President George W Bush has asked officials to draw up formal “rules of engagement” to govern cyber warfare in which military hackers use computers to attack everything from an enemy’s communications networks to power grids it emerged yesterday. get-music-on-pandora-radio,
The secret presidential directive seeks to establish formal rules for its use, similar to those which have governed the use of nuclear weapons for decades, administration officials told the Washington Post.
America is one of several nations get-music-on-pandora-radio, to have developed advanced military cyber warfare units, in anticipation of the day when states may be brought to their knees by remote attacks over computer networks and the internet.
American cyber operations are governed currently by a fouryear old “basic primer” on computer attacks, which urges commanders to avoid disproportionate or indiscriminate attacks, which pay no heed to civilian casualties. In the world of real weapons, bombing or shortcircuiting a power grid vital to the military is usually deemed acceptable, even if it harms civilians.
Virtual attacks could theoretically cause mass civilian casualties, if mishandled wrecking the electricity or water supply in a crowded urban area, or destroying telephone networks used by emergency services.
Richard Clarke, who stepped down last week as a special adviser to the president on cybersecurity, told the Washington Post: “We have capabilities, we have organisations, we do not yet have an elaborated strategy, doctrine, procedures.”
Administration officials would neither confirm nor deny that the cyber rules of engagement, first ordered last summer but kept secret until now, would be put to an early test in Iraq.
“Whatever might happen in Iraq, you can be assured that all the appropriate approval mechanisms for cyber operations would be followed,” a serving administration official said.
The prospect of America being the first to use largescale cyber attacks has raised fears that it might be opening a pandora’s box, and inviting any enemies to launch cyber counterattacks. America is seen as unusually vulnerable, because of its very high levels of automation, and extensive computer networks.
In 1996, a congressional study estimated that Pentagon computer systems were subjected to 250,000 attacks a year by hackers, two thirds of whom succeeded in entering networks containing unclassified, but frequently sensitive, data.
In one series of attacks in 1999 and 2000, scores of “sensitive but unclassified” documents from the Los Alamos and Livermore national laboratories and the Defence Department were stolen by hackers who were traced back to a foreign government.
In 2001, the FBI in California traced hackers exploring the digital systems used to control water, power and other utility systems in the Silicon Valley area. The hackers, who passed through digital switches in Saudi Arabia, Pakistan and Indonesia, were found to have studied nuclear power stations, water plants and emergency telephone systems.
Sweaters have come a long way since the days when they were part of an itchy school uniform. pandora-charms-offers, They are an easy way to update your look and make the most of your figure. By paying attent pandora-charms-offers,ion to necklines, ties, prints and fabrics, you can accentuate your assets and downplay your defects.
This season, knitwear is much more than a comfortable wardrobe staple, with designers and highstreet shops offering new, exciting and luxurious styles.
The revival of a ladylike silhouette at Alexander McQueen and Roland Mouret’s autumn/winter show have sparked a trend for elegant knitwear. Fitted cowlneck jumpers and wrapover sweaters with belt ties or brooch fastening are in abundance on the high street. Monsoon (020 7313 3000) has a fantastic range, including a soft angora Vneck jumper with a silk satin belt and “antique coin” embellishment (50).
Continuing the summer’s bohemian trend, much of this season’s knitwear is inspired by Tibet, India, Mexico, Russia and China, with colourful embroidery, fringing, pompoms and beading. A meltingpot of cultures was evident in both Kenzo’s and Cacharel’s autumn/winter shows and is now on the high street. Look out for Whistles’ olivegreen cardigan with brass buttons and wool flower appliqu (89; 0870 770 4301 ).
Cashmere is still the height of chic and goodquality cashmere jumpers are now widely available on the high street. Both Marks Spencer (0845 302 1234) and Gap (0800 427789) stock a selection of pure cashmere jumpers that start at 69. Tesco does a pure cashmere jumper for just 25 (0800 505555).
Opt for either Vneck sweaters such as the cashmere ones at M (69; as before), available in an array of colours, or a wrap style sweater such as the pandora wrap from French Connection (50; 020 7399 7200), as the “V” will break up the neckline, drawing attention away from the bust.
Light wool also works better on women with larger chests rather than Aran or chunky knits because it doesn’t add additional bulk. Warehouse’s superfine Vneck jumper (25; 0870 1228813) is slightly longer in length and won’t ride up around the stomach. Avoid poloneck jumpers or anything with a high neck, because they broaden the chest.
Prints, ruffles or any detail on the front of a sweater will divert the attention away from a flat chest. French Connection has a capsleeve Fair Isle sweater with sequin detail (70; as before). Chunky knits or horizontal stripes are also a good option.
Go for a beatnik look with a striped boatneck sweater such as the ones at Topshop or French Connection (50, as before). Alternatively, poloneck or highneck sweaters are elegant and flattering. Try Gap for a classic ribbed polo neck available in 10 colours (25; 0800 427789).
Reiss has an elegant, long, silkandangora mix, roundneck jumper with a tie around the waist (89; 020 7473 9630) that is perfect for taller women who don’t want to show off their midriff. Bracelet or threequarterlength sleeves should be avoided by women with long arms, because they will make a sweater look as if it has shrunk in the wash.
Try the Victorian polo top from Oasis (30; 01865 881986), which has long puff sleeves, a ribbed waistband and is available in black, grey and a beautiful peacock blue. Horizontal stripes will help minimise a long torso.
Don’t be tempted to hide under massive sweaters as the additional fabric will only make you look larger. Choose merino wool or superfine cashmere available in many styles from Pure (). Create a waistline with sweaters that tie around the middle such as the cowlneck, belted jumpers available in brown and pink at Warehouse (40; as before), but be careful it is not too tight because this will only emphasise any bulges. Block colours usually work best on round figures, but vertical stripes can also be slimming.
The fit is key because anything too large will drown a petite figure. Principles has a good selection of sweaters in its petite range, which, rather than simply being shorter in length or having shorter sleeves, have narrow shoulders and scaleddown embellishment. Look out for the red frilledged cardigan that ties at the front with beaded ties (39; 0870 122 8802). Avoid deep Vnecks if you have a flat chest, because they only make you look smaller. Opt instead for highneck jumpers or try Warehouse’s boatneck, cableknit jumper in a vibrant indigo (35; as before). Block colours help to keep a petite silhouette streamlined.
The consulting firm Booz Allen Hamilton fired Edward J. mom-charms-pandora, surveillance programs. Booz Allen said Snowden, employ mom-charms-pandora,ed for less than three months, was paid $122,000 a year for his work as a systems administrator on contract to the NSA. phone call records and its surveillance of online communications to and from foreign targets. government agencies for substantially all of our revenue. It is majorityowned by the Carlyle Group, the Washingtonbased privateequity company. Booz has 24,500 employees, $5.8 billion in revenue for its 2013 fiscal year, $219 million in profits and a stock market value of $2.5 billion.
Dole Food chief executive David Murdock, 90, offered about $645 million to buy out other shareholders of the fresh fruit and vegetable producer, saying stock markets are too concerned with shortterm results. Murdock will pay $12 a share in cash for the 60 percent stake that is not owned by him or his family.
Coda Holdings, parent of an electriccar maker that sold fewer than 100 vehicles, won court approval of a $25 million sale to a group led by a Fortress Investment Group unit.
Exxon Mobil was sued by the Justice Department and Arkansas over the Pegasus pipeline oil spill in March, which contaminated 22 homes.
Monsanto, the world largest seed maker, had its shares climb the most in 17 months after Argentina and Brazil said China agreed to accept imports of its genetically modified Intacta soybeans.
Goldman Sachs accepted almost 15,000 bottles of fine wine primarily from the Burgundy and Bordeaux regions of France as loan collateral from Andrew Cader, a former senior director at its specialisttrading unit, according to a regulatory filing. tax probe after one chamber of lawmakers voted to allow banks to sidestep strict secrecy laws to end the threat of criminal charges for helping wealthy Americans evade taxes.
Lululemon Athletica said that chief executive Christine Day will step down. The yogawear retailer has tripled sales in three years but faltered this year when a production defect forced it to pull black Luon pants that were too sheer.
Revlon was charged by the SEC with misleading shareholders about a transaction with its controlling shareholder, billionaire Ronald Perelman, and the cosmetics company agreed to pay a fine of $850,000.
Five US Airways executives will follow chief executive Doug Parker when he takes control of the new American Airlines after the airlines complete their proposed merger.
McDonald said global sales rose 2.6 percent in May at restaurants open at least a year, helped by the Dollar Menu and its new chicken wraps and eggwhite breakfast sandwiches.
The criticism comes from every corner: conservatives, people of color, paraplegics and atheists. pandora-radio-login-in,
“I don’t think it’s a need to take the movie down,” Greg Kilday, the Hollywood Reporter’s fi pandora-radio-login-in,lm editor, said. “At this point, there’s not much anyone can do to stop its success.”
At Sunday’s Golden Globes, the film took home two of the biggest prizes, best picture and best director for Cameron. And it’s poised to win big at the Academy Awards in March.
Indeed, it’s the film’s success on which, Kilday says, different interest groups are hoping to capitalize.
Kilday says he believes Cameron is unfazed by all the back talk. “This time around he has the luxury of perspective,” he said. “He went through the whole ramp up of to the release of ‘Titanic’ and people saying it was going to be an enormous flop. He came out on other side the most successful commercial film director.”
A Russian journalist wrote that Cameron copied elements in “Avatar” from brothers Arkady and Boris Strugatsky’s 10book “Noon Universe” series. Most notably, the name of the lush, green planet where the film takes place, Pandora, is the same name of the utopian setting that the Strugatskys wrote about.
Both “Avatar” and “Noon Universe” take place in the 22nd century. Then, there’s the name of the humanoids inhabiting Pandora: in “Avatar,” they’re the Na’vi; in “Noon Universe,” the Nave. “The Na’vi are unequivocally reminiscent of the Nave.”
Arkady Strugatsky passed away in 1991 but his brother has denied quotes attributed to him accusing Cameron of stealing ideas from their bestselling books.
“I did not accuse the creators of the film ‘Avatar’ of plagiarism,” Strugatsky wrote on his Web site, adding, however, that he has not seen the movie. All he knows, Strugatsky says, is that it involves “monsters on Pandora.”
Nearly every successful movie attracts charges of plagiarism and 99 percent of the time such charges go nowhere, film editor Kilday said
Lately, the filmmaker has also had to defend his film against charges of racism and overt political messaging.
The Associated Press reported last week on how hundreds of people have responded to what they see as racist themes in “Avatar,” accusing the film of being everything from “a fantasy about race, told from the point of view of white people” to “the white Messiah fable.”
Largely meant for charting family trees and as a genealogy community, the website also boasts an addictive face recognition technology that blurs the boundary between the great unwashed and the thoroughly groomed. pandora-with-charms,To find out which celebrity you most resemble, download a photo of yourself, and you’ll quickly receive a list of stars with similar facial features. The results, which can include men and women, are often surpris pandora-with-charms,ing.LOOK LIKE ASHLEY OLSEN? Pop Candy’s Whitney Matheson gets recognizedIn one trial, a white, goateed, middleaged man came up as most resembling the young black comedian Chris Tucker and onlookers exclaimed, “You know, I can see that.”The Israelbased site uses algorithms to compare faces. From a database of 3,200 celebs, ten ranked results are provided, which can be quite disparate. Which makes sense, since many of my friends think of me as a comedic (if womanly) painter, with a strong penchant for governmental interventionist fiscal policy.Whatever our differences, though, MyHeritage suggests we at least share some superficial similarities. The lesson, as always, is that machines know us better than ourselves.On Pandora, you plug in a band or artist for example, Beck. After listening to his Fourteen Rivers, Pandora next cues up Jackson C. Frank’s (Tumble) in the Wind, and continues with songs by the Microphones, Iron Wine and Travis.
Happy Castle Monday, everyone! Tonight will see the start of the twoparter episodes, beginning with “Pandora”, and following up with “Linchpin” on February 20th. pandora-bracelets-store,
Following in the footsteps of Season 2′s Special Agent Jordan Shaw (played by Dana Delany) and Season 3′s Mark Fallon (played by Adrian Pasdar), Beals will b pandora-bracelets-store,e portraying CIA Agent Sophia Turner (or is it Sophia Conrad? The press release and sneak peeks contradict each other!)
As has been revealed previously through interviews and sneak peeks of the episode, Sophia not only works in the CIA, but she also shares a history with novelist Richard Castle! When Rick was researching for his first Derek Storm book, he turned to Sophia for insight into the life of a female CIA Agent. Yeah. So that makes things tricky.
Tricky indeed, especially when Beckett finds out that she’s not Castle’s first inspiration! Will the detective become jealous (such as in the case with Kristen Lehman’s character Serena Kaye back in October), or perhaps just feel a little insecure with where she stands with Castle in light of learning about the reallife Clara Strike? Beals gives her insight with The Hollywood Reporter:
“Beckett may see aspects of herself in Sophia or in that relationship. At a certain point, Sophia knows Castle well enough that they start to finish each other’s sentences in the way that Beckett would finish Castle’s sentences or Castle would finish her sentences,”
We know from the promo for the episode that the case in Pandora is going to be an explosive one, “catastrophic” even. How will this partnership between the reallife Clara Strike and Nikki Heat factor in when it comes to solving the case? Tune in tonight to find out!
Head over to The Hollywood Reporter and TVLine for the full interviews with Jennifer Beals.
Castle 4×15 “Pandora” airs tonight at 109c on ABC.
Would you like to receive instant updates on Castlerelated news, including upcoming cast member appearances, guest star and casting information, promos, sneak peaks, spoilers and more? Click the subscription link at the top of this article for automatic email updates, or follow National Castle Examiner on Facebook, Tumblr, or Twitter.
The Nokia Lumia 900 was launched in April 2012. a-pandora-bracelet, It’s one of the nicest looking cellular phones a-pandora-bracelet, on the market and provides some awesome features. For starters, it is one of the first 4G LTE Windows Mobile handsets available and the very first Nokia Windows phone offered in the US. It has a strong, attractive design constructed using a unibody polycarbonate frame and is available in black, white and blue. Its measurements are 127.8mm x 68.5mm wide x 11.5mm and has a weight of 160g, making it slightly heavier then the iPhone 4S along with some of its other rivals. The cellphone comes bundled with some excellent applications such as Youtube, Radio Controlled Pandora app, Hey DJ, voice search and voice to launch, in addition to over 100,000 apps offered from the Windows Phone app Marketplace. Another excellent thing about this phone is that the applications that come preinstalled can in fact be erased, allowing you to clear out some of that unwated bloatware. The Nokia Lumia 900 can function on 2G networks (GSM 850 / 900 / 1800 / 1900), 3G networks (HSDPA 850 / 1900 / 2100), and 4G networks (LTE 700 MHz Class 17 / 1700 / 2100).
If you purchased this phone and have decided to switch service providers, you will have to get it unlocked. Below are the instructions you will need to unlock your Nokia Lumia 900:
1. Input a non accepted simcard and power on the cellphone.
2. Soon after the phone completes starting up, it shall show the message “this sim card can only be used on specific networks. Contact Your customer service center for the unlock code’. It will also tell you exactly how many unlocking attempts you have remaining. Don’t bother attempting to make use of an unlock code if you have 0 tries remaining, it will not work.
3. Under that will be the message “Enter PIN”. On your keypad, type in the unlock code and press the “enter” button. For those who do not have an unlock code, take a look at the footer of this article for links on where to get one.
The moment your cellphone unlock code has been entered and accepted, the phone will be unlocked. You may then insert any sim card from just about any service provider and your cellphone should immediately acquire the network. Sometimes you might need to adjust certain configurations on your phone (email as well as other web affiliated services) by pointing them to your new provider. Understand the elementary areas of wine before you embark about tasting it. This article will assist you in . Like with any problem, you need to manage the . Downside Secret To Cooking And Keeping FriendsUse Logo your . In the following you will find a short summary on what XLSMedical can do, how it works and also at whom i . Simply finding the bike they like the look of is all there is to it, right? As long as it is comfortable that’s all you need to worry abou . Dampness can it harm in a big way. As soon as the caravan is purchase .
It has been a while since we heard anything about Avatar and it sequels. art-pandora-charm, James Cameron recently spoke with Play Goes Strong about 3D Films, Cirq art-pandora-charm,ue Soleil and more importantly Avatar 2 and 3.
Cameron is reportedly working in New Zealand so that he can get into the proper mind set of living in Pandora. When asked about the scope and where he drawing his inspiration from Cameron had this to say.
“Oh believe me, it’s not that little! It’s not exactly a little, intimate drama. I’m working on ‘Avatar 2′ and ‘Avatar 3.’ I was talking the other day with Peter Jackson and said, ‘You had it easy dude. You had the books when you did the second and third ‘Lord of the Rings.’ I have to create my own books in my head and extract a script from it. I’m deep into it and I’m living in Pandora right now. There is that start up torque where you feel it’s coming to you. Then you build up momentum. That’s when it gets fun. The characters talk and it’s writing itself. I’m almost there right now. It’s building fast.”
Cindy Pearlman, who conducted the interview, asked the best and probably most obvious question. Is there there any pressure to top yourself?
no. It’s a little daunting because sequels are always tricky. You have to be surprising and stay ahead of audience anticipation. At the same time, you have to massage their feet with things that they know and love about the first film. I’ve walked that line in the past, so I’m not too worried about it. At the same time, I definitely have to deliver the goods for a release date that will be determined by when I get the script out. No pressure!”
If anything we know that Cameron understands what it takes to make a sequel. His follow ups to Terminator and Alien have been ear marks for all other filmmakers to follow. Cindy question is the right one. Can he do it again?
Check out Mania 5 Possible Plots for Avatar 2 by Hanso. You love it.
Not to mention he stole his story from like.2 or 3 other well known stories that were already out there. Maybe his next movie will copy Wrath of Khan mixed in with Empire Strikes Back, with a little Field of Dreams sprinkled on top.
He wasnt putting peter jackson down at all. They were having a conversation. Peter jackson PROBABLY agreed, becasue the statement is true
so tired of James cameron hate. he’s an AMAZING director that has done so much for the film industry. not to mention the marine exploration industry.
and he didnt “steal” anything more than anybody else. there isnt a film or book made that wasnt inspired by anotyher film or book.
Though Avatar has elements that are similar to dances with wolves, so does Dune, fern gully, The Last Samurai. but the backdrop of each is what makes them unique.
In this issue, Botton and coworkers demonstrate in vitro and in vivo antimelanoma effects of ciglitazone, a synthetic ligandactivating PPAR articlebody start >Top of pageMelanoma: a deadly diseaseCutaneous melanoma is the most deadly form of skin cancer. pandora-app-for-nook-tablet, Progress in the systemic treatment of patients with metastatic melanoma has been quite limited over the past 25 years. Recently, however, several randomized clinical trials have laid the groundwork for an evidencebased assessment of available therapies. pandora-app-for-nook-tablet, (In Germany, the anticancer agents dacarbazine, vindesine, and cisplatin are registered for metastatic melanoma; in other countries, fotemustine and the cytokine IL2 are also registered.) The combined conclusion of these randomized trials is that there is no survival benefit for patients treated with combination chemo(bio)therapy, contrary to initial expectations. Therefore, singleagent approaches and treatment under controlled clinical trials are now recommended. A possible exception may be the treatment of patients whose significant tumorrelated symptoms justify the use of more toxic polychemotherapy for palliative reasons.
Although various agents with novel modes of action CTLA4 antibodies, signal transduction inhibitors, and reactive oxygen species agents such as elesclomol being tested in clinical phase III registration trials worldwide, alternative and more effective treatment approaches are needed to improve the outcome for these patients. However, the route from target identification to an anticancer molecule suitable for complete pharmaceutical development is long, cumbersome, and expensive. Therefore, drugs already registered for the treatment of one disease but potentially effective for melanoma cells are of high interest. Activation of PPAR causes insulin sensitization and enhances glucose metabolism, and activation of PPAR enhances fatty acid metabolism.
PPARs and their corresponding ligands have recently been shown to regulate important cellular functions in the skin and other organs, including cell proliferation and differentiation, as well as inflammatory responses. These functions suggest that PPARs and their corresponding ligands are potential targets in treating various skin diseases and other disorders (Sertznig et al., 2008; Boyd, 2007). In inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, expression of both PPAR and PPAR is decreased. In addition, PPAR immunoreactivity is reduced in keratinocytes from patients with squamouscell carcinoma and actinic keratosis, whereas PPAR appears to be upregulated. Additionally, microvessel density is apparently significantly higher in actinic keratoses and squamouscell carcinomas that express high levels of PPAR PPAR also plays an antiapoptotic role and helps to maintain survival and differentiation of epithelial cells, whereas PPAR and PPAR activators induce differentiation, inhibit proliferation, and regulate apoptosis. In melanoma, the growthinhibitory effect of PPAR activation is independent of apoptosis and seems to occur primarily through the induction of cell cycle arrest in the G1 phase of the
The next step for melanoma: combining therapiescell cycle or induction of redifferentiation. PPAR activation causes inhibition of the migration of melanoma cells and anchorageindependent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPAR ligand, a significantly smaller number of patients treated with this lipidlowering drug were diagnosed with melanoma compared with controls. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, as well as cutaneous malignancies.
Top of pageThiazolidinediones: potent PPAR agonistsThiazolidinediones (TZDs), also known as glitazones, represent a relatively new class of medication used for glycemic control in patients with type II diabetes mellitus (Balakumar et al., 2007). These drugs interact with PPAR a member of the nuclear receptor superfamily, which in turn heterodimerizes with retinoid X receptors to stimulate gene transcription (Figure 1). At a physiological level, glitazones stimulate adipocyte differentiation, enhance insulinsensitive glucose uptake by muscle and fat cells, suppress angiogenesis, inhibit tumor cell growth, and normalize keratinocyte differentiation. They have also demonstrated the capacity to diminish inflammatory cytokine production, most notably, that of tumor necrosis factor Several basic and clinical studies have illustrated beneficial effects of PPAR and PPAR ligands in preventing cardiovascular risk. Moreover, recent findings indicate that PPARsignaling pathways may be a promising therapeutic target in the treatment of hyperproliferative skin diseases, including skin malignancies. Studies also suggest that oral TZDs not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. Certain members of the TZD family of PPAR agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanisms are unknown. HDAC, histone deacetylase; PGJ2, prostaglandin J2; PPAR peroxisome proliferatoractivated receptor Rb, retinoblastoma protein; RXR retinoid X receptor TRAIL, tumor necrosis factorrelated apoptosisinducing ligand; TZD, thiazolidinediones. From Chou et al., 2007.
Full figure and legend (134K)
Top of pagePPARs, TZDs, and melanomaPPARs are expressed in benign and malignant melanocytic cells at different levels. It has been recognized for some time that TZDs such as rosiglitazone inhibit colony formation by arresting melanoma cells in the G1 phase, leading to inhibition of tumorigenesis in nude mice (Liu et al., 2006). Several lines of evidence indicate significant thiazolidinedionemediated antitumor activity. An emerging view is that some antitumor effects are totally or partially PPAR whereas others are PPAR independent. Mechanistic studies from various laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complex of PPAR mechanisms (Chou et al., 2007). Evidence indicates that troglitazone and ciglitazone block BH3 domain interactions between the antiapoptotic Bcl2 (Bcell leukemia 2) members Bcl2 and proapoptotic Bcl2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase8related, Fasassociated, death domain protein ILlconverting enzyme protein through proteasomemediated proteolysis, and downregulate the gene expression of prostatespecific antigen by inhibiting activation of the androgen response elements in the promoter region (Chou et al., 2007).
Further work has indicated that in mouse melanoma S91 cells, activation of PPAR induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology, and enhanced tyrosinase expression. These events were preceded by an initial transient increase in expression of the microphthalmiaassociated transcription factor (MITF) gene promoter. Exposure to a PPAR ligand, ciglitazone, caused a gradual decrease in MITF. an MITF transcriptional activator, showed a similar pattern of decline during ciglitazone treatment, indicating that activated PPAR inhibits the Wnt pathway through the induction of proteasomal degradation (Grabacka et al., 2008).
Hoeck and coworkers hypothesized that the metastatic potential of melanoma cells is dependent on the activation of the MITF and Wnt pathways; recently, they demonstrated that these pathways are of critical importance in melanoma biology based on their analysis of gene profiles of large sets of human melanoma cell lines(Hoeck et al., 2006). Subsequent work on human melanoma tissues demonstrated that MITF gene amplification in melanoma metastases was a prognostic marker for patient survival (Ugurel et al., 2007).
The work reported by Botton et al. (2009) focuses on ciglitazoneinduced effects on normal melanocytes and melanoma cells. Biological effects, such as apoptosis and cell cycle arrest, which were reported to be ciglitazone concentration and occurred only in low concentrations, depended on the PPAR pathway. These in vitro observations were accompanied by substantial tumor growth inhibition in nude mice.
Top of pageReferences
Balakumar P, Rose M, Ganti SS, Krishan P, Singh M (2007) PPAR dual agonists: are they opening Pandora’s box? Pharmacol Res 56:91 Article PubMed ChemPort Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG et al. (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635 PubMed ISI ChemPort Botton T, Puissant A, Bahadoran P, Annicotte JS, Fajas L, Ortonne JP et al. (2009) In vitro and in vivo antimelanoma effects of ciglitazone. Int J Dermatol 46:557 Article PubMed ChemPort Chou FS, Wang PS, Kulp S, Pinzone JJ (2007) Effects of thiazolidinediones on differentiation, proliferation, and apoptosis. Mol Cancer Res 5:523 Article PubMed ChemPort Grabacka M, Placha W, Urbanska K, Laidler P, Plonka PM, Reiss K (2008) PPAR gamma regulates MITF and beta catenin expression and promotes a differentiated phenotype. Pig Cell Mel Res 3:388 Article ChemPort Hoek KS, Schlegel NC, Brafford P, Sucker A, Ugurel S, Kumar R et al. (2006) Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pig Cell Res 19:290 Article ChemPort Liu Y, Meng Y, Liu H, Li J, Fu J, Liu Y et al. (2006) Growth inhibition and differentiation induced by peroxisome proliferatoractivated receptor gamma ligand rosiglitazone in human melanoma cell line A375. Med Oncol 23:393 Article PubMed Sertznig P, Seifert M, Tilgen W, Reichrath J (2008) Peroxisome proliferatoractivated receptors (PPARs) and the human skin: importance of PPARs in skin physiology and dermatologic diseases. Am J Clin Dermatol 9:15 Article PubMed Ugurel S, Houben R, Schrama D, Voigt H, Zapatka M, Schadendorf D et al. (2007) Microphthalmiaassociated transcription factor gene amplification in metastatic melanoma is a prognostic marker for patient survival, but not a predictive marker for chemosensitivity and chemotherapy response. Clin Cancer Res 13:6344 Article PubMed ChemPort
In 1970, I was a normal kid, involved in everything and afraid of nothing. custom-charms-for-pandora-bracelets, I had never experienced back pain in my life and couldn’t even spell scia custom-charms-for-pandora-bracelets,tica! Bad back? A bad back was something old people had and complained about, not me. In other words, I was the typical fifteen or sixteen year old kid. It was at a wrestling match, beforehand actually, when my world changed forever. Prior to a wrestling match, as was always the case, our coach would crack our backs. Getting your back cracked was kind of a ritual and involved getting back to back with the coach, hooking arms, and then being hoisted upwards while hyperextending the spine. Yes, I can hear the groans from here, but it workedand it was ritual. You see, wrestlers, like most athletes, are really big on habit, ritual, and tradition. I once knew a wrestler who wore the same socks, never washed, for an entire season. Of course, we stayed away from him after a while, particularly towards the end of the season. So, we had our backs cracked.
Well, the season progressed, I’d felt a twinge that night but nothing to get upset about, just a twinge, certainly no back pain or sciatica. Up until then, I had only lost once, in the ninth grade, to a human wrecking machine by the name of Scott Clifford. Scott had been wrestling since birth, or so it seemed, particularly on that day! But since then, nevernot once. A funny thing happened on my way to sixteen, I started to lose, and lose big. After a while, I was hearing phrases like “flash in the pan” and ” glory boy,” and “it went to his head.” Kids and high school coaches, as we all know, can be very cruel, especially when the “king” is dethroned. And I was summarily dethroned and dismissed by the end of the season.
Anyway, I went on to track, I was never so happy to start running again in my life, all fifteen and a half years of it. Well, I had a horrible time! I went from holding school records to not being able to get around the track. Kids who had never come close to beating me were blowing by me. It was a terrible season. Halfway through, disgusted and completely disillusioned, I went to see the family doctor. I described my symptons, minimizing and denying of course. I told him about losing in wrestling and then in track, I complained of about the pulled muscle in the back of my leg. I had no idea what sciatica wasbut he knew. By that time, I did know what back pain was and, in a moment, I was going to be educated about my pulled muscle.
A Pulled Muscle: Back Pain and Sciatica
The Doc asked me if I had injured myself, felt anything pull in my back? The rest is history! A light went on, I told the doctor about the back cracking incident, told him about the pain, I came clean and admitted it all. What a relief! I had completely removed the back cracking from my consciousness, never giving it another thought, until that moment, but in an instant it was all clear. It was also clear to Dr. Rush and he immediately sent me to an orthopedic surgeon, the next day. I learned all about back pain, sciatica, and leaned new words like spondylolysis, spondylolisthesis, and spinal fusion. On June 12, 1971, I learned all about real back pain. I woke up in the recovery room at Fairview Hospital, Cleveland, Ohioit wouldn’t be the last time.
Fast forward and it’s twentynine years later, the year 2000Y2K! I am in a whole new world of back and sciatic nerve pain, sciatica, by now. In fact, I am on so much pain medication, have had so many back surgeries, many doctors wouldn’t even see me. The ones who would see me said things like arachnoiditis, chronic pain syndrome, failed back, and a whole array of terms meaning everything and nothing. By 2000, I had undergone 10 major surgeries on my spine, I was to suffer through 4
more. That’s right, fourteen major “procedures” on my lower thoracic, lumar, and sacral regions by the age of fifty.
Little did I know it at the time, and every doctor I saw missed it, I had advanced, chronic osteomyelytis. Osteomyelitis may present with no symptoms at all or may have signs and symptoms so hard to separate from other conditions that doctors miss the diagnosis entirely. Osteomyelitis of the back (vertebrae/spine) or hips (pelvis) may have few overt signs and symptoms, no back pain, and no sciatica. Osteomyelitis that occurs after surgery or a fracture or deep wound may present with swelling and pain but you may attribute that to the traumatic event, not an infection. And it was the infection, in 2000, probably there since 1994, that almost took my life. Had it not been for an amazing doctor at a noted Cleveland hospital, the other one, the one attached to the noted eastside university, the really famous hospital missed it too, I wouldn’t be writing this today.
So, five surgeries and nine years later, yes, that’s a total of fifteen, I am finally getting my life back. As far along as a year ago, it was still touch and go, major complications as a result of the osteomyelitis, combined with other health issues, almost did the job that we avoided back in 2000. Yes, that’s right! The math doesn’t work. That’s because I also crushed my shoulder in 2007, a consequence of weak bones due to the infection and other problems. Now, the only metal left in me is in my shoulder and that makes fifteen!
Now, should you have surgery number one? No one can answer that for you, that’s something you must face, and answer for, yourself. Back pain and sciatica can be terrible and there comes a time where anything will do, any solution seems OKas long as they get rid of the pain. However, before I opened Pandora’s Box again, for the first time, I would do everything humanly possible, exhaust every option, before having back surgery. Don’t open Pandora’s Box if you can avoid it! You will never be the same and, of the half a million or so who undergo surgery every year, only 3035% have a total and complete recovery, 20% never recover and are worse off. Not the kind of odds I’d go to Vegas with, if you know what I mean. Back pain and sciatica can be terrible, I’ve been there, this isn’t just a topic I drew out of a hat. My doctoral research was on the spine and sacroiliac (hip joint, the ilium meets the sacrum or hips to tail bone), so I know the situation, inside out you might say.
Back pain and sciatica? Yes, they are a reality after so many surgeries, they really can’t be avoided. Are they as bad as they were? No, absolutely not. A program of exercise, to regain muscle tone and lose weight; ice, with the use of an icecompression brace, to reduce inflammation; sleeping with five pillows (yes, five!) or, when I need to, in a recliner fully reclined and a pillow under the knees, try it, it really works wonders on the nights when nothing else works; and finally, and a good pair of New Balance running shoes. Yes, New Balance and, if you must wear a harder shoe or boot, orthotics for cushioning. No, another kind of running shoe isn’t as good, I’ve tried them all over the years and New Balance, for the heel cushioning, are the absolute best. And no, you can’t get the relief or the cushioning from the insoles of Doctor S, it’s not the same! Am I “spamming” you? No! Go anywhere you want buy anything you wish. But if you want relief, these are the ultimate in bad back strategies, strategies developed over three decades, give or take, for dealing effectively, and not so effectively, with back pain and sciatica.