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New treatments for...
New treatments for atopic dermatitis
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7353.1533 (Published 29 June 2002) Cite this as: BMJ 2002;324:1533
Good news, but when and how to use tacrolimus and pimecrolimus is a muddle
Hywel Williams (hywel.williams{at}nottingham.ac.uk), professor of dermato-epidemiology
Centre of Evidence-Based Dermatology, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH
Atopic dermatitis now affects 15% to 20% of children in developed countries, and prevalence in cities in developing countries undergoing rapid demographic changes is quickly following suit.1 Most cases of atopic dermatitis in a given community are mild, but children with moderate to severe disease can have continuous itching and associated loss of sleep. The social stigma of a visible skin disease can also be soul destroying for both patient and family. A few studies have suggested that some degree of prevention of the disease is possible,2 although these measures have not been taken up widely. In the absence of any treatment that is known to alter the clinical course of the disease, most treatment is aimed at reducing symptoms and signs. After a relative lull of almost 40 years, new drugs—tacrolimus and pimecrolimus—have appeared that offer different approaches to managing this miserable disease. Do they work? Are they safe? And how do they compare with existing treatments?
A suitable place to start putting the 47 existing treatments into context is the NHS health technology assessment systematic review of randomised controlled trials for atopic dermatitis.3 This report concluded that the evidence base for the treatment of atopic dermatitis is characterised by poor standards of reporting of clinical trials and a lack of common outcome measures that are important to patients. The direction of trials over the past 40 years has been driven largely by the agenda of the pharmaceutical industry with a profusion of short term trials of "me too" products and a lack of comparative data that help clinicians answer the question "which is the best?" Good randomised controlled trials support some treatments, such as ultraviolet light, but provide no evidence for some commonly used rituals such as combinations of topical antibiotic and corticosteroid or antiseptic bath additives. Enough evidence to make clear recommendations on interventions like Chinese herbal treatment is lacking, and there is no evidence from randomised controlled trials on issues such as organisation of care or use of water softeners. So, do the new treatments help us to move forward?
Tacrolimus and pimecrolimus are two new topical preparations that have been or are in the process of being licensed throughout the world for use in atopic dermatitis. They are similar macrolactam molecules that probably work by suppressing T lymphocyte responses through inhibiting calcineurin.4 Unlike topical steroids, they do not cause skin thinning, which could be a major advantage for long term use.5
Do they work? In comparison with placebo, the answer is an unreserved yes. However, clinicians are often more interested in how new treatments compare with existing treatments such as topical corticosteroids, and this is where the evidence is unclear. Tacrolimus seems to be equivalent to potent topical steroids,6–8 and it is clearly superior to weak preparations such as 1% hydrocortisone.9 Pimecrolimus, on the other hand, has not been compared with 1% hydrocortisone, and when compared with betamethasone, a commonly used potent topical steroid, it seems to be nowhere near as effective.10 Interestingly, topical tacrolimus and pimecrolimus seem not to have been compared, but it takes little imagination to predict which would emerge as the most effective.
If topical tacrolimus is indeed equivalent to a potent topical steroid, how should it be used - as monotherapy, instead of topical steroids, or only when topical steroids fail? The current wording of product licences suggests that it should be used for people with moderate to severe disease "who have failed to respond adequately to conventional therapy"—that is, as a second line agent. None of the randomised controlled trials, however, have included such people. True tropical steroid failures—that is, those patients who "get stuck" needing continuous use or those who develop local side effects such as thinning of the skin—are rare nowadays. Nevertheless, it seems reasonable to use topical tacrolimus in such people, especially in more sensitive sites such as the face or eyelids where local side effects of topical steroids might be more of a problem.
The place of pimecrolimus is even more unclear, although given its probably lower potency, it is clearly positioning itself to take on the weaker topical steroids in people with mild to moderate atopic dermatitis. To secure such a market, a recent study (published in abstract form) found that early use of pimecrolimus prevented more flares—which then needed treatment with a potent topical steroid—when compared with the vehicle (10th congress of European Academy of Dermato-Venereology, Munich, 2001). This study documented a steroid sparing effect and examined long term control, which is appropriate in a chronic condition like atopic dermatitis. But it was a placebo controlled study, and early use of another active compound such as weak 1% hydrocortisone may have also prevented such flares.
Both products have not been tested against current optimal use of topical steroids in a pragmatic way—that is, short bursts of once daily products for flare ups of disease followed by periods of rest when only emollients were used. Data on cost effectiveness are also missing—an important consideration given that topical tacrolimus is at least 10 times as expensive as standard topical steroids.
Are these drugs safe? Studies done so far suggest that they are—at least in the short term. It is, however, worth remembering that these products are immunosuppressive drugs. Oral tacrolimus is one of the most powerful immunosuppressive drugs known—hence its use to prevent rejection of transplants.
Although systemic absorption seems to be low in most people using these preparations, there is a need for careful and long term surveillance for visceral and skin cancers. This concern was recently reinforced when the US Food and Drug Administration granted the product licence for pimecrolimus on the basis of preclinical studies showing increased photocarcinogenicity and an increase in lymphomas and thyroid adenomas in mice.11
It is tempting to discuss only pharmacological developments and ignore other developments in the management of atopic dermatitis, such as biological approaches. Probiotics (harmless cultures of bacteria) prevented atopic dermatitis in half the individuals who participated in one study.12 Another study showed that vaccination with Mycobacterium vaccae can have substantial effects in ameliorating existing disease.13 Further trials are going on using these approaches, and both approaches may make big contributions in the prevention and management of atopic dermatitis.
Both topical tacrolimus and pimecrolimus are welcome additions to the treatment of atopic dermatitis. Little doubt exists that they work and that they are probably safe, at least in the short term. Yet, because of the lack of essential comparisons, clinicians are left confused as to how and when to use these drugs and whether they are cost effective. Given the widespread and often irrational fear of topical corticosteroids, manufacturers of both drugs are likely to make a handsome profit in return for their investment—an inevitable consequence of the current licensing processes and the complete lack of independent studies using appropriate comparators.
Yukihiro Ohya, National Children's Hospital, Tokyo, identified and translated the Japanese studies.
Williams H,
Robertson C,
Stewart A,
Ait-Khaled N,
Anabwani G,
Anderson R,
. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol 1999; 103: 125–138.
Williams HC
Mar A,
Marks R
. Prevention of atopic dermatitis. In: Williams HC, ed. Atopic dermatitis. The epidemiology, causes and prevention of atopic eczema. Cambridge: Cambridge University Press, 2000:205–220.
Hoare C,
Li Wan Po A,
Williams H
. Systematic review of treatments for atopic eczema. Health Technol Assess 2000; 4: 1–191.
Nghiem P,
Pearson G,
Langley RG
. Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002; 46: 228–241.
Queille-Roussel C,
Paul C,
Duteil L,
Lefebvre MC,
Rapatz G,
Zagula M,
. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001; 144: 507–513.
FK506 Ointment Study Group
. Phase III comparative study of FK506 ointment versus betamethasone valerate ointment in atopic dermatitis (trunk/extremities) [in Japanese]. Nishinihon J Derm 1997; 59: 870–879.
. Phase III comparative study of FK506 ointment versus aclometasone dipropionate ointment in atopic dermatitis (face/neck) [in Japanese]. Hihuka Kiyo [Dermatology Bulletin] 1997; 92: 277–282.
Reitamo S,
Rustin M,
Ruzicka T,
Cambazard F,
Kalimo K,
Friedmann PS,
. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002; 109: 547–555.
Van Leent EJ,
Ho V,
Harper J,
. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002; 109: 539–546.
Luger T,
Graeber M,
Hedgecock S,
Thurston M,
Kandra A,
. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001; 144: 788–794.
FDA/Center for Drug Evaluation and Research
. Elidel (pimecrolimus) cream. www.fda.gov/cder/foi/nda/2001/21–302_Elidel.htm (accessed 22 Apr 2002)
Kalliomaki M,
Salminen S,
Arvilommi H,
Kero P,
Koskinen P,
Isolauri E
. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001; 357: 1076–1079.
Arkwright PD,
David TJ
. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107: 531–534.
Hywel Williams
Williams H.
BMJ 2002; 324 :1533 doi:10.1136/bmj.324.7353.1533
Articles by Hywel Williams
You are going to email the following New treatments for atopic dermatitis
Immunology (including allergy)


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Julia Ioffe
Follow @juliaioffe
11 Sep, 4 tweets, 2 min read
Completely floored by the beautiful, poignant story-telling I'm seeing on this anniversary of 9/11.
Here's @LeilaFadel's powerful story on a young Muslim man whose life was changed by the surveillance and religious profiling of Muslims after 9/11:
npr.org/2021/09/11/103…
And @vermontgmg elegant and sad story of one of the few who survived the towers' collapse:
politico.com/news/magazine/…
And @eberkon's story about the guilt and trauma that continues to plague those who survived the attack on the Pentagon:
wamu.org/story/21/09/10…
This story, about the airline worker who checked in two of the hijackers who were running so late they nearly missed the flight, nearly broke me:
Keep Current with Julia Ioffe
More from @juliaioffe
@juliaioffe
Today, my good friend Roman @Dobrokhotov, head of @the_ins_ru and Russian partner of @bellingcat, had his home searched and was taken for questioning. He's been released but all his electronic equipment and passport have been seized. All part of the wave of repression in Russia.
@Dobrokhotov @the_ins_ru @bellingcat The current wave of political repression in Russia is unlike anything we've seen in the post-Soviet era. Yet the world seems resigned that that's just how Russia is. But there are real people at the heart of this, fighting for their freedom at great risk to themselves.
Roman has two small children and two elderly parents, whose apartment was also searched today. But knowing Roman, this isn't going to stop him. Would that we all had that kind of bravery and commitment to the cause.
Sunday read: For a long time, people like me who were foreign correspondents saw Facebook as a tool that would *help* democracy, not hurt it. I asked @sheeraf about this: ckarchive.com/b/68ueh8h84wpr
Sheera, the author, with @ceciliakang, of a new best-selling book about how Facebook became so dangerous to democracy, told me how she witnessed the shift from "Facebook will spread democracy" to "Facebook helps authoritarians" in real time while based in Cairo.
She also talked about how no one in Facebook's executive ranks anticipated this because they all come from similar, sheltered backgrounds. It is another point in why diversity at the top matters.
"There are so many fucking Trump books," says one book editor, wondering what we're learning from any of them. Or as one industry insider quipped, "What are we going to find out in these books? That Trump threw a banana at John Kelly?" My latest:
ckarchive.com/b/68ueh8h8md7z
Is it really news that Trump kind of admires Hitler? Or that he ran a wildly chaotic administration?
Also, who is reading these books? Who spends $30 on a hardcover to think about Trump for a few hundred pages?
"It's largely people who didn't vote for him," said one book editor.
So about that Guardian story about that document Putin allegedly signed authorizing an operation to put Trump in the White House? I spoke to a fmr intelligence officer who handled that intel in real time and they were…skeptical. (My latest: ckarchive.com/b/68ueh8h8md7z)
The other thing that should make you skeptical: the byline on that story.
And it's not just that Manafort/Assange story that Luke got wrong. He was known for stories that sounded amazing and sensational—but were thinly sourced.
As one White House reporter told me, "Trump has been good for many journalists professionally, myself included."
How do White House reporters feel now that the Trump circus has left town?
My latest:
ckarchive.com/b/k0umh6h0wo69
"Everything seems more buttoned up than the streaking convention that was the Trump White House," says @Olivianuzzi.
"The truth is the Biden White House is very opaque," said @sbg1.
"The mechanics of reporting have changed so much," another reporter said. "It was just this really aberrant period in which you could almost guarantee that, with enough effort, you could find out what's going on in the Situation Room. Now you can't—and it's infuriating."
For Jews like myself who have lived anti-Semitism and carry the intimate details of our families' trauma—pogroms, the Holocaust, the Pale of Settlement, the Doctors' Plot—the fear that this peace is just a temporary blip is always right under the skin. nytimes.com/2021/05/26/us/…
What frustrates me about the discourse on the left is the assumption that because Jews have assimilated into whiteness in the last three generations in America, that Jews have always been white and powerful, as if discrimination by skin tone weren't a uniquely American creation.
Ignoring the history of Jews as the underclass of Christian Europe, for a good 2000 years, constantly slaughtered and discriminated against, as second-class dimi in the Muslim world (where they were also subjected to religious violence) is in and of itself anti-Semitic.
Get emails when @juliaioffe has new unrolls!
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redpajama_set_name: RedPajamaCommonCrawl


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DeKalb Market Hall creator bringing new food hall to Midtown
Boston Properties inks lease with operator at the Citigroup Building; broker claims landlord squeezed him out of the deal
By Rich Bockmann
Anna Castelini and 601 Lexington Avenue (Credit: LinkedIn and Andrew Moore via Flickr)
Manhattan's iconic Citigroup Center is about to get a taste of Brooklyn.
The creator behind Downtown Brooklyn's DeKalb Market Hall is opening a 10,000-square-foot food hall at the base of the Midtown East tower at 601 Lexington Avenue, The Real Deal has learned.
Anna Castellani, who opened the 40 vendor Brooklyn market in 2017, signed a lease with Boston Properties to bring her newest concept to the retail annex tucked 59 stories below the landmarked building's 45-degree sloping roof.
The new hall will be dubbed "The Hugh" and is scheduled to open in three or four months.
Representatives for Boston Properties did not immediately respond to a request for comment, and Castellani's company, Local Culture Management, declined.
The lease for the space has a term of 15 years and is valued at more than $1 million per year. The new deal is not without controversy, however.
Larry Roberts, a broker at Arch Brokerage, claims he represented Castellani in negotiations with Boston Properties and that the landlord cut him out of his commission on the deal. Arch filed a lawsuit against the real estate investment trust seeking $770,000 in compensation.
"Arch Brokerage did the work and should have gotten paid for it," said Alan Sash, Arch's attorney at Manhattan based McLaughlin & Stern. "They didn't, and that's why the lawsuit was filed."
In Brooklyn, the DeKalb Market Hall features stalls from vendors like Jackson Heights' famous Arepa Lady, Katz Deli and Guss' Pickles spread across 27,000 square feet at the City Point Center.
Across the city, landlords have brought in food halls as amenities to help draw and retain tenants to their office properties. Popular examples include the Hudson Eats marketplace at Brookfield Office Properties' Brookfield Place and The Pennsy at Vornado Realty Trust's Penn Plaza.
Just two blocks from Boston Properties' Citigroup Building, the Feil Organization signed the Urbanspace market to an 11,000-plus square-foot space at 570 Lexington Avenue in 2017.
Boston Properties has had its eye out for a destination-type food attraction for at least the past three years, ever since it shut down the listless Atrium Shops and Cafes in 2016 as part of a major redevelopment of its 1.6 million-square-foot Citigroup Center between Lexington and Third avenues.
The REIT committed $150 million three years ago to reposition the annex building at the Citigroup Tower and gut renovate its retail spaces.
The landlord last year signed NYU Langone to the entire 200,000-square-foot renovated atrium portion of the property. Chicago-based law firm Kirkland & Ellis in 2017 expanded its footprint to more than half a million square feet inside at 601 Lexington, which the city had landmarked the year earlier.
Nightingale partnership closes on $175M purchase of 111 Wall
Extell scores $700M refi for three Manhattan buildings
Banks see uptick in mortgages, but remain wary ahead of potential Fed interest rate cut
NYC is on the hunt for an Amazon replacement in Queens
Richman Group lands $189M for massive East Harlem project
Citigroup downsizing will leave big void at One Court Square
White House attorneys investigating whether loans to Kushner Companies violated law: report
Kushner lands $200M Citigroup loan for Trump Bay Street


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Home ᐳ News ᐳ GameChangers 2021: How Organized Crime Devoured the Amazon Rainforest
GameChangers 2021: How Organized Crime Devoured the Amazon Rainforest
BRAZIL / 28 DEC 2021 BY KATIE JONES, MARIA FERNANDA RAMÍREZ AND JUAN DIEGO CÁRDENAS EN
ILLEGAL MINING
TIMBER TRAFFICKING
There was record destruction of the Amazon in 2020, as the rainforest lost an area around the size of Belize, and the situation looks to be even bleaker in 2021. Deforestation reached record levels in Brazil, Peru and Bolivia. Colombia may break the trend, having reported moderate improvements in 2021.
In July came perhaps the worst news so far. A study by Nature showed tracts of Brazil's Amazon were now no longer a carbon sink, emitting more carbon dioxide than they absorbed. The Amazon as a bulwark against rising global temperatures had finally cracked.
In November, the United Nations Climate Change Conference in Glasgow issued dire warnings about deforestation but with few assurances it would make a difference.
Deforestation is more intertwined with criminal activities than ever. Those involved in gold mining, cattle ranching, drug trafficking and illegal logging are working hand-in-hand, either with each other or with public and private interests to destroy the lungs of the planet.
SEE ALSO: 4 Reasons Why Ruin of Brazil's Amazon Keeps Getting Worse
Organized Crime in Deforestation
The battle against deforestation is complex. Agriculture and cattle ranching, for example, are legal industries, critical to the economies and encouraged by the governments of Bolivia, Brazil and Colombia, among others.
But these activities are all too often associated with flagrantly illegal acts. Cattle ranching, for instance, is now the main motor of illegal land grabs in the Amazon, according to a major report on the Amazon by Amnesty International. It is carried out with a well-established model: Fires are set illegally, clearing huge areas of rainforest cover and opening up pastures.
The aggressive spread of cattle ranching has also claimed the lives and threatened the livelihoods of those who stand in the way, from Indigenous communities to small farmers and public officials, the Amnesty International report stated.
All of this is done with tacit and sometimes overt government approval, said Eduardo Franco Berton, a journalist who has followed environmental crime in Bolivia.
"Over the last 15 years, successive governments have promoted settlement in protected areas in the Amazon for agriculture and livestock," he told InSight Crime.
Simultaneously, criminal organizations have also accelerated their activities. In 2021, criminal groups across the Amazon expanded their seizures of gold, coltan and protected timber. The expansion of these criminal portfolios has gone hand in hand with the drug trade. Land cleared to build runways for drug planes has provided timber to be sold. Clandestine roads built through the forest can be used to move drugs, minerals, timber and contraband.
Efforts made to fight this are paltry. Largely ineffective military operations have sought to combat illegal mining and other crimes driving forest loss in Peru, Brazil and Colombia.
And while environmental defenders have attempted to fend off soaring deforestation driven by organized crime, this has resulted in bloodshed across the region, as activists and Indigenous communities seeking to protect their lands have been threatened and killed in Colombia, Brazil and Peru.
Criminal groups also further expanded in areas that were already hot spots for deforestation. In Peru, mining camps wreaked havoc on the Boca Pariamanu Native Community land in the heart of the nation's gold-rich Madre de Dios region.
Coca plantations are spreading outside Peru's traditional coca-growing areas of the Valley of the Apurímac, Ene and Mantaro Rivers (Valle de los Ríos Apurímac, Ene y Mantaro – VRAEM) deeper into Peru's Amazon. And cocaine laboratories and illegal airstrips are being found increasingly in other parts of the rainforest.
In 2021, the sad trend of previous years has only accelerated. The battle against criminal deforestation in the Amazon is being lost.
Old Threats Renewed
Despite close to record amounts of coca production in 2021, cattle replaced coca as the main driver of deforestation in Colombia's Amazon. This shift had been underway since the demobilization of the Revolutionary Armed Forces of Colombia (Fuerzas Armadas Revolucionarias de Colombia - FARC) in 2016. The FARC had acted as de facto custodians of the rainforest, an effective albeit illegal park service. Their departure led to a renewed invasion of the forest in southern Colombia, with locals paid to illegally fell colossal areas of rainforest for cattle ranching.
Official data published in July showed deforestation in Colombia's Amazonian departments of Meta, Caquetá, Guaviare and Putumayo had soared in 2020. This became even more apparent in 2021. In the first three months of 2021, these departments still witnessed the highest concentrations of deforestation.
Increasingly scarce fine woods were also ransacked to feed international markets. For example, timber mafias based along Ecuador's borders have been cashing in on a balsa wood boom, especially from the wind power industry, since balsa wood is used to make wind turbine blades in China and the United States. The quantity of illegal balsa wood found in Ecuador jumped by 180 percent in 2020. Seizures have continued apace this year.
Ana Cristina Basantes, a journalist who has followed environmental crime in Ecuador closely, told InSight Crime that illegal balsa logging has contributed to increased deforestation on territories owned by the Indigenous Achuar people, which straddle the nation's border with Peru.
Milagros Aguirre Andrade, a journalist who wrote a book on Ecuador's timber trade, added that beyond deforestation, the arrival of balsa loggers to these indigenous communities has also brought acts of violence. And this is only set to worsen, according to Aguirre. "During the pandemic, the trade has sparked increased violence along the Ecuador-Peru border," she told InSight Crime.
There, women and girls have been the victims of sexual violence, and clashes have occurred when loggers are not paid the agreed amount. The illegal timber trade has also driven arms and munitions into indigenous communities.
New tactics were also used to facilitate old crimes that have long driven deforestation.
Smaller patches of forest were cleared to confuse authorities. In Colombia's central Meta department, for example, former FARC soldiers -- working under the direction of a former FARC commander, Miguel Botache Santillana, alias "Gentil Duarte" -- ordered local people to clear land for coca crops one hectare at a time to avoid detection.
New technologies are also accelerating the trend. In Brazil, plots of Amazon rainforest were sold illegally on Facebook, prompting the social media giant to undertake a crackdown on the illegal sales of land via this platform.
Corrupt Cooperation
Petty and systemic corruption continued to grease the wheels of environmental crimes and deforestation across the Amazon.
From Brazil to Bolivia, government officials were enmeshed in illegal activities.
In May, the Brazilian government faced accusations that it not only turned a blind eye to illegal deforestation in the Amazon but actively participated in its pillage. The nation's environment minister was investigated and resigned, and the head of its environmental protection agency was suspended. Both men allegedly helped timber companies export more wood logged from the Amazon than legally permitted.
In June, it was reported Brazil's Rural Environmental Register (Cadastro Ambiental Rural - CAR) was being used to designate millions of hectares of Amazon forest as rural lands, in a process that critics say fuels state-sanctioned land grabs and deforestation by criminal actors.
Elsewhere, Bolivia's minister for rural development and land was arrested with another senior official for allegedly accepting a cash bribe to allow illegal land grabs in the Amazon for agricultural use.
Similar cases happen in Peru. Corrupt officials at the Regional Agricultural Directorates (Direcciones Regionales Agrarias - DRA) orchestrate the illegal issuance of land ownership titles that are then sold to palm oil companies, according to Magaly Ávila, the director of the forest governance program for Proética, the Peruvian chapter of Transparency International. Under these land trafficking schemes, thousands of hectares of forest have been deforested.
Colombia's Autonomous Regional Corporations for Sustainable Development (CARs), the regional government bodies designed to regulate the environment, continued to face corruption charges. Several sources who spoke to InSight Crime agreed that CAR officials had issued transit permits with false information to benefit those involved in the illegal timber trade. Fresh attempts were made to clean up the CARs in April 2021, but the results of this are yet to be seen and illegal logging continues to thrive.
Meanwhile, powerful networks of businessmen and politicians, who rely on corruption to title their stolen lands, continued to orchestrate land grabbing for agro-business and cattle ranching, a principal driver of deforestation for the nation.
In Guyana, allegations of corruption within the Guyana Geology and Mines Commission (GGMC), which monitors mining activities, are also widespread. Mining industry observers in the country, who agreed to speak to InSight Crime on the condition of anonymity for security reasons, told InSight Crime that GGMC inspectors are routinely paid off to overlook illegal mining practices. The GGMC allegedly deliberately use inaccurate maps of Indigenous territories to issue permits within their lands, even though this is prohibited under the Mining Law.
"The overall intention is to provide a cover for corrupt officials," one environmental crime expert in Guyana told InSight Crime.
Security forces were also involved. In Ecuador, police and soldiers received bribes from timber traffickers to ensure the smooth transfer of illegal wood out of Ecuador, Aguirre Andrade told InSight Crime.
In Venezuela, a former army lieutenant allegedly recruited Venezuelan soldiers to provide firepower for the Tren de Guayana gang's bid to take over illegal gold mining operations. The alliance was part of a complex web of collaboration between the military and criminal gangs which has fuelled mining and, consequently, rampant deforestation.
SEE ALSO: Why South America's Armies Are Losing the War for the Amazon
Amazon Road Trip
Criminal groups have also taken advantage of the increasing number of roads and other infrastructure cutting through the Amazon. The effects of this became more apparent in 2021.
Illegal and irregular roads continue to open the gates of Colombia's Amazon to criminal groups. In 2021, illegal road construction around Chiribiquete National Park, in the southern department of Caquetá, attracted both farmers and criminal entrepreneurs. The Llanos del Yarí-Yaguara II Indigenous Reserve, located between the municipalities of San Vicente del Caguán (Caquetá), La Macarena (Meta) and Calamar (Guaviare) also saw further encroachment.
This trend looks set to continue. In July 2021, it was reported that Brazilian president Jair Bolsonaro was planning to construct a new railway that would cut through the Amazon. This infrastructure would not only lead to mass deforestation, but could also be coopted, as other transport infrastructure has been, to move cocaine and illegal timber.
To be sure, these roads are constructed by local officials or by criminal networks — lacking the proper permits — and are direct drivers of deforestation in the region. They have also paved the way for other activities like coca cultivation, illegal logging and illegal mining. What's more, roads have increased the value of surrounding land, making land grabbing more likely.
A Losing Battle
As in previous years, armies in Brazil, Colombia and Peru failed again to win a battle in the war against deforestation.
Colombia recorded soaring deforestation despite its deployment of troops as part of Operation Artemisa, a militarized attempt to combat forest loss and win back the country's national parks from criminal groups. Discontent among military ranks who believed police should not be charged with this task hampered efforts.
In Brazil, President Jair Bolsonaro's Operation Green Brazil came to an ineffectual end after its second phase. A lack of specialized training for soldiers seems to have severely hampered its success.
As militaries remained at the forefront of a region-wide fight against deforestation, environmental agencies faced increased hurdles.
Brazil's environmental agency (Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis — IBAMA) saw its funding and personnel slashed. And the nation's mining regulator (Agência Nacional de Mineração — ANM) was no match for its gold rush, as 250 inspectors monitored some 35,000 mining sites.
Multilateral cooperation in the Amazon also remained low, hampering efforts to fight organized crime's regionwide encroachment.
On April 22, the Escazú Agreement came into force. This treaty has set out to support environmental defenders fighting deforestation across Latin America and the Caribbean. But several important governments remain on the sidelines. Suriname and Venezuela are not signatories, while Colombia has yet to ratify the agreement.
In November, at the United Nations Climate Change Conference, 110 countries pledged their commitment to rein in global deforestation by 2030. However, one note marred the moment. Bolivia and Venezuela, two of the worst culprits when it comes to Amazon deforestation, abstained.
BRAZIL COLOMBIA ENVIRONMENTAL CRIME FEATURED GAMECHANGERS GUYANA ILLEGAL MINING INFOGRAPHICS PERU TIMBER TRAFFICKING
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Alabama. Office of the Governor 10
King, Bernice A. 10
King, Dexter 10
Wallace, George C. (George Corley) 10
March on Washington for Jobs and Freedom, Washington, D.C., 1963 2
Aquarian Spiritual Center Bookshop (Los Angeles, Calif.) 1
Eastside Settlement House (Los Angeles, Calif.) 1
Martin Luther King, Jr. Center for Nonviolent Social Change 1
McGann, James A. 1
National Association for the Advancement of Colored People (NAACP) 1
National Association of Colored Women's Clubs 1
The John Henry and Mary Louisa Dunn Bryant Foundation 1
West Indian American Club 1
Oxford, Miss. 10
I Have a Dream 10
Police - Complaints against 10
Afro-Americans - Economic conditions 9
Discrimination in housing 5
Discrimination in public accommodations 5
Voter registration 3
Martin Luther King, Jr. - Publications - Reprints 2
Civil rights demonstrations 1
Martin Luther King, Jr. - Publications 1
''I Have a Dream,'' Address delivered at the March on Washington for Jobs and Freedom
Hollywood, Calif. 90028: Motown Record Company, MCA Distributing, Inc., 1963
King, Dexter
King, Bernice A.
Stone Mountain, Ga.
Lookout Mountain, Tenn.
March on Washington for Jobs and Freedom, 1963
Discrimination in public accommodations
MLKEC-INP
Martin Luther King, Jr. Estate Collection, In Private Hands
SCLCT-INP, Southern Christian Leadership Conference Tape Collection, In Private Hands
7/24/2012 kpp
''I Have a Dream,'' Address at March on Washington for Jobs and Freedom
Martin Luther King, Jr. Center for Nonviolent Social Change
''I Have a Dream,'' Address at the March on Washington for Jobs and Freedom
''I Have A Dream,'' Address at March on Washington for Jobs and Freedom, 1963
Speeches by the Leaders, New York: NAACP, 8/28/63.
labc, Labadie Collection
Isaiah 40:4, 5
''I Have A Dream...,'' Address at the March on Washington for Jobs and Freedom
[Washington, D.C.]
March on Washington for Jobs and Freedom, Washington, D.C., 1963
''Full Text of Dr. King's Washington Address,'' Address at the March on Washington for Jobs and Freedom on 8/28/1963
SCLC Newsletter 1 (September 1963): 5, 8.
''I Have A Dream,'' Address at March on Washington for Jobs and Freedom on 8/28/1963
McGann, James A. [West Indian American Club]
The John Henry and Mary Louisa Dunn Bryant Foundation
National Association of Colored Women's Clubs
Eastside Settlement House (Los Angeles, Calif.)
Aquarian Spiritual Center Bookshop (Los Angeles, Calif.)
West Indian American Club


text:
> Blog> What's new>Join us to protect the planet... and those who inhabit it
Join us to protect the planet... and those who inhabit it
DRINK LOCALLY, ACT GLOBALLY
For two years now, Swissline has been a partner of DRINK & DONATE, an innovative non-profit organization (NPO) based in Zurich that provides clean, drinking water for those in need in developing countries. The NPO encourages people in Switzerland to purchase DRINK & DONATE branded carafes/bottles of zuriwasser (tap water from Lake Zurich) at participating restaurants and concert venues in Switzerland. The proceeds from the sales go to funding sustainable water projects around the world, selected by Swiss organizations, Helvetas, Skat Foundation and Waterkiosk Foundation.
A WORD FROM SWISSLINE BRAND DIRECTOR, CUSTODIO D'AVO
WATCH MORE VIDEOS FROM THE AGE TRAVELLER >>
OFFSET YOUR WATER FOOTPRINT
Regardless of whether you live in Switzerland, or not, you can offset your water footprint to ensure those in developing countries have clean drinking water. DRINK & DONATE accepts private and corporate donations. In 2019, Swissline purchased water footprint certificates on behalf of all of our Swiss based employees. In 2020, we will purchase water footprints on behalf of our employees in other parts of the world.
Unlike many other countries, Switzerland has an abundance of excellent drinking water. However, around 780 million people worldwide do not have access to clean drinking water. According to UNICEF, over 4,000 people die every day from the effects of contaminated water. For the majority, the problem is not the lack of availability, but rather the poor quality of the water. If people consume water from rivers, lakes, puddles or stored rainwater, this is usually not suitable for direct drinking. It is microbiologically contaminated and leads, among other things, to serious bowel diseases, which can be fatal for many people without medical care.
Photo Credit: HELVETAS
DRINK & DONATE IMPACT
Since its launch in August 2010, up until 2018…
- ZH 2 O züriwasser has been ordered more than 738,322 times in Zurich restaurants
- CHF 1,838,491 has been collected
- Over 79,623 people worldwide have been given long-term access to clean Drinking water
Watertight Results:
- 27 schools and 3 universities in Tanzania (with over 19,500 students) now have drinking water treatment plants
- 1090 drinking water points have been built in the mountainous regions of Nepal
- 226 people in Tanzania and Zimbabwe were trained to build wells and pumps
- Over 924 drinking water wells/drinking water pumps have been built in Tanzania and Zimbabwe
- 4 hospitals with 200,000 patients and 500 doctors now have drinking water systems
- 491 rainwater storage tanks were built in 5 villages for 1191 households in Bangladesh
So, what are you waiting for… it's time to give back to the Earth!
FIND OUT MORE ABOUT DRINK & DONATE>>
Teamwork: The Fabric Of Life
Join us in supporting Momentum Foundation, a Swiss non-profit organization dedicated to female empowerment, education and gender equality in Rwanda.


These black stretch cotton-blend denim Kate Skinny jeans are a staple this season. Featuring the lab..
Anchor your casual look in these flowing culotte pants from Vince Camuto, styled to flatter with..
Take your off-duty style to the next level this season wearing these modish boots from Bata. Designed with plush synthetic leather upper and pning for a durable wear, these men's shoes promise good spp and abrasion resistance too, courtesy the rubber sole.


Listen up jar-heads... We've got a little training exercise lined up for today. The Attacking Team must unlock 3 sets of security gates to gain access to a Prototype Plasma Scorpion and then escape with it. The Blue Team must prevent this at all costs. (For information regarding your vehicles, you should have already read your enclosed file). Good luck.


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'Agents of SHIELD' star Clark Gregg doesn't go 'Dirty Dancing' with wife Jennifer Grey
As Agent Coulson on ABC's "Agents of S.H.I.E.L.D.," Clark Gregg knows what it's like to work alongside superheroes on a regular basis. But he's more cautious about super activities when he's at home with his wife, "Dirty Dancing" actress Jennifer Grey.While visiting TODAY Thursday, Gregg joked that the pair regularly perform the run-and-lift dance move Grey famously did with Patrick Swayze in th
June 5, 2014, 2:53 PM UTC
By Randee Dawn
As Agent Coulson on ABC's "Agents of S.H.I.E.L.D.," Clark Gregg knows what it's like to work alongside superheroes on a regular basis. But he's more cautious about super activities when he's at home with his wife, "Dirty Dancing" actress Jennifer Grey.
While visiting TODAY Thursday, Gregg joked that the pair regularly perform the run-and-lift dance move Grey famously did with Patrick Swayze in the classic 1987 movie.
"We do it every morning," he grinned. "I brew some tea, I hold the cup, she runs and then I feed it up to her."
Actually, not really, because Gregg knows his limits. "There's only one man who can really do that lift and sadly he's no longer with us — the amazing Patrick," the actor said. "I will never try it. That was one of our wedding vows."
Meanwhile, Gregg is setting superheroes aside in his new movie, "Trust Me," which he wrote, directed and stars in. He's Howard, an "aging loser" who works as a less-than-successful agent for child actors.
"I wouldn't say that it's representative of all kind of agents for child actors," said Gregg. "There was just something kind of heartbreaking and lovable about these people who are looking for a kind of 10-year-old who's going to take them to the big time, and running to get the parents coffee."
"Trust Me" opens in select theaters on Friday, and is available now on VOD and iTunes.
Follow Randee Dawn on Google+.


← Jimmer Update – Career high 51 pts.
I also got a chance to meet your Mom and Whitney in Westchester not too long ago, and I agree with Bill, you have a special family.
Thanks for the blog posts. Keep up the great work!
Just finished reading the book "back from the dead". Great read!!!! May areas of Bill Waltons life I did not know about…. Plus I'm a Deadhead!
I remember Bill Walton calling a Kings game and he kept pointing out all the things Jimmer does so well on the court …He really appreciates his game (like me and so many other knowledgeable basketball fans) and phenomenal skill. All Jimmer needs is a GM and a coach that will put the ball in his hands and leave him alone.


With the increasing severity of offenses, it is crucial to fight aggressively against your DUI charges the first time. Need a lawyer for your DUI case in Dublin, CA? Team up with a Dublin DUI lawyer from the Law Office of Ivan O.B. Morse. When facing these charges, you need to obtain representation from an experienced DUI attorney in Dublin who has handled DUI cases before. With decades of experience and a history as a police officer, Attorney Morse is the aggressive and knowledgeable legal representation you need. Call today to schedule your free case evaluation!


As the year begins to draw to a close, we once again come to you asking for your financial support to sustain and grow our programs.
Our social media presence has continued to bring the teaching to people locally and around the world. Currently, we connect with over 5,000 people on Facebook and Twitter alone. Our YouTube teaching videos of talks by Zen Master Bon Soeng and others have received over 440,000 views. We also made a major improvement to the Berkeley dharma room by having a contractor re-wire the room and install modern room lighting, a ceiling fan, and dedicated lights for the altar.
As we look out toward the coming year, we anticipate continued expansion of our programs and teaching. Our Santa Clara branch is growing quickly and is in need of a larger facility to provide a supportive practice space for new and returning practitioners. We have also begun the work of opening a new branch in Fresno, CA where two of our Sangha members live. And at the Berkeley location we are planning to offer monthly training workshops for Dharma Teachers and Dharma Teachers-in-Training beginning in 2016. We need your support to make these things happen!
Please take a moment to consider what tax-deductible donation you can afford. You can send all donation checks to Empty Gate or donate online using a credit card or PayPal account. Many thanks for your practice and your continued support of Empty Gate Zen Center.
Many thanks for your practice and your continued support of Empty Gate Zen Center.
As the year begins to draw to a close, we once again come to you asking for your financial support to sustain and grow our programs.Over the last year, we continued our program of monthly retreats and twelve practice sessions per week, with the active participation of a growing sangha. We have also increased our efforts to bring Zen teaching to students near and far. In addition to our San Francisco satellite group, we have two new satellite groups in Santa Clara, California and Boise, Idaho. These satellite groups offer consistent and supportive practice space for practitioners and sangha members who are unable to join regular practice at our Berkeley location.
Our social media presence has continued to bring the teaching to people locally and around the world. Currently, we connect with 4300 people on Facebook and Twitter alone. Our YouTube teaching videos of talks by Zen Master Bon Soeng and others have received over 360,000 views. We also reached another important milestone: in August of this year, we reached our goal of paying off the mortgage on our 2200 Parker Street building. Thanks to all of you and to Searle Whitney for making this possible!
As we look out toward the coming year, we anticipate continued expansion of our programs and teaching. Our Santa Clara satellite group is growing quickly and we are predicting the need for a larger space in the next year. Our San Francisco satellite group has lost their space and is seeking a new one. As each of these satellite groups continues to grow, we would like to help them provide a supportive practice space to new and returning practitioners. We also hope to offer more training workshops for our Dharma Teachers and Dharma Teachers-in-Training. We need your support to make these things happen!


We examined whether plasma C-reactive protein (CRP) levels at the time of diagnosis of breast cancer are associated with overall survival, disease-free survival, death from breast cancer, and recurrence of breast cancer.
We observed 2,910 women for up to seven years after they were diagnosed with invasive breast cancer (median follow-up time was three years). Plasma levels of high-sensitivity CRP were measured at the time of diagnosis and we assessed the association between CRP levels and risk of reduced overall and disease-free survival, death from breast cancer, and recurrence of breast cancer by using the Kaplan-Meier method and Cox proportional hazards regression. During follow-up, 383 women died (225 of whom died from breast cancer) and 118 women experienced recurrence of breast cancer.
Elevated CRP levels across tertiles at the time of diagnosis were associated with reduced overall and disease-free survival and with increased risk of death from breast cancer (log-rank trend for all, P < 0.001), but not with recurrence. The multifactor-adjusted hazard ratios (HR) of reduced overall survival among women in the middle and highest versus the lowest tertile of CRP were 1.30 (95% CI, 0.97 to 1.73) and 1.94 (1.48 to 2.55), respectively. Corresponding HRs of reduced disease-free survival were 1.16 (0.89 to 1.50) and 1.76 (1.38 to 2.25) and of death from breast cancer 1.22 (0.84 to 1.78) and 1.66 (1.15 to 2.41). Dividing CRP levels into octiles resulted in a stepwise increased risk of reduced overall survival (P for trend <0.001) and the multifactor-adjusted HR among women in the highest versus the lowest octile of CRP was 2.51 (1.53 to 4.12). Compared to women with CRP levels in the 0 to 25% percentile (<0.78 mg/L), the multifactor-adjusted HR of reduced overall survival among women with CRP levels ≥95% percentile (≥16.4 mg/L) was 3.58 (2.36 to 5.42). Among women with HER2-positive tumours, the multifactor-adjusted HR of reduced overall survival for the highest versus the lowest tertile of CRP was 8.63 (2.04 to 36.4).
Elevated CRP levels at the time of diagnosis of breast cancer are associated with reduced overall and disease-free survival and with increased risk of death from breast cancer.
Elevated plasma levels of C-reactive protein (CRP) may be associated with poor prognosis after breast cancer. CRP is a classical acute-phase protein displaying rapid and pronounced rise of its plasma concentration in response to acute inflammation, infection, and tissue damage [1, 2]. Circulating levels of CRP are also moderately elevated during chronic inflammatory diseases and cancer . CRP is produced in the liver, predominantly under transcriptional control by the cytokine interleukin-6 originating from the site of pathology . Many tumours arise at sites of chronic inflammation or they trigger inflammatory responses that result in the formation of an inflammatory microenvironment around the tumour [5–9]. In fact, it has recently been suggested that cancer-related inflammation may represent the seventh hallmark of cancer in addition to the six hallmarks identified by Hanahan and Weinberg . Since inflammation in the tumour microenvironment stimulates tumour growth, invasion, and metastasis, inflammation seems to favour invasion and metastasis more than to mount an effective host anti-tumour response [5–9].
Previous epidemiologic studies have reported that elevated CRP levels may be associated with poor prognosis of several types of solid cancers , including endometrial , cervical , colorectal, pancreatic, hepatocellular, esophageal, renal cell, bladder, prostate, ovarian, and non-small-cell lung cancer [13, 14]. Although breast cancers rarely are characterized by significant histological inflammation, emerging evidence nevertheless suggests that inflammatory pathways also play an important role in breast cancer progression [15–20]. However, results from prospective epidemiologic studies are conflicting, with some studies showing an association between elevated CRP levels and poor prognosis [21–24] and others showing no association [25, 26]. The largest study so far comprised 700 women treated successfully for early stage breast cancer and found that elevated levels of CRP measured two and a half years after the time of diagnosis were associated with reduced disease-free and overall survival . Thus, it is unclear whether CRP levels measured at the time of diagnosis are associated with breast cancer prognosis.
We used a prospective cohort study of 2,910 patients with invasive breast cancer to examine whether plasma CRP levels at the time of diagnosis of breast cancer are associated with overall survival, disease-free survival, death from breast cancer, and recurrence of breast cancer.
We studied patients with invasive breast cancer from the Copenhagen Breast Cancer Study, which is an ongoing cohort study of Danish breast cancer patients. Since January 2002, all patients that are referred to the Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital with suspected breast cancer are asked to participate in the study (participation rate 93%). At study enrolment the patients answer a questionnaire regarding sociodemographic factors, lifestyle factors, anthropometric characteristics, medical history, and family history of cancer. Furthermore, they give blood for measurements of biochemical parameters.
In the present study, we included patients who were diagnosed with breast cancer in the period 1 January 2002 until 31 January 2009 (n = 3,634) (Figure 1). Since our intention was to study the association between CRP levels and prognosis among women with invasive breast cancer, we excluded patients without a measurement of CRP (n = 131), men (n = 23), and women with in situ breast cancer (n = 135). To avoid potential bias by the influence of surgery on CRP levels, we also excluded women who underwent breast cancer surgery before blood sampling (n = 137). Finally, to ensure that plasma CRP was measured at the time of diagnosis, we excluded women who had plasma CRP measured more than 30 days before or after the date of diagnosis of breast cancer (n = 298). Thus, we included 2,910 women aged 26 to 99 years in the analysis of overall survival. For the analysis of disease-free survival and recurrence, we additionally excluded 72 women for whom information about recurrence was missing, 15 individuals who, according to the register, had recurrence less than 90 days after their date of diagnosis, and 40 women who had distant metastasis at diagnosis. The latter two groups were excluded to ensure that the registered recurrences were indeed true recurrences. Thus, 2,783 women aged 26 to 99 years were included in the analysis of disease-free survival and recurrence. For the analysis of death from breast cancer, we excluded 38 women who were enrolled after 31 December 2008, since we did not have information about cause-specific death after this date. Thus, we included 2,872 women aged 26 to 99 years in the analysis of death from breast cancer (Figure 1). Follow-up time for each patient began at blood sampling and ended for overall survival at occurrence of death, emigration, or May 2009, whichever came first. For disease-free survival and recurrence, follow-up time ended at occurrence of recurrence, death, emigration, or May 2009, whichever came first. For death from breast cancer, follow-up time ended at death from breast cancer, death from other causes, emigration, or December 2008, whichever came first. The median follow-up period was three years (range = 0 to 7 years). During follow-up, 383 women died, 225 women died from breast cancer, 118 women experienced recurrence of breast cancer, and 4 women emigrated.
Flowchart illustrating enrolment and exclusions. CRP, C-reactive protein.
Information about diagnoses and prognostic tumour characteristics (tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status) of index breast cancers was obtained from the national Danish Breast Cancer Cooperative Group (DBCG) . Diagnoses and prognostic tumour characteristics were pathologically verified by clinical pathologists. Date of recurrence was obtained from DBCG and date of death and emigration was obtained from the national Danish Civil Registration System, which is 100% complete. Information about death from breast cancer was obtained from the National Danish Causes of Death Registry in which all death certificates in Denmark are registered. Danish death certificates register courses of diseases which lead to the death, with the underlying cause of death being the disease which started this course. In the present study, patients who were registered with the World Health Organization (WHO) International Classification of Diseases (ICD), Tenth Revision (ICD-10) codes C50.0 to C50.9 as the underlying cause of death were recorded as having died from breast cancer.
Information about diagnosis of cardiovascular diseases was obtained from the national Danish Patient Registry which all public and private hospitals in Denmark report to. Diagnoses were classified according to the WHO ICD, Eighth Revision (ICD-8 codes 410 to 414 and 432 to 435) or Tenth Revision (ICD-10 codes I20 to I25 and I63 to I64 and G45).
The ethical committee of Copenhagen and Frederiksberg, Denmark approved the study (KA-02152). All patients gave written informed consent.
We determined the plasma CRP levels in fresh plasma samples by using a high-sensitivity nephelometry assay (CardioPhase hsCRP, code OQIY21, Dade Behring, Deerfield, IL, USA) performed on a Behring Nephelometer or a high-sensitivity turbidimetry assay (Code LX001, Dako, Glostrup, Denmark) performed on a Konelab 60 analyzer. All analyses were performed in the same laboratory at the Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital. The detection limit was 0.17 mg/L for the nephelometry assay and 0.20 mg/L for the turbidimetry assay. Prior to the switch from the nephelometry to the turbidimetry assay, the two assays were compared by measuring plasma CRP with each method in 29 individuals. Spearman rank correlation coefficient between the two CRP assays was 0.96, and a Wilcoxon signed-rank test for difference between the two assays yielded a P-value of 0.87. If measured CRP changed over calendar time, due to analytical fluctuations, this could bias our risk estimates, but we found no evidence for an interaction between CRP level and date of measurement (= diagnosis). When statistical analyses were run separately by assay, the results were similar; we, therefore, only present combined results in the paper. The assays were assessed daily for precision by using internal controls for each assay (coefficient of variation was 3% at a level of 1.7 mg/L for the nephelometry assay and 6% at a level of 2.1 mg/L for the turbidimetry assay) and monthly for accuracy through a Scandinavian quality control program.
The data were analyzed using STATA statistical software (version 10.1; StataCorp, College Station, TX, USA), and a two-sided P-value less than 0.05 was considered statistically significant. On the basis of the measurements of plasma CRP with the nephelometry and turbidemetry assays, we divided patients into assay-specific tertiles of CRP and thereupon combined these assay-specific tertiles into common tertiles of CRP. To test the robustness of our findings, we used the same approach to divide patients into octiles of CRP, and to examine extremely high CRP levels, we divided patients into five groups of CRP levels (0 to 25% percentile, 25 to 50% percentile, 50 to 75% percentile, 75 to 95% percentile, and ≥95% percentile). The decision to examine tertiles as well as robustness using octiles, and extreme phenotypes was decided a priori, as we have done previously in similar studies, but for other questions [28, 29].
To test whether covariates differed across tertiles of plasma CRP, Kruskal-Wallis one-way analysis of variance was used for continuous covariates and the chi square test was used for categorical covariates. We used the Kaplan-Meier method to plot overall survival, disease-free survival, or cumulative incidence of death from breast cancer and recurrence against follow-up time and used the log-rank test to test for differences across tertiles of CRP. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of reduced overall and disease-free survival, death from breast cancer, and recurrence as a function of elevated plasma CRP levels. Patients were censored at their date of death (or emigration), dates that are 100% complete in the Danish registries. We used a model that included age at diagnosis only (Model 1), a multifactor-adjusted model that included age at diagnosis, tumour size (≤20 mm, 20 to 50 mm, >50 mm, or unknown), lymph node status (negative, positive, or unknown), presence of distant metastases (yes, no, or unknown), tumour grade (well differentiated, moderately differentiated, poorly/un-differentiated, or unknown), estrogen receptor status (positive, negative, or unknown), progesterone receptor status (positive, negative, or unknown), and HER2 status (negative, positive, or unknown) (Model 2), and a multifactor-adjusted model that included the above-mentioned covariates and the lifestyle factors smoking (<10, 10 to 20, ≥20 cigarettes per day, or unknown), alcohol consumption (≤168 or >168 grams per week, or unknown), and body mass index (<18.5, 18.5 to 24.9, 25 to 29.9, or ≥30.0 kg/m2, or unknown) as well as menopause status (pre-menopause, post-menopause, or unknown) and cardiovascular disease (yes, no, or unknown) (Model 3). For trend tests in log-rank and Cox statistics, the CRP groups were coded 1, 2, 3, and so on, corresponding to CRP tertiles and octiles.
For Cox proportional hazards regression analyses, we assessed the assumption of proportional hazards graphically by plotting log(cumulative hazard) as a function of follow-up time. We detected no major violations of the proportional hazards assumption. Interactions between tertiles of plasma CRP and covariates in the regression models was tested for by computing a likelihood ratio test comparing the statistical fit of models with and without a two-factor interaction term.
Baseline characteristics of the patients by CRP tertiles at the time of diagnosis of breast cancer are shown in Table 1. Levels of CRP were associated with several of these characteristics. The median duration from date of diagnosis to date of blood sampling was seven days (IQR, two to nine days). Table 2 shows the risk of reduced overall and disease-free survival, death from breast cancer, and recurrence by age at diagnosis, prognostic tumour characteristics, lifestyle factors, menopause status, and presence of cardiovascular disease. Causes of deaths in the present cohort were breast cancer (64%), other cancer (11%), cardiovascular disease (11%), respiratory disease (4%), other disease (11%), and unknown cause (1%).
Blood samples were drawn and CRP measured at time of diagnosis of breast cancer.
P-values were calculated using χ2 tests for categorical variables and Kruskal-Wallis one-way analysis of variance tests for continuous variables. For the evaluation of P-values, patients with unknown values were excluded.
*Cut-off values are based on the recommendation from of the Danish National Board of Health.
† Body mass index was calculated as weight in kilograms divided by height in meters squared.
The overall survival among breast cancer patients decreased with increasing levels of CRP (Figure 2A; log-rank trend, P < 0.001). The five-year survival rates were 90%, 81%, and 74% among women in the lowest, middle, and highest tertile of CRP. Corresponding age-adjusted HRs were 1.00, 1.39 (95% CI, 1.04 to 1.85), and 2.13 (1.63 to 2.79); P for trend <0.001 (Figure 3). Multifactorial adjustment for prognostic tumour characteristics (Model 2) slightly reduced the HRs to 1.00, 1.28 (0.96 to 1.70), and 1.91 (1.46 to 2.50); P for trend <0.001. Additional adjustment for lifestyle factors, menopause status, and cardiovascular disease (Model 3) resulted in similar HRs of 1.00, 1.29 (0.96 to 1.72), and 1.84 (1.39 to 2.45); P for trend <0.001.
Overall survival (A), disease-free survival (B), death from breast cancer (C), and cumulative incidence of recurrence after a breast cancer diagnosis (D). Results are shown by tertiles of plasma C-reactive protein (CRP) and are based on 2,910 women from the Copenhagen Breast Cancer Study who were observed for up to seven years.
Risk of reduced overall survival, disease-free survival, and recurrence after a breast cancer diagnosis. Hazard ratios by tertiles of plasma C-reactive protein (CRP) are based on 2,910 women from the Copenhagen Breast Cancer Study who were observed for up to seven years after a diagnosis of breast cancer. Model 1: adjusted for age at diagnosis. Model 2: adjusted for age at diagnosis, tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status. Model 3: adjusted for the above-mentioned covariates and smoking, alcohol consumption, body mass index, menopausal status, and cardiovascular disease.
The disease-free survival among breast cancer patients decreased with increasing levels of CRP (Figure 2B; log-rank trend, P < 0.001). The five-year disease-free survival rates were 87%, 80%, and 74% among women in the lowest, middle, and highest tertile of CRP. Corresponding age-adjusted HRs were 1.00, 1.25 (95% CI, 0.96 to 1.63), and 1.82 (1.42 to 2.34); P for trend < 0.001 (Figure 3). Multifactorial adjustment for prognostic tumour characteristics (Model 2) slightly reduced the HRs to 1.00, 1.16 (0.89 to 1.51), and 1.70 (1.32 to 2.18); P for trend <0.001. Additional adjustment for lifestyle factors, menopause status, and cardiovascular disease (Model 3) resulted in similar HRs of 1.00, 1.16 (0.88 to 1.52), and 1.65 (1.26 to 2.15); P for trend <0.001.
The cumulative incidence of death from breast cancer among breast cancer patients increased with increasing levels of CRP (Figure 2C; log-rank trend, P < 0.001) reaching 11%, 19%, and 20% among women in the lowest, middle, and highest tertile of CRP at the end of follow-up. Corresponding age adjusted HRs were 1.00, 1.41 (95% CI, 0.98 to 2.04), and 2.12 (1.50 to 2.99); P for trend <0.001 (Figure 3). Multifactorial adjustment for prognostic tumour characteristics (Model 2) slightly reduced the HRs to 1.00, 1.22 (0.84 to 1.76), and 1.78 (1.26 to 2.52); P for trend = 0.001. Additional adjustment for lifestyle factors, menopause status, and cardiovascular disease (Model 3) resulted in similar HRs of 1.00, 1.22 (0.84 to 1.78), and 1.66 (1.15 to 2.41); P for trend = 0.005.
The cumulative incidence of recurrence among breast cancer patients was highest among women in the highest tertile of CRP, but the incidence of recurrence did not increase stepwise with increasing levels of CRP (Figure 2D; log-rank trend, P = 0.24). The cumulative incidence of recurrence at the end of follow-up was 7%, 6%, and 10% among women in the lowest, middle, and highest tertile of CRP. Corresponding age adjusted HRs were 1.00, 1.11 (95% CI, 0.70 to 1.76), and 1.53 (0.98 to 2.37); P for trend = 0.06 (Figure 3). The HRs remained similar after multifactor-adjustment for prognostic tumour characteristics and additional adjustment for lifestyle factors, menopause status, and cardiovascular disease.
Dividing CRP levels into octiles also resulted in a stepwise increased risk of reduced overall survival (Figure 4; P for trend <0.001). The multifactor-adjusted HR of reduced overall survival among women in the highest versus the lowest octile of CRP was 2.50 (95% CI, 1.52 to 4.10) (Figure 4). Compared to women with CRP levels in the 0 to 25% percentile (<0.78 mg/L), the multifactor-adjusted HR of reduced overall survival was 3.59 (2.37 to 5.44) among women with CRP levels ≥95% percentile (≥16.4 mg/L) (Figure 4).
Risk of reduced overall survival after a breast cancer diagnosis. Hazard ratios by octiles or extreme levels of plasma C-reactive protein (CRP) are based on 2,910 women from the Copenhagen Breast Cancer Study who were observed for up to seven years after a diagnosis of breast cancer. Model 1: adjusted for age at diagnosis. Model 2: adjusted for age at diagnosis, tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status. Model 3: adjusted for the above-mentioned covariates and smoking, alcohol consumption, body mass index, menopausal status, and cardiovascular disease.
In sub-analyses stratified for age at diagnosis and prognostic tumour characteristics, elevated CRP levels across tertiles were associated with reduced overall survival irrespective of presence of distant metastases, and estrogen and progesterone receptor status (Table 3). Furthermore, elevated CRP levels were associated with reduced overall survival separately in women above 57 years, with small and middle-sized tumours, positive lymph node status, moderately and poorly/undifferentiated tumours, and HER2 positive tumours. The multifactor-adjusted HR of reduced overall survival for the highest versus the lowest tertile of CRP was 8.63 (2.04 to 36.4) among women with HER2 positive tumours. However, tests of interaction between the CRP tertiles and the prognostic factors were all non-significant, suggesting that elevated CRP levels are associated with similarly reduced overall survival irrespective of age at diagnosis, tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status (Table 3). Exclusion of patients with CRP values above 40 mg/L, which likely reflect bacterial infection, resulted in similar hazard ratios for all endpoints (data not shown).
Hazard ratios are multifactor-adjusted for age at diagnosis, tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status, smoking, alcohol consumption, body mass index, menopause status, and cardiovascular disease (Model 3), excluding the factor stratified for; however, age stratified analyses were still adjusted for age.
Due to differences in numbers of missing values for the covariates in question, numbers of patients and deaths do not necessarily add up to 2,910 and 383, respectively.
Using a prospective cohort study of 2,910 Danish women with invasive breast cancer, we have demonstrated that elevated CRP levels at the time of diagnosis of breast cancer were associated with reduced overall and disease-free survival and with increased risk of death from breast cancer. These are novel observations.
Mechanistically, three components might explain the observed association between elevated CRP levels and poor breast cancer prognosis. First, tumour cell behavior: plasma CRP levels may reflect the aggressiveness of the tumour, that is, plasma CRP levels might sum up some prognostic information of well-known tumour characteristics, such as tumour stage and grade. In the present study, elevated CRP levels were indeed associated with larger tumour size, presence of distant metastases, and lower tumour grade (although CRP was not linearly associated with tumour grade), and these prognostic factors were associated with poor prognosis. Second, adjacent inflammation: plasma CRP levels might express the magnitude and the nature of any inflammation in the breast tumour microenvironment. Inflammatory pathways play important roles in all stages of tumourigenesis, including tumour initiation and promotion, malignant transformation, tumour invasion, and metastasis [3–6]. Thus, solid tumours typically trigger inflammatory responses that result in the formation of a pro-tumourigenic and pro-angiogenic microenvironment around the tumour. Immune and inflammatory cells in the tumour microenvironment interact with malignant cells in a complicated fashion, the net result of which is stimulation of tumour growth, invasion, and metastasis [5–9]. Despite the fact that breast cancers rarely are characterized by significant histological inflammation, inflammation might also play a role in breast cancer prognosis [15–20]. Thus, macrophage infiltration into invasive breast carcinomas was associated with high vascularity of the breast tumour as well as with reduced recurrence-free and overall survival , and targeting of cancer associated fibroblasts resulted in favourable changes of the immune tumour microenvironment and improved anti-metastatic effects of doxorubicin chemotherapy in a murine model of metastatic breast cancer . Furthermore, a recently published study showed that blockade of the IL-8 receptor selectively targets breast cancer stem cells and retards tumour growth and reduces metastasis . Third, host behaviour: plasma CRP levels may outline the general health of the woman at the time of diagnosis of breast cancer. In the present study, elevated CRP levels were indeed associated with smoking and elevated body mass index at the time of diagnosis. However, whereas smoking was not associated with poor breast cancer prognosis, body mass index <18.5 or ≥30 at the time of diagnosis was associated with poor prognosis. Previous studies have shown that elevated CRP levels are associated with all-cause mortality in the general population [29, 30]. Thus, it is possible that the present finding of an association between elevated CRP levels at the time of diagnosis of breast cancer and overall survival may not be breast cancer specific but can simply be due to CRP acting as a general marker of health and longevity. However, as 64% of the deaths in the present study were due to breast cancer, breast cancer was the leading cause of death in the present cohort. The fact that the observed association between elevated CRP levels and increased risk of death from breast cancer was of the same magnitude as the observed association between elevated CRP levels and overall survival suggest that CRP may indeed be associated with mortality through a breast-cancer-related mechanism. Elevated plasma CRP is a well-known marker of cardiovascular disease , which could imply that elevated CRP levels are associated with overall survival through the association with cardiovascular disease. However, the fact that only 11% of the deaths in the present cohort were due to cardiovascular diseases and the fact that we adjusted for cardiovascular disease at baseline limit the possibility that our finding on overall survival is severely confounded by deaths from cardiovascular disease.
Our findings of a positive association between elevated CRP levels and poor breast cancer prognosis are in contrast to negative studies with 110 to 300 patients [25, 26], but are indirectly supported by findings from other studies with 85 to 734 patients which did report a positive association [21–24]. The largest study so far which comprised approximately 700 women treated successfully for early stage breast cancer found that elevated levels of CRP measured two and a half years after the time of diagnosis were associated with reduced disease-free and overall survival . Thus, the combined evidence from this and our own study suggests that elevated plasma CRP levels are associated with short-term as well as long-term prognosis after breast cancer. Whereas studies that measure CRP after diagnosis and treatment reflect long-term prognosis, studies that measure CRP at the time of diagnosis more likely reflect breast cancer specific survival. In fact, approximately 55% of the deaths, 60% of the deaths from breast cancer, and 68% of the recurrences in the present study occurred during the first two and a half years after a diagnosis of breast cancer. Therefore, our results may not be comparable to studies that have measured CRP after diagnosis and treatment.
The large sample size of our study allowed us to stratify for well-established prognostic tumour characteristics, and interestingly our data suggest that elevated CRP levels are associated with reduced overall survival irrespective of age at diagnosis, tumour size, lymph node status, presence of distant metastases, tumour grade, and estrogen receptor, progesterone receptor, and HER2 status. However, we observed a very strong association between elevated CRP levels and reduced overall survival among women with positive HER2 status which may warrant further investigation by future studies.
Dividing plasma CRP levels into octiles resulted in a stepwise increased risk of reduced overall survival, demonstrating the robustness of the observed association between elevated CRP levels and risk of reduced overall survival. Furthermore, we observed that compared to women with CRP levels in the 0 to 25% percentile (CRP <0.78 mg/L), women with CRP levels ≥95% percentile (≥16.4 mg/L) had a 3.5-fold increased risk of reduced overall survival, suggesting that women with high CRP levels at the time of diagnosis have a particularly poor survival.
Although the age-adjusted HR for recurrence for the highest versus the lowest tertile of CRP was borderline significant, we did not detect a statistically significant association between elevated CRP levels and recurrence of breast cancer, which may suggest that no such association exists. However, as we only detected 118 recurrences in our study in contrast to 383 deaths, it is also possible that our statistical power was too small to detect an association. Therefore, other, larger studies are needed to answer unequivocally whether increased CRP levels at the time of diagnosis associate with recurrence of breast cancer or not.
As CRP is one of several acute-phase proteins, whose concentrations increase during acute or chronic inflammation, other inflammation-related biomarkers may also be associated with breast cancer prognosis. Prior studies have reported that lower serum albumin concentrations , elevated serum amyloid A concentrations , and elevated YKL-40 concentrations  are all associated with poor breast cancer prognosis.
So far, the present study is by far the largest study that has examined whether an association exists between CRP levels at the time of diagnosis and breast cancer prognosis. However, certain limitations must be acknowledged. Although we did adjust for potential confounders, we cannot exclude residual confounding by factors not taken into account, such as socioeconomic status, physical activity, and treatment, or by imperfectly or incompletely measured confounders. Since patients are referred to different treatment regimes on the basis of tumour characteristics, which we did adjust for, it seems unlikely that our results are confounded by differences in treatment. Also, we did not measure serum amyloid A, which has previously been associated with an even stronger increase in risk of death than CRP . Finally, since the present study is a single-center study of Danish women diagnosed with breast cancer, our findings may not necessarily apply to other ethnic groups. Since our department for breast surgery treats all patients with breast cancer from a geographically well-defined area of Copenhagen regardless of severity or sub-diagnosis, our results may indeed be generalized to comparable populations of unselected patients with breast cancer.
In conclusion, in 2,910 Danish women with invasive breast cancer, elevated CRP levels at the time of diagnosis of breast cancer were associated with reduced overall and disease-free survival and with increased risk of death from breast cancer, independently of well-established prognostic tumour characteristics and lifestyle factors.
We are indebted to the staff and participants of the Copenhagen Breast Cancer Study for their important contributions. This work was supported by the Danish Medical Research Council; the Research Council at Herlev Hospital, Copenhagen University Hospital; and Chief Physician Johan Boserup and Lise Boserups Fund. The study sponsors had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
All authors contributed to the conception and design of the study. HF and SEB contributed to the acquisition of data. KHA performed the statistical analysis and drafted the manuscript. BGN, HF and SEB critically revised the manuscript. All authors read and approved the final manuscript.


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I was a stranger in a strange land. Gone were the familiar greens and blues. Everything was white. And cold. Very cold!
I knew that it had been a harsh winter in Michigan. I heard about the polar vortex and kept current on conditions because our son and his family live there. But I was not prepared to be dropped into a setting of white.
As we began our descent into Grand Rapids, this was my view.
Close up was a lot more intimidating. Driving with snow drifts higher than your car is stranger than driving after Hurricane Irma left piles of debris along our Florida streets. Our Irma debris held on for over two months. I think the Michigan snow drifts might beat that.
It was embarrassing finding myself commenting on the snow. As a Floridian, I'm used to people talking about the weather. Our summers are long and hot. The heat can be oppressive and unrelenting. And the rain – the rain can sneak up on you and be delivered not only downward but sideways in sheets that take all visibility away. But just as suddenly as it began, it can be gone.
Snow is not like that. Snow stays and gets pushed around by convoys of plows. It gets piled high as an elephant's eye. It gets dirty and then covered by fresh snow. The plows come day after day. The piles grow. Ice storms mess with your footing. You have to borrow boots from your daughter-in-law (thanks, Dacia!). You have the feeling that you don't belong here. It's otherworldly.
So, comment I did. I couldn't stop talking about how white everything was. My sweet daughter-in-law seemed amused by my snow befuddlement. I did grow up in Maryland. We had snow there. But not like this! I stared out the window in amazement. I couldn't get over it. Finally, I realized I needed someone to help me with my culture shock, so I called in an expert – my four-year-old grandson. Felix loves snow. He was a little baffled by my lack of experience with it, so he offered his point of view.
I figure if it's a little too much snow for a four-year-old, it's okay that it's a lot too much for me.
Look up the meaning of vortex.
Play a drinking game. Whenever someone says "polar vortex" they have to take a shot of hot chocolate.
Read. Something by Robert Frost would be appropriate.
Watch movies, maybe something with a tropical theme or even The Polar Express might feel warmer than your current circumstances.
I caught this on the news this morning.
Ashton, you're killing me. You want us to be real with each other. You want connections. But your last line tells it all: You want to share your latest and greatest with us. Sounds a little one-way, if you ask me.
Anyway, Ashton, thanks for the chuckle. After I started writing this, I contemplated texting you, but I was afraid you'd text me back. So, I checked with Google and it looks like you have taken your number down or changed it or something equally non-communicative as far as your community goes. Silly boy.
Number 6 – Get excited about my post for tomorrow's blog. I'm doing a give-away.
On a serious note, I have family who are in Michigan, so I am praying that this dangerous cold weather passes through quickly and that people will be safe. Until tomorrow.


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Build-A-Bear Workshop Recalls Pin Due to Lead Paint
In a news release, Build-A-Bear Workshop in cooperation with the U.S. Consumer Product Safety Commission announced a voluntary recall Thursday of their Love.Hugs.Peace. lapel pins due to excessive levels of lead in the accessory's surface paint, which is illegal.
The recall affects approximately 26,500 pins sold in the United States and 2,200 in Canada. The pin is has a 1.5 inch diameter and features images of a red heart, blue peace sign and a brown bear head in the foreground and a globe in the background. The phrase "love.hugs.peace." is at the bottom of the lapel pin.
No injuries have been reported in connection to the pins, which were sold at Build-A-Bear Workshop stores nationwide and at the buildabear.com Web site from July 2009 through October 2010 for $3.50 in the U.S. and $4 (CDN) in Canada.
Consumers are advised to stop using the lapel pin and return it to any Build-A-Bear Workshop store in exchange for a $5 store coupon. If it is not possible to return the pin to a store, customers should contact Build-A-Bear Workshop for instructions on an alternate way of receiving a refund.
Lead has been shown to be harmful to children, affecting both physical and cognitive development. As a Los Angeles personal injury lawyer, I encourage anyone who is has one of the lapel pins to stay healthy by returning it right away.