text:
Ashmolean ImagesPosted by Greg at 06:10, 10 May 2004
With the talk recently of creating an image gallery here at TDG, it's worth pointing out the definitive resource on the 'net for quality images of Egypt (copyright free no less!). Jon Bodsworth's Egypt Archive is, to me at least, a treasure of the internet - the site houses images from every point of Egyptian history and geography. Jon's just updated his 'Ashmolean Museum' section, so it's as good a reason as any to go visit the site (who needs a reason?)...
News Briefs 10-05-2004Posted by Rich at 02:37, 10 May 2004
Several interesting history related stories this weekend, as always feel free to post your thoughts...
- A rock carving on Ilkley Moor in West Yorkshire is reportedly of a four-armed boomerang which dates back as far as 4000BC.
- Ancient Iranian site may date back 6000 years.
- Cuneiform goes digital, illuminating life in ancient Iraq.
- Jade bear-dragons corroborate 5,000 year-old Yellow Emperor legend in China.
- Unmasking China's Sanxingdui Ruins.
- Oman had ancient trade links with India and Africa during the 3rd millenium BC.
- Maya culture 'ahead of its time'.
- Newest room of discoveries from the Pyramid of the Moon at Teotihuacan to be unveiled on Wednesday.
- The Miracle of Great Cheops Pyramid is a new title written by Dr. Zahi Hawass.
- Archaeologists discover alma mater of Archimedes, the fabled University of Alexandria.
- Carthage, a lost empire.
- The final resting place of the Holy Grail is shrouded in mystery - or is it?
- Group says dinosaurs are in the Bible.
- Does modern science make religion unnecessary?
- New fast, hot breed of planets found.
- Scientists confront 'weird life' on other worlds.
- Formaldehyde, ammonia and benzene molecules on Mars?
Would probably mean life.
- Thirteen space advocacy groups band together to promote President Bush's moon and Mars mission,
- Saturn's mysterious moon Titan, lifting veil on Xanadu.
- Swirling dust near black hole too thick for theory.
- NASA funds sci-fi technology.
- Mars and the teachable moment for pseudoscientific claims.
- The latest UFO reports from NUFORC, Filer's Files and UFO Roundup. George Filer of Filer's Files and Peter Davenport of NUFORC can each be found talking about UFO reports every month in the Jeff Rense Program archives.
- National science panel warns of US scientist shortage.
- Lack of scientists threatens Natural History Museum.
- Health freedom rights: a call to act now before your right to choose is gone.
- World's forests potential medical treasure trove.
- Drug for depression helps irritable bowel syndrome.
- Parasitic invasion credited with evolution of sex.
- It is possible, even common nature, to see without observing.
- The secrets of sleep: it's a mystery, but it clearly makes us smarter and healthier.
- Global dimming? Scientists say less sunlight reaching Earth.
- Despite implausible plot, scientists warm up to climate flick.
- Science brings squid mystery to the surface.
- Scientists discover what could be the instruction manual of life genetics.
- Scientists say they're close to creating the blue rose.
- Alcoholic rats treated with gene therapy.
Quote of the Day:
There is truth in the high opinion that in so far as a man conforms, he ceases to exist.
Max Eastman
Image Gallery?Posted by Greg at 00:13, 10 May 2004
User JeffNutter has an interesting idea in his recent blog - community image galleries of sacred sites around the world:
...what a large reservoir of images we, collectively must have all of which will be related to areas that someone out there will be researching or have an interest in. So there we have it, on the one had a bank of useful images and on the other a group of researchers who could benefit from those images. The only problem being a gulf between them.
I think JeffNutter's got some great ideas here, so I may look into creating a section of the site dedicated to image galleries, with clickable thumbnails. If you've got any suggestions, or would just like to voice your support for such an idea, please leave your comments.
LONELY PLANETS ReviewPosted by Greg at 04:54, 07 May 2004
I've just added a new book review to the site, this one a brilliant piece of work on the search for extraterrestrial life. LONELY PLANETS (available from Amazon US and UK), by planetary biologist David Grinspoon is a great read, I recommend it to anyone interested in this subject area. For those who find the review interesting, you can get more of an idea about David Grinspoon at his Funky Science website, and also in this multi-part feature over at the Astrobiology Magazine website.
News Briefs 07-05-2004Posted by Bill at 03:49, 07 May 2004
Welcome to the eclectic news center. It all made sense when I wrote it ........
- Dinosaurs may have been wiped out by a mighty Verneshot, an underground explosion with the energy of 7-million atom bombs.
- Arthropod animals were molting to make room for growth more than 500-million years ago.
- Hummingbirds may be 30-million years old.
- Physics meets archaeometry in ancient Greece.
- The tomb of a Mayan queen has been found in the rain forest of Guatemala.
- An ancient musical instrument has been found in the central highlands of Vietnam.
- Archaeologists have made a sensational discovery in Turkmenistan -- a royal mausoleum.
- Zahi Hawass, the man in charge of Egypt's antiquities and the greatest archaeologist of all time, is leading the hunt for to recover ill-gotten artifacts. Classic pic of Zahi and the Sphinx.
- The Mudslingers protect an ancient ruin.
- More than 2,000-years ago this ancient Maya community may have been major city.
- It took ancient peoples in Great Britain a millennium or more to create Stonehenge, but the New Zealand version will be built in a little more than a year. Kiwihenge.
- The drugstore culture threatens ancient Arab medicine.
- Far-away Easter Island has become an exotic port-of-call for medical researchers.
- The infamous, crawling, air-breathing, predatory snakehead fishes may be indicators of ancient climate shifts.
- The humpback whale is believed to sing its mysterious songs for the same reason generations of teens have started bad garage bands.
- A rising tide of micro-plastics is plaguing the seas. Where did you think those 2-liter bottles went?
- Here's a follow-up on that lion in Ohio that Greg told you about yesterday.
- In Wassaw Sound off Savannah, Georgia there's an 11-foot-long bullet with a snub nose and four stubby fins, an aluminum cylinder with No. 47782 written on it lying in the silt. Enclosed in its metal skin is 400-pounds of conventional explosives and a quantity of bomb-grade uranium. Take a guess what No. 47782 is.
- Scientists uncover how the brain retrieves and stores older memories.
- Ex-Nazi corporal says Germany attempted to kidnap Ike. If I told you more you would swear I made it up. Just read it.
- No one is pretending the forthcoming climate change filmThe Day After Tomorrow is anything but implausible, but that the public is probably smart enough to distinguish between Hollywood and the real world. I wish.
- Monsters like Godzilla may be scary, but they could be a parent's best friend.
- Man is not a useless speck lost in the Universe.
- You're invited to participate in the Massive Medicine Wheel Ceremony set for tomorrow. One Heart, One Mind, One Circle.
- The James E. Webb Space Telescope is scheduled to take a few baby pictures in 2011.
- Life in the universe could be everywhere.
- Join the quest to unlock universe's missing link.
- One-third of the universe still eludes us.
- Our map of the Milky Way will have to be redrawn after Australian astronomers made the astonishing discovery that our spiral galaxy has a huge, out-flung arm.
- Four vast petro-chemical oceans on the surface of Saturn's giant moon Titan wait the arrival of the ESA Huygens probe.
- Mars scientists find some tempting new rocks.
Quote of the Day:
Nobody succeeds beyond his or her wildest expectations unless he or she begins with some wild expectations.
Ralph Charell
Inside DaVinciPosted by Greg at 03:50, 06 May 2004
As mentioned in my initial post here on Daily Grail version II, TDG is now just one piece of a larger concept which we call DUAT. Let me introduce you to another facet of what we are doing: Inside the DaVinci Code. This website contains information regarding Simon Cox's new book CRACKING THE DAVINCI CODE (Amazon UK or Barnes & Noble), as well as a DVD that we are producing called INSIDE THE DAVINCI CODE.
The DVD, which is now available for pre-order for delivery from May 28th, will give a unique insight into some of the stunning backdrops used by Dan Brown in THE DAVINCI CODE - St Sulpice, the Louvre, Rosslyn Chapel, as well as the enigmatic village of Rennes le Chateau. Also included will be interviews with researchers and experts concerning some of the 'facts' in Brown's novel.
The website also features a forum to discuss the topics - from Rennes and the Priory of Sion, to the gnostic gospels and the divinity (or not, as the case may be!) of Jesus. Please do register and join in the chat - all we ask is that you treat all other members with respect.
News Briefs 06-05-2004Posted by Greg at 03:47, 06 May 2004
Come on over and check out our Da Vinci website, join in on the forums...
- Space.com's image of the day: the astronomer's dilemma...when you look so far back in time that the stars haven't formed yet, what do you look for?
- Five designer babies created for stem cells. Make mine a Gucci thanks.
- The dispute over the infamous Patterson Bigfoot film. I know you can't get enough of this, so here's more.
- Obesity and high-blood pressure are becoming endemic.
- Ancient map confirmed by satellite images.
- NASA must transform to put men on Mars. I'm sure they meant to say humans. Or perhaps men are to Mars, women are to Venus?
- A day in the life of the Spirit rover. What do they tell the little fella when he asks when he's coming home?
- Tuna and sharks a prime example of convergent evolution. If you believe in that sort of freaky stuff, personally I'll take my chances with God creating the Earth a few thousand years ago (n.b. before starting those emails...that was a joke).
- NASA releases 180 degree view of Endurance Crater. Looks good.
- Archaeologists uncover oldest evidence of bedding. For a good night's sleep, you just can't beat a grass and clay mattress.
- Dr Richard Leakey suggests fencing in the Great Apes to save them from extinction.
- Laser technique may allow creation of devices within living cells. You have to follow the link just to see the cool image at the very least.
- Comet NEAT debuts in the Northern Hemisphere. That's for sky-watchers, not an impact prediction...
- Uber-physicist Brian Greene tell you all about the Fabric of the Cosmos. If the article is interesting, make sure you check out his books THE FABRIC OF THE COSMOS (Amazon US and UK) and THE ELEGANT UNIVERSE (Amazon US and UK). There are not enough hours in the day to read everything cool out there...
- Giant 'masks' suggest ancient Maya flourished.
- Ghost hunters encounter some spirits at local pub. Insert punchline here.
- Houses of Pharaonic gold miners found near Red Sea.
- African lion roaming central Ohio? See also links in Heck's blog and Sonicreducer's blog. Thanks guys.
- Giant squid isn't picky, and will mate blind, not caring if other squid is male or female. So bit like humans and nightclub closing time then.
- Builder survives nail gun incident. Trust me, check this one out...new meaning to 'a pain in the neck'.
Quote of the Day:
Spirits and conjurations...gods, spheres, planes and many other things which may or may not exist. It is immaterial whether they exist or not. By doing certain things, certain results follow.
Aleister Crowley
The Secret TeachingsPosted by Greg at 00:22, 06 May 2004
A strange synchronicity: I was recalling just the other night how my interest in esoterica was ignited as a child when I discovered Manly P. Hall's THE SECRET TEACHINGS OF ALL AGES in my local library. I remember opening this big old book, full of magickal and alchemical diagrams - literally like a scene from a movie, sweeping the dust off the cover. Only later in life did I learn that this heavy tome was one of the absolute classics of esoterica.
Funnily enough, the day after recalling this I coincidentally came across the website of Mitch Horowitz. In his job as executive editor for Tarcher/Penguin, Mitch has been involved with the production of a new, more compact and reasonably priced edition of Hall's classic book (see Amazon US and UK for details on this "Reader's Edition"). As such, on his website you'll find a number of interesting articles, a couple of which deal with this seminal book and its enigmatic author. Well worth a look - I'm hoping to talk more to Mitch about this new edition soon, so stay tuned for more details.
News Briefs 05-05-2004Posted by Jameske at 00:00, 05 May 2004
We've had Phatarhs as a candidate name for a moon discovered orbitting Uranus. Didn't make it past go, though. I would certainly favour Phuket as the name of any new planet that gets discovered. Better than Sedna, and more in keeping with how astronomers really feel about having to name newly discovered bodies in this endless cosmos in which we live. Post your thoughts.
- Cometary panspermia explains the Kerala red rains. You'll need Adobe Acrobat Reader.
- That natural smile could be just a few years away.
- Scientists announce cosmic rays breakthrough.
- The birds are singing in outer space.
- The science behind climate change forecasts adds up to a lot of hot air.
- Weather changes may effect stroke.
- The mystery of mind control.
- Fortune telling Bangkok septuagenarian has supernatural breasts that produce milk able to ward off black magic. She invites people to suck'em and see. The Phuket Gazette? Is that a joke or is it named by a bunch of very unhappy journalists?
- Chinese were the world's first modern astronomers.
- Ancient maps of the world.
- Flourescent fish spark GM row.
- AIDS theory renegade returns with challenging cancer theory.
- The promise of artificial photosynthesis.
- This time it's real: an antimissile system takes shape.
- Mammals have multiple timers. Any of them fit any planetary motion in the solar system?
- Flying saucer franchise.
- Ancient cave in Central Iran dated to 15 Millennia B.C.
- The myth of the beginning of time.
- Breaking the chains of illusion. Part I. Part II.
- Physics meets archaeometry in ancient Greece.
- I believe that intelligent life must exist somewhere in the vast universe of stars and galaxies. Is he including or excluding Earth. I suppose there's a case for the latter.
- Today's conspiracy, tomorrow's truth.
- 18 year-old has severe reaction to prescription drug.
Quote of the Day:
With most people unbelief in one thing is founded upon blind belief in another.
Georg Cristoph Lichtenberg
Techgnosis TrippingPosted by Greg at 05:24, 04 May 2004
I was surprised and delighted to read in this week's edition of the LA Weekly an article on the entheogenic library The Vaults of Erowid. I've mentioned this marvellous resource for modern neo-shamans before on TDG, but this article gives a peek behind the scenes at the philosophy and work being put in behind the scenes.
If that wasn't enough, the article was written by a great writer, Erik Davis - author of TECHGNOSIS: Myth, Magic and Mysticism in the Age of Information (see Amazon US and UK). Davis is a regular writer on the blend between spiritual thought and modern technology - for a (large) sample of his writings, check out his website "Figments and Inklings". I think there's a couple of years worth of reading in all those links...


text:
8月 10, 2014 合計視聴数:: 5523 今日は: 1
Old Flat Hotel on Grecheskiy Saint Petersburg, Located in the city centre of Saint Petersburg, an 8-minute walk from Nevsky Prospekt, Old Flat Hotel on Grecheskiy features a fully equipped shared kitchen, a shared lounge area, and free Wi-Fi throughout the property. The colourful and air-conditioned rooms here are equipped with a TV with cable channels, セーフティボックス, デスク, and a private bathroom with a shower. Other property facilities include a 24-hour front desk, 荷物保管, スナックバー. The Field of Mars is 2.5 ㎞, Kazanskaya Square is 3 キロ, and the State Hermitage Museum is 3.5 ホテルから2km. Old Flat Hotel on Grecheskiy is a 9-minute walk from Ploshchad' Vosstaniya Metro Station, a 10-minute walk from Moskovskiy Train Station, と 21 km from Pulkovo Airport. (Old Flat Hotel on Grecheskiy Saint Petersburg hotels 予約).

subset: commoncrawl


text:
New Delhi, Jun 8: Greenpeace, the environmental NGO revealed that it had given the informations about the whereabouts of Warren Anderson to CBI. The revelation of the NGO came on Tuesday, Jun 8, a day after the Bhopal tragedy verdict came.
Warren Anderson, the then CEO of Union Carbide Corporation was declared as an absconder in the Bhopal gas tragedy case. Bhopal sessions court did not mention his name during the verdict on Monday, Jun 7.
Nirmala Karunan, the public relation officer of Greenpeace said that an unknown person called them and told about the whereabouts of Anderson, during a photo exhibition in 2002, in America.
"On the basis of the information we had gone to his (Anderson) residence but his wife told us that he was not at home. Later we saw Anderson escaping from the back door of his house," Nirmala said.
Nirmala said that she had shared this information with the US and Indian courts and CBI.
"All the information regarding the incident has been explained in detail on our website also," Nirmala said.
Veerappa Moily, the Law Minister said that Anderson could be extradited and CBI has the power to pursue the case.
OneIndia News


text:
wedding flowers packages
dresswe.com is wonderful website, it provide wedding flowers packages more than ten thousand dresses for women. No matter how big or how small your size is, you will get a dress that will fit you as dresswe.com is a custom making website. All the dress styles are latest and trendy. We also can custom made wedding flowers packages for you and no matter you are tall or short, the dresss will fit you, cause the tialor can custom made the size to the customers. The wedding flowers packages are all made specially for the customers. Start to buy now.
4267 results in wedding flowers packages
wedding flowers packages Related Product
- wedding silk flowers bridal bouquetwedding shower flowerswedding fall flowerswedding arch flowerswedding dress wedding dress wedding dresswedding dresses wedding dresses wedding dresseswedding flowers wrist corsagewedding flowers corsagewedding car flowerswedding in a box flowerswedding ceremony flowers
New Products of wedding flowers packages
Sweetheart Appliques Flowers A-Line Court Train Wedding Dress
Glittering Ball Gown Sweetheart Zipper-Up Flowers Button Court Train Wedding Dress
Delicate Sweetheart Little Flowers Tiered Court Train Wedding Dress
- 50
- Delicate Wedding Bridal Flower
- 65
- Best Cloths Flowers Wedding Bouquet
- 65
- Best Cloths Red Flowers Wedding Bouquet
- 65
- Best Cloths Pink Flowers Wedding Bouquet
- 65
- Best Cloths Flowers Wedding Bouquet
- 80
- Best Cloths Purple Flowers Wedding Bouquet
- 65
- High Quality Wedding Bouquet
- 70
- Charming Pink Wedding Bouquet
- 55
- Fancy Floral Lace Alloy Wedding Jewelry Sets (Including Hair Flowers, Earrings, and Necklace)
- 60
- Best Lace Pearl Starry Sky Wedding Bouquet
- 75
- Appliques Flowers Bridal Hair Flower
Related Items Reviews about Tag wedding flowers packages
Reviews of Latest Sheath/Column V-neck Flowers Chapel Train Wedding Dress
The moment I saw this gown I was in love with it! I ordered the gown in ivory the same day I found it because I knew it was "the dress". I had the gown custom altered for my specific measurements just to make sure there were no sizing issues once the dress had been delivered. When the gown arrived it was even more beautiful then I had ever imaged it would be in person! Not only was the gown stunning but it fit perfectly! The detailing on the gown is classic and beautiful. The gown itself is constructed very well and is made with fine, soft fabric. Overall I have no complaints regarding this wonderful gown; I received nothing but compliments from everyone who saw it. More importantly, I have never felt more beautiful than the day I wore this gown.I would highly recommend this gown to any bride looking for the perfect dress, it helped to make my wedding day the perfect day it was!
Reviews of Graceful Ball Gown Strapless Flowers & Lace Floor Length Wedding Dress
Didn't want to buy this dress because of course,cheap and online shopping isn't usually a good choice.. Definitely I am shocked... Dress shipping Super FAST!!! Gorgeous!!!! Love It, Love It!!! Worth the price , worth the risk.. I read the reviews and take in consideration what Ppl said about the sizing and works great. I'm a size 12 and I took the chance to order a 16 thinking I might have to adjust it a Lil bit.. But NO.. Perfect fit..By Heloise Jul 24,2016
- silk wedding flowers packages
- wedding party flowers
- wedding altar flowers
- wedding flowers for hair accessories
- wedding flowers and candles
- wedding flowers candles
- wedding flowers reception centerpieces
- wedding flowers for reception
- end of year discount wedding flowers


text:
While 15 states are pushing against civil-asset forfeiture, the rest of the US is still seeing local, law enforcement legally obtaining personal property but not bringing charges against the respective person(s). Civil-asset forfeiture is hopefully at the end of its rope. The change started with an initial, bipartisan effort of DIY folks around the nation.
To bring everyone into the know, civil forfeiture enables authorities to take possession of an array of personal effects including cash, cars and the very roof over law-abiding citizens' heads—on suspicion alone. Cops can then use such civil assets to increase budgetary spending among other, questionable activity. Further, they've stood their ground on this practice amid public intolerance.
[Video: courtesy of Institute for Justice]
Recall The Caswells enduring civil-asset forfeiture due to some of their customers being busted for drugs.
While authoritarian abuse still runs rampant in the US, public interest is finally seeing the justice scales starting to tip in their favor—both Republicans & Democrats. All Americans are waking up to the crookedness that is civil-asset forfeiture.
Iowa is among the states pushing back. Previously, the Midwest state's police were required to only avail that respective property was tied to criminal activity via preponderance of evidence—i.e., the evidence outweighs hard facts. This term's common use in civil cases. However, it's not even comparable to the "clear and convincing" or "beyond a reasonable doubt" stance used to legitimately convict one for a crime.
But the nation is seeing an event horizon for ethical, legal jurisprudence—"clear and convincing" has become the proverbial bar… In order for the prosecution to even get their hands on possessions valued at under $5,000, a criminal conviction is mandated to be on the judicial table. It's progress, but this legislation is but a small grasp at what Institute for Justice Counsel Lee McGrath calls "perverse financial incentives that warp law enforcement priorities to pursue cash instead of criminals." Hey, it's better than nothing.
Fighting The Status Quo
Tennessee's on top of it too—with a somewhat-different avenue. Their legislators are considering civil-forfeiture property going toward general funding in an attempt to thwart corruption in law enforcement—it's actually working. Institute of Justice's Dick Carpenter availed research that proves "the financial incentives baked into civil-forfeiture laws influence law-enforcement behavior," as it's not uncommon for cops to retain 100 percent of what's obtained via said laws. Looking at 2009 and going to 2014, Tennessee authorities raked in roughly $86 million from forfeiture justifications—in addition to whatever the seized automobiles and electronics were worth.
However, while states are implementing countermeasures, law enforcement's still loopholing through those efforts. Through "equitable sharing," law-enforcement officials bypass the aforementioned blocks via federal-agency aid—as the latter stands to gain profits too. Federal authorities kick over up to 80 percent of the take to state or local law. Out in New Hampshire, equitable sharing enabled local authorities to obtain over $1 million per year (2000-2013). Because of this, state officials are pushing for legislation to seal off that crooked crack in the law.
The solution lies within upping the evidential bar, cutting corrupt motivations and quashing local law's loophole tactics of conspiring with federal authorities—state-law makers are on the case!
United States voters can take comfort in knowing the Legislative Branch and governors are pushing state representatives to drive reform revisions. By doing this, the Bill of Rights will sustain and perpetuate—"no state shall deprive any person of life, liberty, or property without due process of law."


text:
Proper metabolism depends on the type of foodMonday, March 15th, 2010
In people with obesity always comes a time when the accumulated weight have increasingly greater impact on the appearance and activity of various organs. According to the specialists Dieting Tips, the unloaders days have effective only briefly. Why is that? This issue have tried to meet scientists from the American Institute of Nutrition and overweight. The results of their long and extensive study has confirmed the statement by many nutritionists believe that the secret of good figure is balanced metabolism. The Diet Reviews are telling that the lack of such balance and can lead to weight than normal, and extreme weakness. The main problem with nutritionists to give universal advice on diet comes from the individual characteristics of each organism. Everyone absorb nutrients differently and therefore consumes energy so accumulated. It is quite easy to normalize your weight with Colon Cleansing, which are balancing your metabolism. In slower absorption of energy expenditure is lower, namely unspent calories cause weight per person to rise, even if it is fed plenty. Experts advise in this case the food to dominate small amounts of carbohydrates and more rapid processing proteins (poultry, fish). Other suitable people for this kind of foods are soy products, those containing many fiber (carrots, beets, bad, cucumbers) and various milk derivatives, but with lower fat content. People whose body has accelerated metabolism, respectively "burn" faster energy. Scientists say this is due to a higher level of adrenaline and thyroid hormones in the body.


text:
Currently not available.
Kick chic up a notch with this faux-leather "cage-pattern" zipper-front peep-toe booty. 2 3/4" covered heel. Synthetic. Scarlet Red.
Sign in to your Address Book.
To check if any specific restrictions for this item apply to any United States shipping address, please enter the information below.Sorry, this service is not available to Canadian addresses.
This is being shipped to a P.O. Box
This product has no shipping restrictions.
Stay Connected! Get the scoop on great deals, new arrivals, hot trends & more!


text:
|Home | About | Journals | Submit | Contact Us | Français
Oxidative stress is an important feature in the pathogenesis of COPD. Targeting oxidative stress with antioxidants or boosting the endogenous levels of antioxidants is likely to be beneficial in the treatment of COPD. Antioxidant agents such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn), dietary polyphenols (curcumin, resveratrol, green tea, catechins/quercetin), erdosteine, and carbocysteine lysine salt, all have been reported to control nuclear factor-kappaB (NF-κ B) activation, regulation of glutathione biosynthesis genes, chromatin remodeling, and hence inflammatory gene expression. Specific spin traps such as α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419 have also been reported to inhibit cigarette smoke-induced inflammatory responses in vivo. Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD, it is possible that therapeutic administration of multiple antioxidants will be effective in the treatment of COPD. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in COPD are discussed.
Reactive oxygen species (ROS), such as superoxide anion (O2•−) and the hydroxyl radical (•OH), are highly unstable species with unpaired electrons capable of initiating oxidation. Lungs are continuously exposed to oxidants, generated either endogenously by metabolic reactions (eg, from mitochondrial electron transport during respiration or during activation of phagocytes) or exogenously, such as from air pollutants or cigarette smoke. Production of ROS has been directly linked to oxidation of proteins, DNA, and lipids, which may cause direct lung injury or induce a variety of cellular responses through the generation of secondary metabolic reactive species. ROS may alter remodeling of extracellular matrix and blood vessels, stimulate mucus secretion, inactivate antiproteases, cause apoptosis, and regulate cell proliferation (Rahman and MacNee 1996a, 1999). Furthermore, increased levels of ROS have been implicated in initiating inflammatory responses in the lungs through the activation of transcription factors such as nuclear factor-kappaB (NF-κ B) and activator protein-1 (AP-1), signal transduction, chromatin remodeling, and gene expression of proinflammatory mediators (Rahman and MacNee 1998; Rahman 2003) (Figure 1). Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD, it is possible that therapeutic administration of a variety of antioxidants will be effective in the treatment of COPD.
This paper discusses the rationale for antioxidant therapeutic intervention in the light of oxidative stress in the management of COPD.
COPD is a slow, progressive condition characterized by airflow limitation, which is largely irreversible (ATS 1995; Pauwels et al 2001). Cigarette smoking is the major etiological factor in this condition. More than 90% of patients with COPD are smokers, but only 15%–20% of cigarette smokers show a rapid decline FEV1 and develop the disease (Snider 1989). An increased oxidant burden in smokers derives from the fact that cigarette smoke contains more than 1017 oxidant/free radical molecules per puff and more than 4700 chemicals (Church and Pryor 1985).
The common feature of COPD is the development of an inflammatory response, characterized by activation of epithelial cells and resident macrophages and the recruitment and activation of neutrophils, eosinophils, monocytes, and lymphocytes (Rahman and MacNee 1996a). The activation of macrophages, neutrophils, and eosinophils generates O2•−, which is rapidly converted to H2O2 under the influence of superoxide dismutase (SOD), and •OH is formed non-enzymatically in the presence of Fe2+ as a secondary reaction. ROS can also be generated intracellularly from several sources. The primary ROS-generating enzyme is NADPH oxidase, a complex enzyme system that is present in phagocytes and epithelial cells. In addition to NADPH oxidase, phagocytes employ other enzymes to produce ROS, which involves the activity of heme peroxidases (myeloperoxidase, MPO) or eosinophil peroxidase (EPO). Superoxide anion and H2O2 can also be generated by mitochondria and the xanthine/xanthine oxidase (XO) reaction. XO activity has been shown to be increased in cell-free bronchoalveolar lavage (BAL) fluid and plasma from COPD patients, compared with normal individuals. This has been associated with increased O2•− and lipid peroxide levels (Pinamonti et al 1998).
Identification of non-invasive biomarkers of oxidative stress is important because antioxidant clinical trials or supplementation studies could potentially be monitored by measuring markers of oxidative stress. Recent studies have focused on applying non-invasive techniques, such as biomarkers in exhaled breath condensate to evaluate oxidative stress in COPD (Rahman and Kelly 2003; Rahman and Biswas 2004). Smokers and patients with COPD have higher levels of exhaled H2O2 than non-smokers, and levels are even higher during exacerbations of COPD (Kharitonov and Barnes 2001; Montuschi and Barnes 2002). The levels of 8-iso-prostaglandin F2α (8-isoprostane) in exhaled breath condensate are elevated in healthy smokers and more markedly in patients with COPD, reflecting the degree of oxidative stress (Rahman and MacNee 1998; Montuschi et al 2000). Non-specific lipid peroxidation products, such as thiobarbituric acid reactive substances (TBARS), have also been shown to be elevated in breath condensate and in lungs of patients with stable COPD (Pratico et al 1998; Nowak et al 1999). Other specific products of lipid peroxidation such as malondialdehyde and 4-HNE have also been shown to be increased in exhaled breath condensate of COPD patients (Rahman et al 2000; Rahman, van Schadewijk, et al 2002; Aoshiba et al 2003).
Smoking and exacerbations of COPD result in decreased antioxidant capacity in plasma in association with depleted protein sulfhydryls in the plasma (Rahman et al 1996, 1997; Corradi et al 2003). The decrease in antioxidant capacity in smokers occurs transiently during smoking and resolves rapidly after smoking cessation. In exacerbations of COPD, however, antioxidant capacity remains low for several days after the onset of the exacerbation, tending to return towards normal values at the time of recovery from the exacerbation (Rahman et al 1997). The depletion of antioxidant capacity could in part be explained by the increased release of ROS from peripheral blood neutrophils, as shown by a significant negative correlation between neutrophil superoxide anion release and plasma antioxidant capacity (Rahman et al 1996). Thus, there is clear evidence that oxidants in cigarette smoke markedly decrease plasma antioxidants, which may play an important role in the pathogenesis of COPD. Furthermore, it is possible that interindividual differences in antioxidant capacity may contribute to the differences in susceptibility to cigarette smoke-induced COPD. Therefore, it is imperative to propose the rationale for antioxidant therapy ameliorating the increased oxidative stress and consequently the inflammatory response in COPD. There are various options to enhance the lung antioxidant screen (Table 1).
Depletion of total antioxidant capacity in smokers is associated with decreased levels of major plasma antioxidants in smokers (Pelletier 1970; Petruzzelli et al 1990; Duthie et al 1991; Antwerpen et al 1993; Bridges et al 1993; Mezzetti et al 1995; Rahman and MacNee 1996a). These studies show depletion of vitamin C, vitamin E, β-carotene, and selenium in the serum of chronic smokers and in patients with COPD (Pelletier 1970; Chow et al 1986; Duthie et al 1991; Antwerpen et al 1993; Bridges et al 1993; Mezzetti et al 1995; Tug et al 2004). Moreover, decreased vitamin E and vitamin C levels were reported in leukocytes and BAL fluids from smokers (Barton and Roath 1976; Bridges et al 1990; Theron et al 1990). Ascorbate appears to be a particularly important antioxidant in the plasma (Pacht et al 1988). Cigarette smoke-induced lipid peroxidation of plasma in vitro is decreased by ascorbate (Cross et al 1994). Reduced levels of vitamin E and a marginal increase in vitamin C have been shown in the BAL fluid of smokers, compared with non-smokers (Rahman and MacNee 1996b). Similarly, alveolar macrophages from smokers have both increased levels of vitamin C and augmented uptake of ascorbate, suggesting that these cells are trying to redress their antioxidant balance (Rahman and MacNee 1996b).
Dietary antioxidant supplementation is one of the simplest approaches to boost antioxidant defense systems. Supplementation of vitamin C, vitamin E, and β-carotene has been attempted in cigarette smokers and patients with COPD (Cross et al 1993; Allard et al 1994; Rautalahti et al 1997; Steinberg and Chait 1998; Aghdassi et al 1999; Habib et al 1999; Lykkesfeldt et al 2000) (Table 2). In the general population there is a positive association between dietary intake of antioxidant vitamins and lung function. Epidemiological studies have demonstrated negative associations of dietary antioxidant intake with pulmonary function and with obstructive airway disease (Grievink et al 1998). Britton and co-workers (1995) showed a positive association between dietary intake of the antioxidant vitamin E and lung function in a population of 2633 subjects, supporting the hypothesis that this antioxidant may have a role in protecting against the development of COPD. Another study has suggested that antioxidant levels in the diet could be a possible explanation for differences in COPD mortality in different populations (Sargeant et al 2000). Dietary polyunsaturated fatty acids may also protect cigarette smokers against the development of COPD (Shahar et al 1999). These studies support the concept that dietary antioxidant supplementation including polyphenols may be a possible therapy to prevent or inhibit oxidative stress and inflammatory responses, which are key features in the development of COPD.
Antioxidant vitamin supplementation reduces oxidant stress in smokers, measured as a decrease in pentane levels in breath as an indication of lipid peroxides in the airways (Euler et al 1996). Dietrich and colleagues (2002) have recently shown that vitamin C or an antioxidant mixture containing vitamin C, α-lipoic acid, and vitamin E decreases plasma F2-isoprostane levels in smokers with high body mass index, suggesting modulation of lung oxidative stress with these dietary supplements. This study suggested that cigarette smoking depletes a variety of multiple antioxidants needed to quench an array of free radicals present in cigarette smoke and inhibit inflammatory response induced by cigarette smoking. However, robust clinical trials using dietary antioxidant vitamins and polyphenols are urgently needed to address the beneficial effects of these antioxidants in COPD.
The development and progress of COPD are associated with increased oxidative stress or decreased antioxidant resources (Boots et al 2003). The most direct way to redress the oxidant imbalance in COPD would be to increase the lung's capacity to produce antioxidants. A variety of means by which to do this have been attempted with varying success.
The thiol antioxidant glutathione (GSH) is concentrated in epithelial lining fluid compared with plasma (Cantin et al 1987; Pacht et al 1988) and has an important protective role in the airspaces and intracellularly in epithelial cells. Several studies have suggested that GSH homeostasis may play a central role in the maintenance of the integrity of the lung airspace epithelial barrier. Decreasing the levels of GSH in epithelial cells leads to loss of barrier function and increased permeability (Li et al 1996; Morrison et al 1999). Human studies have shown elevated levels of GSH in epithelial lining fluid in chronic cigarette smokers compared with non-smokers (Cantin et al 1987; Morrison et al 1999). However, this increase is not present immediately after acute cigarette smoking (Morrison et al 1999). The twofold increase in BAL fluid GSH in chronic smokers may not be sufficient to deal with the excessive oxidant burden during smoking, when acute depletion of GSH may occur (Harju et al 2002). Harju and colleagues (2002) found that the immunoreactivity of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis, was decreased in the airways of smokers compared with non-smokers, suggesting that cigarette smoke predisposes lung cells to ongoing oxidant stress. Neurohr and colleagues (2003) recently showed that decreased GSH levels in BAL fluid cells of chronic smokers were associated with a decreased expression of GCL light subunit without a change in GCL heavy subunit expression. Increasing the activity of GCL would be expected to increase cellular GSH levels. The induction of GCL by molecular means to increase cellular GSH levels or GCL gene therapy also holds great promise in protection against chronic inflammation and oxidant-mediated injury in COPD.
Direct increase of lung cellular levels of GSH would be a logical approach to enhance the antioxidant potential in the treatment of COPD. In fact, extracellular augmentation of GSH has been tried through intravenous administration of GSH, oral ingestion of GSH, and aerosol inhalation of nebulized GSH in an attempt to reduce inflammation in various lung diseases (Rahman and MacNee 1999, 2000). However, all these routes of administration lead to undesirable effects, which suggests that direct GSH therapy may not be an appropriate way of increasing GSH levels in lung epithelial lining fluid and cells in COPD. The bioavailability of GSH, pH, and osmolality in the inflammatory microenvironment, and resultant formation of toxic products (GSSG and GSH-adducts) are further challenges for direct GSH administration. Alternative formulations may address bioavailability, such as liposomal delivery, but at present it seems that direct administration of GSH will not be successful in treating COPD.
NAC, a cysteine-donating reducing compound, acts as a cellular precursor of GSH and becomes deacetylated in the gut to cysteine following oral administration (Cotgreave 1997). NAC may also reduce cystine to cysteine, which is an important mechanism for intracellular GSH elevation in vivo in lungs. It reduces disulfide bonds (a property of a good reducing agent), but also has the potential to interact directly with oxidants. NAC is also used as a mucolytic agent, to reduce mucus viscosity and to improve mucociliary clearance. A Cochrane systematic review evaluated the effects of treatment with mucolytic agents in patients with COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, by breakdown of sulfhydryl groups, or through antibacterial or immunostimulatory effects (Poole and Black 2001, 2003). Although small-scale trials failed to demonstrate any clear clinical benefits, a few meta-analyses have shown a small but significant clinical benefit in COPD (Grandjean et al 2000; Dekhuijzen 2004).
Pharmacological administration of NAC has been used, with varying success, in an attempt to enhance lung GSH in patients with COPD (Rasmusse and Glennow 1988; Bridgemen et al 1994). Van Schooten et al (2002) have reported that in a randomized, double-blind, placebo-controlled phase II trial, a 6-month oral dose of 600 mg twice daily reduced various plasma and BAL fluid oxidative biomarkers in smokers. Similarly, it has been shown that treatment with NAC 600 mg once daily for 12 months also reduced the concentration of H2O2 in exhaled breath condensate compared with placebo in stable COPD patients (Kasielski and Nowak 2001). A more recent clinical trial also proves that oral administration of NAC 600 mg twice daily for 2 months rapidly reduces the oxidant burden in airways of stable COPD patients (De Benedetto et al 2005). This reduction in oxidative biomarkers results in clinical benefit such as reduction in bronchial hypersecretion (Aylward et al 1980) in addition to a decline in FEV1 and in exacerbations (Stey et al 2000). Orally administered NAC has been shown to increase phagocytic activity of BAL macrophages from healthy smokers (Linden et al 1993); similar results were not seen in COPD patients, possibly owing to active concentrations of NAC not reaching the lung, as in vitro analysis of cells supports an induction of phagocytosis by NAC (Vecchiarelli et al 1994). It has also been reported recently that orally administered NAC increased the quadriceps endurance time of severe COPD patients (Koechlin et al 2004), thus suggesting that NAC administration may have beneficial effects on the systemic oxidative stress associated with COPD. However, a multicenter study using NAC delivered by metered-dose inhalers in patients with chronic cough failed to show a positive effect on wellbeing, sensation of dyspnea, cough, or lung function (Dueholm et al 1992).
Although there is a body of evidence that the administration of NAC provides benefit for COPD patients, it is not clear whether this represents a maintenance therapy (Decramer et al 2001). A phase III multicenter trial, Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS), has recently been completed, with the aim of addressing this question and determining whether the effectiveness of NAC as an "antioxidant" results in an alteration in the rate of decline in FEV1, exacerbation rate, and quality of life in patients with moderate to severe COPD and hence supporting NAC administration as a maintenance therapy for COPD (Gerrits et al 2003) (Table 2). The results of the phase III BRONCUS trial showed no effect on decline in FEV1 but a reduction in overinflation in patients with severe COPD and exacerbation rate in patients not treated with inhaled glucocorticoids (Decramer et al 2005).
NAL, a lysine salt of NAC, is a mucolytic and antioxidant (reducing) thiol compound. The advantage of NAL over NAC is that it has a neutral pH in solution, whereas NAC is acidic. NAL can be aerosolized into the lung without causing significant side effects (Gillissen et al 1997). Gillissen and co-workers compared the effect of NAL and NAC and found that both drugs enhanced intracellular GSH in alveolar epithelial cells and inhibited hydrogen peroxide and O2• − released from human blood-derived polymorphonuclear leukocytes from smokers with COPD. NAL also inhibited ROS generation induced by serumopsonized zymosan by human polymorphonuclear neutrophils. This inhibitory response was comparable to the effects of NAC (Gillissen et al 1997). Recently, Antonicelli and colleagues (2002) have shown that NAL inhibited oxidant-mediated interleukin (IL)-8 release in alveolar epithelial A549 cells, suggesting an antiinflammatory effect of NAL. Therefore, NAL may represent an interesting alternative approach to augment the antioxidant screen, thereby inhibiting inflammatory responses in the lungs, and it has the advantage over other antioxidant agents in that it may be administered by inhalation. A clinical trial using NAL in the treatment of COPD is in progress.
Because NAC becomes hydrolyzed in biological systems, the measured bioavailability of the drug is low. Thus, it was speculated that a drug might be synthesized that had greater bioavailability than NAC and could be used as a more effective treatment for chronic bronchitis. NIC is a NAC-like thiol compound that does not undergo effective first-pass hydrolysis and hence has higher oral bio-availability than NAC (Ekberg-Jansson et al 1999). The oral bioavailability can be as high as 80%, depending on food intake. However, when evaluated as a therapy for exacerbations of chronic bronchitis, NIC performed no better than placebo and not as well as NAC (Gillissen et al 1997). Furthermore, a study of NIC also failed to reduce exacerbation rates in patients with COPD (Ekberg-Jansson et al 1999).
Erdosteine is a new thiol compound that acts as an antioxidant, but in addition has mucoactive properties and reduces bacterial adhesiveness. In the "Equalife" randomized, placebo-controlled clinical study, erdosteine was administered orally 300 mg twice daily for 8 months (Moretti et al 2004). Patients receiving erdosteine had significantly fewer exacerbations and spent fewer days in hospital than the placebo group. Moreover, patients receiving erdosteine showed no reduction in lung function over this period and showed a significant improvement in health-related quality of life. It is not clear whether this clinical benefit is due to antioxidant effects of erdosteine. The mucolytic effect of erdosteine is perhaps due to the presence of a sulfhydryl group. It may be possible that erdosteine reduces bacterial colonization through a direct effect on adhesion.
Procysteine (L-2-oxothiazolidine-4-carboxylate) is a cysteine-donating compound that increases the cysteine levels of the cells and has greater bioavailability than NAC. This thiol compound is well tolerated and has been shown to increase mitochondrial levels of GSH in alveolar type II cells (Guidot and Brown 2000). Glutathione esters, particularly GSH monoethyl esters, can increase the GSH levels of the cells by cleavage of ester bond (an ethyl group esterified to glycine). GSH esters have been shown to increase GSH levels in the lungs of rats; however, this compound can be cytotoxic, and variation in the uptake levels of GSH has been shown in various cellular models (Butterworth et al 1993).
Increased activity of antioxidant enzymes (SOD and superoxide catalase) in alveolar macrophages from young smokers has been reported (McCusker and Hoidal 1990). However, Kondo and co-workers (1994) found that the increased superoxide generation by alveolar macrophages in elderly smokers was associated with decreased antioxidant enzyme activity when compared with that of non-smokers. The activities of CuZn superoxide dismutase (CuZnSOD), glutathione-S-transferase, and glutathione peroxidase are all decreased in alveolar macrophages from elderly smokers (Gilks et al 1998).
The activities of SOD and glutathione peroxidase have been shown to be higher in the lungs of rats exposed to cigarette smoke (York et al 1976). McCusker and Hoidal (1990) have also demonstrated enhanced antioxidant enzyme activity in alveolar macrophages from hamsters after cigarette smoke exposure, which resulted in reduced mortality when the animals were subsequently exposed to >95% oxygen. They speculated that alveolar macrophages undergo an adaptive response to chronic oxidant exposure that ameliorates potential damage to lung cells from further oxidant stress. The mechanisms for the induction of antioxidant enzymes in erythrocytes (Toth et al 1986), alveolar macrophages (McCusker and Hoidal 1990), and lungs (York et al 1976) by cigarette smoke exposure are currently unknown.
Spin traps such as α-phenyl-N-tert-butyl nitrone react directly with reactive oxygen and reactive nitrogen species at the site of inflammation (Chabrier et al 1999). Smith and colleagues (2002) have shown that intratracheal instillation of a catalytic antioxidant, manganese(III) mesotetrakis (N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150 and AEOL 10113), inhibited the cigarette smoke-induced inflammatory response (decreased number of neutrophils and macrophages) in rats after 2 days or 8 weeks (6 hours/day, 3 days/week) exposure. These compounds also mimic extracellular SOD and superoxide catalase, scavenging both lipid peroxides and peroxynitrite, and have been shown to be effective in a number of animal models of lung disease.
SOD mimetic M40419 has been shown to block the development of emphysema and significantly reduce lung markers of oxidative stress in an animal model (Tuder et al 2003). Animal studies have shown that recombinant SOD treatment can prevent the neutrophil influx to the airspaces and IL-8 release induced by cigarette smoking through a mechanism involving down-regulation of NF-κ B (Nishikawa et al 1999). This further substantiates the idea that compounds with antioxidant enzyme properties may be able to act as novel antiinflammatory drugs by regulating the molecular events in COPD.
Small molecules with enzymatic activity similar to glutathione peroxidase, such as the selenoorganic compound ebselen, have been developed. Ebselen increases the efficiency of GSH as an antioxidant and can thus be used as therapy against oxidative stress and inflammation. Recent studies have shown that ebselen inhibits airway inflammation (neutrophil recruitment and chemokine expression) in response to lipopolysaccharide in various animal models (Haddad et al 2002; Zhang et al 2002). It would be interesting to see whether similar results can be obtained with ebselen in response to smoking in vivo.
There is a range of small redox molecules such as β-strand mimetic templates MOL-294 and PNRI-299 that have been shown to inhibit NF-κ B and AP-1-mediated transcription and block allergic airway inflammation in a mouse asthma model (Henderson et al 2002). The mechanism of inhibition is based on the reversible inhibition of redox sensor proteins (similar to redox effector factor-1). These redox compounds are novel and have been shown to reduce airway eosinophil infiltration, mucus hypersecretion, edema, and cytokine release in a mouse asthma model. However, the activity of these compounds in cigarette smoke-induced oxidative stress and proinflammatory mediator release assays in vitro or in vivo has not been reported.
Various mechanisms inhibit superoxide production in vitro through increasing intracellular levels of cyclic adenosine monophosphate (cAMP); the most advanced of these being the use of phosphodiesterase 4 (PDE4) inhibitors. These inhibitors act by increasing intracellular concentrations of cAMP, which has a broad range of antiinflammatory effects on various key effector cells involved in asthma and COPD (Lipworth 2005). Raising cAMP in neutrophils blocks the assembly of NADPH oxidase and hence inhibits superoxide production. These compounds also potently inhibit expression of a variety of cytokines, such as tumor necrosis factor (TNF)-α and monocyte inflammatory protein (MIP)-1β , and therefore may have a broad antiinflammatory profile. Clinical benefit of PDE4 inhibitors has been demonstrated in COPD (Compton et al 1999; Soto and Hanania 2005), although these compounds are dose limited by emetic and cardiac effects (Sturton and Fitzgerald 2002). This is perhaps due to inhibition of a wrong isoform of PDE4 isoenzyme (PDE4D), instead of PDE4B (antiinflammatory). Currently the PDE4 inhibitor daxos and roflumilast (Altana) is in phase III trials and may represent the most likely new mechanism to enter the market for the treatment of COPD in the short term.
A number of transcription factors involved in the regulation of a variety of inflammatory genes, such as NF-κ B and AP-1, are activated by oxidative stress (Rahman 2002). NF-κ B exists as a heterodimeric complex usually of p50 and p65/RelA subunits. Di Stefano and colleagues (2002) demonstrated increased expression of the p65 protein of NF-κ B in bronchial epithelium of smokers and patients with COPD. The increased expression of p65 in epithelial cells was correlated with the degree of airflow limitation in patients with COPD. Similarly, Caramori and co-workers (2003) have shown that the p65 subunit of NF-κ B was increased in sputum macrophages but not in sputum neutrophils during exacerbations of COPD, suggesting cell-specific activation of this factor. The activation of NF-κ B in monocytes/macrophages can then trigger the release of proinflammatory mediators in lung epithelial fluid, which would then amplify the inflammatory cascade by activation of epithelial cells as well as recruitment of neutrophils to the airways. Activation of NF-κ B by oxidative stress is inhibited by co-incubation with NAC in vitro, providing evidence for activation of this transcription factor in these patients being due to oxidative stress (Schreck et al 1992). Small molecule inhibition of this pathway is currently of great interest as a potential means to down-regulate the inflammation characteristic of COPD. I-κ B kinase-2 (IKK)-mediated phosphorylation of I-κ B is required for its subsequent ubiquitination and degradation; therefore small molecule inhibitors of this enzyme would be expected to block the nuclear translocation of NF-κ B. A variety of compounds are in preclinical development for this target from GlaxoSmithKline, AstraZeneca, Altana, and Tularik, but as yet no compound suitable for clinical studies has been reported in the literature. Alternative means to inhibit NF-κ B activation, such as inhibitors of ubiquitin ligase (Wertz et al 2004), peptide inhibitors of NEMO (a protein that forms a complex with IKK 2) (Choi et al 2003), PPARα agonists, and direct inhibition of NF-κ B transport through nuclear pores, are being investigated in preclinical studies.
A recent study reported on the potential therapeutic effect of the small molecule antagonist siRNA against NF-κ B subunit p65 in airway epithelial cell lines (McIntyre et al 2003). In this in vitro study, cells treated with TNFα showed reduced NF-κ B p65 expression and concomitant IL-6 and CXCL8 expression. An antisense antagonist for NF-κ B p65 may be beneficial in inhibiting the NF-κ B-mediated inflammatory genes in patients with COPD.
NF-κ B-targeted therapies, inhibitors of IKK, may prove to be useful in antiinflammatory therapies (Table 3). The potential disadvantage of using inhibitors of cell signaling molecules is that mitogen-activating protein kinase (MAPK), NF-κ B, and IKK are general signal transduction proteins involved in multiple processes and therefore inhibitors may have unacceptable side effects. In addition, inhibition of these molecules may also impair defense mechanisms against infections.
It has been suggested that oxidative stress may have a role in the poor efficacy of corticosteroids in COPD. Ito and coworkers (2001) showed a role for histone acetylation and deacetylation in IL-1β-induced TNFα release in alveolar macrophages derived from cigarette smokers. They also suggested that oxidants may play an important role in the modulation of histone deacetylase (HDAC) and inflammatory cytokine gene transcription. Furthermore, we have shown that both cigarette smoke/H2O2 and TNFα caused an increase in histone acetylation (HAT activity) leading to IL-8 expression in monocytes and alveolar epithelial cells both in vitro and in vivo in rat lungs (Rahman, Gilmour, et al 2002; Marwick et al 2004; Moodie et al 2004).
Glucocorticoid suppression of inflammatory genes requires recruitment of HDAC2 to the transcription activation complex by the glucocorticoid receptor (Ito et al 2001; Rahman et al 2004). This results in deacetylation of histones and a decrease in inflammatory gene transcription. A reduced level of HDAC2 was associated with increased proinflammatory response and reduced responsiveness to glucocorticoids in alveolar macrophages obtained from smokers (Ito et al 2001; Rahman, Gilmour, et al 2002; Marwick et al 2004; Moodie et al 2004; Rahman et al 2004). Culpitt and co-workers have shown that cigarette smoke solution stimulated release of IL-8 and granulocyte-macrophage colony-stimulating factor, which was not inhibited by dexamethasone, in alveolar macrophages obtained from patients with COPD compared with those of smokers (Culpitt, Rogers, Shah, et al 2003). They suggested that the lack of efficacy of corticosteroids in COPD might be due to steroid insensitivity of macrophages in the respiratory tract. Thus, the cigarette smoke/oxidant-mediated reduction in HDAC2 levels in alveolar epithelial cells and macrophages will not only increase inflammatory gene expression but also cause a decrease in glucocorticoid function in patients with COPD (Figure 2). HDAC activity has also been measured in bronchial biopsies and alveolar macrophages from COPD patients and smoking controls, demonstrating a significant decrease in HDAC activity, the magnitude of which increased with severity of disease (Ito et al 2005). Moreover, protein expression of HDAC2 was decreased in a similar manner in COPD patients.
Consequently, a potential means by which to treat COPD would be to increase HDAC2 expression and activity such that steroids regain their antiinflammatory activity. We have shown that co-incubation of cells with NAC and H2O2 protects HDAC2 from down-regulation and reduction of specific activity (Moodie et al 2004). In addition, it has been reported that theophylline has a similar effect in lung macrophage cells, increasing HDAC2 expression and re-sensitizing the cells to steroids (Borja et al 2004). Alternative means of up-regulating HDAC2 activity would be of great interest for potential combination therapies of the future.
Dietary polyphenols have antioxidant and antiinflammatory properties that may explain their beneficial effects (Arts and Hollman 2005). Curcumin is an active principle of the perennial herb Curcuma longa (commonly known as turmeric). Turmeric has a long traditional use in the Orient for many ailments, particularly as an antiinflammatory agent. Recent studies have reported that curcumin inhibits NF-κ B expression/activation, IL-8 release, cyclo-oxygenase (COX)-2, heme oxygenase-1, cytokines, and neutrophil recruitment in the lungs (Shishodia et al 2003; Biswas et al 2005). Curcumin has multiple properties to protect against cigarette smoke-mediated oxidative stress (Shishodia et al 2003). It acts as oxygen radical and hydroxyl radical scavenger, increases antioxidant glutathione levels by induction of GCL, and acts as an antiinflammatory agent through inhibition of NF-κ B and IL-8 release in lung cells. Resveratrol, a flavonoid found in red wine, is an effective inhibitor of inflammatory cytokine release from macrophages in COPD patients (Culpitt, Rogers, Fenwick, et al 2003). This antiinflammatory property of resveratrol may be due to its ability to induce sirtuins and HDAC activity (Howitz et al 2003). A recent in vivo study has shown that resveratrol inhibits inflammatory cytokine expression in response to lipopolysaccharide in rat lungs (Birrell et al 2005). The molecular mechanisms of antiinflammatory properties of dietary polyphenols against cigarette smoke/ oxidative stress have not yet been studied. This compound may induce phase II detoxifying genes by Nrf-2-dependent mechanisms.
Recent studies from our laboratory show that these dietary polyphenols restore glucocorticoid functions in response to oxidative stress imposed by cigarette smoke by up-regulation of HDAC activity in the monocyte/ macrophage (U937) and MonoMac6 cell lines (Rahman et al 2005). This was associated with restoration of HDAC1, HDAC2, and HDAC3 levels, suggesting that dietary polyphenol-mediated inhibition of proinflammatory cytokines increases formation of HDAC-p65 complex with glucocorticoid receptor, hence rendering NF-κ B ineffective. The other possible mechanism of polyphenol-mediated inhibition of inflammatory response is by quenching oxidants and aldehydes and inhibiting histone deacetyl-transferase activity. Catechins present in green tea (epigal-locatechin-3-gallate) in addition to theophylline may be effective in cigarette smoke-mediated oxidative stress and inflammatory response (Schwartz et al 2005). However, this compound has never been tested in in vitro or in vivo smoking models. Overall, these dietary polyphenols and flavonols may not only act as antioxidant/antiinflammatory agents, but also possibly increase the efficacy of glucocorticoids in COPD.
Bioflavonoids possess both antioxidant and antiinflammatory properties and hence may influence chronic inflammatory diseases such as COPD. Tabak and colleagues (2001) studied the intake of catechins, flavonols, and flavones in relation to pulmonary function and COPD symptoms in 13 651 adults from three Dutch cities. Dietary intake of catechin (eg, green tea polyphenols, epigallocatechin gallate), flavonol (eg, quercetin and kaempferol), and flavone (eg, apigenin and luteolin) was positively associated with FEV1 and inversely associated with chronic cough and breathlessness, but not chronic phlegm. More importantly, single-component (such as catechin) intake was independently associated with FEV1 and all three COPD symptoms, whereas flavonol and flavone intake was independently associated with chronic cough only. The importance of this study was further substantiated by a study by Walda and colleagues (2002), who showed the beneficial protective effect of fruit containing polyphenols and vitamin E against COPD symptoms in 20-year COPD mortality from three European countries, in Finnish, Italian, and Dutch cohorts. These important studies certainly encourage further multinational studies to demonstrate the beneficial effects of a high intake of nutraceuticals (polyphenols/bioflavonoids) against COPD symptoms.
There is now considerable evidence for the increased generation of ROS in COPD, which may be important in the pathogenesis of this condition. There are several small molecule compounds in clinical trials that target oxidant signaling or quench oxidants derived from cigarette smoke. Antioxidant and/or antiinflammatory agents such as thiol molecules, spin traps, dietary polyphenols, antioxidant mimetics, and inhibitors of oxidative stress-induced signaling pathways present potential means by which to treat this element of COPD. Antioxidant compounds may also enhance the efficacy of glucocorticoids by quenching oxidants and aldehydes, increasing histone deacetylase activity in COPD patients. Dietary polyphenols, such as resveratrol and curcumin, inhibit cigarette smoke/oxidant-induced NF-κ B activation, histone acetylation, and proinflammatory cytokine release and restore glucocorticoid functions via a mechanism involving up-regulation of HDAC activity. Thus, dietary polyphenols regulate inflammatory response at the molecular level, and possibly this is a way forward to restore glucocorticoid efficacy in the treatment of smoking-induced chronic inflammatory diseases. An effective wide-spectrum antioxidant therapy that has good bioavailability and potency is urgently needed to control the localized oxidative and inflammatory processes that occur in the pathogenesis of COPD. Although thiol antioxidant treatments have shown promising effects in targeting ROS and oxidant-mediated cellular alterations, in vivo cigarette smoke studies and human clinical trials of other small molecule antioxidants with dual activities (antioxidant and antiinflammatory) are urgently needed to validate these compounds as clinical therapies.
This study was supported by the Environmental Health Sciences Center (EHSC) Support ES01247 and an EHSC pilot project grant.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
Our Leaders Now event series, run in partnership with The House of St Barnabas, brings together inspirational leaders from the social sector and beyond to encourage debate and new thinking.
Open to everyone in the sector, the free breakfast events provide an opportunity to network and meet and exchange ideas with other leaders.
Upcoming Leaders Now events:
Previous guest speakers have included Julia Unwin, previously CEO of Joseph Rowntree Foundation, Geoff Mulgan, CEO of Nesta, and Baroness Maeve Sherlock, Labour life peer.
Here is Channel 4 journalist and television presenter Jon Snow sharing his thoughts about leadership which he says requires 'consultation, decisiveness, charm and humour'.
Sign up to our Leaders Now newsletter for updates about these events, and keep checking our website for announcements.
Contact us ►
0207 812 3770
5th Floor, Kings Place, 90 York WayLondon, N19AG
Registered Charity Number 1136727
Company limited by guarantee in England & WalesRegistered Number 7222275
Cookie Policy
Our website uses cookies, small data files, on your computer or handheld device. For
more information about cookies, including how to disable them, see
Full Cookie Policy


text:
Geography Teacher - East London
Required: September 2017
Contract: Temporary ongoing contract
Pay Scale: £140 - 220 per day depending on experience and pay scale
One of our mixed, 11 to 18 community secondary schools in East London are currently seeking an enthusiastic Geography Teacher to fill a position they've had come available for September 2017. The role will involve teaching KS3+4 Geography, and would be a great role for an experienced teacher. The school is based in the borough of Hackney and has great transport connections, as well as excellent CPD opportunities. This is a great opportunity for a strong teacher to join a passionate Humanities department who aim to provide a positive learning experience for their students, as well as a positive working experience for their teachers. The schools have excellent facilities and teaching spaces in a beautiful Grade II listed building. They are welcoming applications from all experienced Geography teachers with great behaviour management and the ability to inspire students, to join them in September 2017.
The successful candidate will:
- Be a qualified Geography teacher (ideally with PGCE, GTP, B'ed, Cert Ed, BA with QTS).
- Demonstrate two years' recent experience as a Geography teacher.
- Be proven to raise and maintain attainment levels, keeping standards high.
- Be an enthusiastic, highly motivated individual who leads by example.
- Demonstrate good communication and interpersonal skills with excellent behaviour management strategies.
GSL Education is an ethical, independent recruitment agency serving Teachers across Greater London. Our advertised teaching roles relate to real vacancies that exist at our client Schools. We welcome applications from all teachers who feel that they can add value to this school and whom can prosper in a highly effective, fast-paced environment.
Candidates wishing to apply are requested to forward a copy of their CV to our Education Consultant, Brittany Allan, as soon as possible.
GSL Education15. Cottons Gardens, ShoreditchLondon E2 8DNUnited KingdomTel: +44 (0) 20 7739 2211Email: firstname.lastname@example.com
Copyright © 2017, GSL Education. All rights reserved Privacy Policy | Sitemap | Contact Us


text:
Kirklees Stadium Development Ltd is looking to recruit the following matchday staff to work at The John Smith's Stadium from July/August 2017 onwards: Safety Stewards, Car Park Stewards and Courtesy Stewards.
Matchday staff are expected to work a minimum of 75% of all Huddersfield Town and Huddersfield Giants games, along with any other events or matches held at the Stadium. 'Matchdays' can be any evening during the week or weekends throughout the year.
The primary role of a Steward is to ensure the safety of the general public at all times during an event taking place at the Stadium. Ideal candidates will be those who enjoy interacting with people, have good communication skills and are willing to attend training to achieve an NVQ Level 2 (or equivalent) in Spectator Safety. Applicants must be aged 18 or over.
Job descriptions and an application form are available to download on The John Smith's Stadium website www.johnsmithsstadium.com. Completed application forms should be sent to the HR Manager, KSDL, The John Smith's Stadium, Stadium Way, Huddersfield, HD1 6PG to be received no later than Friday 23 June 2017 All applications will be scored on their content and those achieving the required level will be invited to an Assessment Centre where they will be further assessed for their suitability for the role for which they have applied.
Copyright Huddersfield Giants. All Rights reserved. Registered Office: The John Smith's Stadium, Stadium Way, HUDDERSFIELD, HD1 6PG.
Reg No: 1810029 Registered in England. Site managed by www.fluidcm.co.uk


text:
Εξερευνήστε σχετικά θέματα
No Bake Pumpkin Cheesecake -Super easy fall and Holiday dessert. Pumpkin dessert that looks and tastes like a million bucks.
Pepperidge Farm Puff Pastry Holiday Dessert Recipe Collection. Spread season's greetings and holiday cheer with these delectable dessert recipes. From the super simple (like easy layers of Puff Pastry topped with chocolate cream and raspberry jam in the Chocolate-Raspberry Mini Napoleons recipe) to the seriously sophisticated (like Apple Cranberry Tarte Tatin) this collection has all your holiday dessert needs covered.
Save these Holiday trifle recipes for later! Don't forget to follow Woman's Day on Pinterest for more great recipes.
This Chocolate Crinkle Cookies recipe is a classic for a reason! They're easy to make, wonderfully sweet and chocolatey, and perfect for the holidays!
The BEST Cinnamon-Sugar Cake Recipe Thanksgiving Desserts, Christmas Desserts, Cake Recipes, Holiday Desserts, Easy Dessert Recipes, Cinnamon, Buttercream Frosting Recipes
Cranberry Christmas Cake is the ULTIMATE holiday dessert! Get the recipe at barefeetinthekitc...
Sparkling Cranberry White Chocolate Cupcakes - a hidden creamy center & fresh berry frosting makes these cupcakes a fun recipe to make for your holiday dessert tables.
Peppermint Bark Dip Recipe - Peppermint Bark Dip is a quick and easy holiday dessert dip
This recipe for three-ingredient S'mores Cups are an easy chocolate candy just perfect for holiday dessert trays or gift giving!


text:
Inflamax Research are a full-service Clinical Research Organization (CRO) with a strong and highly experienced scientific team that is eager to partner with industry. Inflamax Research provides a broad range of services in all areas of clinical trial research to assure the successful completion of both R&D and marketing studies. Inflamax Research collaborate with academia and the scientific community to continuously develop, improve and publish innovative methods, models and standards.
Inflamax Research
Contact: firstname.lastname@example.com
Website: http://www.inflamaxresearch.com


text:
2015 Toyota Tacoma
Truck 4x4
2015 Toyota Tacoma
Truck 4x4
|Used Clear Title
|4.0L V6 Cylinder
|5 Spd Automatic
|Four Wheel Drive
|Exterior Color
|Super White
|Graphite Fabric
|Stock #
|Warranty Available
Vehicle Overview4WD. Crew Cab! Gasoline!
This stunning 2015 Toyota Tacoma is the rare family vehicle you have been searching for. It is nicely equipped with features such as 4WD. This truck hits the mark in impressive performance and pleases the eye with its flawlessly sculpted design.
At Richfield Bloomington Honda we believe in ''MARKET VALUE PRICING'' all vehicles in our inventory. We use real-time Internet price comparisons to constantly adjust prices to provide ALL BUYERS The BEST PRICE possible. We do not mark them up, to mark them down! Our entire team is committed to helping you buy a car the way we would want to buy a car! We utilize state-of-the-art technology to constantly monitor pricing trends in order to offer our shoppers the best competitive pricing and value.
We sell and service all makes and models of Pre-owned / Used Vehicles Used Cars, Used Trucks, Used Sport Utility, 10K under used cars, Ford, Chevrolet/Chevy, Honda, Toyota, Porsche, Land Rover, Jaguar, INFINITI, Audi, Nissan, Mazda, Hyundai, Chrysler, Jeep, Dodge, Ram, SRT, Mitsubishi, Lexus, Kia, Volkswagen, Mini, BMW, Mercedes, Fiat, Volvo, GMC, Cadillac, Lincoln as well as other brands.
Financing Information
Contact us today at 612-866-8832 for more information, or fill out our Online Credit Application to begin the pre-approval process today.
Warranty InformationThis Vehicle is Being Sold "As-Is." Extended Warranty Available. Contact seller for details.
Contact Us at 612-866-8832
Richfield Bloomington Honda501 West 77th Street, Richfield, Minnesota 55423
Call Us About This Vehicle: 612-866-8832
- Super White with Graphite Fabric Interior
- Air Conditioning
- Telescoping Steering Wheel
- Tilt Steering Wheel
- Tire Pressure Monitor
- Power Mirrors
- Power Steering
- Power Windows
- Anti-Lock Brakes
- Child Proof Door Locks
- Daytime Running Lights
- Driver's Air Bag
- Dynamic Stability Control
- Four Wheel Drive
- Intermittent Wipers
- Passenger Air Bag
- Roll Stability Control
- Side Air Bags
- Side Curtain Airbags
- Traction Control System
- Center Console
- Clock
- Overhead Console
- Tachometer
- Vanity Mirrors
- Bedliner
- Tow Hooks
- Aux. Audio Input
- Bluetooth
- CD Player
- Factory System
- Touch Screen
- Voice Control
- 6 Speakers, MP3 decoder, Anti-whiplash front head restraints, Dual front impact airbags, Dual front side impact airbags, Front anti-roll bar, Front wheel independent suspension, Low tire pressure warning, Occupant sensing airbag, Overhead airbag, Brake assist, Power door mirrors, Rear step bumper, Driver door bin, Front reading lights, Illuminated entry, Overhead console, Passenger vanity mirror, Telescoping steering wheel, Front Bucket Seats, Front Center Armrest, Split folding rear seat, Passenger door bin, 3.727 Axle Ratio
- 22,615 Miles
- No Known Mechanical Problems
- Excellent Interior
- Excellent Carpets
- Excellent Seats
- Excellent Dashboard
- Excellent Panels / Headliner
- Excellent Exterior
- Excellent Original Paint
- Excellent Trim Condition
- Excellent Glass Condition
- No Visible Rust
- No Known Accidents
- No Known Bodywork
- Fully Detailed
- Spare: Good Condition


text:
MICHELIN Guide
A chic and sleek crowd of Mission foodies gathers at this trendy restaurant, nestled in a complex beside sister shop/deli Salumeria, cocktail bar Trick Dog, and coffee shop Sightglass. Wend your way to the central courtyard, with a trickling fountain and large glass doors leading into the main space, where a large open kitchen faces the simple wood tables. Recent kitchen renovations resulted in a wood-burning hearth and expanded pasta program. Along the way, you might taste a mound of burrata surrounded by melon cubes, cucumber slices, and purslane tossed in a chili-herb vinaigrette. Gamey pork trotter agnolotti is balanced by lemon verbena; while hearth-roasted hen served in a black chili sauce and paired with chicken cracklings is nothing less than compelling.
MICHELIN guide inspectors
Additional information
Useful information
Nearby restaurants
More restaurants in San Francisco
Nearby hotels
More hotels in San Francisco
Nearby tourist attractions
More tourist attractions in San Francisco


text:
Sooo unfit!
I started the 025k this morning with my 12yr old daughter and I was horrified as to how unfit I really am! I am 50, about 3 stone overweight and gave up smoking 5 months ago. My daughter really wants to support me and do the course as well as she wants to be better at running (she is tall and slim but could do with being a bit stronger) The problem could be us both finding time to do it together what with her school, my job and an eight year old who will need minding. Hubby leaves for work at 6.15 and back about 7.30pm. Anyone found ways around this and have some tips on fitting in the 3 runs?
Featured Content
Join the NHS Couch to 5K community
Couch to 5K has been designed to get you off the couch and running 5km in just 9 weeksStart today!
Featured by HealthUnlocked


text:
In the last 90 days, 15 listings have been listed, which means new listings are probably going fast. You'll want to be prepared to make an offer immediately. About 7% of the available leases in the Peekskill are subleases, so you will probably need to sign a longer term lease with the landlord directly. There aren't many listings below 2,000 square feet posted, so finding a space for a small business might be tough.
The standard measurement for office space in this area is around sqft. Most buildings in this area are around 3 floors. Most buildings in this market were built in 1980 and are Class B.
Real time and historical data on commercial real estate listings in Peekskill.
Get email notifications when new listings are posted that match your requirements.


text:
Condition: Standard
All Product Details
Log on and listen. Created with Naxos, the world's largest classical music label, the book includes a unique Web site featuring more than 500 examples cited in the text. Look up barcarolle. First read about its swaying 6/8 meter and Venetian origins; then log on to the music Web site and hear it performed in Act IV of Offenbach's Les contes d'Hoffmann. If that whets your curiosity about Offenbach, click to hear the cancan in his La vie parisienne. All online samples are marked by an icon in the text.
A treasure trove of over 500 music examples will be available on the web from Naxos via a login that allows for multiple accounts. Unlike Julius H. Jacobson's The Classical Music Experience (SourceBooks MediaFusion, 2003), which was published with two CDs containing about 120 usually abbreviated tracks, purchase of Libbey's book allows the listener many hours of very full samples, e.g., the complete Beethoven Waldstein Sonata, Vaughn Williams's complete The Lark Ascending, and the full 20 minutes of Bruckner's opening movement of the Seventh Symphony—a perfect way to sample great music. Bottom line, this is an excellent source for the biography, lore, and terminology of classical music, nicely enhanced by the many photographs and illustrations. As a general introduction to classical music (and especially as an encyclopedia for listeners), this book is superior to recent ventures, such as Jacobson's work or Fred Plotkin's Classical Music 101 (Hyperion, 2002). Those interested purely in recordings will also want one of the general review compendiums of classical recorded music, e.g., The Penguin Guide to Compact Discs & DVDs, Backbeat's Classical Music: The Listener's Companion, or The Rough Guide to Classical Music. Libbey's book is both a listener's encyclopedia and a guide to recordings, but it does not replace such standards as Oxford's Grove Music Online or Gale/Schirmer's Baker's Biographical Dictionary of Musicians. Recommended for all libraries.—Library Journal, Bruce R. Schueneman, Texas A&M Univ. Lib., Kingsville
Libbey, a spirited, selective guide, writes "lyrically and lucidly about music and music makers" (Chicago Tribune) and knows how to ground abstract ideas in the real. How does it work? Look up barcarolle, and he not only defines the term vividly ("the melody is a gentle, rocking rhythm suggestive of the swaying of a boat") but suggests three exemplary pieces of music to listen to—Offenbach's Tales of Hoffman, Mendelssohn's Songs Without Words, and Chopin's Barcarolle. Then go to the Web site and hear what he's writing about.
What is the tonic? Why is there such a satisfying psychological impact at the end of a sonata? Who is Thomas Tallis? What is the idea behind Bach's Well-Tempered Clavier, and was there ever an ill-tempered clavier? For the music lover, impossible to put down.


text:
A few seconds only noise was the screen. "Pirate copy, everything is fine" –
Marina caught a thought, but then, finally, there was the image. It was quite unexpected.
Instead of the film on the screen saver has been the usual hallway apartment, the door which shut medium height, slender pretty woman of about thirty or thirty-five, dressed in bright summer dress on a palm above the knee. Chat with horny_dasha in a live adult video chat room.


text:
Above is iFolloSports.com original video of Oklahoma Sooners men's basketball coach Lon Kruger exiting the Wyndham Anaheim Garden Grove hotel, prior to OU's 80-68 victory over Oregon, in Saturday's West Region Final. Like Buddy Hield and the other departing Sooner players, Kruger was serenaded by... Read More
Below is iFolloSports.com original video of country music superstar Toby Keith exiting the front door of the Wyndham Anaheim Garden Grove hotel, in Anaheim, California on Saturday. The 54-year-old Oklahoma native and resident was at the Oklahoma Sooners hotel, in conjunction with the school's... Read More
Thursday and Saturday, the South Regional of the 2016 Men's NCAA Tournament is taking place at the KFC Yum! Center in downtown Louisville. This six-year-old venue represents one of the most interesting concepts in all of college basketball.Since 2010, the Louisville Cardinals' men's and women's... Read More
Here are photos of the Duke Blue Devils practicing on the floor of Anaheim's Honda Center, Wednesday, one day prior to the program's Sweet 16 matchup with the Oregon Ducks. The shot is provided by Deluxe Signature Collection.Tuesday, Mike Krzyzewski ran his team through a practice at Chapman... Read More
Monday night, Alabama head football coach Nick Saban won his fifth national title, when the Crimson Tide defeated Clemson 45-40, in the College Football National Championship Game. Saban's 5 titles (4 at Alabama & 1 at LSU) places him 1 behind iconic Alabama coach Bear Bryant for most all-time... Read More


text:
Discussion in 'Streetwear and Denim' started by KingJulien, Oct 29, 2012.
yet another reason to kick it with tween
I'm so excited for Doris to come out
New JT is streaming on iTunes and it sounds fucking gorgeous.
JT = sounding good
on a totally different note, I was listening to minimal-garage-psyche all day. This reminded me of something from the concptul4st.
Going through my cd collection while cleaning out the basement the other day. Found a couple of real gems I hadn't heard in a loooooooooooooooong time.
-Underworld - Dubnobasswithmyheadman
-Autechre - LP5
-Air 10000 htz / moon safari double disc
-Island - Return to the Sea
All in all, good score, ripped to flac and re-stored.
Earl is a god.
Ran through that new Justin Timberlake. Liked 8 outta 10 songs. Gonna listen again tomorrow.
hook on that earl track is beyond terrible.
Yeah... no
This is one that's overlooked a lot I think, but it's a good one. Particularly for the opening track Acroyear2 and Fold4,Wrap5
Send me minimal-garage-psyche! The 4est needs more
love me some autechre. d/led their new album but haven't taken the dive through more than like three tracks. it's a sprawling listen.
Honestly, though, I've been getting my autechre fix lately from listening to Atoms for Peace. thom has been edging closer and closer to making an autechre album since the beginning of the aughts and this is the closest he's come.
You're nuts, it's pretty fantastic.
Starkey puts on a really killer show if you ever get a chance to see him.
Separate names with a comma.


text:
Mother Nature Solar
Mother Nature Solar
Our solar company sells and installs solar electric anywhere in Calfornia. Licensed (B548164), bonded and insured.
What size system do you need?
Divide the yearly amount of kwhs (kilowatt hours) that you need replaced by 1.65, and that will get you the system size for a south-facing roof.
Example- If your roof faces due south, and you would like to produce 7,000 kwhs per year: 7,000/1.65= 4,242 which means a 4.24 kw system. If your house faces due west, then multiply the total by 1.055 (4,242 x 1.055= 4,475 = 4.47kw), and if due east multiply by 1.15.
Do you have a Leaf, Volt or Tesla? All you need is 5- 280 watt panels to get over 8,000 free miles per year.
1,400 watt solar system (1.4kw)
x 1.65
2,310 kwh's produced per year
x 3.75 miles per kwh driven
8,662 miles driven - powered by solar
$1,038.00 saved in gas costs per year. (8,662mi/25 mpg=346 gallons x $3.00 per gal=$1,038.00)
Mother Nature Solar electric systems - sales and installation
Main components-
Canadian Solar 285 mono black panels- 25 year guarantee (and 25 year free labor for replacement by Mother Nature Solar)
Enphase IQ6+ inverters- 25 year guarantee (and 25 year free labor for replacement by Mother Nature Solar)
Snapnrack racking
Enphase IQ Combiner box
Enphase S metered Envoy computer- 5 year guarantee
Balance of system- 10 year guarantee by Mother Nature Solar
The S metered Envoy is Enphase's latest, just out the first week of January, 2016. It will allow you to monitor both your electric consumption and solar production. It is also "battery ready", so that you could add a battery system at a later date. Enphase has battery systems available, as does Tesla.
Don't get overcharged by bay area solar companies. Mother Nature Solar installs complete solar systems for as low as $2.59 per watt! That makes us the absolutely cheapest solar energy installation company in the Bay Area, Los Angeles, and San Diego, as well as the entire state of California! The average installed price in 2016, charged by bay area solar companies, is an outrageous $4.15 per watt. We also use the best solar panels and the best inverters with the longest warranties. Our prices are so low that on average a system will normally pay itself off in less than 60 months!
We sell and install solar PV systems anywhere in California!
The $3.00 per watt price barrier has been smashed!
Our current prices for composition shingle roofs-
Canadian Solar or SolarWorld panels or LG panels
5.0+kw $2.59 per watt installed $2.79 per watt installed
4.00kw $2.69 per watt installed $2.89 per watt installed
3.00kw $2.79 per watt installed $2.99 per watt installed
2.50kw $3.09 per watt installed $3.29 per watt installed
Add 5 cents per watt for Concrete tile roofs and 10 cents per watt for Spanish tile roofs


text:
Hi, it's me, Yolanda, here to give you an update as our communications officer has been deployed for a very important mission to check out some of the 09E project sites.
It was not all work for the venturers at the 4-day induction; there were also some fun and games for everyone to join in! Besides the name games and energisers, the venturers were in for a little friendly competition in the Raleighlympics!
The Raleighlympics is a teambuilding medley of games that tests the strength and teamworking abilities of the group but most importantly, above all other importance, it's FUN! Teams competed in games such as crab football, tug-of-war and a special race that is Mac's Special (as it was designed by Mac, our Country Programme Manager.)
And after just four days of training, playing and acclimatising to the weather and culture of Borneo, the Sabah Ministry of Youth and Sport gave a spectacular send-off to the team with an official opening ceremony for Borneo 09E, which was attended by the Assitant Minister of Youth and Sport Datuk Jahid Jahim, the deputy permanent secretary of Youth and Sport, Tuan Haji Awang Damit Awang Anak, Raleigh Borneo project partners Leap and Asian Forestry, as well as Borneo Divers, the Sabah Support Group and a few ex-Raleigh Borneo venturers.
AJ meets the assistant minister of youth and spots, Jahid Jahim. Looking on is Jim Clements, Country Director of Raleigh Borneo
The event was a happy and successful one and it was clear that the venturers and PMs alike were raring to get out there. After some speeches, song and dance, the day of deployment was upon 09E! But not before the venturers got allocated to their Phase 1 projects:
Off to start the construction of the Mapan-Mapan kindergarten with project managers Colin Burman and Sandra Pitropia in Alpha 1 are:
- Geralvonno Williams
- Will McNess
- Christian B Cassem
- Duanette R Symonds
- Madeleine Colmar
- Joseph d'Ursel
- Alneisha J Outerbridge
- Maurice A Pomeroy
- Michael G Petrie
- Razis Bin Nasri
- Jessica V Richards
It's Kampung Pinapak for Alpha 2, together with the lovely Bobby Rebeiro and Tony Adamson, with a gravity water feed project to begin building. And the winners are:
- Catarina D Correia
- Henry J Routh
- Darreana M Burchall
- David Miller
- Koong Hui Yein
- Charlie R Green
- Tom J Beirne
- Trusha Kothari
- Seleta Q Williams
- Jack L Deith
Off to the virgin jungles of Borneo in the Imbak Canyon of Alpha 3 with PMs Miles Bullock , Pip Edwards and Sarah Young are:
- Bryony Tedder
- Edward C Ottley
- Amy Harcus
- Julian Akole
- Emily Nash
- Callum Adams-Carr
- Gere' A Scraders
- Richard Taylor
- Alex J Barrow
- Zuraimi b. Rahman
Alpha 4, who have the privilege of being the pioneers of the sunbear conservation centre project together with PMs Ruthie Taylor, Tom Godfrey and Pete Broomhead are:
- Saskia R Bartlett
- Stephen Pendrigh
- Shavaughn S Dill
- Mandy L Scott
- Gareth Mountain
- Philip E Holmes
- Gwen Reid
- Katherine Taylor
- Sophie M Farrelly
- Thomas McGowan
- Yang Su Lan
Last but not least, Alpha 6 is off to an amazing adventure in the jungles of Long Pasia with PMs Toria Reid (medic), Leon Warner and Chris Ashford
- Alisha R Chapman
- James P Croke
- Anna J Harte
- Christian E Faulkner
- Gregory J Cowan
- Tessa L Wharton
- Robert Lamont
- Sean Rice
- Tasha A Gomes
- Yap Shon Lee
Also deployed are our Photographer Dom Edwards, who has been sent out to Alpha 4 and Ed Ptilidi, our communications officer who is out to get the scoop on Alpha 1.
We wish all the venturers and project managers a blast, and we'll be keeping you updated with the happenings of the teams, so watch this space!


text:
Integrated tools, charts and graphs transform complex financial concepts into easy to understand visuals, giving clients a "big picture" view of their retirement plan. Immediately engage clients, who become eager and active participants in the planning process.
Quickly assess a client's most critical income risks using powerful real-time tools and "what if" scenarios. Explore solutions by test driving pre-modeled products inside the client's portfolio. Together, you arrive at decisions in just minutes.
Expedite the business submission process with powerful data integration and a fully automated application system. Built-in smart logic reduces application errors, speeds compliance review and eliminates frustrating paperwork reroutes. Say goodbye to NIGOs.
I want to know more. Contact me about test driving RetireUpPro.


text:
Application to Principal for Permission Visit to Pakistan Steel Mills 10 Class
Application to Principal for Permission Visit to Pakistan Steel Mills. This application is asked many times in 10 Class exams. We will be sharing further X Class applications for the benefit of student who can gain best marks. These applications are unique and can make your exam solution different from others. So, feel free to use this application.
The Principal,
X-Y-Z School, Karachi
Dear Sir/Madam
I am taking this opportunity to introduce myself as the student of 9 Class monitor. I am writing on behalf of the whole class X. Due to the increased demand of economic strength in our country, we are eager to visit one of the Pakistan's big company Pakistan Steel Mills, Karachi. This trip could help us better understand the functioning of the mill and its benefit for the economic development of our country.
Not just that, we will be seeing heavy duty machines there and the way, employee of the mills manages its day to day operations. In order for your satisfaction, three top senior teachers from our school will be with us for our safety and look after. These teachers will also help us in getting valuable information which could be a vital difference for our school as well in the upcoming technical exhibition in Expo Center, Karachi at the end of this month.
In this regard, your kind permission and patronage is required for the school bus in order to travel to and from Steel Mill.
Thanking You,
Your's sincerely,
Monitor of Class IX
10 November 2016


text:
You can challenge your classmates to a bot vs bot match, and view the results of other's scrimmage matches.
Please be courteous near deadlines: don't run a large number of games under "Long" time control. Your bots will be most heavily tested on time controls similar to Blitz and Regular.
Exhibition scrimmage matches between teams are now running on 8-core instances. Use all 8 cores to maximize your chances of snatching Elo.
Currently running 0 game(s), and 0 game(s) are queued.
Running 0 serial game(s), and 0 serial game(s) are queued.
Running 0 parallel game(s), and 0 parallel game(s) are queued.
Number of enqueued autotest games: 0


text:
Discussion in 'Transformers Toy Discussion' started by Boardwise, Feb 23, 2011.
Me ? I'm fine.
Spaceballs reference FTW!
Nice Cougarman, nice..
Nice! (a severe case of no Saturn going on here but nice nonetheless!)
Can't take pics of a consoles meeting right now but -appart from my arcade machine- my favorite catch is probably my Game Boy Light Tezuka.
Bah, heading to Asda tomorrow and I know that I'm gonna see cheap TLK toys because I only have money for petrol and food until payday...first world problems
Thank you! I would love to do that. Just don't know where I would go for it.
Yep, went five hours to a dune park on the coast to do that.
My favorite MP Autobot:
Having @Jetbolt in here is like having the really cool guest presenter on Catfish or something.
Those are some awesome WJ pics!
And Ript apparel are killing it again :
I took the test and got Chromedome.
The only things I disagree on is desperate (I'm not), and even though I am blunt (my boss at work told me so in a performance meeting once) and teasing (just ask my wife, kids, dog, co workers, etc...), I don't think they are negative traits.
Oh man, I'd forgotten about the Springsteen issue! So good.
Sun came out a moment ago, so...
I know in England its getting near midnight, so I do hope most of you had a good Friday.
Not strictly Transformers but close enough.
Sir, I love you
So Roy Focker, plus M.F Jenius equals Mother Focker Genius!
All the best
A MISB M.A.S.K. can be very expensive nowadays.
It's alright mate. But let's just see how bluntly desperate you can be about convincing us that you're not.
Neat! I love you too.
I got Chromedome too!
From the positive side I agree with most of it, particularly where family and my animals are concerned and on the negative side it's hard for me to discount anything there, as with anyone else I'm shaped by personal events and there's no question that I'm cynical and I've always been blunt, often too much so for my own good and I'm certainly desperate to escape my present life situation as I've been trapped in a shitty position with no apparent way out for way too long.
These are SO, SO GOOD.
Ah, so much joy here. That MD/MCD combo is still the sexiest console ever made, I reckon. At the time it just looked SO futuristic, otherwordly even. Shame there were so few good games for it. Sold mine a while back but still miss it.
Excellent work my friend.
Now for something poor and ridiculous, was interesting to mess with so many settings.
All the best
Nice to see you experimenting. The M.A.S.K. pictures you have been posting have been magnificent. Thanks for sharing.
Separate names with a comma.