daughter, who is an analytic pedagogue, considers herself one of your disciples."


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By critical consensus, Showgirls is the worst movie of the year. By Hollywood's near consensus, it's also the worst thing that ever happened to its star, Elizabeth Berkley, who has gone from red-hot hype to ice-cold chill faster than a $5 lap dance. United Artists' $40 million sex-travaganza was designed to be Hollywood's first big-budget, wide-release NC-17 blockbuster, and to do for Berkley a 22-year-old who had never acted in films what Basic Instinct did for Sharon Stone. But Showgirls tanked. Screenwriter Joe Eszterhas and director Paul Verhoeven have taken their critical lumps and moved on, careers intact, but Berkley is being held by moviegoers and moguls alike as almost singlehandedly responsible for its failure.
In the five weeks since the NC-17 Vegas breast-fest opened and inched to an embarrassing $20 million at the box office, Berkley has been dropped by Creative Artists Agency; rejected as a potential client by William Morris and ICM; linked romantically with her Showgirls director, Paul Verhoeven; harshly dismissed by Hollywood as a no-talent bimbo; and left without a definite follow-up feature role. New representation by United Talent Agency which piloted the rocket-ship careers of Jim Carrey and Sandra Bullock may reverse Berkley's nosedive, but for now the actress is left with the worst film credit since Heaven's Gate on her resume.
And at least some of the fault might lie in the star.
Berkley, who appeared on NBC's Saved by the Bell from 1989 to 1993, first attached herself to Showgirls in 1994, when she phoned producer Charles Evans and gave her name as ''Nomi.'' Evans, not recognizing that as the name of his Showgirls lead, initially refused to take the call. But the actress persisted, and when they met later that day Berkley introduced herself by saying ''Mr. Evans, I am Nomi Malone.'' She then went on to prove it. The dialogue that followed, recounted by Evans, could have been lifted from Showgirls itself. ''I'm a great dancer,'' Berkley told Evans. ''Can you act?'' he asked her. ''Fair,'' she said. ''How do you feel about being photographed nude?'' asked Evans. ''I have a nice body,'' Berkley said. ''Yes,'' Evans agreed, ''you do.'' Verhoeven, similarly impressed, cast the former sitcom actress in the lead role at a reported $100,000 salary. Even at a bargain price, a star was apparently born.
Shortly after Berkley landed the lead in Showgirls, CAA's Michael Menchel who three years earlier had declined to represent Berkley took her on as a client. By August, as Showgirls neared release, every agency in town was angling to steal her away from CAA. Yet the prized client wasn't landing any roles. Her costar Gina Gershon was lining up post-Showgirls projects (including another Eszterhas script, Original Sin), and Verhoeven signed to direct Starship Troopers. But Berkley? Nada.
Why? The agency's relations with the actress began to sour as she was finishing work on Showgirls. A source close to CAA says that Berkley didn't return phone calls from agents assisting Menchel, and that, in one instance, she refused to take a second meeting with a director who wanted her for a role. ''I don't need to go back,'' the source reports Berkley saying. ''He should just give me the part.'' Concludes the source, ''This is a young lady captured by the bright lights and the bulls -- -.'' By the time Showgirls was released, Berkley wanted another agent, but by then no other CAA agent would have her.
Unfortunately, William Morris and ICM were feeling the same way. They'd been wooing Berkley for many months, as Showgirls jiggled its way to the big screen. By the time they had seen the movie, though, and heard the CAA stories, they'd changed their minds.
Showgirls screenwriter Eszterhas, director Verhoeven, and producer Evans protest that Berkley has been unfairly blamed for their shared failurewhich Eszterhas calls, with a rueful laugh, "the kind of belly flop that empties all the water out of the pool." Insists Evans, "This is the script Joe wrote and the movie Paul directed, and she is the girl Paul wanted. She's getting a bum rap."
Asked about rumors that he and Berkley were more to each other than director and star, Verhoeven says, "I reject them." The actress burst into tears several times during difficult dance numbers on the set, Verhoeven says, and he comforted her. And, of course, she was naked at the time. And so people drew their own conclusions. Verhoevenwho has been married for nearly 30 years and has two daughters Berkley's agemaintains that sleeping with your leading lady is a bad idea anyway. "I have a very emotional relationship with all my leading actresses," he says. "But you want that emotion on the screen, not in the bed."
Berkley won't field questions about the rumored affair or her CAA difficulties other than to state: "As far as I'm concerned, I left Mike on the most amicable terms, and I continue to have respect for him and everyone at CAA. Anything to the contrary simply isn't true." What she will discuss, midway through a world publicity tour for Showgirls, is the movie: "I'm really proud of this performance and of this movie, and I have the utmost respect for Paul." She describes her mood as "great," and her reaction to the rough reviews, which she insists she doesn't read, is "We've all been hit equally badly." Berkley hints that she has "so many exciting new prospects," but won't say what they are. "Let's just say I'm not going to play a nun."
For his part, Verhoeven says he predicted Berkley's plight. "I told her six months ago, 'If people don't like the movie because of the society it portrays, they won't write about that. They'll write that you can't act, and you can't dance.' I told her that."


text: The Benjamin Harrison Presidential Site is host to changing exhibits each year. We mount a major exhibition in our 3rd floor ballroom that launches on Presidents' Day in February and remains part of our daily tours through December. Our current exhibition is "Who Do You Think They Were?". The Site also features smaller, seasonal exhibitions at commemorative times such as Flag Day, Columbus Day, and anniversaries of Civil War battles, War of 1812, etc.


text:
Research Topics
Jüri Reimand
Affiliation: University of Toronto
Country: Canada
Detail Information
- The mutational landscape of phosphorylation signaling in cancerJüri Reimand
The Donnelly Centre, University of Toronto, Canada
Sci Rep 3:2651. 2013..This analysis shows that incorporation of information about protein signaling sites will improve computational pipelines for variant function prediction. ..
- Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer driversJüri Reimand
The Donnelly Centre, University of Toronto, Toronto, Canada
Mol Syst Biol 9:637. 2013..This study demonstrates new ways of interpreting cancer genomes and presents new leads for cancer research...
- Domain-mediated protein interaction prediction: From genome to networkJüri Reimand
The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario, Canada
FEBS Lett 586:2751-63. 2012....
- m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescenceJüri Reimand
EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK
Genome Biol 13:R55. 2012..m:Explorer (http://biit.cs.ut.ee/mexplorer/) is instrumental in interrogating eukaryotic regulatory systems using heterogeneous data...
- Comprehensive reanalysis of transcription factor knockout expression data in Saccharomyces cerevisiae reveals many new targetsJüri Reimand
EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK
Nucleic Acids Res 38:4768-77. 2010..compendium. The dataset is available from ArrayExpress (accession: E-MTAB-109) and it will be invaluable to any scientist interested in the yeast transcriptional regulatory system...
- Subgroup-specific structural variation across 1,000 medulloblastoma genomesPaul A Northcott
Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
Nature 488:49-56. 2012..Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy...


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Check Point Raises the Bar on Performance of Antivirus and URL Filtering Software Blades
Also significantly increases firewall performance for UTM-1 appliances
Redwood City, CA —
Check Point® Software Technologies Ltd. (Nasdaq: CHKP), the worldwide leader in securing the Internet, today announced new streaming technology that dramatically increases antivirus and URL filtering software blades performance, benefiting all Check Point security gateways through a software upgrade at no additional cost. In addition, Check Point has extended its patented SecureXL acceleration technology to all UTM-1 appliances, significantly boosting firewall throughput performance. Now, customers can activate additional software blades to expand all layers of security for uncompromised protection and performance with a simple software upgrade to R71.
"We are proud to continue to challenge ourselves and provide customers with new technologies that deliver both uncompromised security as well as performance," said Dorit Dor, vice president of products at Check Point. "Customers can now deploy Check Point Antivirus and URL Filtering software blades on their existing gateways without having to choose between performance and more security protection."
Performance and throughput are important factors for businesses to remain protected, maximizing all levels of security without impeding the flow of business. Check Point's new streaming technology enables a record performance for antivirus and URL filtering software blades:
- Up to 20 times antivirus throughput improvement, with over 1Gbps for a 2-core system and 3Gbps for a 4-core system
- Up to 80 times antivirus and URL filtering connection capacity improvements with over 500,000 concurrent connections
Check Point's Software Blade architecture gives businesses the ability to create and extend their own security gateway from a library of centrally managed security applications or "software blades," such as firewall, virtual private network (VPN), intrusion prevention (IPS), anti-virus, URL filtering and many others. For more information about Check Point Network Security solutions, visit: http://www.checkpoint.com/products/network_security/.
For those businesses running Check Point software blades, the patented SecureXL technology boosts firewall throughput performance for UTM-1 appliances with a simple software upgrade. Already available on the UTM-1 3070, the upgrade extends these performance gains across all Check Point UTM-1 appliances, including: UTM-1 130, 270, 570, 1070 and 2070 series. New performance gains include:
- Up to four times greater firewall performance
- Up to four times connections per second improvement
"With Check Point's new levels of performance, we are able to deliver our customers richly layered, all-inclusive protection on a single appliance with central management," said Earl DeFrates, chief executive officer at NCC Networks, Inc. "These significant performance enhancements mean that customers can add more security protections while maintaining stellar performance levels."
Check Point UTM-1 appliances are all-inclusive, turnkey solutions that provide organizations of any size with all they need to secure their network. UTM-1 appliances can include the following software blades: firewall, intrusion prevention (IPS), Antivirus & Anti-malware, URL filtering, Web Security, and Anti-spam & Email security. Each appliance comes with integrated management, security updates and support. More information about UTM-1 appliances can be found at: http://www.checkpoint.com/products/utm-1/.
"Increasing gateway security performance through a simple software upgrade is an easy decision for most companies, especially in a market where performance and throughput are critical. Large and small companies alike will significantly benefit from upgrading immediately," concluded Dor.
Customers can upgrade to Check Point's new software release R71 immediately at no additional cost. Check Point Software Blades and UTM-1 appliances can be purchased through the Check Point worldwide network of value-added resellers. To find a Check Point partner, visit http://partners.us.checkpoint.com/partnerlocator/.
About Check Point Software Technologies Ltd.
Check Point Software Technologies Ltd. (www.checkpoint.com), the worldwide leader in securing the Internet, is the only vendor to deliver Total Security for networks, data and endpoints, unified under a single management framework. Check Point provides customers with uncompromised protection against all types of threats, reduces security complexity and lowers total cost of ownership. Check Point first pioneered the industry with FireWall-1 and its patented stateful inspection technology. Today, Check Point continues to innovate with the development of the Software Blade architecture. The dynamic Software Blade architecture delivers secure, flexible and simple solutions that can be fully customized to meet the exact security needs of any organization or environment. Check Point customers include tens of thousands of businesses and organizations of all sizes including all Fortune 100 companies. Check Point's award-winning ZoneAlarm solutions protect millions of consumers from hackers, spyware and identity theft.


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Sprouts Farmers Market Announces Commencement Of Public Offering By Selling Stockholders
PHOENIX, March 25, 2014 (GLOBE NEWSWIRE) -- Sprouts Farmers Market, Inc. (the " Company") (Nasdaq:SFM) today announced the commencement of an underwritten public offering of 15,000,000 shares of its common stock by affiliates of Apollo Global Management, LLC (" Apollo"), and certain other stockholders of the Company (collectively, the " Selling Stockholders"). The underwriters of the offering will have the option to purchase up to an additional 2,250,000 shares of common stock from the Selling Stockholders. The Selling Stockholders will receive all of the proceeds from the offering.
The offering is being made through an underwriting group led by Goldman, Sachs & Co., Credit Suisse, BofA Merrill Lynch, Apollo Global Securities, Barclays, Deutsche Bank Securities, UBS Investment Bank, Guggenheim Securities and Wolfe Research Securities. Goldman, Sachs & Co., Credit Suisse and BofA Merrill Lynch are acting as joint book-running managers of the offering and the representatives of the underwriters.
This offering will be made only by means of a prospectus. Copies of the preliminary prospectus and, when available, final prospectus relating to the offering may be obtained from: Goldman, Sachs & Co., Attention: Prospectus Department, 200 West Street, New York, NY 10282, Telephone: 866-471-2526, Facsimile: 212-902-9316 or by emailing firstname.lastname@example.com; Credit Suisse Securities (USA) LLC, Attention: Prospectus Department, One Madison Avenue, New York, NY 10010, Telephone: 800-221-1037, or by emailing firstname.lastname@example.com; or Merrill Lynch, Pierce, Fenner & Smith Incorporated, 222 Broadway, New York, NY 10038, Attention: Prospectus Department or by email at email@example.com registration statement relating to these securities has been filed with the Securities and Exchange Commission but has not yet become effective. These securities may not be sold nor may offers to buy be accepted prior to the time the registration statement becomes effective. This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor will there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
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text:
Less than a week into hunting season, State Police in Warsaw have distributed several tickets for violations in Wyoming County involving the enforcement of hunting rules and violations.
The issues ranged from failure to tag a deer, illegal taking of an antlered deer, failing to accompany youth hunters, and accepting a buck carcass tag of another and more.
The seven Wyoming County hunters were issues appearance tickets for their respective town courts for the infractions.
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The Saudis want to convince their people that democracy in Iraq or anywhere would lead to divisions, insecurity and instability."
These attacks are being carried out by al-Qaeda, which has been revitalized and reinvigorated that is largely due to the protests, which are taking place in western Iraq, which are wholeheartedly and emphatically backed up by Saudi Arabia and Qatar as a new potent instrument to actually ratchet up sectarian tension in Iraq.
And that's why we see that al-Qaeda have used it and exploited that to increase the radicalization and also ramp up the recruitment and to reactivate those areas, which have been the safe havens and sanctuaries for al-Qaeda previously.
So the two branches of al-Qaeda are working hand in hand and let's not forget that Saudi Arabia desperately and strenuously needs now sectarian tension and ultimately sectarian war in Iraq to convince its people that it is engaged in dealing and confronting existential threats coming from the Shias and principally from the Islamic Republic of Iran - because the Saudis, which is a Wahabi government has been portraying itself that it is the defender and the guardian of the Sunnis.


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Osho continues:
"Arhatas never, never think about anybody else. If they speak, they are just speaking to themselves. Most probably they remain silent. They have a profound respect for others, but they know that to tell them about the ultimate is to disturb their ordinariness. It is an interference in their mundane minds – although it is for their own benefit. But they are not asking for it, and unless they invite the truth, the truth is not going to knock on their doors.
"The truth is almost like the sun in the morning. It risesit does not knock on your doors saying, 'I am here and the night is over and you can wake.' It does not go to every nest of the birds, to tell them, 'Now it is time to sing, I have come,' nor does it go to every flower to open its petals and release its fragrance. It simply comes. Those who are receptive will receive it. Those who are not receptive will not receive it. Those who are awake will know that the morning has arrived, but those who are fast asleep will not know, even in their dreams, that the night is over. But the sun does not interfere.
"The understanding of the arhatas is that compassion means not to interfere, not to trespass, even though it is for the benefit of those against whom you are trespassing. Trespassing in itself is against the dignity of individuals and it is a humiliation. To say to someone, 'You are asleep,' means you are putting yourself on a higher pedestal. You are saying, 'I am awake and you are asleep,' you are saying 'I am holier than thou, higher than thou; I have arrived to the ultimate peak of my consciousness and you are still wandering in the world of darkness, groping everywhere, stumbling, falling and finding no way out.'
"Even to advise anyone is to take a certain position: 'I know and you do not know.' The arhatas' standpoint is that it is against compassion, it is against reverence for life; hence they remain silent. If anybody feels their presence on his own accord and comes close to them to drink the living waters of their experience, they are available – just like the river passing by."
In deze titel Osho spreekt over de volgende onderwerpen:
moment… chain… response… sages… arhatas… miss… outside… diogenes… gurdjieff… kirlian
moment… chain… response… sages… arhatas… miss… outside… diogenes… gurdjieff… kirlian