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Just in case he decides to run for president again, Rick "Son of an Immigrant Meself" Santorum yesterday joined an ever-growing Republican chorus in assuring the former job-stealing, benefit-swindling Hispanic voting bloc that, in fact, they are towers of economic strength and moral goodness. [Politico]
Rick Santorum Gives Up Entirely on the Mainstream, Writes for WND
Rick Santorum is running out of respectable gigs. When he lost his Senate seat to Bob Casey a few years back, he started writing columns for the Philadelphia Inquirer—back when that publication was under the control of Brian Tierney and intent on acting as a semi-retirement home for disgraced Republicans. Now that the 2012 election is over, and Santorum's presidential dreams dead for four more years, he's going to work for World Net Daily, which the Washington Post calls a "conspiracy-minded" conservative website. "Known for propagating "birtherism," WND has also questioned Florida Sen. Marco Rubio's eligibility to run for president," the Post observes. In other words: Santorum's audience now resides entirely on the fringe. [Washington Post]
Arlen Specter and the Death of Pragmatic Politics
Arlen Specter was a pragmatist. That's the kind of thing we say we want in a politician—somebody who will ignore ideology and just get stuff done—but the truth is we mostly reward ideologues. Which is why when he died Sunday at age 82, Pennsylvania's former longtime U.S. senator was out of power and all-too-unloved in a state and city he served for a very long time. Read more »
Rick Santorum Endorses Rep. Todd Akin
Remember Todd Akin? The GOP Rep. from Missouri whose comments on "legitimate rape" made him a national goat back in August? Well, Former Republican presidential hopeful Rick Santorum has backed Akin's Senate bid. Less than 24 hours after the deadline to withdraw from the Senate race passed, Santorum and tea party Sen. Jim DeMint issued a statement in support of Akin. Mitt Romney thought Akin should have dropped out of the race back in August. [Politico]
Rick Santorum Named to List of Biggest Homophobes of Last 45 Years
The Advocate has released its list of "The 45 Biggest Homophobes of Our 45 Years." Among the collection of the most anti-gay people is former Senator from Pennsylvania and unsuccessful Republican presidential candidate Rick Santorum.
The "man on dog" senator from Pennsylvania got an astonishing number of votes in the Republican presidential primaries this year with his unabashedly antigay agenda. Can that many people really agree with his plan to annul all same-sex marriages and reinstate the "don't ask, don't tell" policy? His homophobic ideas are too many to list here. Just Google "Santorum" and you'll find plenty.
Rick Santorum Will Be a Headliner at the Republican National Convention
Rick Santorum will be featured as a speaker at the Republican National Convention in Tampa this month. The keynote speaker has yet to be officially announced (Chris Christie?), but Santorum will join a dais that includes Senator John McCain, former Secretary of State Condoleezza Rice, former Florida Governor Jeb Bush. We're pretty sure that Santorum is going to be stumping for Republican candidate Mitt Romney at this thing, but a site set up for Bob Casey's campaign in 2005 has continued to pay attention to the goings on and points out that you never can be too sure. [Daily News]
Santorum Sure Loves His Chick-Fil-A
Are we surprised? Not a bit. But just when we thought we'd heard enough from former PA senator and one-time presidential hopeful Rick Santorum – he's resurfaced. Why? Because this guy loves some Chick-fil-A.
He tweeted recently that he and his family were enjoying a meal at the fast food chain. The management of Chick-fil-A recently admitted that they are proud to stand against LGBT rights and same-sex marriage. They've also donated millions to anti-gay hate groups in recent years and are facing an enormous boycott. Even the Jim Henson Company pulled its support. And the mayor of Boston told the chain that they're not welcomed in the city.
But because Santorum pretty much espouses the same homophobic rhetoric (heck, he launched a campaign from it – a failed one, we should add), he said he'd be joining Chick-fil-A on August 1 for an appreciation day launched by another failed GOP presidential contender Mike Huckabee.
"I have been incensed at the vitriolic assaults on the Chick Fil-A company because the CEO, Dan Cathy, made comments recently in which he affirmed his view that the Biblical view of marriage should be upheld," Huckabee shared on Facebook this week. He accuses the left of vicious hate speech against the company, which is ironic considering it's Cathy and his cronies who seem to be doing their fair share of hateful smearing (not to mention donating to organizations that have been defined by their own anti-gay attacks).
If these two guys don't make you want to give up chicken sandwiches, we don't know what will.
Click here to watch Huckabee defend Chick-fil-A's so-called "Biblical" principles on (where else?) Fox News.
Rick Santorum Is Still Really Jazzed About Chick-Fil-A
You know who's really excited about Chick-Fil-A's chick-in-strips? Rick Santorum, that's who! The former Republican presidential candidate tweeted that he was enjoying some of the delicious prejudiced poultry along with a peach shake with two of his sons this afternoon. The shame of it is that Santorum's boys missed out on the Jim Henson kid's meal toy. The horror. [The Atlantic Wire]
Rick Santorum Is the Spokesman for a Catholic Stem Cell Research Organization
Give Cures is an "ethical" stem cell research organization that only uses adult stem cells and restricts its research to experiments and procedures OKed by the Catholic Church. The organization is launching an initiative to raise awareness and funds—along with a cord blood bank—and has tapped everybody's favorite former Republican presidential candidate, Rick Santorum, to be its spokesman. [Politics PA]
Will Rick Santorum Move to Canada?
There's a whole sect of people who were so upset with the Supreme Court's decision on President Barack Obama's controversial health care law that they've announced they're moving to Canada. Rick Santorum has made it clear that he's less than thrilled with the ruling SCOTUS delivered yesterday. In fact, the former Republican presidential candidate was so incensed that he went ahead and fired off an angry email to supporters:
Today's outcome is the worst of all scenarios. Not only are our rights being taken away and Americans are being forced to do something we don't want to do, but now we are being burdened with the biggest permanent tax increase in our nation's history. This is a sad day.
But it doesn't stop at sad, does it, Rick?
President Obama believes he is above the law, entitled to abusing his power to get what he wants, and willing to violate the constitution and the oath he was sworn to uphold. He has proven to be a very dangerous person to have this kind of power, and if he is not stopped this November, I am fearful that the make-up of this country as established by our founders will never be the same.
He also made a TV appearance last night to point out that President Barack Obama is more arrogant than Tricky Dick. All of this "danger" talk has us wondering if Santorum's going to pack up his sweater vests and head for the border. He has to have at least considered it a viable option at this point, eh?


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IT-ProjektmanagementSpringer Fachmedien Wiesbaden 2015; US$ 9.99
Christian Aichele und Marius Sch�nberger haben aktuelle wissenschaftliche Methoden und Praxiserfahrungen aus IT-Projekten in unterschiedlichsten Bereichen und Branchen zusammengefasst. Zur erfolgreichen Durchf�hrung von Projekten stellen sie hierbei aktuelle Methoden und Vorgehensweise kumuliert vor und erkl�ren sie so, dass interessierte Leser ein... more...
Practical Linux InfrastructureApress 2014; US$ 38.49
Practical Linux Infrastructure teaches you how to use the best open source tools to build a new Linux infrastructure, or alter an existing infrastructure, to ensure it stands up to enterprise-level needs. Each chapter covers a key area of implementation, with clear examples and step-by-step instructions. Using this book, you'll understand... more...
Advances in Artificial EconomicsSpringer International Publishing 2014; US$ 89.99
?The book presents a peer-reviewed collection of papers presented during the 10th issue of the Artificial Economics conference, addressing a variety of issues related to macroeconomics, industrial organization, networks, management and finance, as well as purely methodological issues. The field of artificial economics covers a broad range of methodologies... more...
Wireless Multimedia Sensor Networks on Reconfigurable HardwareSpringer Berlin Heidelberg 2013; US$ 109.00
This book shows how reconfigurable hardware technology like field-programmable gate arrays (FPGAs) offer cost-effective, flexible platforms for implementing WMSNs. Offers a complete specification of a low-complexity FPGA WMSN node processor, plus case studies. more...
Hardware and Computer OrganizationElsevier Science 2005; US$ 84.95
Hardware and Computer Organization is a practical introduction to the architecture of modern microprocessors for students and professional alike. It is designed to take practicing professionals ?under the hood� of a PC and provide them with an understanding of the basics of the complex machine that has become such a pervasive part of our everyday... more...
Design Concepts for a Virtualizable Embedded MPSoC ArchitectureSpringer Fachmedien Wiesbaden 2014; US$ 89.99
Alexander Biedermann presents a generic hardware-based virtualization approach, which may transform an array of any off-the-shelf embedded processors into a multi-processor system with high execution dynamism. Based on this approach, he highlights concepts for the design of energy aware systems, self-healing systems as well as parallelized systems.... more...
Modeling, Simulation and Optimization of Complex Processes - HPSC 2012Springer International Publishing 2014; US$ 139.00
This proceedings volume gathers a selection of papers presented at the Fifth International Conference on High Performance Scientific Computing, which took place in Hanoi on March 5-9, 2012. The conference was organized by the Institute of Mathematics of the Vietnam Academy of Science and Technology (VAST), the Interdisciplinary Center for Scientific... more...
Integration of Services into Workflow ApplicationsCRC Press 2015; US$ 99.95
Describing state-of-the-art solutions in distributed system architectures, Integration of Services into Workflow Applications presents a concise approach to the integration of loosely coupled services into workflow applications. It discusses key challenges related to the integration of distributed systems and proposes solutions, both in terms of... more...
Channel Estimation for Physical Layer Network Coding SystemsSpringer International Publishing 2014; US$ 54.99
This SpringerBrief presents channel estimation strategies for the physical later network coding (PLNC) systems. Along with a review of PLNC architectures, this brief examines new challenges brought by the special structure of bi-directional two-hop transmissions that are different from the traditional point-to-point systems and unidirectional relay... more...
Emerging Trends in Communication NetworksSpringer 2014; US$ 54.99
This book covers the state of the art in communication networks with the help of illustrative diagrams and recent references published in reputed journals and magazines. The book gives readers a glimpse into the next generation of communication networks. It explores topics that are currently in the research phase and/or are expected to be deployed... more...

subset: commoncrawl


text:
Report | 4 months ago
Dr. Bean was very good.
Follow this business and get notified when they run a deal.
Across 11 offices, Oklahoma Foot & Ankle Associates' team of experienced podiatrists devote themselves to tailoring services to meet all podiatric needs. Treatments address orthopedic, nail, skin, and disease-related complaints, and include the use of lasers that blast away nail fungus and shrink toe-stomping supervillains.


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Simon Cowell Worried That One Direction Will 'Burn Out'
One Direction are going full-speed ahead -- and it has Simon Cowell worrying about them.
One Direction are going full-speed ahead -- and it has Simon Cowell worrying about them.
Liam Payne just tweeted a split image of two girls who look so much like him and Niall Horan that we practically had to do a double take.
We couldn't resist getting our 2014 holiday gift guide started just a little bit early, even though we're firm believers of waiting to celebrate the holidays after Thanksgiving.
Yes, Directioners, the 'Night Changes' teasers just keep on coming. Today's look into the world of dating One Direction takes us on an amusement park adventure with smooth crooner Liam Payne.
See One Direction, Justin Bieber, Miley Cyrus, Big Time Rush, Demi Lovato, 5 Seconds of Summer and more celebs react to fans throwing their bras on stage.
Directioners, can't wait for One Direction's 'Steal My Girl' vid? Well, neither can we -- especially after what director Ben Winston just teased.
How would you react if your favorite artist popped up out of nowhere to give you the surprise of your life?
When 5 Seconds of Summer took the stage on Sept. 16, they surprised the audience (and the band!) with their adorable ode to One Direction.
Directioners, One Direction just announced such huge news that we're having trouble keeping our fangirl shrieks in check.
Liam Payne busted out a verse of Michael Jackson's 'The Way You Make Me Feel' at a recent One Direction concert, and he totally kills it! Watch the video here.
One Direction as Legos. That is all.
One Direction's Liam Payne decided to let it "all hang out" as he was catching some sun on a motorboat on Sunday.


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Bioactive compositions that induce or enhance the repair of damaged or diseased connective tissues upon contact of the tissues with the compositions in vivo include an effective amount of pleiotrophin. A delivery vehicle is also included in the compositions. The compositions may be delivered to the repair sites by injection or by implantation.
1. A method for inducing localized connective tissue growth at a predetermined in vivo site of a vertebrate species, said method comprising
contacting said site with a composition comprising substantially purified pleiotrophin, in an amount effective to induce connective tissue growth, and a pharmaceutically acceptable carrier.
2. The method of
3. The method of
4. The method of
5. The method of
6. The method of
7. The method of
8. The method of
9. The method of
10. The method of
11. The method of
12. A method for treating a pathogenic condition in a connective tissue in a warm-blooded vertebrate, said method comprising
administering a composition systemically to said warm-blooded vertebrate, wherein the composition comprises substantially purified pleiotrophin, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier.
13. The method of
14. The method of
15. The method of
This invention relates to implantable biocompatible compositions that induce the repair of damaged or diseased bone, cartilage or other connective tissues upon contact of the damaged or diseased tissues with the composition in vivo. The invention also relates methods of inducing repair. More particularly the present invention is directed to the use of a composition comprising an effective amount of pleiotrophin to induce repair of damaged or diseased connective tissues.
Currently, bone defects are typically repaired by autografts or banked bone. Autografts have a good ability to unify the bone, and physicians often prefer to use bone from sources such as the iliac crest. However, procedures using autografts suffer from several drawbacks. First, autografts require a separate harvest operation, resulting in increased operative time and the use of blood transfusions. Secondly, patients often lack adequate amounts of material for harvesting and often experience donation site morbidity. Implantation of banked bone does not require the harvest operation, but its bone healing capability is not as high as that of autografts. Therefore, it is undesirable to use banked bone in severe conditions such as nonunion.
Because of these drawbacks, researchers have searched for compositions and methods for promoting bone growth without necessitating the use of autografts or banked bones. One potential source for bone growth promoting factors is the extracellular matrices of healthy bone and cartilage tissues. Extracellular bone matrix contains predominantly mineral (hydroxyapatite) and an organic matrix, where the major component of the organic matrix is collagen type I. The remaining components of bone matrices include a number of less abundant non-collagenous proteins and growth factors. For example, since the mid-1960's the osteoinductive activity of both demineralized bone matrix (DBM) and bone morphogenetic protein (BMP) has been studied (Ijiri, 1992). In addition to DBM and BMP, many non-collagenous bone matrix protein components possess biological activity and find wide use in medical applications such as prosthetic devices, drugs, blood components, and the like.
One non-collagenous protein found in bone matrix is pleiotrophin (also known as HB-GAM, HARP, P18, and OSF-1). Pleiotrophin is a heparin-binding protein belonging to a recently described family of developmentally regulated cytokines. Pleiotrophin has been reported to exhibit both neurite outgrowth-promoting activity, on embryonic rat brain neurons in culture, and mitogenic activity toward rat and mouse fibroblasts. The biological activity of recombinant human pleiotrophin is measured by its ability to enhance neurite outgrowth of cerebral cortical neurons of E10 chicken embryos. The EC50 is defined as the effective concentration of growth factor that elicits a 50% increase of neurite outgrowth from E10 chicken embryos.
Pleiotrophin protein was initially isolated from early postnatal rat brain and bovine uterus, and can be isolated from warm-blooded vertebrate bone and cartilage tissues using standard extraction techniques known to those skilled in the art, including extracting with guanidine hydrochloride. Human pleiotrophin protein is initially produced as a 168 amino acid residue precursor that is processed to remove the 32 amino acid residue signal peptide and produce the 136 amino acid mature protein. DNA sequences encoding the protein have been recently cloned and recombinant pleiotrophin protein is commercially available from Sigma chemical company (St. Louis, Mo.). Gene sequences (cDNA clones) encoding for pleiotrophin have been prepared from rat, bovine and human cell mRNAs. The predicted amino acid sequence of pleiotrophin is highly conserved between these three species, and each encoded protein contains a signal sequence, suggesting that the protein is secreted.
Pleiotrophin binds strongly to bone extracellular matrix in vitro and may have an autocrine or paracrine action. Pleiotrophin shares some chemical similarities with the family of fibroblast growth factors (FGF), namely the heparin-binding ability, however pleiotrophin does not belong chemically to the FGF family. The deduced amino acid sequence of pleiotrophin is distinct from any other known growth factor family. Pleiotrophin is known to be expressed by osteoblasts, cartilage and osteosarcoma cells, and has been isolated from bone and cartilage. The expression of pleiotrophin has been associated with bone and cartilage progenitor cells, as well the mesenchyme of lung, gut, kidney, and reproductive tract of developing rat tissues.
Numerous compounds have been isolated from biological sources and have been identified as having potential bone growth enhancing activities based on the response of cultured cells to those compounds. In particular, due to the association of pleiotrophin with developing bone in animal tissues, and the response of various cultured cells to pleiotrophin in vitro, it has been suggested that this molecule may play a role in bone and/or cartilage development. However, in vitro results may vary due to a variety of factors, including cell type, cell density, cell isolation procedures, and type of growth medium. Therefore, while useful, in vitro studies are not always predictive of in vivo activity.
For example over the last two decades prostaglandins had been reported as both increasing bone resorption as well as increasing bone formation. Analysis of the literature references reporting the conflicting activities of prostaglandins reveals that almost all reports of bone resorption were performed in vitro and almost all the studies reporting bone formation were done in vivo (Mark and Miller, 1993). Previous studies of bone growth in vitro were performed with tissue/organ cultures of bone or relatively pure isolated bone cell populations. The apparent conflicting reports of the predominant skeletal affects of the prostaglandins can be explained on the basis of the limitations of the cell culture systems used to study those effects. Similarly, initial reports of TGF- activity based on cell culture assays failed to correlate with observed in vivo activities. Therefore, skilled artisans appreciate that in vitro activity does not always predict in vivo results.
What is needed are compositions shown to repair connective tissue in vivo.
In accordance with the present invention, compositions comprising pleiotrophin are used to induce growth of bone or cartilage at an in vivo site in need of repair. The disclosed composition is administered to a warm-blooded species, either by implanting or injecting the composition, for in vivo contact with the site in need of repair. This invention is the first demonstration that pleiotrophin alone is capable of enhancing the repair of bone or cartilage tissues by endogenous tissues.
Another aspect of this invention is a method for inducing new bone or cartilage growth at a predetermined in vivo site of a vertebrate species comprising the steps of contacting the site with a composition comprising substantially purified pleiotrophin, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier. In a preferred embodiment, the composition is in liquid form and the site is contacted by injection of the composition. In another preferred embodiment, the carrier is a polymer matrix comprising a polymer selected from the group consisting of polyesters, ionomers, poly(amino acids), polyvinyl acetate, polyacrylates, polyorthoesters, polyanhydrides, collagens, fibrins, starches, alginate, and hyaluronic acid. Alternatively, the carrier may be a metal, glass, or mineral salt. Preferred mineral salts include tricalcium phosphate, hydroxyapatite, and gypsum.
Still another aspect of this invention is a method of treating a bone or cartilage pathogenic condition in a warm-blooded vertebrate by administering a composition systemically to the warm-blooded vertebrate, wherein the composition comprises substantially purified pleiotrophin, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier.
Additional features of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of embodiments including those exemplifying the best mode of carrying out the invention.
The present invention is directed to compositions comprising pleiotrophin in a substantially pure form, and the use of such compositions to enhance the repair of bone and cartilage defects in vivo. As used herein the term "pleiotrophin" is intended to include native pleiotrophin protein isolated from human or other warm-blooded vertebrates, recombinant protein produced from pleiotrophin encoding nucleic acid sequences, and protein fragments/peptides of pleiotrophin proteins. A pleiotrophin gene is defined herein to include any nucleic acid sequence encoding for pleiotrophin, including the native gene sequences isolated from human or other warm-blooded vertebrates, any nucleic acid sequence encoding active fragments of pleiotrophin, or any recombinant derivative thereof. As used herein, the term substantially pure is intended to mean purified to at least 90% pure, and preferably to 95% purity, as determined by polyacrylamide gel electrophoresis or amino acid analysis.
The compositions of the present invention can be used in a method for inducing the repair of damaged or defective tissues of a warm-blooded vertebrate. More particularly, pleiotrophin can be used to repair the tissues of orthopedic and non-orthopedic wound sites, including bone, cartilage, tendon, ligament, muscle, skin, and other soft tissues. In one embodiment the compositions of the present invention are used to repair fractures effectively and fill or bridge bone defects including for example, craniofacial defects or periodontal defects, joint fractures, chondral defects, superficial chondral defects, full thickness defects, osteochondritis dissecans, minuscule tears, ligament tears, tendon tears, muscle lesions, myotendinitis junction lesions, skeletal reconstruction following secondary bone loss to infection or neoplasm, and the treatment of various bone or cartilaginous diseases resulting in defects.
Many compounds that have been isolated from connective tissues have been reported as having osteogenic properties based on the response of cells to those compounds in vitro. However, in vitro-established activities often fail to provide sufficient guidance for selecting compounds that will exhibit the desired in vivo bone and cartilage repair enhancing activity. Accordingly, the present invention uses an in vivo assay technique to identify bioactive agents that induce the repair of bone and cartilage tissues. Advantageously, the present in vivo assay avoids the use of delivery carriers, such as collagen, which are known to exhibit osteogenic properties themselves.
This unique in vivo assay was used to identify compounds that enhance bone repair. More particularly, the in vivo assay described in Example 1 demonstrates that pleiotrophin enhances the repair of bone in vivo.
Pleiotrophin may enhance the repair of these tissues either directly or indirectly. For example, pleiotrophin may increase new bone formation at a localized site by directly stimulating osteoblast activity (i.e. by enhancing matrix production or by recruiting additional osteoblast cells), by increasing angiogenesis, or by inhibiting osteoclast resorption. In addition, the compositions of the present invention may participate in the recruitment of bone progenitor cells or bioactive agents to the localized site either by selective binding of pleiotrophin to the progenitor cells or the bioactive agent, or pleiotrophin may participate in the recruitment of cells through chemotaxis. It is also anticipated that pleiotrophin can be used in a wound repair context in combination with a carrier material such as a ceramic or polymer, including the use of proteins such as collagen as the carrier material. In addition pleiotrophin can be combined with autologous cells (such as bone or cartilage progenitor cells) or autologous proteins (such as fibrin).
In an embodiment the compositions of the present invention comprise a delivery vehicle and a bioactive mixture comprising an effective amount of a substantially pure pleiotrophin. In another embodiment, the compositions of the present invention comprise a delivery vehicle and a bioactive mixture comprising a pleiotrophin gene. Delivery vehicles suitable for use in delivering bioactive agents to bone and cartilage in vivo are well known to those skilled in the art. In one embodiment the delivery vehicle comprises a polymer matrix, and the polymer matrix is formed from one or more biocompatible polymers. As used herein, "biocompatible" means that the polymer is non-toxic, non-mutagenic, and elicits a minimal to moderate inflammatory reaction. Preferably the biocompatible polymer is also biodegradable and completely degrades in a controlled manner into non-toxic residues. In this embodiment, the polymer matrix serves as a delivery vehicle for the bioactive mixture, concentrating the bioactive agent at a localized site of administration and controlling the release of the bioactive composition. The controlled delivery and release of pleiotrophin to localized bone and cartilage sites is based on the use of biodegradable, biocompatible polymers in combination with bioactive molecules to achieve both efficacious release of molecules and removal of the polymer from the treatment site within a physiologically useful time period.
A variety of polymers can be used to form the implant for the purposes of delivering bioactive molecules to a predetermined in vivo site, including polyesters, polyvinyl acetate, polyacrylates, polyorthoesters, polyhydroxyethylmethacrylate (polyhema) and polyanhydrides. One of the advantages of polyesters in such applications is that they are both biodegradable and biocompatible. Aliphatic polyesters have been widely used in the area of biomaterials for implantable drug delivery devices, sutures, and general tissues supports, after injury or surgery. The polyesters traditionally of greatest interest for localized delivery of compounds, are derived from lactide, glycolide, and -caprolactone monomers, with a fairly broad range of degradation profiles accessible through various termonomer combinations. The ester linkages in these aliphatic polyesters are hydrolytically and/or enzymatically labile and render the polymers degradable in aqueous environments.
In a preferred embodiment, polymers such as polyanhydrides, polyester anhydrides, or ionomers are used. Alternatively, other polymers such as polylactic acid and polyorthoesters can also be used. In another embodiment the polymer matrix comprises collagen fibers. Collagen has been reported to exhibit bioactive properties and enhances the repair of bone and cartilage tissues in vivo. Accordingly collagen fiber can function as both a component of the delivery system as well as an active agent of the present bone and cartilage repair compositions. Other polymers suitable for use in forming the polymer matrix comprise fibrins, starches, alginate, and hyaluronic acid.
The composition of the polymer used to form the delivery vehicle matrix, as well as the molecular weight and physical properties of the polymer, can be varied according to the application. For example, hydrophobic polyanhydrides can be used where it is desirable to increase the time of degradation. Compounds can be mixed into, or polymerized with the polymer as required for additional strength or other desirable physical properties, using materials known to those skilled in the art of polymer chemistry or materials science. For example, tricalcium phosphate or hydroxyapatite particles that provide better physical handling properties can be added to the composition.
In general, for repair of bone breaks, the polymer should release the material over a period of approximately 3 to 42 days (generally six weeks are required for sufficient repair to occur in humans before the bone is capable of bearing weight). The polymer should also degrade completely over a period no longer than about sixteen to twenty weeks. Release and degradation times will depend in part upon the polymer used and the bioactive materials to be released. In addition to polymers, various other time-release vehicles are known. An approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a more or less constant rate of drug release is maintained. See, e.g., U.S. Pat. No. 3,710,795. Another approach is the use of an osmotic pump, as described in Example 1.
In accordance with an embodiment of the present invention, the delivery vehicle comprises polyester ionomers (salts of carboxy-terminated polyesters). The polyester ionomers exhibit good solubility even at higher molecular weights dictated by implant structural/functional requirements. The polyesters are prepared from and degrade into naturally occurring metabolites for enhanced biocompatibility. The polyester ionomers are prepared from the corresponding carboxy-terminated polyesters by neutralization or partial neutralization with biocompatible, pharmaceutically acceptable salt-forming bases. In an embodiment the delivery vehicle comprises biodegradable carboxy-terminated polyesters in combination with the corresponding ionomers. The physical properties of polyester ionomers can be controlled by the degree of neutralization of the corresponding carboxyterminated polyesters and to some extent by selection of the neutralizing base. The polyester ionomers can be used alone or in combination with their carboxy-terminated polyester precursor for use in construction of a biocompatible delivery vehicle for tissue repair and/or prolonged release of biologically active compounds.
The use of polyester ionomers as delivery vehicles is described in U.S. Pat. No. 5,668,288, the disclosure of which is incorporated herein by reference. In general the polyester ionomers are divalent residues of a polyester. The polyester can comprise a homopolymer, copolymer, or terpolymer of biocompatible hydroxy acids, for example, lactic acid, glycolic acid, -hydroxy caproic acid, and -hydroxy valeric acid. Alternatively, the polyester can be formed using copolymerization of a polyhydric alcohol and a biocompatible polycarboxylic acid. Most typically such copolymers are formed between dihydric alcohols, for example, propylene glycol for biocompatibility and biocompatible dicarboxylic acids.
The bioactive component of the present compositions comprises pleiotrophin optionally combined with a pharmaceutically acceptable carrier, solubilizing agent, or filler material. To induce bone growth formation, pleiotrophin should be administered at a concentration ranging from about 50 ng to about 10 mg/ml of the defect area. In an embodiment pleiotrophin is administered in a concentration ranging from about 5 μg to about 1 mg/ml of the defect area. In addition, tricalcium phosphate, hydroxyapatite, gypsum, or other suitable physiological mineral sources can be combined with the compositions to assist in repair of damaged or diseased bone. In accordance with an embodiment, a physiological compatible mineral comprises up to 80% of the bioactive mix of the present composition. Alternatively, the physiological compatible mineral may comprises about 5% to about 50% of the bioactive mix, and more preferably comprises about 5% to 30% of the bioactive mix. In addition, the present compositions can be combined with known pharmaceuticals and bioactive agents to create a delivery system for the local treatment of bone disorders or diseases.
In addition, the bioactive component of the present compositions can be further combined with growth factors, growth factor binding proteins, or eukaryotic cells. Examples of suitable growth factors comprise: fibroblast growth factor, transforming growth factor (e.g., TGF- ), bone morphogenetic protein, epidermal growth factor or platelet-derived growth factor. Examples of growth factor binding proteins are insulin-like growth factor binding proteins (IGFBP's) such as IGFBP 3 and 5. Examples of suitable eukaryotic cells comprise bone marrow cells, osteoblasts, and mesenchymal stem cells. The bioactive composition of the present invention can further include an osteogenic agent that stimulates or accelerates generation of bone upon implantation into a bone defect site. Examples of osteogenic agents comprise demineralized bone powder, morselized cancellous bone, aspirated bone marrow, bone or cartilage forming cells, and other bone sources.
The bioactive compositions of the present invention are useful for stimulating the growth of bone and cartilage tissues at a predetermined localized site in a warm-blooded vertebrate. The method comprises contacting the site in need of repair with a composition comprising substantially pure pleiotrophin. In one embodiment the composition is surgically implanted at the site in need of repair and the composition comprises pleiotrophin and a polymer matrix, wherein the polymer matrix controls the release of pleiotrophin and concentrates pleiotrophin at the desired site. Alternatively, the composition may be in an injectable form and the method of contacting the site in need of repair comprises injecting the composition into or adjacent to the site. The injectable form of the present composition typically comprises pleiotrophin in combination with a pharmaceutically acceptable carrier. The viscosity of the compositions can be adjusted by controlling the water content of the compositions or by the addition of pharmaceutically acceptable fillers or thickening agents known to those skilled in the art. In one embodiment, the injectable forms include collagen fibers and the viscosity of the composition is controlled by adjusting the pH of the composition from about 6.0 to about 7.5.
The compositions of the present invention can be combined with an effective amount of antibiotics, chemotherapeutic agents, additional growth factors, antigens, antibodies, enzymes, or hormones. For example, a composition comprising pleiotrophin and an antibiotic may be useful in the treatment of osteomyelitis, thereby reducing the need for and risk of parenteral antibiotics. In addition, a composition comprising pleiotrophin and an antineoplastic agent could be used for the local treatment of bone neoplasm, or a composition comprising pleiotrophin and an osteogenic or other growth factor (e.g., osteogenin, bone morphogenetic protein, parathyroid hormone, or TGF- ) could be used to accelerate the repair of skeletal defects as occurs with excessive trauma and with skeletal deficiency disorders such as osteogenesis imperfecta.
As noted above the present compositions can be prepared in fluid forms for injection into a warm-blooded vertebrate. In one embodiment the injectable forms are used systemically to treat a warm-blooded vertebrate and provide therapeutic value for conditions such as arthritis or other pathogenic situations that involve bone and/or cartilage. The injectable pharmaceutical formulation may be administered via the parenteral route, including subcutaneously, intraperitoneally, intramuscularly and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active agent, in an isotonic saline, 5% glucose, or other well-known pharmaceutically acceptable liquid carrier. In one embodiment the injectable composition comprises pleiotrophin and a pharmaceutically acceptable carrier and the composition is administered intravenously.
In a preferred embodiment, the pleiotrophin compound is dissolved in a saline solution containing 5% of dimethyl sulfoxide and 10% Cremphor EL (Sigma Chemical Company). Additional solubilizing agents are well-known to those familiar with the art and can be utilized as pharmaceutical excipients for delivery of the pleiotrophin compounds. Other delivery vehicles are contemplated for use in accordance with the present invention and can be used to administer the fluid forms of the present invention systemically to a warm-blooded vertebrate. For example the delivery vehicle may be an oral dosage form, an epidermal patch or other delivery vehicle known to those skilled in the art.
A. In Vivo Testing of Pleiotrophin Osteogenic Potential:
Rat Calvarial Defect Model
To determine the osteogenic ability of pleiotrophin, a well established model was used for measuring the in vivo induction of endogenous growth of bone tissue. In general, the model involves the formation of circular defects (approximately 6-8 mm in diameter) in the parietal bones of adult (greater than 6 months in age) Sprague Dawley rats. The defect is of a critical size such that the intraosseous wound would not naturally heal by bone formation during the life of the animal.
The surgery is conducted with sterile technique, cap, mask, gown, and gloves. Animals are sedated with a cocktail of Ketoset 10 ml, with 0.15 ml of 100 mg/ml Xylazine and 0.3 ml of 10 mg/ml acepromarzine added, and the dosage is 0.1 ml/100 g body weight. If additional sedation is needed Ketoset alone is used in 0.05 ml increments. After the rats are sedated, their heads are shaved from behind the ears to the tip of the nose and laterally, ventral to the ears. A three cycle scrub, alternating betadine and alcohol is performed. An ointment is placed in the eyes prior to scrubbing. After the animal surface has been scrubbed, the animals are placed on V-trays with their heads positioned on a small stack of 4�4 gauze to make a level surgery site. The animals are immobilized by taping them to the tray using strips of tape running across the nose, ears, and back.
The tray with the immobilized animal is placed under a sterile drape on the surgery table. A skin incision is made in the midline of the skull, the periosteum is scraped off and retracted to expose the midline site. A 6 or 8 mm trephine is used in a micro-drill under 40 pounds or less of pressure. Irrigation of the site while drilling is necessary to avoid thermal necrosis. As the bone is cut care is taken to avoid damage to the dura and sagittal sinus. The dura should be left intact if possible. If bleeding occurs the area is packed with gelfoam for a few minutes, then removed when bleeding stops. The defect edge is then scraped smooth.
A 6-8 mm circle of gelfilm was placed between the brain and the composition comprising pleiotrophin. Once the composition was placed in the defect, the periosteal layer was sutured closed over the defect region using a 5-0 proline continuous suture pattern. The skin was closed with staples. Animals recovered in an incubator to avoid hypothermia, and once the animals are walking, they were returned to their cages.
B. Method of In Vivo Testing of Bioactive Compositions
In a novel modification of the rat calvarial defect model, the compositions of the present invention were administered directly to the localized in vivo defect site (the calvaria defect site in the rat calvarian defect model) of adult rats through the use of ALZET osmotic pumps. ALZET osmotic pumps (ALZA Scientific Products Palo Alto, Calif.) were implanted subcutaneously into Sprague Dawley rats on their backs, slightly posterior to the scapulae. The pumps were connected to a catheter wherein the catheter directs delivery of the pump's contents (pleiotrophin) into the calvaria defect to deliver a local dose ranging from about 7.14 μg/ml to about 714 μg/ml of total defect volume.
The osmotic pumps were assembled prior to implantation. The pump assembly was first filled with the pleiotrophin composition by attaching a syringe containing the solution to be delivered to the catheter tubing and filling the osmotic pump with the solution to be delivered. The filled osmotic pump is fitted onto its flow moderator. The pump assembly is then incubated in sterile saline (0.9%) at 37� C. for at least 4-6 hours. Optimal results are obtained by priming overnight. This step ensures that the osmotic pump is pumping continuously prior to implantation and minimizes the chance of clotting within the cannula or occlusion by tissue during delivery of the test agent. The assembly is then implanted into the host animal.
The rat was anesthetized and the pump apparatus was implanted into a subcutaneous pocket in the midscapular area of the back of the rat. To prepare the implantation site, the skin over the implantation site was shaved and washed, and a mid-scapular incision was made into the back of the animal. A hemostat was inserted into the incision and, by opening the jaws of the hemostat, the subcutaneous tissue was spread to create a pocket for the pump. The pocket should be large enough to allow some free movement of the pump (e.g. 1 cm longer than the pump). A filled pump was inserted into the pocket and connected to a catheter. The distal end of the catheter is placed into the calvaria defect for direct delivery of the pleiotrophin composition to the defect. The pump insertion site is then closed with wound clips or sutures.
The manufacturer's guidelines are followed regarding the maximum drug delivery rates and durations utilized to minimize any nutrition-impairing stress or disruption of normal behavior. After its pumping lifetime has ended, the ALZET osmotic pump is removed.
Experiments were conducted using an ALZET osmotic pump model 2001D which delivered its contents (200 μl volume) over a 24 hour period to the defect site. The experiment was continued for a total of 28 days after implantation of the pump. The rats were sacrificed at day 28 and a section through the center of the defect (extending from head to tail) was viewed histologically for bone growth. Two control animal groups were used, where the defect region received either saline only, or nothing at all (i.e. the pump was "empty"). The sections were scored in a blind manner for bone growth using a scale of 0-5 wherein the score is based on the amount of new bone growth observed in accordance with the following scale:
0=no growth or resorption of existing bone;
1=greater than zero to about 10% of the gap bridged with bone;
2=about 10% to about 33% of the gap bridged with bone;
3=about 33% to about 66% of the gap bridged with bone;
4=about 66% or greater of the gap bridged with bone;
5=complete bridging of the gap.
Tables 1 describes results of analysis of the in vivo bone growth response of rats to pleiotrophin.
Interestingly, islands of cartilage were observed in defects of some of the treated animals. This result is surprising because endochondral bone formation does not ordinarily occur in the cranium.
In summary the introduction of recombinant human pleiotrophin protein into a rat calvarial defect via the osmotic pump method enhanced new bone formation. Furthermore, at least a portion of the newly formed bone arose through an osteochondral mechanism (in a model where cartilage does not usually form) thus suggesting that pleiotrophin could be used to repair cartilage as well as bone.
The pleiotrophin compositions of the present invention can also be administered intravenously to provide systemic administration of the composition. Such systemic administration may provide therapeutic value for orthopedic or pathogenic conditions involving bone or cartilage. As described in Example 1 the ALZET pumps can deliver fluid compositions directly into the venous or arterial circulation via a catheter. ALZET pumps have been shown to pump successfully against arterial pressure with no reduction in flow. The following procedure details placement of a catheter in the external jugular vein. In many cases this site is preferable because of its size and ease of access, however, other sites may be used successfully.
An osmotic pump flow moderator is connected to one end of a catheter (inside diameter≦0.030 inches). The catheter should be 25% longer than the distance between the site of subcutaneous pump implantation (the midscapular region) and the site where the catheter enters the external jugular vein. The flow moderator and catheter is filled by attaching a syringe filled with pleiotrophin composition to the free end of the catheter. The osmotic pump is filled with the pleiotrophin composition and fitted onto the flow moderator. The syringe, which was used to fill the catheter, can now be detached and the flow moderator inserted until the white flange is flush with the surface of the pump. The pump and catheter should be completely filled and free of air bubbles. The filled pump and catheter are incubated in sterile saline (0.9%) at 37� C. for at least 4-6 hours. This step ensures that the osmotic pump is pumping continuously prior to implantation, minimizing the possibility of clotting and catheter occlusion during delivery of the test agent.
The complete assembly is then implanted into the animal as follows. The ventral portion of the animal's neck is shaved and cleaned and the neck is incised to one side of the midline, and the tissues spread along the head to tail axis. Using blunt dissection, the external jugular vein is located just beneath the skin and is elevated and cleaned for a distance of 1.5 cm. A silk ligature (3.0) is then placed around the head end of the cleaned vein and tied, and all large branches of the vein are tied off, but not cut. Two loose, overhand knots are placed at the heart end of the vein. Using the belly of sharp, curved iris scissors, the mid-portion of the vein is grasped, elevated and cut, so that an ellipsoidal piece of the vein wall is removed. (This technique is preferable to making a nick with the tip of the scissors.) The free end of the catheter is inserted into the hole in the vein wall, and advanced gently to the level of the heart (about 2 cm in an adult rat). The proximal (heartend) ligatures are tied snugly around the catheter, being careful not to crimp the catheter. The distal (head-end) ligature is then tied around the catheter. The ends of all three ligatures are then cut off close to the knots.
A hemostat is then used to tunnel over the neck creating a pocket on the back of the animal in the midscapular region. The pump is positioned into this pocket, allowing the catheter to reach over the neck to the external jugular vein with sufficient slack to permit free head and neck movement. The incision in the skin of the neck is then closed with 2 or 3 wound clips or with sutures.
Although the invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.
Ijiri, S., Influence of Sterilization on Bone Morphogenetic Protein, Fourth World Biomaterials Congress, April 24-28, (1992).
Mark, S. and Miller, S., Journal of Endocrinology, Vol. 1 (1993).
U.S. Pat. No. 3,710,795
U.S. Pat. No. 5,668,288
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Gunmetal Black Ep 01
episode 14.26 / 5.00 5,147 Views
Lucina's First Day
A look at the first day of Lucina in Super Smash4.24 / 5.00 17,294 Views
BATMAN v SUPERMAN final showdown
SPOILERS!!4.19 / 5.00 14,897 Views
Awsome sweet
this is frekin awesome that was a unespected ending
that is a great movie. It acts like a story line and it has an enexpected turn of events (to be honest though I did know he killed Nene and not Convict). 10/10 points and all of my 5s belong to this movie.
Unlike some other bad submissions to Pico Day 2006, you did a great job! Liked the soundtrack. And funny how Nene said for Pico to protect her, but he was acting like a sissy and not using his crime-fighting guns to kill the demon thing. It sucked how Nene had to save Pico and herself from that clone, and ended up so close from killing it, but to realize that Pico accidently shot her. lol, I really wondered what happened next. The part that shocked me the most though was the harsh, bloody violence that was happening in the cafeteria, you know, Nenes taking knives and slicing each other to death. I guess Pico feels that kind of shock too!
not bad but could u have put a less sad ending plz??!!!!!!! my sister is never gonna stop cryin now!!!!!!!!!


text:
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Whale's Belly Bangkok
Winner of Iron Chef Thailand
Whale's Belly - whose head chef recently won the prestigious title of Iron Chef Thailand on television - is a restaurant that exceeds expectations. The playful name comes from a fairytale but the comfortable surroundings, friendly service and astonishing creative cuisine are a real winning combination. Located on Sukhumvit Soi 39, the restaurant is open every day from 17:30 until 23:00, and for lunch on weekends from 11:30 to 14:30. Taxi or car is the best way to get here.
The kitchen is under the supervision of a young, visionary chef who trained in the seafood section of Le Normandie at Bangkok's Mandarin Oriental. With an interest in molecular gastronomy, some of the techniques used are inspired by those used at the famed Spanish culinary school elBulli, so expect jellies, mousses and espuma whipped up from surprising raw ingredients for an eye opening and extremely fun dining experience. Ingredients are imported to ensure that Whale's Belly serves the finest quality produce available.
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New for 2015: A 9 Course Culinary Advenutre created by Whale's Belly's Iron Chef Champion
For food lovers who want an extra special treat, Whale's Belly has released a new 9 course degustation menu featuring stunning dishes revolving around the theme of molecular gastronomy.
This is truly a culinary advenure with dishes as diverse as yellowfin tuna tartare with jellied apple and horseradish, to 12 hours braised lamb belly. The price for this memorable feast is 2,250 baht which we feel is unbelievably good value when you consider the quality of the food and overall fine dining experience. There is a 3 glass wine pairing for an addtional 1,200 baht.
Great Value Weekend Lunch Menu at Whale's Belly
Also new for 2015, Whale's Belly now offer a great value 3 course lunch menu for just 590 baht. This price is set low to encourage everyone to come and sample some of Chef Mai's finest dishes. Only available on Saturday and Sunday from 11:30 to 14:30.
The actual menu Chef Mai created on the acclaimed television show, Iron Chef, is available in la carte form too, on the lunch menu and dinner menu.
At this sophisticated yet quirky restaurant, the whale's belly is central to the theme, with white slats on the roof making up the bones of the large mammal and the walls decorated in a deep sea blue. Although the tables are laid with crisp white cloths and a selection of wine glasses, there is a childlike playfulness in the dining space as well. Pinocchio was the inspiration, and you will find a framed puppet in the private room to honour him. Other quirky decorations include the Rose's necklace from Titanic and the Captain's Hook. The food may be fine dining but the atmosphere is designed to be welcoming and comfortable. The staff are efficient and quickly serve signature charcoal bread buns with butter and duck liver terrine; a lovely little extra treat.
Welcome mocktails are served to every guest, with a new blend mixed every day. The refreshing juice was an aquamarine colour on our visit, fluke rather than a nod to the restaurant's ocean theme. It's nice to have something to sip on whilst you relax in the comfy bucket chairs with their jolly navy and gold nautical cushions. There are eight wines by the glass, which makes it easy to mix a match with the fish and meat courses.
We start with the unique yellowfin tuna tartare. This dish is a medley of textures and tastes, the fish served with delicate cubs of soya jelly, granny smith apple, buttered croutons and a sweet and sour reduction. The lime gives it an extra zing and the micro greens offered a hint of warming pepper with every mouthful. It takes someone who really knows their ingredients to create a balance in the different flavours so well, and this dish really showed that keeping it simple is not always best.
Although this restaurant comes under the banner of European cuisine, there are some Asian influences on the menu. The cold capellini pasta with crab and mentaiko is another dish that delivers in particular. Here, the chilled pasta is refreshing, and the slightly spicy blend is infused with yuzu (a Japanese orange style fruit), truffle and served with crab and black cod roe.
Moving through the courses at Whale's Belly Restaurant is like a journey, with gourmet ingredients reimagined and paired with surprising flavours and textures. Crab salad canneloni in a beetroot jelly wrap, a blanced 62 degrees onsen egg seved with bacon as a reimagined breakfast dish, and Hokkaido scallop served with foie gras in a carrot and carrot puree. Yet the names alone don't do the chef justice as he manipulates ingredients in a way few other chefs can imagine. For example, buillabaise stock is turned into a mousse to enhance the excelelnt silver sea bass, lamb skin is crisped and turned into paper in the lamb dish and kalamata olives are dried and candied to match with the bacon wrapped tiger prawn.
The chef may be a fish connoisseur but he's pretty good with all things meaty as well. We try the slow braised wagyu beef cheek, cooked over 36 hours and served with a peppercorn sauce. This tender meat has an intense flavour, but the accompanying honey pickled radish has a clean, fresh taste that prevents it from becoming too rich.
Dessert is the chef's take on tiramisu, a tower of lady fingers, cashews and cream with a gooseberry garnish. The crunchiness added an extra depth to the creamy coffee notes and it wasn't overly sweet.
The passion at Whale's Belly is evident and brings a certain charm to the place. Here, the cooking is from the heart with plenty of style and skill. This isn't a cheap night out, but we think such interesting cooking is worth it. There is a la carte available here and new for 2015, the nine course gourmet set menu costs an excellent 2,250 baht (not including tax or service).
Whale's Belly
- Opening Hours: Every day from 17.30-23.00, Lunch on Saturday and Sunday from 11:30-14:30
- Address: 39 Boulevard tower, 2nd floor, Sukhumvit Soi 39, Sukhumvit Road.
- Tel: +66 (0)2 1600 333


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Sandy Hook Student Chorus to Perform at SUPER BOWL Pre-Game Show
CBSSports.com reports that twenty-six students from Newtown, Conn.'s Sandy Hook Elementary School will perform the song 'America the Beautiful' during the pre-game show of Super Bowl XLVII. Brian McCarthy, spokesman for the NFL, confirmed the news yesterday to USA Today. The performance will air live and will occur just prior to Alicia Keys singing of the National Anthem.
The choir will perform in memory of the 26 students and faculty who were tragically gunned down on December 14th in what has become the second deadliest school shooting in American history.
The NFL has been a source of strength to the town of Newton. Each team held a moment of silence before the games which immediately followed the tragedy. The athletes also donned "S.H.E.S" decals on their helmets to show their support for the Connecticut community.
In addition, NFL players, such as Giants' Victor Cruz, reached out personally to the families who lost loved ones. Cruz met with the family of 6-year-old victim Jack Pinto, who was buried in Cruz's No. 80 jersey.
The Sandy Hook choir recently performed 'Somewhere Over the Rainbow' with Grammy-nominated singer Ingrid Michaelson on the one-month anniversary of the shooting.
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- Telemundo to Give Viewers Sneak Peek at Upcoming Programming on LO NUEVO, Today


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Once that dude sobers up he'd better poop the other guy's face back on and apologize.
May 29, 2012 @ 2:31pm
After watching episodes of Basketball Wives, I've realized basketball players love assholes.
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Castles in the Sky: Miyazaki, Takahata & the Masters of Studio Ghibli
Various venues
Until Thu Dec 20 2012
- $
Not yet rated
Time Out says
Mon Nov 19 2012
This comprehensive retrospective of the Japanese animation studio best known for Spirited Away and My Neighbor Totoro was so popular during its run last winter that IFC has brought it back for another go-round. The fest runs through Dec 20. Visit ifccenter.com/series/castles-in-the-sky-miyazaki-takahata-the-masters-of-studio-ghibli for more information. All ages.
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text: Imakeitboom Radio #24 Post Ultra Edition by imakeitboom published on 2013/04/13 04:20:36 +0000 Every week, Imakeitboom podcast's, with Benjamin Boom, delivers a brand new mix. Each with a different vibe, emotion and genre. No two shows are the same. ALL EDM, from old school, to unreleased and about to be hot tracks. House to Trance, and everything in between, Imakeitboom podcast is the sound the continues to define Benjamin Boom. It is the soundtrack to your life.


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Cantor Gaming released its NFL over-under odds for the season and puts the Vikings at 6 victories.
Gut instinct, right now, would you bet the over or the under?
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An amused Kerry told the man, "They're behind you," referring to the seemingly benign cluster of reporters at the back of the room. Rather than continuing a discussion of his press coverage, Kerry instead stressed his determination: "That's what the campaign is about over the next weeks. I'm focused like a laser beam, folks. I'm ready to carry this message. And I'll tell you this, I'm going to fight every single day until 8 p.m. — or whenever it is — on Nov. 2 when we're going to change the direction of this country."
The candidate's fiery statement was marred only by that Kerry-esque clause that he added ("or whenever it is") in an apparent effort to define at precisely what time on Election Day he would stop campaigning. But every candidate has his foibles on the stump. In the annals of mangled presidential discourse, it is hard to top Bush's line last week about malpractice: "Too many OB-GYNs aren't able to practice their love with women all across the country."
But Kerry, who has become a crisper candidate in recent weeks, still can exasperate his supporters. Probably the most common phrase uttered by prominent Democrats this month has been "Kerry needs to ..." The remedies vary widely, and the level of candor depends on whether the speaker is inside the campaign. But the persistence of George W. Bush's lead in the polls since the Republican convention has easily-panicked Democrats hearing the ominous theme from Jaws.
The seven weeks until the election can have the sweep of an epic novel. And there is no evidence that Bush is immune from the forces of gravity that can deflate a lead after a convention's glow fades. But an examination of the Gallup Polls in years with presidential debates indicates that the horse race does not gyrate much between Labor Day and the first presidential faceoff.
This static portrait makes sense, since there is rarely any single dramatic moment when the candidates occupy center stage between the conventions and the first debate. Instead, we are now in a period when candidates connect with the voters through TV clips, newspaper articles and, yes, commercials.
Watching Kerry go through his paces Tuesday, both in Toledo and earlier in Wisconsin, was a reminder of the difficulty of quickly rewriting a campaign's narrative arc. All political set pieces have an inherent artificiality at this stage, since the most atypical voters in America are those who actually see a candidate in the flesh in the final sprint to the finish line.
Tuesday morning, Kerry tried to give off the air of a man who just happened to drop by the facility for the elderly and disabled in St. Francis, across the street from the Milwaukee city line. The 100 or so senior citizens present were obviously not Kerry's primary audience. Instead, they were a dramatic backdrop designed for the TV cameras, as ersatz as the grove of transplanted-to-Wisconsin palm trees growing in the indoor (and obviously well heated) atrium where Kerry spoke.
At moments like this, a candidate like Kerry has to play to two realities simultaneously. He has to convey the impression that he is having a conversation with the people in the room when he is really concerned about how his sentences will come across on TV and in print. Yet in this environment, Kerry has to surmount the most difficult challenge facing him — defining for the voters exactly why he wants to be president.
For Kerry, a serious man who is animated by his long-standing disdain of what he regards as Bush's overly unilateral and hair-trigger foreign policy, this continually comes back to the enduring issue of America's global role in an age of terrorism. In lambasting the Bush record Tuesday, Kerry departed from the message-of-the-day emphasis of health care costs to stress, "The most catastrophic decision of all was the decision that he made about the war in Iraq."
If the Democrats have made a tactical misstep in this campaign, it probably was in the smile-button blandness of the Boston convention that failed to draw sharp distinctions with the Bush administration. Such a nice-to-a-fault style is not Kerry.
As Democratic media consultant Mandy Grunwald, who is not affiliated with the campaign, put it, "Kerry sounds strongest not when he's being positive or laying out his plans, but when he's tough on Bush and does it from a moral high ground."
That seems to be the way that Kerry has decided to conduct the rest of the campaign, excoriating Bush not on a personal level but over the choices he has made as president. This always-attack approach runs the risk of antagonizing undecided voters, but it offers the authentic version of who Kerry is as a candidate.
Walter Shapiro's column appears Monday, Wednesday and Friday through Election Day. E-mail him at email@example.com


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Terry Anderson, , Tim Fitzgerald, , Donald Leal, Jane Shaw 12/01/2001
Hank Fischer 12/01/2001
By Hank Fischer
By Blake Hurst
By Wallace Kaufman
Andrew Morriss 09/01/2001
By Andrew P. Morriss
Roger Meiners, Andrew Morriss 09/01/2001
Rachel Carson didn't start it; the U.S. government did.
, Robert Nelson 09/01/2001
What Zimbabwe did right.
By Deborah Jacobs
Roger Meiners, Andrew Morriss 06/01/2001
Malaria makes a comeback.
Jane Shaw 06/01/2001
Does commercial activity destroy diversity?


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Exotic Longhair Kittens
I have 2 Exotic Long haired kittens that are up for Adoption They will be ready for there forever home in 2 weeks. Kittens are fully litter trained, will be current on vaccines and will be wormed. They were born May 10.
They have been raised as part of the family, very playful, love to be held and are very sweet and loveable.
Black/white male
Silver Tabby/white male
Please email, call or ...
Jul 3 -
3 little kittens in need of a new loving home, small re-homing fee
I have 3 little kittens that are ready to go to their fur-ever homes. 1 is an orange and white girl, 1 is a blue/grey male, and the other is a black and white male. They were born May 10th and are weaned from their mom. They are litter box trained, and eating hard food. They have been de-wormed and de-flead. They have never been outside. I would prefer they go to indoor homes. they are use to ...
Jun 30 -
3 Sweet little Purebred Manx kittens Calico and Black & White
I have 3 precious little Manx kittens that are ready to go to their new fur-ever homes. One is a calico and the other 2 are black and white. They are super playful and are eating hard food and are litter box trained. They have been de-wormed and de-flead. They have been raised indoors and have never been outside. They are use to other cats and small dogs. They were born May 10th, 2015. Please ...
Jun 26 -
Ragdoll kitten, Reg.
Ragdoll kittens, TICA reg. first and second shots, dewormed, Vet .health papers/warranty. Loveable blue eyed babies raised in our home, never caged. Raising Ragdolls the right way since 1990. Our cats are tested negative for HCM/FIV/Fel. Leuk. Mitteds, Bicolors and Colorpoint, Blue, Seal, and rare Flame colors. Pictures may be seen on Facebook at:
Appalachian Ragdolls or call: 336-469-1829. ...
Jun 22 -
Ragdoll Kittens, reg.
Ragdoll kittens, reg. Loveable blue eyed balls of low shedding fluff. Shots, dewormed, Letter from Vet, registration papers. Health guaranteed. Different colors. Parents on site. TICA registered. Raised in our home and never caged. New litters that were just born will be ready the first of November, some ready to go now. See pictures of older kittens on Facebook at Appalachian Ragdolls. 336 ...
Jun 14 -
exotic shorthair female
12 week old calico shorthair exotic....all shots and wormed very pretty markings CFA registered pet papers will be given.. photos available e-mail or call 4235479009 for more info NO shipping located in N.E. TENNESSEE available 6/21/2015
Jun 14 -
F5 Savannah Kittens
F5 Savannah kittens. 3 girls and one boy. Ready to go now. Please contact us with any questions you may have.
Jun 14 -
Awesome Himalayan kittens
2 beautiful male kittens left from rocky and koko's litter. CFA registered with health record.
1st shots and worming.
Beautiful coats and gorgeous rich color.
Jun 9 -
Church Hill
TICA reg Traditional Kittens
Beautiful and fluffy Ragdoll kittens! Will come fully vetted and completely spoiled! 2 Male Flame Mitted Traditionals, 1 Female Seal Mitted Tortie, 1 Female Seal Mink. $750 Prices are for Pet Only homes. Breeding rights to approved homes on select kittens only. Visit our website & facebook page (Heartstring Ragdolls) for pics from our last litter as well as weekly pics of these little ...
Jun 7 -
Half Bengal/ Half Savannah kittens
2 male half Bengal/ half Savannah kittens ready for new homes. Mom is full blooded Bengal and dad is registered F5 SBT Savannah. For more information please call or text 423-737-2153
Jun 3 -
Ragdoll kittens for adoption
Reg. Ragdoll kittens. Adorable blue eyed bundles of fluff. Very Social. Shots, Vet checked, health guarantee. Different colors. Kittens born May 16, 2014. Ready to go after July 18, 2014. Phone 336-469-1829. See more pictures on Facebook at: Appalachian Ragdolls
[email removed]
May 25 -
Ragdoll kittens
Ragdoll kittens, TICA Reg. $650. Traditional lines and colors. Raising healthy Ragdoll kittens since 1990. Health guarantee. First and second
sets of shots. Several litters available different ages. 336-469-1829 or 276-479-3521
Adorable Ragdoll Kittens Need Homes!
Taking deposits on 5 adorable Ragdoll kittens! 3 males, 2 females. Parents on site. Kittens are very sweet and used to being handled and litter box trained! Ragdolls are known for their beautiful blue eyes! My camera phone simply cannot do them justice! You have to see them for yourself to appreciate how beautiful they are! I get compliments on their parents all the time! Kittens were born ...
May 6 -
Two beautiful blue Russian cats
Jul 5 -
Louisville :
New Albany
We have 2 litters of TICA Registered Ragdolls. Both litters were born on May 25, 2015. We have 6 males and 2 females available. They are all Seal or Blue in color. We have Lynx, Color Point and Mitted in patterns. They will be vet checked, wormed and age-appropriate shots before leaving us. They are being raised in a home with young adults and other pets. Kittens will have been handled ...
Jul 5 -
Columbus (OH) :
Gorgeous Maine Coon kittens.DOB 2/28/15. CFA registered.Papers with proof of neuter/spay.All appropriate vaccinations and health garantee by a licensed veterinarian.$200.00 deposit will hold your kitten.All our cats and kittens are raised in our home as part of the family,constantly loved on,never caged. Please feel free to contact me via phone or text...770-876-4161...I will return all ...
Jul 5 -
Atlanta :
TICA Ragdoll kittens. Adorable! 10 weeks old. Born April 22, ready for forever homes now. Raised in our home, well socialized and spoiled.
We are a small hobby breeder. I have always had cats and kittens. When the opportunity to breed ragdoll cats came about I was ecstatic. Ragdolls are an amazing breed, so friendly and fluffy!
Mink bicolor flame - $850
Mink seal mitted - $850
Tradional ...
Jul 5 -
Knoxville :
Beautiful Himalayan and Persian kittens from Champion stock. Bred for sweet personalities too. Contact John at (423) 847-2250 for more information. Pet price is $650.00 and up. Breeding rights are more, but only to small reputable breeders.
Jul 5 -
Chattanooga :
Seal point kitten , weaned and eating , uses litterbox. he is 2 1/2 mo. old ready anytime.
Jul 5 -
Charleston (WV) :
Meet Beauty! She is looking for his forever home... She is affectionate and playful, craves love, and follows you wherever you go. She loves to sit on your shoulder, plays in water, and chases balls. She is already exhibiting the personable traits that the "coon cat" is known for. Her mother is a double registered TICA/CFA queen from a good bloodline......she is pictured too. Beauty is 10 ...
Jul 4 -
Nashville :
We have two male TICA registered Ragdoll kittens available. price reduced to $400 for quick sale. kittens are very relaxed and affectionate. Parents on site. Written health guarantee. Up to date on shots and dewormed. We are licensed and inspected by the department of agricuture. Located near Hartwell and Lavonia Ga, easy to find off interstate 85. Please call for more info 706-245-8368 or ...
Jul 4 -
Atlanta :
Beautiful CFA registered American Shorthair Kittens. Health guaranteed, taking deposits now ready to go NOW. One male white, One white female available.
Jul 4 -
Charleston (WV) :
Baby silver tabbies! Two available. They will be 8 weeks and ready to go on June 19th. Taking deposits through Paypal NOW!
White with brown Ragdoll about 6yrs old female not fixed owner moved
This ad was posted with the eBay Classifieds mobile app.
Jul 4 -
Charlotte :