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You are currently browsing the tag archive for the ‘melancholy’ tag.
VOTE 1 FOR WINTER (and melancholics)
June 28, 2013 in General sprays | Tags: A Writer’s Diary, Abraham Lincoln, acquiesce, Camp Hill, Canberra Times, Capital Hill, Ernest Hemingway, From the Diary of a Snail, Gunter Grass, Johan Johansson, Marilyn Monroe, Max Richter, melancholia, melancholy, Moses, panacea, Sigur Ros, trying hard not to be miserable...but not being able to help it (much), Vincent Van Gogh, Virginia Woolf, Vivaldi’s Four Seasons | 10 comments
A place that looks like this could well be predisposed to melancholia. With any luck.
I always look forward to it, through the high dry heat of summer and much of autumn. As the days shorten and shadow, once daylight-saving has finished its run and darkness comes before dinner, it’s one of the things I love most about being alive. And it’s this: at 6pm each night I scrunch up newspaper pages into balls, carefully craft a tee-pee of kindling, and, like placing a cherry on a dollop of ice-cream, I top it all off with a pine-cone, before, with the strike of a match, fire takes hold in the hearth. But wait, there’s more. There’s the pouring of a glass of semillon or ‘sav blonk’, and then, the piece de resistance, the playing of the most deliciously maudlin music I can find – Max Richter is a favourite (his reworking of Vivaldi’s Four Seasons is heartbreaking, in a good way), as is anything by Johan Johansson or those Icelandic post-rockers Sigur Ros.
When everything is in its place like this, I’m as happy as a humble scribe can be. Except, of course, happy isn’t right, because it’s misery that I’m after, or, at the very least, a no-holes-barred melancholy.
Melancholy: it’s a word to be adored. Acquiesce is another, so is panacea, but melancholy is the king or queen of the lexicon; but in these wild days of ours where gender is the be all and end all, let’s just say that melancholy rules the roost. Because it sounds good, and it looks good – as if it’s something that could be diced up and steamed – but it also feels good, no, it feels sublime. Melancholy means, of course, pensive sadness, or the constitutional tendency for said sadness. But it has troubling roots, being derived from the Greek word melas meaning black and khole meaning bile, which puts me off, just a smidgeon. Quick, throw another log on the fire, pour another dash of the white, and turn up the music!
However, there’s no escaping the out-and-out danger of what we’re talking about. It’s widely acknowledged that melancholia refers to a mental disorder marked by depression and ill-formed fears. Please step forward Abraham Lincoln, Marilyn Monroe, Ernest Hemingway and, um, Moses; Vincent van Gogh is also a member of the club but you already knew that. Interesting that my trusty Roget’s Thesaurus Everyman Edition (1972) jumps from melancholy to ‘distressing’ and ‘dejection’, but for melancholia it cuts to the chase by taking us straight to ‘insanity’, which sounds rough to me, but you can’t argue with Roget.
Could it be that the ACT region, in which I include the Southern Tablelands to the north and the Monaro district to the south, might be devilishly fond of putting melancholy on its people? It’s highly likely. Because we have the harshest winters: fog, frost, freezing nights, as well as wind and rain and sleet, and snow if we’re lucky. Because during the day we have a frighteningly blue sky, the sort that can send the best of us into an abyss of existential angst. And because during the night we have a perilously black sky, one that can pinch our breath. The tropics we are not; our winters can kill.
‘Blue Notebooks’ by Max Richter. For those who like to be blue, we salute you. Well, I salute you.
This particular winter, with all the dreadful mess that’s currently oozing out of Capital Hill (or Camp Hill as it was once called, and as some still refer to it, which is divine), could well be sending even the most buoyant amongst our number into a pit of despair. Or into the cult of busyness. And it’s here that I’m reluctantly reminded of what Gunter Grass wrote in From the Diary of a Snail (also first published in 1972): ‘If work and leisure are soon to be subordinated to this one utopian principle – absolute busyness – then utopia and melancholy will come to coincide: an age without conflict will dawn, perpetually busy – and without consciousness.’ No doubt our representatives in parliament house will ensure that over the next three long, slow, sinister months we’ll be fully supplied with conflict, between the future and the past, between fact and fiction, between elevation and condemnation, and – oh it seems absurd but regrettably it’s the case – between male and female*, and many of us may well indeed want to slip into unconsciousness. Which ultimately, irony of ironies, could be a lifesaver.
Virginia Woolf, in A Writer’s Diary (1953), is a bit more positive about us melancholic types, especially, I think, those who’ve fallen into the black hole of social media but are trying to make the most of it: ‘If one is to deal with people on a large scale and say what one thinks, how can one avoid melancholy?’
Amen to that, sister.
So, until mid-September, until spring with its colours that go beyond black and blue, and the lengthening, lightening days that are to come, I will ensure that the woodpile is fully stocked, overstocked if my back and bank-account can manage it, that there are enough bottles of cheap white plonk ready and waiting along the bottom drawer of the fridge, and that the most miserable CDs I own (and I have quite a few) are stacked beside me. But despite all this intentional – and, let’s be frank, gratuitous – desolation, there is hope. Because as winter knows best, particularly the sort of winters we have around these parts, especially the 2013 version, a true melancholic isn’t sick at heart, and a true melancholic doesn’t let cheap political tricks suck the marrow out of his or her bones. A true melancholic is simply realistic, and just a little brave.
First published in The Canberra Times on 22 June 2013. Thanks to Cameron Ross. *Written before Wednesday 26 July 2013, when Australian politics went arse-up. Now insert ‘between male ego and male ego’.
Melancholic ecstacy
November 12, 2011 in Collage Nation | Tags: ecstasy. Mason Cooley, I know I go on about melancholia and ecstasy but I'm afraid that will probably never change, melancholy, seduction | 4 comments
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Shaping A Government Accountable to the People
How our government collects and spends money is critically important. Tax and budget decisions are the most concrete way that communities declare priorities and balance competing values.
Unfortunately, government decisions about how to raise revenue and support public functions often fail to best advance the public interest. Too often, public subsidies, tax breaks or special deals are granted to powerful corporate interests at the taxpayers’ expense. When this happens, taxpayers are stuck with the tab, or public resources and services end up threatened.
It is not possible to ensure that government decisions are fair and efficient unless information is publicly accessible. Likewise, public officials and private companies that receive contracts and subsidies must be held accountable for delivering promised goods and services.
Transparency in government spending checks corruption, promotes fiscal responsibility, and allows for greater, more meaningful participation in our democratic system. NMPIRG Education Fund is working to advance these goals on a variety of fronts:
Promoting public access to online information about government spending at a detailed "checkbook" level including contracts, subsidies and "off-budget" agencies. NMPIRG Education Fund's 2016 Following The Money report is the seventh annual scorecard of state's online budget transparency. This latest scorecard finds that states continue to make progress toward comprehensive, one-stop, one-click transparency and accountability for state government spending, but some states are lagging and in all states there are opportunities to expand transparency to include economic development subsidies and quasi-public agencies.
Ensuring that companies that receive public subsidies are held accountable for delivering clear benefits or required to return public dollars.
Protecting against bad privatization deals that sell off public assets on the cheap and diminish public control of vital public structures such as toll roads, parking systems and traffic enforcement.
Find a full list of our reports here.
Issue updates
News Release | NMPIRG Education Fund | Democracy
New Report: New Mexico Receives C+ “GRADE” in Annual Report on Transparency of Government Spending
Albuquerque, NM March 14 – New Mexico received a “C + Grade” when it comes to government spending transparency, according to Following the Money 2012: How the States Rank on Providing Online Access to Government Spending Data, the third annual report of its kind by the New Mexico Public Interest Research Group (NMPIRG).
> Keep Reading
Report | NMPIRG Education Fund | Democracy
Following the Money 2012
The ability to see how government uses the public purse is fundamental to democracy. Transparency in government spending promotes fiscal responsibility, checks corruption, and bolsters public confidence. In the past few years, state governments across the country have made their checkbooks transparent by creating on- line transparency portals. These government-operated websites allow visitors to view the government’s checkbook—who receives state money, how much, and for what purposes.
New Report Released: Auctioning Democracy: The Rise of Super PACs and the 2012 Election
Washington, D.C. – Today U.S. PIRG Education Fund and Demos released a new analysis of the funding sources for the campaign finance behemoths, Super PACs. The findings confirmed what many have predicted in the wake of the Supreme Court’s damaging Citizens United decision: since their inception in 2010, Super PACs have been primarily funded by a small segment of very wealthy individuals and business interests, with a small but significant amount of funds coming from secret sources.
Auctioning Democracy: The Rise of Super PACs and the 2012 Election
The findings confirmed what many have predicted in the wake of the Supreme Court’s damaging Citizens United decision: since their inception in 2010, Super PACs have been primarily funded by a small segment of very wealthy individuals and business interests, with a small but significant amount of funds coming from secret sources.
Report | NMPIRG Education Fund and Demos
The Dominance of Big Money in the 2014 Congressional Elections
In 2014, large donors accounted for the vast majority of all individual federal election contributions this cycle, just as they have in previous elections. Seven of every 10 individual contribution dollars to the federal candidates, parties, PACs and Super PACs that were active in the 2013-2014 election cycle came from donors who gave $200 or more. Candidates alone got 84 percent of their individual contributions from large donors.
News Release | NMPIRG Education Fund
Big Money Playing an Outsized Role in New Mexico Elections
In New Mexico’s congressional primaries, bigger wallets give a small set of mega-donors an outsized voice, according to new information released today by NMPIRG Education Fund and Demos. Just 302 donors who gave $1,000 or more to candidates in the primaries outspent the at least 6,126 small donors who gave less than $200, and 62% percent of all candidate contributions came from donors giving chunks of $1,000 or more.
Report | NMPIRG Education Fund
Big Money Dominates in Congressional Primaries
Our analysis of fund-raising data from 2014’s congressional primaries examines the way these dynamics are playing out state by state across the country. While some states show markedly more inequity than others, the picture painted by the data is of a primary money race where large donors carry more weight than ordinary Americans. Nationwide, just under two-thirds of all candidate contributions came from the largest donors (those giving over $1,000). And fewer than 5,500 large donors matched the primary contributions coming from at least 440,000 donors nationwide.
Release of New Report: Loopholes for Sale
A new report released Wednesday, March 21 by U.S. PIRG and Citizens for Tax Justice (CTJ) found that thirty unusually aggressive tax dodging corporations have made campaign contributions to 524 (98 percent) sitting members of Congress, and disproportionately to the leadership of both parties and to key committee members. The report, Loopholes for Sale: Campaign Contributions by Corporate Tax Dodgers, examines campaign contributions made by a total of 280 profitable Fortune 500 companies in 2006, 2008, 2010 and to date in 2012.
Loopholes for Sale
A new report by U.S. PIRG and Citizens for Tax Justice (CTJ) found that thirty unusually aggressive tax dodging corporations have made campaign contributions to 524 (98 percent) sitting members of Congress, and disproportionately to the leadership of both parties and to key committee members. The report, Loopholes for Sale: Campaign Contributions by Corporate Tax Dodgers, examines campaign contributions made by a total of 280 profitable Fortune 500 companies in 2006, 2008, 2010 and to date in 2012.
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Your tax-deductible donation supports NMPIRG Education Fund’s work to educate consumers on the issues that matter, and the powerful interests that are blocking progress.
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FG to build 4m houses by 2023 – Minister
NNUYA.COM
Army deploys new strategy to counter Boko-Haram
Okorocha urges IGP to disregard Ihedioha’s petition against him
The Federal Government on Saturday promised to address housing deficit by delivering one million houses per year to close the 17 million shortfall by the year 2033.
The Minister of State, Works and Housing, Mr Abubakar Aliyu, disclosed this in Abuja on Saturday during an inspection of the Federal Housing Authority (FHA) mass housing project in Zuba, Federal Capital Territory.
Aliyu said the government had decided to improve on current construction of 100,000 houses per years in order to meet the basic needs of the people.
“The production now is low; we are constructing 100,000 houses per year and we hope to improve it by constructing one million houses per year in order to close the gap of 17 million to 20 million housing deficits by the year 2033.
“That is the target of government, we are committed to doing that and to ensure that the programmes, policies are accomplished
“We will provide enabling environment to attract investors into the sector to help solve the problem of housing deficit in the country and to achieve the government’s goal by 2033,’’ he said.
Aliyu also said that the problems associated with acquisition of lands would be addressed.
Speaking on the Zuba project, the minister said it was designed specifically to address the huge housing deficit for the middle and low income earners.
He said the project which was to be completed by August was delayed because of the rainy season.
The minister gave assurance that the government would deliver the project as soon as possible.
“We will ensure that the project is completed soon, because it is one of our primary focuses.
“That is why it is our first point of call after inauguration,’’ he said.
Mr Umar Gonto, Acting Managing Director, FHA reiterated government’s commitment to ensuring that the common Nigerians have access to affordable housing
He said that the project was among many others spread across the country by the federal government,.
Gonto said that the houses were designed for low-income earners both in the public and private sector and the self-employed, once they meet up with the criteria.
Mr Ibrahim Shuaibu, the Project Manager, who took the minister round the site, said the 764 housing units were at 75 per cent completion stage.
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Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature
Kai Yu Ho, Michelle Harty, Jessica Kellogg, Kelly Teter, Szu Ping Lee, Yu Jen Chang, Gregory Bashford
A patellar-tendon-bearing (PTB) bar is a common design feature used in the socket of trans-tibial prostheses to place load on the pressure-tolerant tissue. As the patellar tendon in the residual limb is subjected to the perpendicular compressive force not commonly experienced in normal tendons, it is possible for tendon degeneration to occur over time. The purpose of this study was to compare patellar tendon morphology and neovascularity between the residual and intact limbs in trans-tibial amputees and healthy controls. Fifteen unilateral trans-tibial amputees who utilized a prosthesis with a PTB feature and 15 age- and sex- matched controls participated. Sonography was performed at the proximal, mid-, and distal portions of each patellar tendon. One-way ANOVAs were conducted to compare thickness and collagen fiber organization and a chi-square analysis was used to compare the presence of neovascularity between the three tendon groups. Compared to healthy controls, both tendons in the amputees exhibited increased thickness at the mid- and distal portions and a higher degree of collagen fiber disorganization. Furthermore, neovascularity was more common in the tendon of the residual limb. Our results suggest that the use of a prosthesis with a PTB feature contributes to morphological changes in bilateral patellar tendons.
Amputees
Patellar Ligament
Prostheses and Implants
Ho, K. Y., Harty, M., Kellogg, J., Teter, K., Lee, S. P., Chang, Y. J., & Bashford, G. (2019). Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature. Scientific reports, 9(1), [16392]. https://doi.org/10.1038/s41598-019-52747-9
Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature. / Ho, Kai Yu; Harty, Michelle; Kellogg, Jessica; Teter, Kelly; Lee, Szu Ping; Chang, Yu Jen; Bashford, Gregory.
In: Scientific reports, Vol. 9, No. 1, 16392, 01.12.2019.
Ho, KY, Harty, M, Kellogg, J, Teter, K, Lee, SP, Chang, YJ & Bashford, G 2019, 'Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature', Scientific reports, vol. 9, no. 1, 16392. https://doi.org/10.1038/s41598-019-52747-9
Ho KY, Harty M, Kellogg J, Teter K, Lee SP, Chang YJ et al. Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature. Scientific reports. 2019 Dec 1;9(1). 16392. https://doi.org/10.1038/s41598-019-52747-9
Ho, Kai Yu ; Harty, Michelle ; Kellogg, Jessica ; Teter, Kelly ; Lee, Szu Ping ; Chang, Yu Jen ; Bashford, Gregory. / Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{431e0b0a6e624c0487b814b4c79a7737,
title = "Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature",
abstract = "A patellar-tendon-bearing (PTB) bar is a common design feature used in the socket of trans-tibial prostheses to place load on the pressure-tolerant tissue. As the patellar tendon in the residual limb is subjected to the perpendicular compressive force not commonly experienced in normal tendons, it is possible for tendon degeneration to occur over time. The purpose of this study was to compare patellar tendon morphology and neovascularity between the residual and intact limbs in trans-tibial amputees and healthy controls. Fifteen unilateral trans-tibial amputees who utilized a prosthesis with a PTB feature and 15 age- and sex- matched controls participated. Sonography was performed at the proximal, mid-, and distal portions of each patellar tendon. One-way ANOVAs were conducted to compare thickness and collagen fiber organization and a chi-square analysis was used to compare the presence of neovascularity between the three tendon groups. Compared to healthy controls, both tendons in the amputees exhibited increased thickness at the mid- and distal portions and a higher degree of collagen fiber disorganization. Furthermore, neovascularity was more common in the tendon of the residual limb. Our results suggest that the use of a prosthesis with a PTB feature contributes to morphological changes in bilateral patellar tendons.",
author = "Ho, {Kai Yu} and Michelle Harty and Jessica Kellogg and Kelly Teter and Lee, {Szu Ping} and Chang, {Yu Jen} and Gregory Bashford",
doi = "10.1038/s41598-019-52747-9",
journal = "Scientific Reports",
T1 - Patellar tendon morphology in trans-tibial amputees utilizing a prosthesis with a patellar-tendon-bearing feature
AU - Ho, Kai Yu
AU - Harty, Michelle
AU - Kellogg, Jessica
AU - Teter, Kelly
AU - Lee, Szu Ping
AU - Chang, Yu Jen
AU - Bashford, Gregory
N2 - A patellar-tendon-bearing (PTB) bar is a common design feature used in the socket of trans-tibial prostheses to place load on the pressure-tolerant tissue. As the patellar tendon in the residual limb is subjected to the perpendicular compressive force not commonly experienced in normal tendons, it is possible for tendon degeneration to occur over time. The purpose of this study was to compare patellar tendon morphology and neovascularity between the residual and intact limbs in trans-tibial amputees and healthy controls. Fifteen unilateral trans-tibial amputees who utilized a prosthesis with a PTB feature and 15 age- and sex- matched controls participated. Sonography was performed at the proximal, mid-, and distal portions of each patellar tendon. One-way ANOVAs were conducted to compare thickness and collagen fiber organization and a chi-square analysis was used to compare the presence of neovascularity between the three tendon groups. Compared to healthy controls, both tendons in the amputees exhibited increased thickness at the mid- and distal portions and a higher degree of collagen fiber disorganization. Furthermore, neovascularity was more common in the tendon of the residual limb. Our results suggest that the use of a prosthesis with a PTB feature contributes to morphological changes in bilateral patellar tendons.
AB - A patellar-tendon-bearing (PTB) bar is a common design feature used in the socket of trans-tibial prostheses to place load on the pressure-tolerant tissue. As the patellar tendon in the residual limb is subjected to the perpendicular compressive force not commonly experienced in normal tendons, it is possible for tendon degeneration to occur over time. The purpose of this study was to compare patellar tendon morphology and neovascularity between the residual and intact limbs in trans-tibial amputees and healthy controls. Fifteen unilateral trans-tibial amputees who utilized a prosthesis with a PTB feature and 15 age- and sex- matched controls participated. Sonography was performed at the proximal, mid-, and distal portions of each patellar tendon. One-way ANOVAs were conducted to compare thickness and collagen fiber organization and a chi-square analysis was used to compare the presence of neovascularity between the three tendon groups. Compared to healthy controls, both tendons in the amputees exhibited increased thickness at the mid- and distal portions and a higher degree of collagen fiber disorganization. Furthermore, neovascularity was more common in the tendon of the residual limb. Our results suggest that the use of a prosthesis with a PTB feature contributes to morphological changes in bilateral patellar tendons.
U2 - 10.1038/s41598-019-52747-9
DO - 10.1038/s41598-019-52747-9
JO - Scientific Reports
JF - Scientific Reports
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The murder of Jo Cox taught us nothing
October 12, 2016 / Tom King / Leave a comment
Maybe we were all dreaming. Maybe the 16th June 2016 passed without incident in British politics. Maybe that Thursday, a week before the referendum on EU membership, was quiet and peaceful.
Flowers for Jo Cox
But we weren’t dreaming. And the horrific events that day, as a young Labour MP was shot and stabbed multiple times by a British nationalist neo-Nazi, will never stop haunting our country and our democracy.
The slow march of history is providing live context for that terrible day. These events are being shown for what they really were: mere collateral damage in the war of identity perpetrated by fascists. Not an isolated incident, but the natural consequence of ugly rhetoric whipping up outrage and carving division into the soul of a nation.
The newspaper headlines today say it all. The Daily Mail and the Daily Express have spent my lifetime viciously attacking anyone who does not conform to their hateful, racist ideology. Now that the EU is gone and the government has adopted their policies on immigration, they’re turning their fire on the people who have held them at bay for so long.
Daily Mail, October 12th 2016
Daily Express, October 12th, 2016
Thomas Mair, Jo Cox’s alleged murderer, gave his name as ‘Death to Traitors’ in court. And here the two chief attack dogs of the fascist right are, consciously using the same language. People who voted to remain in the European Union are not merely wrong: they are unpatriotic and subversive, and they are actively plotting. They are to be ‘damned’ and ‘silenced’.
We’re not talking about some cesspool backwater of the internet like Breitbart or Stormfront. These are ‘mainstream’ newspapers read by hundreds of millions. The Daily Mail’s website is the most visited English-language newspaper website in the world. Not just in the UK; not just in Europe; in the world.
Liberals have spent their lives mocking these newspapers. We write cutesy little songs about them. Sometimes we write serious songs about them. We pour scorn on their blaring headlines and we chortle at their farcical claims. We know they’re wrong and, confident in our grasp of the truth, we’re comfortable letting other people have the comfort of the lies.
And meanwhile those lies are taking hold. They are creating an environment that is poisonous to its very core. They are legitimising the febrile, turbulent, volatile attitudes that not only appeal to ignorance but demand it, cosset it, feed it, and turn it into something that feels like certainty.
We let this happen all the time. Last week there were a few timid voices against the tide of vitriol spouted by government ministers. One of them was mine: I wrote a long blog post about it. Notable among the many responses both here and elsewhere was a recurring theme: I was upbraided for using the terms ‘fascist’ and ‘racist’ too loosely. I was told that it was too much, that I was being hysterical, and that it undermined the point of the article.
The people who said this should be ashamed of themselves. The clearer it becomes that voices, livelihoods and lives themselves are considered dispensable by powerful people and institutions in the UK, the more we must respond. I’m ashamed of myself for having put mealy-mouthed caveats on some of those statements; ashamed, for attempting to soften my condemnation of an existential threat to humanity.
So I won’t stop using those terms. I won’t stop calling out fascist rhetoric and fascist policy when it is staring me in the face. I refuse to be silenced as the Daily Express demands. And I refuse to stand by and allow these bastards to spit on Jo Cox’s grave.
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Christian wall art can also bring great encouragement for our faith. No matter how long we have been a Christian, we all go through trials and challenges, ups and downs, and we all need encouragement. The more we serve Jesus Christ faithfully, the more warfare and attacks we may face. In these times it can be very helpful to have encouragement in the form of an inspired Christian work of art. God can really use Christian art to change the way we think and give us new courage and strength to go on. Scripture Art
One of the purposes of David Sorensen’s Christian wall art is to help Christians experience the great power and victory of Jesus Christ. We see so much darkness in the world, and can sometimes be discouraged by it. But through it all, Jesus Christ is Lord of lords and King of kings and despite the spiritual warfare, He is building His eternal kingdom throughout the ages. The Bible says that eventually the whole earth shall be filled with the knowledge of the goodness of the Lord. Isaiah prophecied ‘There is no end to the increase of His government and His reign.’ (Isaiah 9:7) Scripture Art
"You shall have no other gods before Me. "You shall not make for yourself an idol, or any likeness of what is in heaven above or on the earth beneath or in the water under the earth. "You shall not worship them or serve them; for I, the LORD your God, am a jealous God, visiting the iniquity of the fathers on the children, on the third and the fourth generations of those who hate Me,read more. Scripture Art
Share your faith with others through scripture art, gorgeous contemporary art featuring favorite Bible verses. Offer inspiration to yourself and others using framed canvases, wall peels or posters. Whether the words are found within the New Testament or the Old Testament, art that incorporates scripture into lovely images is sure to inspire, uplift and motivate. Find your guiding light through the Serenity Prayer, John 3:16 or among many more verses available in our scripture art collection. [less]
He made 300 shields of beaten gold, using three hundred shekels of gold on each shield, and the king put them in the house of the forest of Lebanon. Moreover, the king made a great throne of ivory and overlaid it with pure gold. There were six steps to the throne and a footstool in gold attached to the throne, and arms on each side of the seat, and two lions standing beside the arms. Twelve lions were standing there on the six steps on the one side and on the other; nothing like it was made for any other kingdom. All King Solomon's drinking vessels were of gold, and all the vessels of the house of the forest of Lebanon were of pure gold; silver was not considered valuable in the days of Solomon. Scripture Verse Christian Image
Glory of ChristChrist AtoningThe Effect Of The Word Of GodChrist's Own GloryimageThe Beauty Of NatureGod's Glory RevealedPerfection, DivineGospel, Historical Foundation OfAdoration, Of ChristGod Is TranscendentLight, SpiritualChrist's NatureExaltation Of ChristAccuracyRevelation, In NtHoliness, Believers' Growth InGlory, Revelation OfGlory Of GodDivinity Of ChristEarth, God SustainingGod On High Goodnews Art
Then God said, “Let us make man in our image, after our likeness. And let them have dominion over the fish of the sea and over the birds of the heavens and over the livestock and over all the earth and over every creeping thing that creeps on the earth.” So God created man in his own image, in the image of God he created him; male and female he created them. Scripture Art
He also made two capitals of molten bronze to set on the tops of the pillars; the height of the one capital was five cubits and the height of the other capital was five cubits. There were nets of network and twisted threads of chainwork for the capitals which were on the top of the pillars; seven for the one capital and seven for the other capital. So he made the pillars, and two rows around on the one network to cover the capitals which were on the top of the pomegranates; and so he did for the other capital. The capitals which were on the top of the pillars in the porch were of lily design, four cubits. There were capitals on the two pillars, even above and close to the rounded projection which was beside the network; and the pomegranates numbered two hundred in rows around both capitals. Thus he set up the pillars at the porch of the nave; and he set up the right pillar and named it Jachin, and he set up the left pillar and named it Boaz. On the top of the pillars was lily design. So the work of the pillars was finished. Now he made the sea of cast metal ten cubits from brim to brim, circular in form, and its height was five cubits, and thirty cubits in circumference. Under its brim gourds went around encircling it ten to a cubit, completely surrounding the sea; the gourds were in two rows, cast with the rest. It stood on twelve oxen, three facing north, three facing west, three facing south, and three facing east; and the sea was set on top of them, and all their rear parts turned inward. It was a handbreadth thick, and its brim was made like the brim of a cup, as a lily blossom; it could hold two thousand baths. Then he made the ten stands of bronze; the length of each stand was four cubits and its width four cubits and its height three cubits. This was the design of the stands: they had borders, even borders between the frames, and on the borders which were between the frames were lions, oxen and cherubim; and on the frames there was a pedestal above, and beneath the lions and oxen were wreaths of hanging work. Now each stand had four bronze wheels with bronze axles, and its four feet had supports; beneath the basin were cast supports with wreaths at each side. Its opening inside the crown at the top was a cubit, and its opening was round like the design of a pedestal, a cubit and a half; and also on its opening there were engravings, and their borders were square, not round. The four wheels were underneath the borders, and the axles of the wheels were on the stand. And the height of a wheel was a cubit and a half. The workmanship of the wheels was like the workmanship of a chariot wheel. Their axles, their rims, their spokes, and their hubs were all cast. Now there were four supports at the four corners of each stand; its supports were part of the stand itself. On the top of the stand there was a circular form half a cubit high, and on the top of the stand its stays and its borders were part of it. He engraved on the plates of its stays and on its borders, cherubim, lions and palm trees, according to the clear space on each, with wreaths all around. He made the ten stands like this: all of them had one casting, one measure and one form. He made ten basins of bronze, one basin held forty baths; each basin was four cubits, and on each of the ten stands was one basin. Then he set the stands, five on the right side of the house and five on the left side of the house; and he set the sea of cast metal on the right side of the house eastward toward the south. Now Hiram made the basins and the shovels and the bowls. So Hiram finished doing all the work which he performed for King Solomon in the house of the LORD: the two pillars and the two bowls of the capitals which were on the top of the two pillars, and the two networks to cover the two bowls of the capitals which were on the top of the pillars; and the four hundred pomegranates for the two networks, two rows of pomegranates for each network to cover the two bowls of the capitals which were on the tops of the pillars; and the ten stands with the ten basins on the stands; and the one sea and the twelve oxen under the sea; and the pails and the shovels and the bowls; even all these utensils which Hiram made for King Solomon in the house of the LORD were of polished bronze. In the plain of the Jordan the king cast them, in the clay ground between Succoth and Zarethan. Solomon left all the utensils unweighed, because they were too many; the weight of the bronze could not be ascertained. Solomon made all the furniture which was in the house of the LORD: the golden altar and the golden table on which was the bread of the Presence; and the lampstands, five on the right side and five on the left, in front of the inner sanctuary, of pure gold; and the flowers and the lamps and the tongs, of gold; and the cups and the snuffers and the bowls and the spoons and the firepans, of pure gold; and the hinges both for the doors of the inner house, the most holy place, and for the doors of the house, that is, of the nave, of gold. Thus all the work that King Solomon performed in the house of the LORD was finished And Solomon brought in the things dedicated by his father David, the silver and the gold and the utensils, and he put them in the treasuries of the house of the LORD. Scripture Art
He made 300 shields of beaten gold, using three hundred shekels of gold on each shield, and the king put them in the house of the forest of Lebanon. Moreover, the king made a great throne of ivory and overlaid it with pure gold. There were six steps to the throne and a footstool in gold attached to the throne, and arms on each side of the seat, and two lions standing beside the arms. Twelve lions were standing there on the six steps on the one side and on the other; nothing like it was made for any other kingdom. All King Solomon's drinking vessels were of gold, and all the vessels of the house of the forest of Lebanon were of pure gold; silver was not considered valuable in the days of Solomon.
The porch which was in front of the house was as long as the width of the house, twenty cubits, and the height 120; and inside he overlaid it with pure gold. He overlaid the main room with cypress wood and overlaid it with fine gold, and ornamented it with palm trees and chains. Further, he adorned the house with precious stones; and the gold was gold from Parvaim.read more. Scripture Verse Art
Now King Solomon sent and brought Hiram from Tyre. He was a widow's son from the tribe of Naphtali, and his father was a man of Tyre, a worker in bronze; and he was filled with wisdom and understanding and skill for doing any work in bronze So he came to King Solomon and performed all his work. He fashioned the two pillars of bronze; eighteen cubits was the height of one pillar, and a line of twelve cubits measured the circumference of both. read more. Scripture Art
Our contemporary Christian wall art provides the perfect spiritual ambience for your home. Find Christian paintings with your favorite scripture verse from the Bible. You’ll recognize quotes from the books of Philippians, Proverbs 3:5-6, John 3:16, Romans, Matthew, Mark, Jeremiah 29:11 and many more to inspire you to walk closer to God. Don’t worry as we sell custom Christian wall decor which is framed and available in the NIV (New International Version), KJV (King James Version) or any version of God’s holy word. Finally we sell Christian art such as paintings to prints and pictures which are perfect Christian gifts for men and women. My christian home decor is stunning and I have a large variety of Christian canvas print wall art. Take a look around, I'm sure you'll be happy with what you see. Scripture Verse Christian Image
Solomon made all the furniture which was in the house of the LORD: the golden altar and the golden table on which was the bread of the Presence; and the lampstands, five on the right side and five on the left, in front of the inner sanctuary, of pure gold; and the flowers and the lamps and the tongs, of gold; and the cups and the snuffers and the bowls and the spoons and the firepans, of pure gold; and the hinges both for the doors of the inner house, the most holy place, and for the doors of the house, that is, of the nave, of gold.
Glory of ChristChrist AtoningThe Effect Of The Word Of GodChrist's Own GloryimageThe Beauty Of NatureGod's Glory RevealedPerfection, DivineGospel, Historical Foundation OfAdoration, Of ChristGod Is TranscendentLight, SpiritualChrist's NatureExaltation Of ChristAccuracyRevelation, In NtHoliness, Believers' Growth InGlory, Revelation OfGlory Of GodDivinity Of ChristEarth, God SustainingGod On High Scripture Art
and in the cutting of stones for settings, and in the carving of wood, that he may work in all kinds of craftsmanship. "And behold, I Myself have appointed with him Oholiab, the son of Ahisamach, of the tribe of Dan; and in the hearts of all who are skillful I have put skill, that they may make all that I have commanded you: the tent of meeting, and the ark of testimony, and the mercy seat upon it, and all the furniture of the tent, the table also and its utensils, and the pure gold lampstand with all its utensils, and the altar of incense, the altar of burnt offering also with all its utensils, and the laver and its stand, Scripture Verse Christian Image
For my Christian wall art, my shop uses state-of-the-art machines that print very beautiful and clear images onto frameless and framed canvas art. Read my reviews, all of my customers have been very happy. I created my shop to give the best inspirational and religious scripture prints on frameless artwork but I do know that it is not a low price. But if you email me, I can work with you on some special prices. I believe my bible verse wall art is some of the best in the world and its all custom made. I am currently working on some designs that are wall decals and posters which are great faith based Christian wall decor products that I think you would love. If you have any special requests, please let me know. I have made Contemporary Christian wall decor (wall decals, posters, bible verse art and more). Scripture Art
And when he had taken the scroll, the four living creatures and the twenty-four elders fell down before the Lamb, each holding a harp, and golden bowls full of incense, which are the prayers of the saints. And they sang a new song, saying, “Worthy are you to take the scroll and to open its seals, for you were slain, and by your blood you ransomed people for God from every tribe and language and people and nation, and you have made them a kingdom and priests to our God, and they shall reign on the earth.” Then I looked, and I heard around the throne and the living creatures and the elders the voice of many angels, numbering myriads of myriads and thousands of thousands, saying with a loud voice, “Worthy is the Lamb who was slain, to receive power and wealth and wisdom and might and honor and glory and blessing!” ... Goodnews Art
For my Christian wall art, my shop uses state-of-the-art machines that print very beautiful and clear images onto frameless and framed canvas art. Read my reviews, all of my customers have been very happy. I created my shop to give the best inspirational and religious scripture prints on frameless artwork but I do know that it is not a low price. But if you email me, I can work with you on some special prices. I believe my bible verse wall art is some of the best in the world and its all custom made. I am currently working on some designs that are wall decals and posters which are great faith based Christian wall decor products that I think you would love. If you have any special requests, please let me know. I have made Contemporary Christian wall decor (wall decals, posters, bible verse art and more). Scripture Verse Christian Image
So when’s your next Church retreat? That soon! Well, are you prepared with Christian clothes for you and your group? Here at ChristianGear.com we’ve got a wide selection of Christian clothing including Christian themed hats and every type of Christain t-shirt you can think of! Plus you have the ability to design your very own special Christian t-shirt using our easy to use personalization tools. Scripture Verse Christian Image
To set us free. To transform us. To heal us. To give us a new life, in His loving embrace. Jesus Christ is literally God Himself, the creator of heaven and earth, the master of creation, the Lord of all the heavenly hosts…Jesus Christ is God. He came to us, and He did something incredible. Something literally NOBODY had expected. No prophet, no apostle, no angel and no demon had expected this. Scripture Art
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Joe Heck on Jobs
Voted YES on allowing compensatory time off for working overtime.
Amends the Fair Labor Standards Act of 1938 to authorize private employers to provide compensatory time off to private employees at a rate of 1 1/2 hours per hour of employment for which overtime compensation is required.
Authorizes an employer to provide compensatory time only if it is in accordance with an applicable collective bargaining agreement.
Prohibits an employee from accruing more than 160 hours of compensatory time.
Requires an employee's employer to provide monetary compensation for any unused compensatory time off accrued during the preceding year.
Requires an employer to give employees 30-day notice before discontinuing compensatory time off.
Opponent's Argument for voting No:
Rep. COURTNEY: This is the fifth time that the majority party has introduced [this bill since] 1997; and each time, the huge flaws in this legislation have resulted in its complete collapse. And once again, it doesn't deserve that support. Despite the representations made in its title--that it promotes workers' flexibility, that it gives workers choice--a closer examination of the bill shows the opposite is true. The better way to describe this bill is the More Work, Pay Less bill.
The 1938 Fair Labor Standards Act created a bright line to protect people's right to a 40-hour work week, and make sure that that next hour after 40 hours is paid for with the time-and-a-half of wages. That created the weekend in America. That created the time off that middle class families have taken for granted for decades.
What this bill does is it blurs that line; it creates total chaos in terms of trying to come up with a system to set up ground rules with a case-by-case written contract, and then leaves it to the enforcement of State Labor Departments Wage and Hours Divisions, which are totally incapable of going into the tens of thousands of workplaces all across America.
Reference: Working Families Flexibility Act; Bill H.R.1406 ; vote number 13-HV137 on Apr 9, 2013
Member of House Education and Labor Committee.
Heck is a member of the House Education and Labor Committee
The House Committee on Education and the Workforce's purpose is to ensure that Americans' needs are addressed so that students and workers may move forward in a changing school system and a competitive global economy. The following issues are under the jurisdiction of the Committee:
Elementary and secondary education initiatives, including the No Child Left Behind Act, school choice for low-income families, special education, and vocational and technical education;
Early childhood & preschool education programs including Head Start;
School lunch and child nutrition programs;
Programs and services for the care and treatment of at-risk youth, child abuse prevention, and child adoption;
Anti-poverty programs, including the Community Services Block Grant Act and the Low Income Home Energy Assistance Program (LIHEAP).
Labor: The Committee also holds jurisdiction over workforce initiatives, including:
Pension and retirement security
Access to quality health care for working families and other employee benefits;
Job training, adult education, and workforce development initiatives, including those under the Workforce Investment Act (WIA)
Continuing the successful welfare reforms of 1996;
Worker health and safety, including occupational safety and health;
Providing greater choices and flexibility (including "comp time" or family time options) to working women and men;
Equal employment opportunity and civil rights in employment;
Wages and hours of labor, including the Fair Labor Standards Act;
Workers' compensation, and family and medical leave;
All matters dealing with relationships between employers and employees.
Source: U.S. House of Representatives website, www.house.gov 11-HC-ELC on Feb 3, 2011
Rated 67% by CEI, indicating a mixed voting record on Big Labor.
Heck scores 67% by CEI on union issues
The Competitive Enterprise Institute (CEI), a public policy organization dedicated to the principles of free markets and limited government, has created a Congressional Labor Scorecard for the 112th Congress focusing on worker issues. The score is determined based on policies that support worker freedom and the elimination of Big Labor's privileges across the country.
Votes in the current Congress score include:
Bill: H.R. 658, LaTourette Amendment No. 21: NO on repealing changes to the Railway Labor Act's voting rules.
Bill: H.R. 658, Gingrey Amendment No. 18: YES to prohibit Federal Aviation Administration employees from using official--that is, taxpayer sponsored--time for union activities during the official workday.
Bill: H.R. 1, Price Amendment No. 410: YES to defund the National Labor Relations Board (NLRB).
Bill: H.R. 1, Guinta Amendment No. 166: YES to prohibit imposing "prevailing wage" and other requirements in project labor agreements that advantage unionized contractors.
Bill: H.R. 2017, Scalise Amendment No. 388: YES to prohibit project labor agreements in DHS contracts
Bill: H.R. 2055, LaTourette Amendment No. 411: NO on funding for federal project labor agreements.
Bill: H.R. 1, King Amendment No. 273: YES to eliminate the "Davis Bacon" prevailing wage rate requirement for federal projects.
Bill: H.R. 2017, Gosar Amendment No. 386: YES to eliminate the "Davis Bacon" prevailing wage rate requirement for Department of Homeland Security contracts.
Bill: H.R. 2354: Gosar Amendment No. 655: YES to restrict application of the Davis-Bacon Act to contracts exceeding $20 million.
Bill: H.R. 2017: Rokita Amendment No. 2: YES to prohibit collective bargaining at the Transportation Security Administration (TSA).
Source: CEI website 12-CEI-H on May 2, 2012
Click here for definitions & background information on Jobs.
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Click here for a summary of Joe Heck's positions on all issues.
Click here for a summary of Joe Heck's positions on the AmericansElect.org quiz.
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2016-17 Governor, House and Senate candidates on Jobs: Joe Heck on other issues:
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Office 132 CHOB, Wash., DC 20515
Page last updated: Feb 03, 2017
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Endocrine Disruption in the Omics Era: New Views, New Hazards, New Approaches
Eva Oliveira, Carlos Barata, Benjamin Piña*
Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18, 08034 Barcelona, Spain
Issue: Suppl-1, M3
Received Date: 11/6/2014
Revision Received Date: 11/5/2015
Acceptance Date: 5/6/2015
Abstract HTML Views: 1017
© Oliveira et al.; Licensee Bentham Open.
* Address correspondence to this author at the IDAEA-CSIC, Jordi Girona 18, 08034 Barcelona, Spain; Tel: 34 93 400 6157; Fax: 34 93204 5904; E mail: bpcbmc@cid.csic.es
The genome revolution has brought about a complete change on our view of biological systems. The quantitative determination of changes in all the major molecular components of the living cells, the "omics" approach, opened whole new fields for all health sciences, including toxicology. Endocrine disruption, i.e., the capacity of anthropogenic pollutants to alter the hormonal balance of the organisms, is one of the fields of Ecotoxicology in which omics has a relevant role. In the first place, the discovery of scores of potential targets in the genome of almost any Metazoan species studied so far, each of them being a putative candidate for interaction with endocrine disruptors. In addition, the understanding that ligands, receptors, and their physiological functions suffered fundamental variations during animal evolution makes it necessary to assess disruption effects separately for each major taxon. Fortunately, the same deal of knowledge on genes and genomes powered the development of new high-throughput techniques and holistic approaches. Genomics, transcriptomics, proteomics, metabolomics, and others, together with appropriate prediction and modeling tools, will mark the future of endocrine disruption assessment both for wildlife and humans.
Keywords: Chemicals, endocrine disruption, hormone, metabolomics, proteomics, risk assessment, transcriptomics.
INTRODUCTION - THE "OMICS" PERSPECTIVE
The completion of the Human Genome Project in 2001 represented a complete turning point in Biology. Together with the complete genomes of the yeast Saccharomyces cerevisiae (1996), the nematode Caenorhabditis elegans (1998), the fruitfly Drosophila melanogaster (2000), the cress Arabidopsis thaliana, and the fish Takifugu rubripes (2002), it allowed for the first time the analysis of the genetic makeup of Eukaryotes in its complete extension and to establish new functional, evolutive and physiological correlations between taxa, individuals, organs and cell types. The development of new highly efficient analytical techniques has allowed similar holistic approaches for essentially all components of the live cell. For example, following the biological flow of information, high throughput techniques of specific RNA quantitation (microarrays) allowed the description of the mRNA complement of a given cell or tissue, i.e., the description of its transcriptome. A similar approach, but using completely different methods (2D electrophoresis, advanced mass spectrometry techniques), has been applied to elucidate the protein composition (the "proteome") with unprecedented precision, whereas several analytical methodologies (gas and liquid chromatography coupled to mass spectrometry, capillary electrophoresis, and high resolution nuclear magnetic resonance (NMR) allow the description of the chemical composition of the cell, that is, the nature and composition of its metabolites (the "metabolome"). Fig. (1) summarizes the nature and challenges of each one of these "omic" analyses.
The application of “omics” tools/technologies is now widely employed in many research areas, from medicine to environmental sciences, as they give information on some key regulators of various processes in living organisms. They also represent a tremendous opportunity to improve human and wildlife health by the characterization of the environmental elements that impact public and wildlife health [1]. The recognition of these challenges and opportunities, along with the fact that many of the most prevalent diseases are associated with the endocrine system, has led to a focus on chemical exposures and especially endocrine disruptors. The term ecotoxicogenomics refers to the integration of genomic-based science into ecotoxicology using DNA array-based technologies, proteome and metabolomic analyses [2]. The approach has been fundamental in several aspects of our current comprehension of the effects of endocrine disruption: The elucidation of potential effects on different animal taxa, thanks to comparative genomics, the comprehension of the multiple targets for exogenous ligands in the cell, and the development of new and more precise methodologies to monitor endocrine disruption both in humans and in wildlife.
Fig. (1).
Overview on the generic processes that characterize the differences “omics” technologies. On the left, schematic representation of the Biological information flow from the genome to cellular phenotypes. From top to bottom, the information of DNA (genome) is first transcribed to mRNA (transcriptome), which is afterwards translated into proteins (proteome). A subset of proteins, the enzymes catalyse reactions that both consume and produce the different metabolites (metabolome). The main table summarizes different characteristics of each omic technique.
HORMONES AND PHYSIOLOGICAL PROCESSES
Hormone are endogenous molecules secreted by endocrine glands that travel through the blood stream and induce physiological effects on distant cells and tissues [3]. The mechanism by which hormones exert their actions on target cells remained obscure for decades, although the concept of the existence of an endogenous receptor responsible for the recognition of the hormone (the "ligand") and the triggering of the physiological changes derived from its presence dates from the early 70's [4]. The isolation and cloning of the first hormone receptors in the 80's opened the Molecular Endocrinology era [5, 6]. However, the recognition of the amazing complexity and implication of the hormonal signaling did not appear until the advancement of whole genome sequencing techniques and its extension to evolutionary distant species [6, 7]. Analysis of complete genomes of different species revealed the presence of dozens, if not hundreds, of evolutionary related proteins for which no ligand or function was known. These so-called "orphan" receptors are widespread across Metazoa and their functional characterization implicated a major progress on the understanding of cell regulation, development and even evolutionary links between animal taxa [6-8]. An overview of the different receptor families, their physiological ligands and their distribution among the major Metazoan taxa is shown in Table 1.
ENDOCRINE DISRUPTION
Environmental pollutants in the various ecosystems are a major concern worldwide. Our understanding of the potential adverse effects of anthropogenic contaminants has driven to an increasing public awareness on their influence on health and well-being of both humans and wildlife [3, 9]. The primary observed effects of those pollutants are related to several developmental and reproductive disorders in wildlife species, which have been clearly linked to environmental compounds that act as endocrine disrupting chemicals (EDCs) [3].
By definition “An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations" [10]. Reports of adverse effects by EDCs in the last decades include reproductive impairment (decrease fertility, hermafroditism and sex reversal, altered sex ratios, hatching success), metabolic defects (Thyroid dysfunction, body weight and fat tissue control alteration), and alteration of immunological and behavioural functions have been observed in wild populations of mammals, birds, reptiles, amphibians, fish and mollusks; epidemiological evidences indicate that at least part of these or similar effects may be already occurring in human populations [3, 10-14].
Nuclear receptors and their known ligands. Linkage between the nuclear receptors and their existence in animal taxa.
Unified Name
Ligands (Mammalian)
Taxonomic Distribution
Dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome, gene 1 DAX-1 NR0B1 V, Ar
Short heterodimeric partner SHP NR0B2 V, Ar
Thyroid hormone receptor α TRα NR1A1 thyroid hormones V, UC, Mol, Ann
Thyroid hormone receptor β TRβ NR1A2 thyroid hormones V, UC, Mol, Ann
Retinoic acid receptor α RARα NR1B1 retinoic acids V, UC
Retinoic acid receptor β RARβ NR1B2 retinoic acids V, UC
Retinoic acid receptor γ RARγ NR1B3 retinoic acids V, UC
Peroxisome proliferator-activated receptor α PPARα NR1C1 fatty acids V, UC
Peroxisome proliferator-activated receptor β /d PPARβ/δ NR1C2 fatty acids V, UC
Peroxisome proliferator-activated receptor γ PPARg NR1C3 fatty acids V, UC
Reverse-Erb α REV-ERBα NR1D1 [heme] V, UC, Ar
Reverse-Erb β REV-ERBβ NR1D2 [heme] V, UC, Ar
RAR-related orphan receptor α RORα NR1F1 [sterols] V, UC, Ar
RAR-related orphan receptor β RORβ NR1F2 [sterols] V, UC, Ar
RAR-related orphan receptor γ RORγ NR1F3 [sterols] V, UC, Ar
Liver X receptor β LXRβ NR1H2 oxysterols V, UC, Ar
Liver X receptor α LXRα NR1H3 oxysterols V, UC, Ar
Farnesoid X receptor α FXRα NR1H4 bile acids V, UC, Ar
Farnesoid X receptor βα FXRβ NR1H5 V, UC, Ar
Ecdisone receptor EcR NR1H Ecdysone Ar, Nem*
Vitamin D receptor VDR NR1I1 1a,25-dihydroxyvitamin D3 and lithocholic acid V, UC, Ar, Nem
Pregnane X receptor PXR NR1I2 endobiotics and xenobiotics V, UC, Ar, Nem
Constitutive androstane receptor CAR NR1I3 xenobiotics V, UC, Ar, Nem
Hepatocyte nuclear factor 4 α HNF4a NR2A1 [fatty acids] V, UC, Ar, Nem
Hepatocyte nuclear factor 4 γ HNF4g NR2A2 [fatty acids] V, UC, Ar, Nem
Retinoid X receptor α RXRα NR2B1 9-cis retinoic acid and docosahexanoic acid V, UC, Ar, Mol
Retinoid X receptor β RXRβ NR2B2 9-cis retinoic acid and docosahexanoic acid V, UC, Ar, Mol
Retinoid X receptor γ RXRγ NR2B3 9-cis retinoic acid and docosahexanoic acid V, UC, Ar, Mol
Testicular orphan receptor 2 TR2 NR2C1 V, UC, Ar, Nem
Tailless homolog orphan receptor TLX NR2E1 V, UC, Ar, Nem
Photoreceptor-cell-specific nuclear receptor PNR NR2E3 V, UC, Ar, Nem
Chicken ovalbumin upstream promoter-transcription factor α COUP-TFα NR2F1 V, UC, Ar, Nem
Chicken ovalbumin upstream promoter-transcription factor b COUP-TFβ NR2F2 V, UC, Ar, Nem
Chicken ovalbumin upstream promoter-transcription factor γ COUP-TFγ NR2F6 V, UC, Ar, Nem
Estrogen receptor α ERα NR3A1 estrogens V, UC*, Mol*, Ann
Estrogen receptor β ERβ NR3A2 estrogens V, UC*, Mol*, Ann
Estrogen related receptor α ERRα NR3B1 V, UC, Ar
Estrogen related receptor β ERRβ NR3B2 V, UC, Ar
Estrogen related receptor γ ERRg NR3B3 V, UC, Ar
Glucocorticoid receptor GR NR3C1 glucocorticoids V
Mineralocorticoid receptor MR NR3C2 mineralocorticoids and glucocorticoids V
Progesterone receptor PR NR3C3 progesterone V
Androgen receptor AR NR3C4 androgens V
Nerve-growth-factor-induced gene B NGF1-B NR4A1 V, UC, Ar
Nur-related factor 1 NURR1 NR4A2 V, UC, Ar
Testicular orphan receptor 4 TR4 NR4A2 V, UC, Ar
Neuron-derived orphan receptor 1 NOR-1 NR4A3 V, UC, Ar
Steroidogenic factor 1 SF-1 NR5A1 [phospholipids] V, UC, Ar
Liver receptor homolog-1 LRH-1 NR5A2 [phospholipids] V, UC, Ar
Germ cell nuclear factor GCNF NR6A1 V, UC, Ar, Nem
There are varied sources of environmental contaminants that may disrupt the endocrine system (Fig. 2). The human exposure typically occurs with the environmental contamination of the food chain, especially fresh water fish and meat, contact with contaminated household dust, and occupational exposure [9]. Some chemicals were banned or removed from production years ago but persist in the environment. On the other hand other EDCs are high production volume chemicals found in a many household products. Bisphenol A (BPA), for example, is present in polycarbonate plastics, including beverage and food storage containers; epoxy resins that line the interior of metal cans, and in the ink used for thermal paper receipts. Many textiles contain contaminants, such as flame-retardants, including tetrabromobisphenol A and polybrominated diphenyl ethers. Some individuals have also been exposed to contaminants with adverse effects as a result of medical (diethylstilbestrol; DES), dental (diglycidyl methacrylate; GMA) or dietary (phytoestrogens) interventions. Urban wastewaters are important pollutant sources of natural and synthetic estrogens and other hormones that are subsequently found in surface waters [15, 16]. Thus, exposure to EDCs is ubiquitous and inevitable and there is growing concern that living in an EDC contaminated world may be contributing to adverse health trends, such as early puberty and infertility, because of growing evidence that a number of EDCs can produce varied effects [3, 17], (Fig. 2).
EVOLUTIONARY PERSPECTIVE OF ENDOCRINE DISRUPTION: EDCS IN INVERTEBRATES
From its very first origins, the concept of endocrine disruption has been deeply associated to terrestrial vertebrate wildlife (birds, reptiles) and humans. However, environmental and laboratory research indicate that fish species are particularly sensitive to many forms of endocrine disruption, particularly to estrogens [18]. Finally, the discovery that the presence of TBT in coastal waters is linked to imposex in marine gastropods brought the same concept to mollusks and invertebrates in general [19, 20]. The more recent deleterious effects of neonicotinoid insecticides on bee colonies around the world is probably a further example of the importance of recognizing and controlling environmental EDCs than can effect non-vertebrate species [21]. Nevertheless, information on EDCs in invertebrate species is still limited [22-30].
Summary of the common sources and mechanisms of endocrine disruptors in humans and how they may influence some key developmental processes, in particular through their actions during critical periods of development.
Difficulties in performing invertebrate studies are largely due to the limited knowledge on the endocrine physiology of many invertebrate groups that represent important components of ecosystems. In the first place, the concept "invertebrate" is essentially instrumental, as it covers species from widely different Metazoans. Only among animals with bilateral symmetry (Bilateria), three major taxonomic clades appear: Deuterostomata (which includes Vertebrates and Echinoderms, among others), Ecdisozoa (Nematodes and Arthropods) and Spiralia/Lophotrochozoa (Mollusks and Annelids), the two later forming the group of Protostomata [31, 32] (Fig. 3). These major groups of animals, as well as the ancestral groups of Porifera and Ctenophora, are characterized by their distinct embryonic developments. Last advances on biochemistry, genome sequences and regulatory studies showed that they exhibit fundamental differences in their complements of nuclear receptors, in their ability to synthesize and metabolize molecules with ligand activity, and, most probably, in the physiological roles of these molecules (Fig. 3, Table 1) [8, 31-34].
Despite the great invertebrate genetic and taxonomic diversity, ecotoxicological studies are limited to few worms, mollusks and arthropod species that are easy to maintain and rear in the lab. Furthermore, in regard of their endocrine system, invertebrates have been relatively far less studied than vertebrates, with most of the literature published on invertebrate endocrinology referring to mollusks, insects and crustaceans [19, 34, 35]. When dealing with transcriptomic or proteomic analyses the situation is even worse, because of the relatively low number of invertebrate genomes at least partially sequenced and more or less correctly annotated [36, 37]. For these reasons there is a high degree of uncertainty to relate an adverse effect on invertebrate growth or reproduction to specific changes of its endocrine system. For example, despite the abundance of literature dealing with the development, growth and reproductive effects of EDC in invertebrates, only few studies have assessed unambiguously a truly endocrine disrupting effect [38]. Several studies tested the wrong premise that mammalian or vertebrate EDC should act as endocrine disruptors in invertebrates through identical or at least homologous mechanisms of action. This was especially evident for estrogenic/androgenic compounds tested against different arthropod species, which lack functional estrogenic/androgenic receptors (Table 1). In many cases, the detrimental effects of EDC on growth and reproduction reported, were related to egg mortality or feeding inhibition rather than to effects on endocrine disruption.
Presence of the different types of hormones among animals. Principal taxonomic groups are indicated. Signs ‘‘+’’ indicate that a given class of hormones has been demonstrated to be involved in life history transitions (LHT) for a particular taxon, ‘‘?’’ indicates that such a role has not been demonstrated, and ‘‘+?’’ indicates preliminary evidence for such a roles (modified from [84]). The current model for evolutionary relationships among animal taxa is shown on the left (from [32]).
Research conducted in the crustacean species Daphnia provides conclusive evidence that juvenile hormone agonists enhanced male production disrupting the ultraspiracle receptor signaling pathway during the initial phases of embryo development [39]. There is also evidence that juvenile hormone agonists modulate ecdysteroid activity causing embryo arrest or abnormalities throughout the ultraspiracle- and ecdysone-receptor complex [40]. Studies on the effects of antidepressants show that molluscan and crustacean reproductive and locomotion systems are affected by antidepressants at environmentally relevant concentrations [35].
In particular, antidepressants affect spawning and larval release in bivalves and disrupt locomotion and reduce fecundity in snails. In crustaceans, antidepressants affect freshwater amphipod activity patterns, marine amphipod photo and geotactic behavior, crayfish aggression, and daphnid reproduction and development [34, 35, 41]. The above reported effects are likely to be related through out disruption of neuroendocrine signaling pathways. Like in vertebrates, the endocrine control of growth, reproduction and behavior in invertebrates are initiated by neurohormones [34, 35, 41]. Serotonin and antidepressants targeting these neurohormones induce spawning in bivalves, alter locomotion and foraging behavior in gastropods and alter mimetic and predatory behavior and memory in cephalopods [42-49].
(De)regulation of haemoglobin-related genes by juvenile hormone (JH) or its analogs (Methoprene, Methylfarnesoate, Fenoxycarb, and Epofenonene) in Daphnia magna. (A), Putative pathways of JH disruption (modified from [51]). (B) Example of the hemoglobin deregulated phenotype in D. magna by ectopic activation of the JH pathway.
Neurohormones control a wide variety of biological systems in crustaceans, including reproduction, growth, maturation, larval development, immune function, metabolism, behavior and colour physiology. For example, both serotonin and dopamine have been found to stimulate the release of multiple other crustacean neuropeptide hormones including hyperglycaemic hormone, red and black pigment dispersing/concentrating hormone, neurodepressing hormone, molt-inhibiting hormone and gonad-stimulating hormone [34, 41, 50, 51] (Fig. 4). Although neurohormonal disruption in molluscan and crustacean species have been mostly limited to antidepressants, there are other pharmaceutical drugs targeting neuronal receptors or other enzymes that may also alter neuroendocrinological pathways that regulate key physiological function. One of those are non-steroidal anti-inflammatory drugs (NSAIDs) that interrupt crustacean eicosanoid metabolism, which appears to disrupt signal transduction affecting juvenile hormone metabolism and oogenesis [52].
The implementation of omics approaches to invertebrates is limited to only few model species and studies that have addressed omics and EDCs are scarce [36, 37, 53-56]. Probably the best characterized and solidly established mode of action (MoA) of "canonical" (i.e., active in vertebrates) EDCs is the disruption of the enzymatic pathways for steroid synthesis, which are very well conserved within Metazoans [19, 57, 58]. However, several studies [53, 54, 56, 59-63] reported disruption on regulatory mechanisms in addition to the effects on the steroidogenic pathway. Transcriptomic patterns of intersex specimens of clams Scrobicularia plana showed a deregulation of the androgen receptor signaling pathway [53], an effect also described for Mya arenaria males exposed to TBT [64]. Metabolomic and proteomic analyses revealed different cases of neuroendocrine disruption in crustaceans and mollusks. For example, atrazine and its metabolites affected eicosanoids in the isopode Hyalella azteca suggesting possible perturbations in neuropeptide hormonal systems [55]. Similarly, ibuprofen inhibits reproduction in the crustacean Daphnia magna due to the de-regulation of the ecosanoid signaling pathway, and hence of prostaglandins, which in crustaceans control reproduction [62, 65]. A typical vertebrate estrogenic EDC, ethinylestradiol, alters metabolite pathways related to energy reserves, signal transduction, immune response, and neuromodulation in the unionid mussel Lampsilis fasciola. These effects result in physiological changes, as altered siphon and mantle [54], both in male and females. Conversely, the poly-bromo-diphenyl ether congener (BDE 47) affects differentially male and female specimens of the marine mussel Mytilus galloprovincialis: males show effects in energy metabolism, whereas, in females, BDE 47 disrupts both osmotic regulation and energy metabolism [56].
Very likely, we are just beginning to understand the phenomenon of EDC in invertebrates, and many of the chemicals that are contaminating terrestrial, freshwater and marine ecosystem may have endocrine disrupting effects on invertebrate species. Given the vast genetic diversity of Metazoans, the MoA already defined for vertebrates may or may not apply to any particular taxon. Therefore, EDC toxic effects may have unanticipated, and many times unnoticed until they reach global scale, deleterious effects in the ecosystems that depend upon invertebrate populations.
OMICS’ APPLICATION ON EDCS ASSESSMENT
Transcriptomics and EDCs
The availability of studies that report the transcriptomic changes of different EDCs on several organisms, including human cells is reported in Table S1. One of the goals of the transcriptomic analysis is to discover mechanistically based molecular biomarkers with utility for risk assessment and develop modeling approaches for predicting adverse outcomes. The understanding of population-level impacts of EDCs in biological systems is, however, dependent on an enhanced knowledge of their MoA, and development of mechanism-based indicators suitable for application on field work that enable linkage of exposure to adverse effects at both individual and population levels.
The elucidation of the signaling pathways and transcription factors (TF) networks affected by EDCs could be successfully addressed by examining the transcriptomic responses in model species such as the zebrafish (Danio rerio). Among the several fish species with a sequenced genome, zebrafish is one of the best model systems for omics, which is addressed by considerable high number of studies, reporting the effects of EDCs in different tissues and in differential stages of development. In addition, it has relatively abundant genomic resources such as genetic maps, mutants, and markers available [66].
The biological responses to external stressors, including toxicants, involve changes in normal patterns of gene expression [67, 68]. Many responses are a direct result of the chemical, such as alterations in gene expression caused by the binding of a steroid hormone (or analogue) to a specific steroid hormone receptor, which acts as a TF and subsequently modulates (activates or represses) the transcription of its target genes. Importantly, however, different mechanisms of toxicity can generate specific patterns of gene expression that can potentially provide us with molecular biomarkers of disruption of a biological process and be reflective of mechanism or mode of action [67].
The search for networks, enabling new hypotheses to be formulated and tested for the mechanisms underlying specific toxic effects are one of the best challenges that transcriptomic is facing. From systems biology perspective, signaling pathways and TF networks are at the center of a complex biological system. As such, signal transducers and TFs provide critical links between chemical exposures and resultant toxic effects manifested at various levels of biological hierarchy, from molecular to organismic [69].
Mechanistically based molecular indicators would also allow for improved extrapolation of effects across species, biological levels of organization, and diverse chemical structures. Finally, given the pleiotropic nature of signal transducers and TFs, organismic endpoints explicitly mapped to specific toxicity mechanisms may be developed by generating gene knockout mutants in targeted pathways. An ensuing greater efficiency and accuracy in the assessment of both EDC exposure and hazard would improve the overall risk assessment process [69].
It should be emphasized, that changes in gene expression are generally rapid and thus potentially provide a capability of a rapid diagnosis of chemical effect. However, the transcription of messenger ribonucleic acid (mRNA) is only an intermediate step in conversion of genetic information into proteins, the biochemical bases of biological function and gene expression and concentration of functional proteins are not necessarily always directly related.
Proteomics and EDCs
Proteomics has gained popularity in the field of ecotoxicology as a holistic tool for unraveling novel mechanisms of toxicity and elucidating subtle effects of contaminant exposure. Proteomic analysis has been used in the field of ecotoxicology to identify new candidate biomarkers for environmental contaminants and stressors such as heavy metals, flame retardants, polyaromatic hydrocarbons, polychlorinated biphenyls, herbicides, pesticides, and anoxia [55]. Although several proteomic studies have included invertebrate species such as mollusks or crustacean; other studies focus on several vertebrates such as fish or even cell lines.
The subject of proteomics offers a potentially powerful approach to ecotoxicology, particularly with respect to providing biomarkers of environmental contamination. The challenges in measuring molecular changes include choosing the appropriate timing of sampling. Cost and logistical considerations often force experimental designs to trade-off between sufficient biological replicates and sampling at different time points. Multiple pathways and modes of action and limited temporal windows necessitate the evaluation of multiple levels of organization to better capture biological effects and to enhance predictive and diagnostic power. Tissue samples from test animals can be simultaneously collected from amenable tissues such as liver or tail fin for transcriptomic, proteomic, and metabolomic analyses. Initial proteomic studies utilized two-dimensional gel electrophoresis (2DGE) to identify changes in the patterns of protein expression under chemical stress, later on, other more sophisticated techniques has been applied. Liquid chromatography (LC) and mass spectrometry (MS) methodologies, along with the growth of available genome sequence information and powerful bioinformatics tools, facilitated protein separation and identification, and enhanced the knowledge from those studies. The number of publications recognized by “Scopus” document search, with the key words terms “endocrine disruption” plus “proteomics” showed only a total of 23 results in May 2014. The summary of the publications and their associated results are shown in Table S2.
Metabolomics and EDCs
As of May 2014, only 17 articles that combine metabolomic and endocrine disruption words appeared in the bibliographic database. This omic technology is advancing at a rapid pace and the resulting knowledge of biological responses has the potential to improve understanding of the molecular pathways that control physiological processes. The metabolome analysis is a method to detect changes in endogenous metabolites originating from biochemical pathways, such as amino acids, lipids, carbohydrates, hormones etc. It has been shown that changes to endogenous metabolites do reflect changes in the physiology and the phenotype of animals treated with test compounds. Therefore, elucidating how organisms respond to stressors, could aid regulatory policy and decision-making processes in chemical risk assessment. Although there are several challenges ahead in view of using such data for regulatory purposes (such as information interpretation and linking to adverse outcomes) the value of metabolomic platforms in the unraveling of the molecular processes involved in chemical toxicity, including endocrine disruption, is generally recognized. For example, metabolomics based technologies was applied to investigate EDCs toxicity (Table S3) in human cell lines, fish and mussels [54, 70-72].
A Practical Approach: Predictive Endocrine Disruption
Most international regulators posed as a major objective to stop the continuous deterioration of the environment by the thousands of new products entering into the marked each year. This objective demands multi-level, multi-tiered approaches, combining chemical analytical and biological methods [73]. Whereas the chemical identification of pollutants has advanced notoriously in recent years, allowing quantification of a wide array of potential pollutants in the environment at sub-ppb levels, the biological characterization of their putative effects on ecosystems and human health is clearly lagging behind in terms of defining new risks ("emerging pollutants"), identifying emerging effects of classical pollutants (behaviour, neurological, immunological or metabolic disorders, for example) or characterizing the mechanism of toxicity [74]. This is a most serious impediment for both the correct evaluation of environmental impacts and for the assessment of risks associated to new substances.
Toxicologists (including Ecotoxicologists) have developed different methods to evaluate the toxicity of new and well-known substances in order to evaluate their possible environmental and human health hazards either before they enter the marked or before their impact in human populations and wildlife exceeds their proved or assumed economic benefits. Classic toxicology relies heavily on the use of standard animal models to evaluate toxic effects, including rodents and dogs as surrogate for human populations, and fish, crustaceans, and algae to evaluate environmental hazards. This approach has two major limitations. First, they are slow and costly, taking several months and thousands of dollars to evaluate a single substance. And second, there is a quasi-universal claim to reduce animal suffering to the absolutely unavoidable minimum, by applying what is known as the 3Rs rules: replacement, reduction and refinement of animal experiments, [75]. Cell cultures, non-animal or non-vertebrate models (yeasts, crustaceans, annelida, nematodes), and free embryos before their autonomous stage have been proposed as valid alternatives to conventional animal testing for both toxicology and food and drug safety studies [76].
Within the general context of toxicology, endocrine disruption presents a further difficulty in their characterization in non-vertebrate models. For one thing, different animal taxa may encompass different complements of receptors, and therefore their susceptibility to a particular substance may differ wildly. In addition, the analysis of binding to a particular receptor, even accounting for species specificity, may not suffice to characterize an endocrine disruptor as such. Many estrogenic compounds do interact with the ER and, therefore, they are recognizable by single-cell or even in vitro or QSAR approaches. But this does not apply to those that affect steroid metabolism or others, like HCB, for which a suitable model of action has not been demonstrated [77]. And these problems increase when more "metabolic" signaling pathways, like thyroid, PPAR, retinoids, and others, in which the so-called non-genomic effects (effects on hormone metabolism, transport or degradation, neuroendocrine control, etc.) may easily shadow the more "classic", receptor-binding linked effects [57, 77-80].
Schematic representation of the proposed prediction model for the identification of mode of action and apical endpoints according to the adverse outcome pathway, which provides a causal linkage from a direct molecular initiating event and adverse outcomes (pink) at all levels of biological organization (red) used in risk assessment. Omics and other techniques relevant for each level of organization are also indicated (green).
Genomic and other omic techniques can be used to infer complex toxic effects, affecting higher levels of organization, from the analysis of a reduced number of well-controlled model species. The basic idea underlying this approach is that the signaling pathways are well conserved during evolution, so the determination of the effect of a given substance on a specific pathway on a model species is transferrable to humans or environmentally relevant species as long as the modes of action are known and the pathways from the molecular initiating effects and the final adverse effects are conserved. This translation of toxic effects through the different levels of biological organization is known as Adverse outcome pathway (AOP) analysis. In this approach, the different organization levels are analyzed, ranking the corresponding data according to their ecological relevance and its predictive capacity and mechanistic utility (Fig. 5) [69, 81]. Once identified, AOPs can be used to develop high throughput omic technology-based predictive assays, providing valuable information for human and environmental risk assessment. By comparing AOPs across species is possible to identify specific and shared mechanisms of toxicity, and hence use this information in understanding and managing environmental risks. Fig. (6) shows an example of the AOP approach and of its application in two cases of endocrine disruption, one in fish and a second in Daphnia [82, 83]. Note the central part of omic technologies in the process of ellucidating the mechanisms of toxicity for each type of disruption (ectopic expression of female proteins in males, disruption of carbohydrate metabolism).
Concluding Remarks: The Need for a Synthetic Approach
The "genome revolution" has modified forever the fundamentals of Biology. For the first time, quantitative approaches can be applied and modeled, using truly holistic points of view. In the field of Ecotoxicology, and particularly in the study of endocrine disruption, the knowledge of complete genomes from very different taxa discovered not only scores of new potential targets in the already know organisms, but also to predict or explain unsuspected effects in non-targeted, less known species of ecological significance.
Conceptual linkages across biological levels of organization. AOPs analyses integrated the different levels of organization, from molecular to population, for effects of endocrine disruptors, either "classical" (xenoestrogens in fish, green boxes) or "non-classical" ones (neuroendocrine disruption in Daphnia, brown boxes). ER, estrogen receptors; SSRI selective serotonin reuptake inhibitors; SERT, serotonine transporter. Data from [82, 83].
The ever-increasing importance of the omic technologies in Ecotoxicology resulted in an overflow of data from multiple techniques and approaches that need to be analyzed, integrated and presented in a useful way to understand the implications at individual, population and ecosystem levels. AOP analyses are useful to tell apart, as well to correlate one which other, the initial (or "key") events of the toxic effects (i.e., endocrine disruption) and the truly adverse effects, those that compromise the health of the individuals, populations, and finally the ecosystems.
Supplementary material is available on the publishers Web site along with the published article.
The authors confirm that this article content has no conflict of interest.
2DGE = Two-dimensional gel electrophoresis
AoP = Adverse outcome pathways
BPA = Bisphenol A
DES = Diethylstilbestrol
EDCs = Endocrine disrupting chemicals
GMA = Glycidyl Methacrylate
LC = Liquid chromatography
MoA = Mode of action
mRNA = Messenger ribonucleic acid
MS = Mass spectrometry
NMR = Nuclear magnetic resonance
TF = Transcription factor
This project was funded by the Spanish Ministry of Economy and Competitivenes (CTM2011-30471-C02-01) and the Catalan Government (2009SGR924 and 2014SGR642). We thank Rita Jordão for the control and JH-disrupted Daphnia pictures in Fig. (4).
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[64] Fleury E, Moal J, Boulo V, et al. Microarray-based identification of gonad transcripts differentially expressed between lines of Pacific oyster selected to be resistant or susceptible to summer mortality. Mar Biotechnol (NY) 2010; 12(3): 326-39.
[65] Hayashi Y, Heckmann LH, Callaghan A, Sibly RM. Reproduction recovery of the crustacean Daphnia magna after chronic exposure to ibuprofen. Ecotoxicology 2008; 17(4): 246-51.
[66] Dai YJ, Jia YF, Chen N, et al. Zebrafish as a model system to study toxicology. Environ Toxicol Chem 2014; 33(1): 11-7.
[67] Merrick BA, Bruno ME. Genomic and proteomic profiling for biomarkers and signature profiles of toxicity. Curr Opin Mol Ther 2004; 6(6): 600-7.
[68] Garcia-Reyero N, Denslow ND. Applications of genomic technologies to the study of organochlorine pesticide-induced reproductive toxicity in fish. J Pestic Sci 2006; 31: 252-62.
[69] Ankley GT, Bencic DC, Breen MS, et al. Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action. Aquat Toxicol 2009; 92(3): 168-78.
[70] Kolle SN, Ramirez T, Kamp HG, et al. A testing strategy for the identification of mammalian, systemic endocrine disruptors with particular focus on steroids. Regul Toxicol Pharmacol 2012; 63(2): 259-78.
[71] van Ravenzwaay B, Kolle SN, Ramirez T, Kamp HG. Vinclozolin: a case study on the identification of endocrine active substances in the past and a future perspective. Toxicol Lett 2013; 223(3): 271-9.
[72] Katsiadaki I, Williams TD, Ball JS, et al. Hepatic transcriptomic and metabolomic responses in the Stickleback (Gasterosteus aculeatus) exposed to ethinyl-estradiol. Aquat Toxicol 2010; 97(3): 174-87.
[73] Fuerhacker M. EU water framework directive and stockholm convention: can we reach the targets for priority substances and persistent organic pollutants? Environ Sci Pollut Res Int 2009; 16 (Suppl (1)): S92-7.
[74] Raldua D, Campos B, Barata C, Pina B, Garcia Regero N, Babin PJ. Deciphering emerging toxicological effects of pharmaceuticals on aquatic organisms by using daphnia magna and danio rerio as model organisms analysis. Removal, effects and risk of pharmaceuticals in the water cycle - occurrence and transformation in the environment 2013; 62: 611-47.
[75] Russell W, Burch R. The principles of humane experimental techniques. London, UK: Methuen 1959.
[76] Raldúa D, Piña B. In vivo zebrafish assays for analyzing drug toxicity. Expert Opin Drug Metab Toxicol 2014; 10(5): 685-97.
[77] Mrema EJ, Rubino FM, Brambilla G, Moretto A, Tsatsakis AM, Colosio C. Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology 2013; 307: 74-88.
[78] Frye CA. Endocrine-disrupting chemicals: elucidating our understanding of their role in sex and gender-relevant end points. Vitam Horm 2014; 94: 41-98.
[79] Viñas R, Jeng YJ, Watson CS. Non-genomic effects of xenoestrogen mixtures. Int J Environ Res Public Health 2012; 9(8): 2694-714.
[80] Wong RL, Walker CL. Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome. Clin Cancer Res 2013; 19(14): 3732-7.
[81] Ankley GT, Bennett RS, Erickson RJ, et al. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 2010; 29(3): 730-41.
[82] Villeneuve L, Wang RL, Bencic DC, et al. Altered gene expression in the brain and ovaries of zebrafish (Danio rerio) exposed to the aromatase inhibitor fadrozole: microarray analysis and hypothesis generation. Environ Toxicol Chem 2009; 28(8): 1767-82.
[83] Campos B, Piña B, Barata C C. Mechanisms of action of selective serotonin reuptake inhibitors in Daphnia magna. Environ Sci Technol 2012; 46(5): 2943-50.
[84] Heyland A, Hodin J, Reitzel AM. Hormone signaling in evolution and development: a non-model system approach. BioEssays 2005; 27(1): 64-75.
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About 1 Surgery
ABOUT ONE.SURGERY
The ONE.SURGERY project was originally created in March 2018 by Saqib Noor, a British orthopaedic surgeon who recently completed higher surgical training in Birmingham, UK. After various experiences in low resource settings over the past ten years, publishing his personal diaries and commencing fellowship training, Saqib began this project to create a unifying platform to further support the global surgery movement.
ONE.SURGERY is now run by a growing international team passionate about surgery and improving standards of care worldwide. Using a combination of surgical experience in austere settings, web technology and story telling, One.Surgery hopes to empower, inspire and enlighten all those believing in the same vision.
With the multitude of organisations and phenomenal projects currently being undertaken throughout the world, One.Surgery believes in bringing these voices together, with a particular focus on listening to and supporting the most important stakeholders in all global surgery projects – the patients and those who dutifully provide surgical care to them on a daily basis.
The One.Surgery Team
Saqib Noor
Saqib is an orthopaedic surgeon, currently on a paediatric orthopaedic fellowship in Toronto, Canada. He has worked in a number of countries throughout the world and remains committed to surgery in low resource settings. After founding One.Surgery, Saqib hopes to continue this work by working with, and developing trauma services for those in the world less privileged than he has been.
Aliyu Ndajiwo
Aliyu is a medical doctor from Nigeria. He has been a strong voice in improving access to safe surgical care globally, founding @SurgeryMatters - a social media advocacy platform for Global Surgery. He is a member of several organizations such as the WHO Global Initiative for Emergency and Essential Surgical care and also an advocacy team member of Incision. He is also the Editor and social media manager of the Global Neurosurgery Initiative.
Ankit Raj
Ankit is a medical intern, a soon-to-be doctor from Manipal University, India and also an education team member of InciSioN. Already passionate about global health and global surgery, he developed interests in health policy after attending 71st World Health Assembly at Geneva. He wishes to capitalize on his experience of working in low-resources settings to further the agenda of global surgery in LMICs such as India.
Florence Van Belleghem
Florence is a medical student from Belgium and has started her masters at the University of Leuven. She developed a passion for global health after completing a volunteer project in Tanzania. By becoming a member of both InciSioN (Surgical Students Network) and One.Surgery, she hopes to raise awareness and empower like-minded people to ensure access to safer surgery worldwide.
Benjamin Price
Ben is a final year medical student from Australia passionate about global surgery following a placement in regional Tanzania. To date, Ben has been an advocate for global surgery through his role as President of the Surgical Students’ Society of Melbourne. Ben hopes to further this advocacy work and to directly work towards equitable access to surgical education and resources globally, particularly for neurosurgery and other under-represented surgical specialities.
Hanne Gworek
Hanne is a 1st year masters medical student in the KU Leuven, Belgium. She always had a passion for global health. After volunteering in the Meru District hospital in Tanzania, she joined InciSioN and One.Surgery because she wants to release a united call for access to safe surgery for everyone.
Nadija Ekinovic
Nadija is a medical doctor from Bosnia and Herzegovina. Throughout her studies, she has volunteered in numerous projects as a passionate member of several students organisations, including InciSion BH and One.Surgery. Nadija wants to make a difference by reaching those who are like-minded, empowering them to see through the eyes of others. Her inspiration is the current state of her homeland.
Bram Hoessels
Bram is a Belgian medical student who has just started his masters at the University of Leuven. After volunteering in a district hospital in Tanzania, his awareness regarding global surgery grew. By joining One.surgery he hopes to spread the word and attract more awareness to the problem.
One.Surgery Principles
We believe every person in the world should have access to universal, safe surgery. There is just too much imbalance currently that needs addressing urgently.
There are many hundreds of organisations all contributing in their great and small ways to the massive problems at hand. We believe we all have a role to play in achieving our goals, supporting each other along the way.
This platform has been designed to be as easy to use as possible, especially in low resource settings. It has been designed by surgeons to make it as powerful and user-friendly as possible.
Free to access
We are committed to providing free services to our global surgery projects. The costs of developing surgical services are expensive enough. We are not one of them.
Ethical funding
We are not seeking profits. We promise to always work efficiently, producing a world class platform with the bare minimum overheads. We will never ask our users for money but seek philanthropic partners and ethical sources of funding to sustain us. It’s amazing what can be achieved with a few dollars fuelled by passion.
Maintaning standards
It is crucial to us that we abide by a high ethical standard in our work, maintaining integrity, dignity, privacy, confidentiality and security in all we do.
We run on hope, passion and a belief we can help. We are a not for profit and currently seeking voluntary team members to facilitate our projects.
New logbook layout launched! April 8, 2019
Index collections released September 15, 2018
Weekly email logbook reports feature June 14, 2018
RT @ ulricksidney: Your OR staff feels unappreciated, overused and underpaid - the last thing they want is for someone to come and tell them… 2020/01/15
RT @ ulricksidney: A big plus of the surgical safety checklist is it's adaptability however it is impractical to use when you can't rely on… 2020/01/15
RT @ ulricksidney: This is reductionism at its best. Sure, there is resistance to change but anyone who has been in the average LMIC facilit… 2020/01/15
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Raymond Parker – September 1975 to February 1981
September 1975, September 1975, Undated, Undated
Our little boy is growing up! I am guessing Raymond would have been around 16 in the first two strips. He is rapidly putting on weight as we see him age. Too many hamburgers and hot chips, eh Ray?
Undated, Undated, Undated, 6 Movember 1977
I don’t think this moustache suits him at all!
Could he really be only 18 or 19 in this 1977 photo? I think he must be. If he was around 18 months or even two years old in the very first photo in December 1961, then we could be reasonably certain he was born in 1959. To me he looks old for his age.
10 March 1978, 20 March 1978, 8 March 1979, 23 March 1979
So the mo is a no-no on its own but I do like the beard. Not sure about the quiff but that has never been a favourite of mine in men’s hairstyling.
14 July 1978, 6 August 1979, 6 August 1979, February 1981
Ugh, that mo is back, but not for long, as he goes all rock ‘n’ roll with those sunnies and then he turns 1950s country squire in the last strip!
I’m almost finished showing you the pictures I have of Ray. There is one more post to come. I love this series for the changes in his face over time but I have barely touched on what he is wearing or his expressions, which have their own stories to tell. I will leave that to you this time.
As with all the photos I buy, I wonder why they have escaped their homes and ended up for sale online. Individual photos are not such a mystery, as they were often given to relatives or traded with friends. Later generations could easily be left looking at dozens of photos of people they have never met or even heard of. Why not sell them off? But when a large series, like this, ends up alone in the world, I feel there must be a tragedy in their past. In the happiest of circumstances Ray should certainly still be alive and his dad would also have a reasonable chance to still be living. But if his father was the custodian of these images and then passed away, why did Ray not value them? Had he a falling out with his father, so wasn’t there when he died, and wasn’t involved in the tidying up of his estate? Did Ray die at a very young age, so when his father passed, there was no one close enough left to want the collection? So many questions!
I suppose there might be a tiny chance that someone who knew Ray Parker and his dad might stumble across these photos and be able to fill in the blanks. Lets hope so.
Raymond Parker
Brett said: April 8, 20181:15 PM
That’s a lot of photobooth pics for that fellow.
Photobooth Journal said: April 8, 20181:59 PM
I haven’t counted them but yes, a huge collection!
Oh! I just saw the other posts about Raymond that you wrote, so I guess this started as a family project.
Yes, indeed! His dad was carrying on the male version of the Victorian tradition of hidden mother photos (in which, mostly, the mother’s form was quite visible) but then, sadly he disappeared. . .
What will those Victorians think of next! 🙂
Photobooth Journal said: April 9, 201812:56 PM
rabirius said: April 8, 20184:02 PM
Cheers! 😄
Tokens of Companionship said: April 8, 20186:16 PM
The beard was a good look for him. He was a serious chap, wasn’t he? Maybe restrained is a better word. The snaps with his dad are really nice.
Yes, restrained is perfect to describe him! I wish his dad appeared in a few more!
Xraypics said: April 8, 20188:44 PM
Yeah, I still like this guy. He grows up as a solid looking man. Wonderful collection. I shall spend some time going through them. The hairstyle and quiff were very 1960s and the beard very 1970s. he obviously kept with the zeitgeist.
He certainly wasn’t averse to trying new styles. Although he isn’t smiling in most of the pics, there is amusement in his eyes in quite a few. I like him too, Tony!
Interesting how some of his facial expressions, especially the hooded-eyes look, persist throughout his life.
So glad you are taking the time to look so closely at these, Tony. The thing I love about the photobooth’s head and shoulder format is that small things like that are easily comparable over time. There isn’t another type of vernacular photography that can capture such subtleties.
roberta m said: April 8, 20189:19 PM
I like his tradition to keep getting his photo taken. He does have a lot of expressions. My favorite is when he tries to look like a tough guy. I think he’s beginning to look like his father…
Yes, he tries! 😄. I will look more closely at his dad as I haven’t seen that similarity.
oglach said: April 8, 20189:28 PM
These are fascinating for the story that they don’t tell…maybe the pictures were got rid of by an ex after a divorce? Or accidentally sold, stored inside a piece of furniture that was sold at a rummage sale. Someone out there is going to recognize this guy.
I like the way you are thinking Og. Accidentally sold is a great possibility. I hadn’t thought of a divorce as a means of them “leaving home”. I hope that wasn’t the case, though. It would’ve been a nasty, spiteful thing to do.
Sure it would have but I’ve heard of worse.
Photobooth Journal said: April 11, 20183:36 PM
Hmm, unfortunately, so have I. I hope that much of the bad stories you hear are not true, as terrible lies were spread about me in the same situation.😭
oglach said: April 11, 20187:55 PM
People will say anything about one another during times like that, so I make it a habit to nod my head sympathetically whilst pretending to listen. 😉
Photobooth Journal said: April 13, 201812:08 PM
He he. Great way to handle it! 😄
Shayne Davidson said: April 8, 201811:07 PM
What a wonderful series! I’m really enjoying the way you explore your interest in the photos through your writing. I wonder why Ray decided on the Johnny Cash hairstyle (we call it a pompadour, lol) in the late ‘70s, when it was out of fashion. Maybe he had a become a man who resisted fashion trends by then? I look forward to the next post about Ray. And I want to find out what happened to him.
Thanks Shayne! I thought the same thing about it being out of fashion in the 70s but with Happy Days and other 50s revivals in TV and cinema, he might have followed that trend? Or maybe he was just really into music of that era for a while?
Shayne Davidson said: April 9, 20189:54 PM
He may have gone through a late Johnny Cash phase!
😃. Definitely possible!
PS- I hope you’re feeling better now and that the WP site is behaving!
My health is an ongoing nightmare. I’ve a genetic condition. 😫. Thanks for the kind wishes, though.
Yes, WP app is behaving. I deleted it and reinstalled and it seems to be fine now. Yay! 😃
I read your about page and was sorry to hear that you are having such serious problems with your Ehlers Danlos. When my daughter got to be a teen her doctors thought she had that syndrome but it turned out to be a false alarm. I hope you feel well again soon.
Wow, that is a coincidence! How is she now? I’m so glad for her that it wasn’t EDS! Thanks for reading my tale of woe. 😊
tedstrutz said: April 9, 20182:20 PM
Holey Moley!!! This guy is as photobooth crazy as you… I did not think that possible.
I think Ray is a cop.
Hmmm 🤔. Please elaborate? 😊
tedstrutz said: April 10, 20181:43 AM
I just get that vibe.
Thanks Ted! That is definitely a compliment to me and my mate Ray! 😃❤️
moorezart said: April 27, 20184:32 AM
And this? 😃 Thanks heaps Douglas! 😄❤️😄
moorezart said: April 28, 201810:54 PM
Must be some kind of addiction. One without a cure I fear!
I wouldn’t normally encourage an addiction, but I will try hard to feed you some good material. 😁.
I love your quotes so much. They are thought provoking and often come from surprising people. Stay addicted to those, too please. 😊
will do and thanks!
Photobooth Journal said: May 4, 20182:49 PM
😃👍🏼
equinoxio21 said: December 13, 20196:09 AM
Facinating… So there is one more post?
Leave a Reply to Photobooth Journal Cancel reply
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Will Wright to leave Electronic Arts
By BARBARA ORTUTAY , AP Technology Writer
(AP) -- Will Wright, the video game designer behind such hits as "The Sims" and "Spore," is leaving game publisher Electronic Arts Inc. after 12 years.
Redwood City, Calif.-based Electronic Arts said Wednesday that Wright is departing to run Stupid Fun Club, a company Wright started in 2001 to develop new forms of entertainment like video games, movies and even toys.
"The entertainment industry is moving rapidly into an era of revolutionary change," Wright said in a statement. "Stupid Fun Club will explore new possibilities that are emerging from this sublime chaos and create new forms of entertainment on a variety of platforms."
Electronic Arts is making an equity investment in Stupid Fun Club, though EA did not say how much. Wright and EA own equal percentages and are the main shareholders.
Wright, 49, co-founded Maxis Software in 1989, and Electronic Arts bought it eight years later. He is behind some of the game company's biggest hits, most notably "The Sims," hailed as the best-selling PC game of all time, with more than 100 million units sold around the world.
But EA has been struggling lately and recently cut 1,000 jobs. The company, said Lazard Capital Markets analyst Colin Sebastian, has been very focused on controlling costs, so the latest news reflects EA's direction.
Sebastian called Wright a very talented developer, but noted that his games tend to take a long time to create. He estimates that "Spore," which took several years, cost somewhere between $30 million and $40 million.
"Spore," launched last fall, is an extremely ambitious game that lets players create an evolving universe, from single-celled organisms to civilizations capable of intergalactic travel. The game has sold 2 million copies so far, which might make it somewhat of a disappointment to EA, noted Sebastian, though he added that the company also has a long-term view of the franchise.
The arrangement with Wright frees EA from putting a lot of financial resources behind him but lets the company share in the benefits of whatever Stupid Fun Club may produce. EA will hold rights to develop games that come from the company. It also frees up Wright to pursue his interests beyond just video games.
©2009 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Vivendi Universal and EA Games Join the Blu-ray Disc Association
Citation: Will Wright to leave Electronic Arts (2009, April 8) retrieved 21 January 2020 from https://phys.org/news/2009-04-wright-electronic-arts.html
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Jump in communication skills led to species explosion in electric fishes
By Diana Lutz, Washington University in St. Louis
In the top group of fishes, species in the genus Paramoryrops that has the complex signal-processing brain, discharges have changed quickly, resulting in dramatically different pulses among closely related species. In the bottom group of fishes, species in the genus Petrocephalus whose midbrain is more simply structured, all of the species have similar pulses. The difference arises because the top group has the anatomical features needed to exploit the signal space -- such as the anatomy needed to make different pulses and the sensory and analytical ability to perceive small differences in pulse shape. Credit: Sebastien Lavoue, Carl Hopkins, John Sullivan and Matthew Arnegard
(PhysOrg.com) -- Bruce Carlson stands next to a fish tank in his lab, holding a putty colored Radio Shack amplifier connected to two wires whose insulation has been stripped. At the bottom of the tank a nondescript little fish lurks in a sawed-off section of PVC pipe.
Carlson sticks the two bare wires into the tank. Suddenly we hear a rapid-fire pop, pop, pop, pop, pop, pop. The pops, which are surprisingly loud, sound rather like the static on an old-fashioned tube radio tuned between stations.
"When there are many fish in a tank," Carlson says, "it sounds like a frying pan".
Carlson, PhD, assistant professor of biology in Arts & Sciences, is studying the African family of weakly electric fishes called the Mormyridae, or mormyrids.
Each fish in this family has an electric signal distinctive to its species, but also, to its sex, dominance status and even its individual identity.
The shape of the discharge is the fish's "face," says Carlson. "It's how they recognize one another."
Filmed and Narrated by Matt Arnegard.
The sensory pathway that detects and analyzes the electric discharges in the Mormyridae had been well studied, but only in two or three species, Carlson says, and the family has more than 200. Given its diversity Carlson asked whether changes in electrical communication might have influenced rates of speciation.
Three anatomical advances underlie the ability to send and receive diverse electrical signals: cells able to produce different discharges, a global distribution of the sensors that detect the discharges' shape, and a more complex signal-processing area of the brain to analyze them.
In 2008 the National Science Foundation awarded Carlson a grant to travel to Gabon (where many mormyrid species are found) to study the mormyrid brain, and how brain anatomy maps onto the evolutionary tree of the fishes.
His team found that changes in brain anatomy and the resulting ability to fully exploit electric signal space did indeed lead to rapid speciation, a result published in the April 29 issue of Science.
The electric organ
Each pop is one discharge of an electric organ located at the base of a fish's tail. The organs consist of stacks of disk-like cells called electrocytes, "pretty much like watch batteries in series," says Carlson.
The electrocytes all fire action potentials simultaneously, and so their tiny action potentials sum to produce a discharge that is typically about a few volts.
"These signals don't propagate as electromagnetic waves," Carlson explains. "Instead they exist as an electrostatic field, just like you'd get by sticking a battery in the water.
"That's why these fish are so good at recognizing pulses with different shapes," he says. Waves are distorted during transmission, so that their fine temporal structure is smeared.
"The discharges are not distorted. They get weaker with distance, but their temporal structure stays the same. That's one reason mormyrids evolved to be exquisitely sensitive to small timing differences in electric signals," Carlson explains.
Amplified electric pulses were recorded at Biroudou Creek in southeastern Gabon. Each click represents a single electric-organ discharge, which is about one millisecond long. Several fish can be heard in this recording. A fish's signal becomes louder when it moves closer to the electrode picking up the discharges. Credit: Bruce Carlson
Detecting the pulse
Weakly electric fish have several types of electroreceptors but the ones important for communication are called knollenorgans, from the German word "Knolle," or tuber, because they consist of bulbous cells buried just under the fish's skin.
The knollenorgans respond to a voltage rise, firing a time-locked spike in response to outside positive-going voltage changes.
The knollenorgans on one side of a fish's body respond to the start of a discharge and those on the opposite side respond to the end of a discharge. This lets a fish recognize a species-specific discharge by comparing the intervals between spikes coming from opposite sides of its body.
The spike time comparison occurs within the central nervous system, in a part of the brain called the extero-lateral nucleus, or EL.
When we began our work, the "standard anatomy" for the "mormyrid" brain—what you'd find if you looked in a textbook-- says Carlson, was a two-part EL, with separate nuclei, or clumps of cells, in the anterior and posterior portions.
"We collected lots of brains in Gabon, and two collaborators, Saad Hasan, a former undergraduate at Washington University, who is now a medical student at Cornell, and Derek Miller, who is an undergraduate at Washington University, did all the histology on the brains.
"In addition to the standard anatomy, we were amazed to see another anatomy, where the EL is substantially smaller and not split into two portions.
"All the fish we looked at either had the large EL that was divided into anterior and posterior halves, or they had the small undifferentiated EL.
Working with collaborator Matthew Arnegard, PhD, a postdoctoral fellow at the Fred Hutchinson Cancer Research Center in Seattle, WA, the scientists mapped the brain anatomy onto a phylogenetic tree (an evolutionary tree based on the similarity of DNA sequences), and they could see that there were two equally parsimonious ways to reconstruct the fishes' evolutionary history.
Either the complex brain was ancestral and the simpler brain evolved twice or the simpler brain was ancestral and the complex brain arose twice. To solve this riddle, they did what evolutionary biologists do, which is look at the "next outgroup member," the closest related fish that's not part of the Mormyridae family.
This fish has an area in the midbrain that is similar to a small, undifferentiated EL. This suggested the EL brain was probably the ancestral brain, and the more complex divided ELa/ELp evolved twice, once within the subfamily Mormyrinae and once within the subfamily Petrocephalinae.
Did fancy anatomy lead to rapid diversification?
If a communication system is to promote species diversity it must have both the capacity to create new signals (flexible stalk morphology) and the ability to distinguish those new signals from other signals (the broad distribution of knollenorgans and the complex brain).
"The only fish that have all three is a group of mormyrids we ended up calling Clade A for simplicity's sake," Carlson says.
To test the importance of these traits on signal divergence we analyzed the discharges of fish collected in two locales: the Ivindo River of Gabon, home to the largest known assemblage of the subfamily Mormyrinae; and Odzala National Park in the Republic of the Congo, home to the largest known assemblage of the subfamily Petrocephalinae.
"Statistical analysis showed us that the rate of signal divergence in Clade A was 10 times higher than among other fish within the Mormyridae," Carlson says. Further analysis by collaborator Luke Harmon, PhD, assistant professor of biology at the University of Idaho, revealed that the number of species in clade A has been increasing three to five times faster than the number of species in other mormyrid lineages.
In other words, the fancier the fishs' communication kit, the more likely it was to come up with new electric discharges and new species that identified one another by those discharges.
Putting it to the test
It all worked out statistically and logically but was it what the fish actually experienced?
"After all," says Carlson, "this sensory world is totally foreign to us. I've worked with these fish a long time, so I can tell a few of the discharges apart by ear. But for the most part I need an oscilloscope to see the differences.
Can the Clade A fish tell the difference between discharges? To test them, Carlson ran behavioral playback experiments on fish caught in Gabon.
"A fish would be going pop, pop, pop and we'd pulse it. Depending on the fish, it would either discharge more rapidly, brrrrrrrrr, or stop discharging altogether.
"But if we repeated the stimulus again and again the fish would stop responding. Once it stopped responding, we hit it with a phase-shifted version of the same pulse. If the fish could tell the difference, the discharge rate or pause duration would increase. If it couldn't tell the difference, there would be no change.
The experiments showed that mormyrid fish in Clade A were able to distinguish among pulses, but other mormyrids (those with the EL brain) were not.
Did the evolution of a fancy signal-processing brain drive speciation in the Mormyridae? "It's always difficult with evolutionary studies to say that any one trait is the cause or the trigger for another," Carlson says. "But in this case we were able to show that the complex signal-processing brain evolved before a burst of speciation, that signal variation was higher among fishes with that brain, and that these fishes could distinguish among subtly different pulses, whereas others could not.
"Together it adds up to a strong case for brain evolution triggering increased diversification."
Fish use electric signals to find the right mate
Provided by Washington University in St. Louis
Citation: Jump in communication skills led to species explosion in electric fishes (2011, April 28) retrieved 21 January 2020 from https://phys.org/news/2011-04-skills-species-explosion-electric-fishes.html
Electric fish conduct electric duets in aquatic courtship
Convergent evolution of molecules in electric fish
The bear necessities of aging
How to Grow a Bigger Brain
Brain size determines whether fish hunters or slackers
Crucial reef species may survive ocean changes under climate change
New study confirms the importance of tiger population in Thailand forest complex
Insecticides becoming more toxic to honey bees
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Scientists made it cheaper to produce hydrogen from water
by KTH Royal Institute of Technology
Electrocatalytic water splitting is about to get less costly, thanks to research at KTH Royal Institute of Technology.
A hydrogen-fuel economy could finally become a reality with the recent discovery of a cheap, stable and efficient means of getting hydrogen from water.
If a cheap, stable and efficient way could be found to produce hydrogen from water, a hydrogen-fuel economy could finally become a reality.
Scientists at KTH Royal Institute of Technology in Stockholm now report that they have unlocked one major barrier to exploiting this renewable energy source.
Because the best-performing catalysts for electrochemical oxidation, or "water splitting", are expensive precious metals, the research team led by KTH Professor Licheng Sun is one of many worldwide searching for cheaper alternatives. Sun had earlier developed molecular catalysts for water oxidation (Nature Chem. 2012, 4, 418) with an efficiency approaching that of natural photosynthesis.
Last week his team reported in Nature Communications that it has discovered that a new material composed of common earth-abundant elements could be used as a catalyst for water splitting, which could help change the economics of large scale hydrogen fuel production.
Researcher Ke Fan says that the new material is a monolayered double hydroxide involving nickel and vanadium, which offers a state-of-art electrocatalyst for water oxidation. The low-cost, highly efficient nickel-vanadium monolayer outperforms other electrocatalysts that are composed of non-precious materials, Fan says. And it offers a competitive, cheap alternative to catalysts that rely on more expensive, precious materials, such as iridium oxide (IrO2) or ruthenium oxide (RuO2).
"This is the first time that the metal, vanadium, has been used to dope nickel hydroxide to form a water oxidation catalyst, and it works very well—even beyond our expectations," Fan says. "No doubt this material can greatly expand the scope of non-precious metal elements of electrocatalysts, and it opens new areas for water splitting."
One possibility the discovery raises is large-scale production of hydrogen fuel using Sun's catalyst.
The material possesses a layered structure with monolayer nickel-vanadium oxygen polyhedron connected together with a thickness below 1 nanometer, says researcher Hong Chen.
"This monolayer feature not only increases the active surface area, but also enhances the electron transfer within the material," Chen says.
Sun expects the research to "open a new area of low-cost water oxidation catalysts, featuring stability and efficiencies that equal or even surpass some of today's best catalysts including RuO2 and IrO2."
Carbon leads the way in clean energy
More information: Ke Fan et al. Nickel–vanadium monolayer double hydroxide for efficient electrochemical water oxidation, Nature Communications (2016). DOI: 10.1038/ncomms11981
Journal information: Nature Communications
Provided by KTH Royal Institute of Technology
Citation: Scientists made it cheaper to produce hydrogen from water (2016, June 28) retrieved 21 January 2020 from https://phys.org/news/2016-06-scientists-cheaper-hydrogen.html
Study advances hydrogen production efforts
Researcher discovers inexpensive catalyst to produce oxygen and hydrogen gas
New catalyst found for clean energy fuel
Clean energy from water
Researchers find a way to harness the entire spectrum of sunlight
Inverse design of porous materials using artificial neural networks
'Mechanical breathing' in smart windows
Newly developed screening processes will accelerate carbon capture research
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Geographic Information System (GIS) Links and Data
The PIE LTER research program is involved with developing GIS datalayers and databases for the watersheds and waterbodies of the Plum Island Sound Estuary. GIS development has focused on understanding the impact of land use change on the watersheds in northeastern Massachusetts and the geomorphological evolution of tidal creeks in the Plum Island Sound Estuary.
Our GIS development has greatly benefited from the use of the Massachusetts Geographic Information System developed by the Commonwealth of Massachusetts Office of Geographic and Environmental Information. Databases and datalayers have been developed by colleagues at Clark University, The University of New Hampshire and The Marine Biological Lab.
Clark University (GIS)
There are two faculty members at Clark University who are members of the PIE research team. They are Robert Gilmore Pontius Jr (rpontius at clarku.edu) and Colin Polsky (cpolsky at fau.edu). Since 1999, Pontius and his students have been creating GIS-based methods for land change prediction. They develop novel techniques of model validation and land change assessment. Much of their work can be found at www.clarku.edu/~rpontius. Most of the maps below were obtained from the Massachusetts Geographic Information System and formatted to facilitate simulation modeling of changes among land cover types over time. Future scenarios of land change are used to make scenarios of nutrient loading. Polsky and his students study the vulnerability of human populations to the possible over-exploitation of water and land.
Clark University contributed GIS data for the Ipswich and Parker watersheds which have been developed in IDRISI with most files raster based. Many will open using ArcGIS 10.x; please contact us if you have questions.
Updated June, 2013: Files are now downloadable in zip files which include all necessary GIS files, original FGDC metadata Word documents, and EML-compliant metadata in XML format.
Clark University, holmes (HERO object-based Lawn Mapping Exploration of Suburbia) group, is focused on producing very high resolution (.45 m) maps of the Plum Island Ecosystem. The group is advancing object-oriented methods for mapping, focusing on issues of accuracy assessment and methodological comparison. holmes is a subgroup of the HERO project. holmes was created in September 2006, when two geography professors at Clark University (Colin Polsky and Gil Pontius) recognized the need for a high-resolution dataset to fostercollaborative research with two ecologists (Chuck Hopkinson and Wil Wollheim). That discussion formed the basis for a successful, $1.4M grant proposal to NSF’s Coupled Natural-Human Systems competition, submitted in November 2006 and awarded in May 2007. This project usesthe premise described above about suburbanization to examine social dynamics, ecological dynamics, and coupled socio-ecological dynamics.
For more info see: The George Perkins Marsh Institute (GPMI) Working Paper, 2012-24: HERO Object-based Lawn MappingExploration of Suburbia: Rationale, Methods and Results for the NSF Plum
Island Ecosystems Long-Term Ecological Research Site [pdf]. Colin Polsky, Robert Gilmore Pontius, Jr., Nicholas M. Giner, Albert Decatur, Daniel Miller Runfola, and Rahul Rakshit, Clark University, December
University of New Hampshire River GIS
University of New Hampshire researchers are developing river network hydrological and biogeochemical models to explore how land use change, climate variability and change, and surface water management affect water and nutrient fluxes throughout the basin and to the estuary. A central requirement for this model is a digital river network that is used to simulate surface water flow paths from source areas to the coastal zone. The river network is grid-based at a 120m by 120m resolution. The gridded river network is used to explore scientific questions regarding the role of different land uses in defining nutrient loading, and the role of river systems in controlling exports to the coastal zone.
Links to additional GIS Information
Massachusetts Geographic Information System -- Mass GIS data direct data access
Massachusetts Interactive Property Map - Lot/parcel and property owner information available by address or zooming in on map of Massachusetts, based on town assessors infomation.
Massachusetts Electronic Atlas -- Harvard University Geospatial Library
USGS Earth Explorer -- Comprehensive remote sensing product access
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“Fiver” Birthday Parties Are Starting to Catch On, and They’re Actually Kind of Genius
What Is a Fiver Birthday Party?
October 6, 2019 by Alessia Santoro First Published: January 9, 2019
A new(ish) trend is emerging in the kids' birthday party realm — "fiver" parties — and I've got to say, I'm on board.
Every year, I attend the birthday parties of the kids I used to nanny. They're getting older now, and I truly think the stuff and toys are just getting bigger and more expensive as time goes on. I have sat there year after year as they rip open their gifts, either exclaiming "I have this already!" or "I don't want this" or "Yay! I hoped for this," and it's of no fault to them that it gets to be just so damn much — it's their birthday, and they want to open the things they've been presented with. And if you're inviting 15 kids to the party and each of them is coming with a gift, of course things are bound to get a little out of hand — not only that, but each gift opened tends to get less and less special.
3 Reasons Kids Should Never Open Up Gifts During Their Birthday Party
This is where the fiver party swoops in to create a more meaningful experience. On the invitation for a fiver party the parent can explain that gifts aren't expected, but should you want to bring something with you (because it can feel awkward to show up empty-handed), a $5 gift card or cash can be gifted to go toward something the child is saving for, or even an experience, like a museum pass or day at the movies. This shifts the birthday party to being more about celebrating with friends and family, rather than a day focused on what gifts they'll get to rip open.
"It was so wonderful and is creating many more memories than a toy could."
Today spoke with Sarah Schultz, a mom of three who threw her son a fiver party. "Birthday parties can be so expensive — spending $20 on a gift . . . really limits the amount of birthday parties I let our kids attend," she said, adding that her son combined his Christmas and birthday money to save up for a pet hedgehog. "Braden was very happy with his fiver party and it was a wonderful lesson to teach him about saving money instead of spending money as soon as you get it." Another mother, Rachel Horan, threw a fiver party for her daughter and put the focus of the $5 gifts on getting Michaela a zoo pass for the year, which was a success. "It was so wonderful and [the zoo pass] is creating many more memories than a toy could," she said. "So many parents said they wish they had thought of it with their own kids but were never sure how to word it."
Party Time! 46 Creative First Birthday Party Ideas
Author Amy McCready, the founder of Positive Parenting Solutions, was skeptical about the concept at first, but shared some of the things she now considers benefits of a fiver party.
With fiver parties, parents and close relatives can still give the child a few gifts, and friends can help contribute to a larger coveted item or experience. To those people [who disagree], I share my insight of being able to have more friends attend, keep the party an affordable event for those kids, and keep those useless gifts that get pushed aside away. I also don't think it's any more tacky than saying your child has a wish list for their birthday and to buy certain gifts for them.
However, Amy thinks that the party idea should be approved by the birthday kid first. Because not every party they go to for their friends and classmates will be a fiver party, they might want a party in which they get a bunch of little toys and gifts from friends. If you're considering a fiver party for your child, chat with them first about the benefits of being able to save up for one or two things they really want, or an experience, and let them approve the idea. If they do, it sounds like you'll all be pleasantly surprised with how it turns out.
Kid PartiesBirthday PartiesParenting News
Today in Very Important News: Build-A-Bear Is Releasing a Baby Yoda Plush
by Alessia Santoro 2 days ago
A Woman Had No Idea Twins Ran in Her Family Until She Had 2 Sets of Twins in a Year
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A Man Found an Old Tape of a Baby Taking His First Steps in 1994, Then Located His Family
Disneyland Tickets Are on Major Sale Right Now! Get Tickets For as Low as $67
by Alessia Santoro 1 day ago
Craving Thin Mints? Here's When (and How!) You Can Score Girl Scout Cookies This Year
29 Trendy Birthday Cakes For Every Kind of Birthday Party
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Status under review (11) started (1) completed (34) declined (9)
Don't allow all my work to dissappear
I worked on a PowerPoint for a long time, then I saved and it said "read only", so I clicked Save As, chose a name, and it saved a blank file.
This SUCKS. Your product SUCKS. This should NOT be possible. I lost a lot of shit I won't remember now.
Text Read during Powerpoint Show
Currently it is possible to activate Text Read in Edit Mode and then activate Show Mode. The option of Text Read may be made available during the Show Mode.
Reuse slides to show slide names
New version of Reuse slides only displays the slides available as "slide 1", "slide 2, etc. instead of using the real name assigned via Outline view. This was available on a previous version. Now, I can't distinguish which slide I want to add as I cannot see the contents. The preview is small and cannot be zoomed in.
Display full file name in the top of the screen
On the edit mode the files names are cut and not displayed in full. This sometimes leads to confusion on the file being edited (mostly on long file names with versions at the end). There's enough space in that section of the screen to display longer file names (in a previous version this was also shown when hovering the mouse pointer on the file but it is gone now.
Set timing to advance after the animations end
There's an option to advance slide on mouse click, or on after a specific amount of time after the slide starts. It would be nice if there was another option to advance after a specific amount of time after all the animations are over.
The text-way animation
there should be a text way animation to apply handwriting effect with the hand picture. there should be an option to set a point of the object i.e. shape or a picture, to move on the way of that animation. in this animation the text should be written like the handwriting
Slide Timer Insert Facility Tools
Actually, We used every time many operation with presentation but actually I need a option that shown every slider timer. Like example - when we start our presentation then slide change page to page but viewer noted the every point that are important in this presentation but sometimes they can't understand how many second keep stay in this slide page and then move to next slide. So I feel that it's better to working and presentation time for showing presentation slide timer input facilicty that are shown analog or digital clock style. Thank you!
Bigger canvas value than 56 inches
56 inches is the maximum that a PowerPoint is going to go up to, however a bigger resolution is what we live to see. Greater value, greater visibility and a greater effect of all the images and designs will surely come together in a dynamic way if this number gets stretched, and literally so! Moreover, PowerPoint presentations are used for large-scale events, and therefore having a feature that extends in size would be beneficial.
Back and forth video play
We have already stressed on videos being an essential part of PowerPoint presentations, and going in sync with that is this one feature which is of the back and forth video play that is yet to be seen and made use of in PowerPoint. If one needs to make a reverse loop quirky content for social media content, then this would be a very useful feature.
Support drag and drop EPS files
While PowerPoint has started supporting .SVG files lately, it is important that a globally known vector format like EPS should also be made available. This would be great, as it would help avoid the unnecessary step of having to convert files before using them.
Save each slide as separate video
If you are using PowerPoint to create Instagram content, or anything related to social media, instead of hiding slides manually in order to export videos, it would be great to have a mechanism through which we could save every slide as a separate video, as that would make the process easy and less cumbersome.
Pre-integrated Animated Icons
Bringing the PPT to life with pre-integrated animated icons is next level innovation that we hope becomes a possibility in the near future. Icon sets are great, but animation is where the world is right now, and we hope that PowerPoint picks up on this soon!
Replace color in the entire deck
Yes, everything on the PowerPoint application is easy, and a lot of things can be executed with just a few clicks, but replacing the entire color in the deck in one go is still not a possibility in PowerPoint. If one has to attempt to change the color, that person has to do it manually, which is definitely more time consuming, and becomes a hassle.
Yes, everything on the PowerPoint application is easy, and a lot of things can be executed with just a few clicks, but replacing the entire color in the deck in one go is still not a possibility in PowerPoint. If one has to attempt to change the colour, that person has to do it manually, which is definitely more time consuming, and becomes a hassle.
make biodiversity theme
Adjust Wrap to shape
I would love to see text in shapes automatically wrapping to the form of the shape. So when rounding the corners of an rectangle for an example, the text-wrapping should automatically adapt to the form and not overflow the borders.
Create a presentation tree
Presentations work on a linear form, one slide after the other. Create a presentation tree, with presentation lines. Linear lines moves with left/rigth arrows or pointer and branched slides with up/down arrows or pointers.
This way, during a presentation, the first slide on the tree can have more condensed information and, depending on the audience or remaining presentation time, go deeper on specific subjects, without the need to create several presentations.
Search for the commands you want to add to the QAT
When adding commands to the QAT from the "All Commands" option, we have to scroll through hundreds of features to find the ones we want to add to the QAT. Could we add a search window in that dialog box, in addition to the list of all PowerPoint's features? It would be a great time saver!
Add support for more 3D file formats
Additional file formats such as .jt or .stp would be great for adding models to presentations.
Zonal OCR for localization of screenshots
I create most of my documentation images in PowerPoint because all text has to be editable. Therefore it would be great to drag a square around the text I need to OCR in a screenshot and just create a text box out of it in PowerPoint. This would make the screenshots easy to translate. Right now, I extract text, but I can't make the text in an image editable without OCRing (and usually destroying) the entire image. I've also found no third-party tools that would offer a workaround.
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Viral Gastrointestinal Illness (Stomach Flu) (Fraser Health) [English] Public
How to prevent the spread of infection in the hospital and at home. Viral gastrointestinal illness, also known as stomach flu, is a common illness. It can occur as a case in just one person or can quickly spread through families and cause outbreaks. Outbreaks occur in the community every year. There are several different viruses that cause illness with vomiting and diarrhea. This fact sheet provides information about how to prevent the spread of infection in hospital ad at home. (English) Colour
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Viral Gastrointestinal Illness (Stomach Flu) How to prevent the spread of infection in hospital and at home (Fraser Health) [Chinese] Public
Viral gastrointestinal illness, also known as stomach flu, is a common illness. It can occur as a case in just one person or can quickly spread through families and cause outbreaks. Outbreaks occur in the community every year. There are several different viruses that cause illness with vomiting and diarrhea. This fact sheet provides information about how to prevent the spread of infection in hospital ad at home. (Chinese) Colour
Viral Gastrointestinal Illness (Stomach Flu) How to prevent the spread of infection in hospital and at home (Fraser Health) [Chinese - Simplified] Public
Viral gastrointestinal illness, also known as stomach flu, is a common illness. It can occur as a case in just one person or can quickly spread through families and cause outbreaks. Outbreaks occur in the community every year. There are several different viruses that cause illness with vomiting and diarrhea. This fact sheet provides information about how to prevent the spread of infection in hospital ad at home. (Chinese - Simplified) Colour
Viral Gastrointestinal Illness (Stomach Flu) How to prevent the spread of infection in hospital and at home (Fraser Health) [Punjabi] Public
Viral gastrointestinal illness, also known as stomach flu, is a common illness. It can occur as a case in just one person or can quickly spread through families and cause outbreaks. Outbreaks occur in the community every year. There are several different viruses that cause illness with vomiting and diarrhea. This fact sheet provides information about how to prevent the spread of infection in hospital ad at home. (Punjabi) Colour
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Tag Archives: phone number
PAKISTAN: CHRISTIAN FACES ‘BLASPHEMY’ ABETTING CHARGE, DANGERS
Human rights activist could face violence long after trial finishes.
CHICAGO, March 13 (Compass Direct News) – A Pakistani investigator has ruled out a charge against a Christian for “blaspheming Islam” but retained another for abetting blasphemy, and advocates worry the stigma of the charges could make him a target for local Islamists.
Hector Aleem, 51, remains in Adiyala Jail in Rawalpindi, near Pakistan’s capital of Islamabad. His lawyer said he believes law enforcement officers and community members framed Aleem for his social activism on behalf of Christians so that the stigma of the charges would subject him to the danger of violence.
The case began last November when a Muslim scholar received a text message insulting the Islamic prophet Muhammad. Authorities charged Aleem with violating sections 295c (blasphemy) and 109bb (abetting) of the Pakistani criminal code.
Investigating Officer Zafer Ikbal on March 4 ruled out the possibility of a blasphemy charge since evidence showed the message came from an unlisted phone number, not Aleem’s. This move followed a Feb. 2 decision by Judge Sakhi Mohammad Kohut to exonerate Aleem of blasphemy by moving the case from an anti-terrorism court to a magistrate court; with the change of court, the investigating officer had considered anew the possibility of a blasphemy charge.
Phone records in the investigation showed the original culprit had a one-hour conversation with someone at Aleem’s phone number. Aleem claimed that his assistant, Bashar Kokar, was the one who talked with the culprit. As a result, both men were incarcerated and charged with abetment.
In the meantime, Aleem’s attorney, Malik Tafik, has filed an application for bail. He said he hopes it will be approved at a session court hearing next week.
The crime of abetting does not carry a severe penalty in Pakistani criminal law. But in this case, Tafik said, its connection to blasphemy against Islam could put Aleem in danger of attacks by Muslim extremists even if he is found innocent.
“He will continue to be in danger from religious extremists after the case finishes,” Tafik said. “Even though he is only charged with abetment, he is still in danger.”
A Pakistani official concurred that those in the community opposed to Aleem’s human rights activism may have used the charges as a pretext to jail him. Khushdil Khan Malik, deputy secretary of Pakistan’s Ministry of Human Rights, said Aleem may have been framed due to his social activism as director of a small Non-Governmental Organization that lobbies for the rights of Pakistani Christians in Islamabad.
Last November, Aleem became involved in a land dispute between a congregation and the Rawalpindi Water and Sanitation Agency, which wanted to demolish their church building.
Blasphemy charges carry a particularly dangerous stigma in certain parts of Pakistan. Within Rawalpindi, there is a dedicated following of the Islamist political movement Sunni Tehreek, which has been involved in violent sectarian clashes with other Islamist movements in the last decade. When Aleem was transferred to a Rawalpindi anti-terrorism court for a hearing on Jan. 30, a crowd of 150 protestors gathered, shouting that his life would not be spared and that the police should hand him over to them.
But Malik said the case has nothing to do with sectarian tensions and resulted only from members of the municipality targeting Aleem because they opposed his campaign to save a church slated for destruction.
“Generally the relations between Muslims and Christians are good,” Malik said. “This was a false case against Aleem.”
Aleem’s bail application is pending. But due to current court strikes in Pakistan, the application may take a few weeks, said Katherine Sapna, a field officer for the advocacy group Centre for Legal Aid Assistance and Settlement (CLAAS). Lawyers are rallying against the government in a bid to reinstate former Supreme Court Chief Justice Iftikhar Chaudry, who was deposed by former President Pervez Musharraf.
More ‘Blasphemy’ Cases
Christian legislators have called on the Pakistani Parliament to strike down its blasphemy laws, as they are frequently used against the Muslim-majority country’s Christian minority.
Punishment for blasphemy in Pakistan can potentially mean death, and the charges are easy to file. Private citizens can register a blasphemy case, whereas normal procedure calls for police officers to file charges.
According to a CLAAS report, police opened blasphemy charges against two Christians on March 1 in the village of Malukay, 55 miles southeast of Lahore. Walayat Masih and his daughter Sarina attended a fair in a graveyard to honor a deceased religious figure, Muharri Shah, revered by both local Christians and Muslims.
In the course of the celebrations, local Muslims thought that the Christians had improperly covered an Islamic inscription on the tomb. Soon a mob gathered and began attacking those Christians who weren’t able to flee. A crowd cornered Masih and his daughter and severely beat them until police arrived and took the victims to the police station, where they were charged with blasphemy.
CLAAS is investigating the case. The organization will represent the two in court if charges are not dropped.
Posted in Christianity, Islam, Pakistan | Tagged abetment, abetting, activism, activist, Adiyala Jail, advocacy, advocates, anti-terrorism, application, approved, arrived, assistant, attacking, attacks, attended, attorney, authorities, bail, Bashar Kokar, beat, behalf, believes, blaspheming, blasphemy, building, calls, campaign, capital, case, celebrations, Centre for Legal Aid Assistance and Settlement, certain, change, charge, charges, Chief Justice, Christian, Christianity, Christians, church, citizens, CLAAS, claimed, clashes, community, concurred, congregation, connection, considered, conversation, cornered, course, covered, crime, criminal, criminal code, crowd, culprit, danger, dangerous, dangers, daughter, death, deceased, decision, dedicated, demolish, deposed, deputy secretary, destruction, director, dispute, dropped, enforcement, evidence, exonerate, extremists, face, faces, fair, false, field officer, figure, file, filed, finishes, flee, former, found, framed, frequently, gathered, generally, good, government, graveyard, group, Hector Aleem, honor, hopes, human rights, Iftikhar Chaudry, improperly, incarcerated, innocent, inscription, insulting, investigation, investigator, involved, Islam, Islamabad, Islamic, Islamists, jail, judge, Katherine Sapna, Khushdil Khan Malik, Lahore, land, law, lawyer, lawyers, legislators, life, lobbies, local, magistrate, majority, Malik Tafik, Malukay, members, men, message, Ministry of Human Rights, minority, mob, movement, Muhammad, Muharri Shah, municipality, Muslim, muslims, non-governmental, normal, officers, official, opposed, organization, original, Pakistan, Pakistani, Parliament, parts, penalty, pending, Persecution, Pervez Musharraf, phone, phone number, police, police officers, political, possibility, potentially, President, pretext, private, procedure, prophet, protestors, punishment, rallying, Rawalpindi, Rawalpindi Water and Sanitation Agency, received, records, register, reinstate, relations, religious, remains, represent, result, resulted, retained, revered, rights, ruled, Sakhi Mohammad Kohut, Sarina Masih, save, scholar, sectarian, sections, session, severe, severely, shouting, showed, slated, small, social, spared, stigma, strikes, subject, Sunni Tehreek, supreme court, talked, target, targeting, tensions, text message, tomb, transferred, trial, unlisted, used, victims, village, violating, violence, violent, Walayat Masih, worry, Zafer Ikbal | 1 Comment
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Pbmom's Blog
American Idol Season 13 Top 13 Perform
Tonight’s theme is “This is me.” The contestants have to choose one song that defines them as an artist and as a person. The sequence with the contestants on how the voting works this season was cute. There is a new voting platform on Google.
Dexter Roberts
5 in 20: Scared of spiders, fell off a horse, did something with a butter knife (?), first kiss was on a slide, broke his finger during football.
Song: “Aw Naw” by Chris Young
My thoughts: That was rough for me. It was out of tune (sharp). He looked great though.
The judges: Keith said he was a likable guy. He thought it was an excellent cover version of the song but now Dexter needs to figure out how to make it a Dexter Roberts performance. Jennifer said something similar. Harry wonders if the ear monitors are causing him to sing out of tune. There was a pitch issue. Jennifer added that it was not the sweet spot for his voice so much.
5 in 20: Afraid of dogs, plays a lot of instruments, wears glasses because she can’t see and she loves everybody.
Song: “Runaway Baby” by Bruno Mars
My thoughts: Nice upbeat song. I don’t think it was the right song for her. It did not showcase her voice well. I felt like I was watching a high school talent show. I really like her though. I hope she will do better next week.
The judges: Jennifer loves her energy. Her performance was A-plus. The song had soul. It, however, was not her best vocal performance but says she is a contender. Harry agrees. He said intonation is huge. He mentions that she appeared nervous. Keith said what can you do from here forward? It’s about growing and learning. Her energy is contagious. She needs to figure out how to get on top of the song and not floating around it.
Kristen O’Connor
5 in 20: Her best friends are quadruplets. She loves swing dancing. She is bad at all sports.
Song: “Beautiful Disaster” by Kelly Clarkson
My thoughts: I like Kristen but it was off key. I don’t think this was the right song for her. Everyone is having pitch issues tonight. I felt like she was just singing. I didn’t feel any emotional connection from her to the song she was singing (and because of that, I did not feel anything).
The judges: Harry thought that she was a really strong pop singer but she is singing out of tune. Keith thought it was a good song choice for her. She was able to show the range and show control and dynamics in a short space of time. Jennifer said to stop thinking (after seeing 3 contestants now). Start thinking about what you know versus what they are afraid of what may happen.
Ben Briley
5 in 20: He can name every capital. He loves Tennessee football. His favorite animal is a kangaroo. He is good at throwing rocks at hitting poles. He wants to sky dive. He has a super power. And then states none of this is true.
Song: “Folsom Prison Blues” by Johnny Cash
My thoughts: Finally a better performance this evening. Who knew I would like it too (because I don’t like country music). So that is how much I did love it.
The judges: Keith said it was particularly brisk. He told him not to sacrifice his artistry in the midst of entertaining. Jennifer liked the fast tempo. She said it was a good example of taking a song that represents you and changing it up to make it yours. She loved it. Harry said he did not think it was kitsch (as Keith mentioned) at all. He liked the up-tempo. He felt it was the best performance of the night so far.
CJ Harris
5 in 20: Doesn’t like climbing high things, hates icy roads in the wintertime, does not like to deer hunt that much, hates people with bad attitudes and no personality, and is very religious.
Song: “Radio” by Darius Rucker
My thoughts: I love CJ but this was the worst performance heard tonight so far. He was always above the note.
The judges: Jennifer thought it was a lot of fun. She acknowledges there were pitch issues going on for everyone. Harry said CJ has this “cry” in his voice that he loves to hear but this song may have been among other ones during a concert. It was just an okay song choice. Harry is then booed. Keith disagrees. He thinks it was a good song choice and it was good to hear a different side to him tonight.
(Okay, the web site says it is Nobilette but the name was Nobillette on the TV screen–look!)
5 in 20: She is a mediocre snowboarder, played soccer her whole life, loves single ladies (and adds “the song”), wishes she was a dancer, loves dogs.
Song: “Satisfaction” by Allen Stone
My thoughts: It was average. She looked scared. The stage kind of swallowed her up. A few times it seemed out of tune (not on purpose), especially in the end part when she is singing “Satisfaction” a lot. I do like her new look and style. She looks wonderful in pink.
The judges: Harry loves watching her grow. He gives her some pointers about her performance. Keith said he loved the way she looks. He said there were patches of good and patches of “deer in the headlights” but it will come. Jennifer loved how she delivered it. She was awesome.
Majesty Rose York
5 in 20: Born in a leap year. She is left-handed, does the longboard, does ballet and likes to make her hair bigger.
Song: “Tightrope” by Janelle Monae
My thoughts: The beginning verses were rough. Too bad. I am a really big fan of hers and I would put her in the middle of the pack.
The judges: Keith said it was a killer song choice. Janelle is a great place for her to tap into. She is just becoming more confident in what she is doing. Jennifer loves her individuality. She said the song was perfect for her and that she is blessed. Harry said his favorite thing about her is the mystery and how it will unravel. He thought it was terrific.
5 in 20: Her hair is actually brown. She is best friends with her brother. Her favorite movie is “The Wizard of Oz.” Her eyes are sometimes green and sometimes blue. She is really short.
Song: “The Scientist” by Coldplay
My thoughts: It started off rough but she found her groove in there. I liked it. This is my second favorite female performance of the night.
The judges: Jennifer said she has such a unique voice, filled with dynamics and nuances–a powerhouse singer, too. It was a tough song but she pulled it off. Jennifer loved it. Harry said he felt the emotion of the song and that she makes interesting choices on a pre-existing melody, that her melodic choices drive the lyrics. Keith said it was pitchy in the beginning but once she leaned into it, she owned the song.
5 in 20: He loves extreme sports. He likes to write poetry. He is a hopeless romantic, loves coffee, and has never been…..(cut off).
Song: “A Beautiful Mess” by Jason Mraz
My thoughts: I had goosebumps. I loved it. My favorite performance of the night so far. He is so unique. A couple of notes were off, but not horribly. It was such an intimate performance.
The judges: Harry said he was brave to do that but cautioned him to try to sing it in tune. He felt it was too inward and that he did not feel what Alex was singing about. Harry is booed again. Keith said he had the complete opposite reaction. It pulled him in. He wanted to know what Alex “had never been” but Alex does not even remember. Jennifer agrees with Keith that she got caught up in the emotion and mood of it. Jennifer did a nice job. She felt it was a nice change from what everyone else is doing.
5 in 20: She uses a lot of hand sanitizer and is obsessed by the supernatural. She likes ponies and has way too many animals. She failed band in school.
Song: “The Crow and the Butterfly” by Shinedown
My thoughts: I LOVED IT! I had goosebumps. Rocker girl after my own heart. It was my favorite female performance of the night.
The judges: Keith said it was a bold but cool song choice. It reminded him of the first time seeing her from the audition cities. There was a dark, haunting quality to it and that is what she has as an artist. The edgy rasp is appealing. Jennifer said that the sound and power of her voice gave her goosies everywhere. It was her favorite vocal performance of the night so far. It was perfect. She would love to see Jessica’s body relax a little bit. It was dope. Harry was distracted by the graphic butterflies. He thought it was strong and that it was cool to hear her sing slightly differently. She did a nice, nice job.
Emily Piriz
5 in 20: Went to chef camp when she was younger. Her eyes change colors depending on environment and clothing. She does a cool whistle.
Song: “Glitter In The Air” by P!nk
My thoughts: She was wearing way too much makeup (not her fault). I did not care for it. I felt like she was singing it and never made an emotional connection to the song. She was hitting the high note (which always brings out the applause) but her lower register was rough. I really don’t know what the judges heard because they had a very different take on it.
The judges: Jennifer said it is a tough song to take on but she did it beautifully. She thought it had a lot of emotion and her pitch was beautiful. Harry said it was great and she sang the melody well and conveyed the emotions well. Keith said it was one of his favorites of the night. He wants more yin-yang though. There was too much yin.
5 in 20: He is afraid of spiders. He wears size 10 shoes. He stepped on a sea urchin once and broke his ankle once falling down the stairs. His middle name is Joseph.
Song: “Unwell” by Matchbox Twenty
My thoughts: It was okay. It seemed to drag a bit. I almost had the feeling that he wanted to sing it faster but the music was lagging behind. He’s in the middle of the pack for me, too.
The judges: Harry said he wished his vocal mirrored the lyrics (that it wasn’t so clean and tight). It was nice but not great. Kevin said the tempo was slow. Sam had a great way of holding the center of his performance. Jennifer said he was a quiet storm. He needs to come alive. Sometimes he is a deer in the headlights.
5 in 20: Unfortunately they caught him brushing his teeth. Did he say he once kissed a cow? The second one was something about a pancake? His favorite band is Rush. He was on the cross country team in high school. He loves biscuits and gravy.
Song: “Pressure and Time” by Rival Sons
My thoughts: GOOSEBUMPS!! (And hey look Taylor Hicks is in the house). Is Idol ready for a rock star winner? My favorite performance of tonight. This looked truly professional. I felt like I was attending his concert.
The judges: Keith and Jennifer were on their feet. Keith said he has some serious pipes and it was a cool song. He said he needs to figure out now how to put on that twist–retro with a twist. Jennifer said he was so ready for the rock-star life. Harry said it was great to hear rock-and-roll on Idol. If something happened to Rival Sons like what happened with Journey, he could be it.
My top picks for tonight
Guys: Caleb and Alex; girls: Jessica and Jena
On the bottom for me
CJ Harris, Dexter Jones, Malaya Watson
Candice Glover sings!! And Jake Bugg.
Tags: "A Beautiful Mess" by Jason Mraz, "Aw Naw" by Chris Young, "Beautiful Disaster" by Kelly Clarkson, "Folsom Prison Blues" by Johnny Cash, "Glitter In The Air" by P!nk, "Pressure and Time" by Rival Sons, "Radio" by Darius Rucker, "Runaway Baby" by Bruno Mars, "Satisfaction" by Allen Stone, "The Crow & The Butterfly" by Shinedown, "The Scientist" by Coldplay, "Tightrope" by Janelle Monae, "Unwell" by Matchbox Twenty, Alex Preston, American Idol, Ben Briley, Caleb Johnson, Candice Glover, CJ Harris, Dexter Roberts, Emily Piriz, Harry Connick Jr., Jake Bugg, Jena Irene Ascuitto, Jennifer Lopez, Jessica Meuse, Keith Urban, Kristen O'Connor, Majesty Rose York, Malaya Watson, MK Nobilette, MK Nobillette, Ryan Seacrest, Sam Woolf, season 13, Theme is "this is me", top 13 perform
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Provincial Mixed Doubles Curling Trials 2014-2015
The inaugural Provincial Mixed Doubles Curling Trials were held at the Crapaud Community Curling Club December 12-14, 2014. The winning team moved on to represent PEI at the National Mixed Doubles Trials in Ottawa in March 2015. The four teams entered play a modified triple knockout format, advancing teams to a two game championship round, unless one team wins all three sections, in which case the champion will be declared without the championship round being played.
Click for live Curlcast event results.
Kyle Holland/Katie Fullerton rink wins PEI’s 1st Mixed Doubles Trials
The Charlottetown Curling Complex and Cornwall Curling Club duo of Kyle Holland and Katie Fullerton scored five points in the fourth end on the way to a 7-3 win in six ends over the Tyler Smith and Chloé McCloskey team from the host Crapaud Community Curling Club and the Cornwall club this afternoon to win PEI’s first-ever Mixed Doubles trials. Both teams are junior (under 21) age, with Holland skipping the PEI Pepsi Junior men’s champs last year, and Smith winning the previous year. Smith also represented PEI in the Canada Games in 2011, and will be going again this winter. Both Fullerton and McCloskey are members of the two-time reigning provincial junior women’s championship rink, skipped by Veronica Smith.
Photo (L-R): Mixed Doubles winners Kyle Holland and Katie Fullerton
Photo (L-R): Mixed Doubles runners-up Chloé McCloskey and Tyler Smith
All four have some experience at the national level, playing in Mixed Doubles mini-tournaments at the Canadian Juniors. The Holland and Fullerton duo will now be the first Island rink to advance to the Canadian Junior Mixed Trials, which take place in Ottawa in March, with the winner of that event advancing to the World Mixed Doubles in Sochi Russia in April. PEI has already had representation at the World’s, with Robert Campbell and Rebecca Jean MacDonald earning a berth in 2011 as part of their Canadian Mixed championship win.
In this afternoon’s championship game, the Holland/Fullerton team scored a single in the first end, with Smith and McCloskey taking singles in the next two for a 3-1 lead. Holland’s five point fourth end, followed by singles by each team in the next two ends brought the game to an early conclusion.
Holland and Fullerton beat the Smith/McCloskey twosome by an 8-1 score in five ends this morning to capture the C qualifier of the four team Modified Triple Knockout draw. As Holland/Fullerton also captured the A section, while Smith/McCloskey won only the B, they had the advantage going into the two game Championship Round at 1 and 4 pm and would win the championship if they won either game, while Smith and McCloskey would have had to win both. As it turned out, only the first Championship round game was needed.
Photo: Mixed Doubles play this weekend
Holland and Fullerton captured the A section on Friday, with an 11-3 win over the Dario Zannier/Vivian Holm pair from the host Crapaud club in the qualifier game, On Saturday morning, Smith and McCloskey beat Crapaud’s Daniel and Nancy MacFadyen team 9-4 to advance to the Saturday afternoon B qualifier match against Holland/Fullerton, who got off to a great start in their game, stealing singles in the first 3 ends. Smith and McCloskey then jumped into the lead with a four point fourth end. The teams then traded deuces and singles to give Smith and McCloskey the B qualifier ,by a 7-6 score.
Down in the must-win C flight, the MacFadyens took on clubmates Zannier and Holm in a Saturday afternoon game, with a six-point 3rd end propelling the MacFadyen rink to an 11-5 victory. Holland /Fullerton then eliminated the MacFadyens with a 6-2 win in the 4 pm draw.
The Mixed Doubles game format, relatively new to curling, is played over eight ends. Each team has only six stones and one of those stones from each team is prepositioned on the centre line before every end of play. One player delivers the first and last stones of the end while the other player throws the second, third and fourth stones. If they choose to, the two players may swap positions from one end to the next. Both team members are also allowed to sweep.
Holland and Fullerton win C qualifier, will have advantage in Ch’ship round at PEI Mixed Doubles
The Kyle Holland and Katie Fullerton duo from the Charlottetown Curling Complex and the Cornwall Curling Club beat the Tyler Smith and Chloé McCloskey twosome from the Crapaud and Cornwall clubs by an 8-1 score in five ends this morning to capture the C qualifier at the inaugural PEI Mixed Doubles Curling Trials at the Crapaud Community Curling Club. Both are junior-age teams. As Holland/Fullerton also captured the A section of the four team Modified Triple Knockout, while Smith/McCloskey won only the B section, they will have the advantage going into the two game Championship Round at 1 and 4 pm. Holland/Fullerton will take the championship if they win either game, while Smith and McCloskey would have to win both Championship Round games to go on to represent PEI at the National Mixed Doubles Trials in Ottawa in March 2015.
In this morning’s contest, Holland/Fullerton took three points with hammer in the first end, and kept Smith/McCloskey to a single point in end two. Holland/Fullerton then took a deuce and stole a single, giving them a 6-1 lead after four ends. A stolen deuce in the fifth game them and 8-1 lead and brought the game to an early conclusion.
Holland and Fullerton captured the A section on Friday, with an 11-3 win over the Dario Zannier/Vivian Holm pair from the host club in the A qualifier game, On Saturday morning, Smith and McCloskey beat Crapaud’s Daniel and Nancy MacFadyen team 9-4 to advance to the Saturday afternoon B qualifier match against Holland/Fullerton, who got off to a great start in their game, stealing singles in the first 3 ends. Smith and McCloskey then jumped into the lead with a four point fourth end.. The teams then traded deuces and singles to give Smith and McCloskey the B qualifier ,by a 7-6 score.
All four junior players in the Championship Round have Mixed Doubles experience at a national level, having competed in Mixed Doubles games as part of the M&M Meat Shops Canadian Juniors, with McCloskey winning a silver medal in Mixed Doubles at last year’s Juniors.
Only two teams remain going into Sunday play at the PEI Mixed Doubles
The four teams that started play on Friday at the inaugural PEI Mixed Doubles Curling Trials at the Crapaud Community Curling Club have now been reduced to two — and they’re both Junior-age rinks — the Kyle Holland and Katie Fullerton duo from the Charlottetown Curling Complex and the Cornwall Curling Club, and the Tyler Smith and Chloé McCloskey twosome from the Crapaud and Cornwall clubs.
Holland and Fullerton captured the A section of the Modified Triple-Knockout round on Friday, with an 11-3 win over the Dario Zannier/Vivian Holm pair from the host club in the A qualifier game, On Saturday morning, Smith and McCloskey beat Crapaud’s Daniel and Nancy MacFadyen team 9-4 to advance to the Saturday afternoon B qualifier match against Holland/Fullerton, who got off to a great start in their game, stealing singles in the first 3 ends. Smith and McCloskey then jumped into the lead with a four point fourth end.. The teams then traded deuces and singles to give Smith and McCloskey the B qualifier ,by a 7-6 score.
Down in the must-win C flight, the MacFadyens took on clubmates Zannier and Holm in an afternoon game, with a six-point 3rd end propelling the MacFadyen rink to an 11-5 victory. Holland /Fullerton then eliminated the MacFadyens with a 6-2 win in the 4 pm draw.
The two junior rinks, Holland/Fullerton and Smith/McCloskey will play up to three games on Sunday, first squaring off in the C Qualifier at 10 am. The winner of that game will have a big advantage going into the two game championship round at one and four, as they will take the championship if they win either game, while the loser of the C Qualifier would have to win both championship round games to go on to represent PEI at the National Mixed Doubles Trials in Ottawa in March 2015.
All four junior players have Mixed Doubles experience at a national level, having competed in Mixed Doubles games as part of the M&M Meat Shops Canadian Juniors, with McCloskey winning a silver medal in Mixed Doubles at last year’s Juniors.
Holland/Fullerton duo 2-0 after Friday play at Mixed Doubles, win championship round berth
The Kyle Holland and Katie Fullerton rink from the Charlottetown Curling Complex and the Cornwall Curling Club are 2-0 after opening day play at the inaugural PEI Mixed Doubles curling trials at the Crapaud Community Curling Club, and have captured the “A” event in the four team triple knockout competition ensuring them a berth in the championship round on Sunday. The duo won their opener 11-3 over the Dario Zannier/Vivian Holm twosome from the host club, taking four points in the third end, and triples in ends five and six to end the game early. Their second match, against Daniel and Nancy MacFadyen of Crapaud was much closer, with the teams tied at 3 after four ends, and at 6 after eight. Holland/Fullerton stole the extra end for the win.
Photo: Draw one action at the Mixed Doubles
The MacFadyens won their opener 7-6 over Crapaud and Cornwall’s Tyler Smith and Chloé McCloskey team, stealing the final end for the win. Smith/McCloskey won their second game, 7-5 over Zannier/Holm.
On Saturday, the Smith and MacFadyen rinks square off at 10 am, with the winner facing Holland in the B qualifier at 1 pm and the loser taking on Zannier at the same time in the C event. At 4 pm, the winner of the C event game takes on the loser of the B qualifier, with the winner of that game facing the winner of the B qualifier in the C qualifier game at 10 am Sunday.
The A, B, and C winners then square off in the two game championship round on Sunday at 1 and 4, unless the Holland/Fullerton team wins all three sections, which would give them the Mixed Doubles title without playing the championship round.
The winning team will move on to represent PEI at the National Mixed Doubles Trials in Ottawa in March 2015.
Skip 3rd Coach Club(s)
Kyle Holland Katie Fullerton Charlottetown & Cornwall
Daniel MacFadyen Nancy MacFadyen Crapaud
Tyler Smith Chloë McCloskey Kevin Smith Crapaud & Cornwall
Dario Zannier Vivian Holm Crapaud
Modified Triple Knockout Draw (A, B, C), Championship Round, and Schedule
(Draw here will not be updated during event – refer to Curlcast for updated draw).
There are three possible outcomes from the Modified Triple Knockout Round:
1. One team wins all three qualifiers: Championship Round is not required.
2. One team wins two qualifiers. They play in X and Z (and win the event if they win either game), the other winner plays in Y (and has to win both games).
3. Three separate winners: the team that played in the most qualifying games (3, 6, 9) plays in Z and the other winners play off in X and Y. If there is a tie in number of qualifying games played, then the team that qualified earliest goes to Z and the other two teams play off in X and Y.
Last stone advantage and stone handle colour:
1. A team that wins 2 qualifiers has last stone advantage AND choice of stone handle colour in both games.
2. If three separate winners, Last stone advantage AND choice of stone handle colour is awarded to the team with the best win/loss record during the knockout round. IF the win/loss records are identical, the higher ranked team will have the choice of last stone advantage OR choice of stone handle colour.
Game Logistics
(a) A team is composed of two players, one male, and one female. Alternate players are not allowed. A team must forfeit any game(s) in which it fails to have both athletes playing for the entire game. One coach will be allowed for each team.
(b) The scoring shall be the same as in a regular game of curling. The “positioned” stones that are placed before the beginning of each end are eligible to be counted in the scoring.
(c) Each game will be scheduled for eight (8) ends.
(d) Each team shall receive twenty-two (22) minutes of thinking time. There will be a four (4) minute break after the completion of the 4th end.
(e) When extra ends are required, the clocks will be reset, and each team shall receive three minutes (3:00) of thinking time for each extra end.
(f) Each team shall deliver five (5) stones per end. The player delivering the team’s first stone of the end must also deliver the team’s last stone of that end. The other team member shall deliver the team’s second, third and fourth stones for that end. The player delivering the first stone can change from end to end.
(g) After the pre-game practice, using all eight (8) stones, teams will choose the five stones they want to play with and shall keep those five stones for the entire game.
(h) Modified Free Guard Zone – No stone in play, including the “positioned” stones and those in the house, can be moved to an out-of-play position prior to the delivery of the fourth stone of an end (the fourth delivered stone is the first stone that can remove any stone from play). If there is a violation, the delivered stone shall be removed from play, and any displaced stone(s) shall be replaced to their original position by the non-offending team.
(i) Before the start of every end, one team shall place their team’s “positioned” stone at the playing end of the sheet in one of two positions, designated A and B. The opponent’s “positioned” stone shall then be placed in whichever position (A or B) remains vacant. The location of these positions shall be as follows:
1) Position A: Placement so that the stone is bisected by the centre line and is either immediately in front of or immediately behind one of 3 points in the ice. The points are placed on the centre line:
at the mid-point between the hog line and the outermost edge of the top of the house
0.915 m. (3 feet) from the mid-point closer to the house
0.915 m. (3 feet) from the mid-point closer to the hog line
Based on the ice conditions, the Chief Umpire shall determine the specific placement for Position A to be used before the start of the pre-game practice and that same placement must be used for the entire game.
2) Position B: Placement so that the stone is in the back of the house, bisected by the centre line and abutting the back edge of the tee.
(j) The team having the decision on the placement of the “positioned” stones shall be:
1) Teams opposing each other in the game shall use the Last Stone Draw (LSD) to determine which team has the decision in the first end. The team with the lesser LSD distance shall have the decision on the placement.
2) Following the first end, the team that did not score shall have the decision on the placement.
3) If neither team scores in an end, the team that delivered the first stone in that end shall have the decision on placement in the next end.
(k) The team whose “positioned” stone is placed in Position A (in front of the house) shall deliver the first stone in that end, and the team whose “positioned” stone is placed in Position B (in the house) shall deliver the second stone in that end.
(l) While the team is in the process of delivery, the non-delivering player must be positioned inside the hog line and on the ice surface at the playing end of the sheet. After delivery, either or both players may sweep their delivered stone and any stones set in motion that belong to their team anywhere in front of the tee line at the playing end.
This applies during all of the team’s delivered stones, including the LSD.
(m) If a player delivers a stone out of proper rotation, that stone is returned to the hack to be delivered by the correct player, after any displaced stones have been replaced to their original positions by the non-offending team.
Should the infraction not be discovered until after the delivery of a subsequent stone, play continues as if the infraction had not occurred.
(n) The event will be fully officiated by a CCA Chief Umpire and appropriate Game Umpires.
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Meet Microsoft's MBA Class of 2018 | Poets&Quants
Meet Microsoft’s MBA Class of 2018
by: Jeff Schmitt on July 10, 2019 | 0 Comments Comments 19,005 Views
What fosters growth? In business, growth is the result of strategy, sweat, and superiority. The rewards are power and prestige, higher stock prices and fawning media coverage. With scale comes the urge to dream big and the resources to transform markets. It is this combination of purpose and positioning that turned Microsoft into the feel-good story of the decade.
When Satya Nadella succeeded Steve Ballmer as Microsoft’s CEO in 2014, the company’s market cap stood at roughly $270 billion dollars. Fast forward five years and that number had swelled to a trillion dollars. No doubt, the news elicited a few private toasts in Microsoft’s Redmond compound. Among the rank-and-file, says Steve Lipner, the milestone was greeted with a business-as-usual shrug. A Wharton MBA who joined Microsoft as an account executive in 2018, Lipner observed that his peers instead remained focused on the future.
“We should never become complacent, but instead constantly strive for more. Microsoft’s growth mindset culture really pushes its employees to learn more and see what else we’re capable of.”
SEEKING CURIOUS “WORKS-IN-PROGRESS”
MBA student trek to Microsoft headquarters
That mindset is rooted in the types of people hired at Microsoft, particularly from the MBA ranks. For Diego Rejtman, general manager for Microsoft Global University Recruiting, growth starts with continuous learning. In fact, Rejtman shares that curiosity – and a love of continuous learning – are his top criteria for making hires. From finance to operations to sales, he tells P&Q in a 2018 interview, Microsoft seeks MBAs whose trajectory demonstrate a zeal for self-improvement…the kind that ultimately leads to innovative thought and committed action.
“Learning comes from getting outside your comfort zone and taking risks,” Rejtman explains. “When I look at resumes, what I am trying to figure out is if this person is using every possible opportunity or experience they have to learn. We like to say that an employee works for Microsoft, but Microsoft also works for that employee. Microsoft is a platform for us to pursue our passion.”
Question is, adds Rejtman, will MBAs take advantage of this platform? In his experience, there are two types of people who apply for jobs. The first are finished products, the ones who stopped learning and believe they have everything figured out. The second type – the MBAs who excel at Microsoft – are works-in-progress. Think of them as life-long students who believe they have barely scratched the surface of what they can learn. Among the Class of 2018, Fabiola Bruny clearly fits into the latter category.
A BANNER CLASS IN A BANNER YEAR
A University of North Carolina grad, Bruny spent three months of her MBA program abroad in South America. As part of her leadership immersion capstone, the indoor-loving Bruny braved the elements in the Carolina mountains, lugging 40 pounds of gear on hikes…sans internet and showers, no less. Such trials gave her the courage to shoulder discomfort and the humility to seek out alternatives. Those lessons came in handy during her first year as a solution sales specialist.
“I’ve learned that success isn’t measured by “knowing it all,” she admits. “Having a growth mindset means being curious, continuously learning, and acknowledging that you won’t always have the answers. It has been difficult to embrace this especially when I want to appear competent and add value. However, I continue to learn from others and on many occasions, others have learned from me.”
Lipner and Bruny are among the hundreds of MBAs added by Microsoft last year. You’d be hard-pressed to find a better time to join the company. Xbox, for one, is slated to release a game-streaming service, xCloud, with the potential to become the “Netflix of Gaming.” Microsoft also continues to transform into a cloud-based company, headlined by its flagship Azure platform. At the same time, its personal computing group remains a revenue driver, as the Surface line continues to snap up market share. On top of that, the number of devices running Windows 10 now tops 800 million.
GOING BEYOND THE TYPICAL JOB DESCRIPTION
Dynamics 365 Guides empowers employees to learn by doing.
How are first-year MBA hires helping to drive this growth? Alexis Apostol, who studied sustainability and human capital at the University of Michigan’s Ross School, prefers her unofficial title: “new employee orientation wizard.” Translation: She helps the 22,000 annual new hires “feel like they are valued and belong” so they can be “their authentic, best selves.” On the surface, Columbia Business School alum Angela Wang is a finance manager in the Movies and TV unit. However, her role goes far beyond reporting and forecasting.
“What makes my job exciting to me is the opportunity to delve deep into user behaviors and strategic drivers of the business in order to ensure continued growth on our platform,” she writes. “An unexpected perk of my role is that I’m frequently watching trailers of upcoming movies under the disguise of market research!”
Microsoft is also a place where the sales role is hardly dialing for dollars. Rather than pitching one-size-fits-all solutions, the sales team are expected to be consultants – experts and creatives who can outline new business models and incorporate cutting edge technologies like artificial intelligence. Like consultants, sales members are often folded into a larger team that can touch on a wider range of solutions. Fabiola Bruny’s role is a perfect example: “As part of an account team, I help enterprise customers identify opportunities where using Microsoft’s cloud Azure can result in business benefits like decreased IT costs, faster innovation, better data security, and scalability.”
A PLACE WHERE YOU’LL NEVER GET BORED
David Ellis, another Michigan Ross MBA, entered Microsoft’s Cloud Marketing OnRamp program, a year-long effort with three rotations. In his first four months, he worked in marketing where he developed strategy and messaging. Ellis’ second rotation took him to the Customer Success team, where he drove improvements in user experience with apps and portals. Now, he is finishing his rotation with the Global Demand Center, where he is creating an engagement program for prospects who are considering moving to cloud storage.
Such rotations are indicative of the transitory nature of roles at Microsoft, which employs over 141,000 people total (including 51,000 in Puget Sound alone). This diversity of products and teams creates a lot of opportunities. Diego Rejtman notes, for example, that MBAs are encouraged to move to a new role or unit every 2-3 years – a flexibility that only adds to their value and stirs their creative juices.
Microsoft interns building camaraderie on a sailboat cruise.
“Microsoft is a large enough company that you can easily spend your entire career in different roles and never get bored,” adds Steve Lipner.
AN EQUESTRIAN AND A SHARK FISHERMAN
What word best describes Microsoft employees? Reijman suggests “eclectic,” people who learn from a variety of sources and live true to who they are. The Class of 2018 is no different. For Alexis Apostol, horseback riding is what “feeds my soul.” She has competed in national equestrian competitions since she was nine, even taking courses with Olympic coach George Morris (falling off her horse in the first five minutes of her first lesson). David Ellis’ passion is sharks – as in fishing for deadly Mako Sharks that can weigh over 250 pounds. In contrast, Angela Wang’s outlet is music…the accordion in particular.
“It was a really cool instrument in Shanghai at the time,” she points out. “When I moved to America, I was shocked to learn that it wasn’t nearly as popular here!”
Popular is also a word that could be applied to Microsoft’s 2018 hires. Many had opportunities to join blue ribbon firms like McKinsey, Google, and JP Morgan. Instead, they headed to Washington, the land of cavernous forests, exotic coffees, and never-ending rain. Aditi Shah, a Chicago Booth grad who leads large scale Azure implementations, sums up the Microsoft appeal in a dozen words: “Great people, amazing leadership, and lots of fun things to work on.”
Tagged: Aditi Shah, Alexis Apostol, Angela Wang, Bufus Outlaw, Business School, Class of 2018, David Ellis, Fabiola Bruny, Inge Groth, MBA, Microsoft, Ryan Bernsmann, Steven Lipner, Susan Sasu
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Pogue's Posts | The Diary of a Low-End Computer Consultant
The Diary of a Low-End Computer Consultant
September 7, 2006 10:34 am September 7, 2006 10:34 am
Today, I’d like to welcome a special guest columnist, half my age: me.
I was fooling with some old backups when I found a stash of articles I wrote nearly 20 years ago. The publication was the Mac Street Journal, the newsletter of my local user group; I was a 24-year-old, fresh-faced rehearsal pianist with a computer hobby. The one I’m excerpting below is about my life as a personal computer trainer.
Here’s hoping you’ll get a kick out of it, if not for the humor, then at least for the references to the computing world of 1987…
Computer Virgins: Diary of a Low-End Consultant
Mrs. Cronkwitz was more than a Computer Virgin. She was a Computer Virgin Victim.
Evidently she’d been misguided by some other Consultant (a businessy word for what I do on the side, which is to help people plug in their VCR’s or stereos or computers, or rush across town to rescue a guy who says “I keep pushing and pushing, but my disk won’t go into the drive” and, upon arriving, have to explain that he’ll have to eject the disk that’s already IN the drive first).
This other Consultant, who no doubt charged her $100 per hour (and here I’m feeling sleazy chasing people who haven’t paid me my $25), guided her into buying a Mac SE (good choice), a hard drive (nice idea) and an IBM daisywheel printer (say what?). Mrs. Cronkwitz was calling to ask me if I’d come over to finish hooking her system together.
Feeling vague rustlings of doubt, I went to her apartment across- and downtown. Her system wasn’t just not hooked together; it was not yet out of the box. She stood, arms crossed, as I turned into a storm of Styrofoam and shredded shrink-wrap, setting up her Mac with the skilled eye of a Consultant.
Mac…check. Hard drive…check. Printer!
This thing looked at me resentfully, a bank of weird-looking jacks in the back. Lemme tell you, there’s no Mac cable made that would fit one of those things. Finally, I straightened and addressed my Client directly.
“Mrs. C,” sez I. “Are you quite certain that you don’t want any graphics ever? That you’ll never want any other typeface besides 12-point? That you’ll never have need for italics, bold or underline?”
At that moment, all Mrs. Cronkwitz could hear was the voice of the man for whose wisdom she had paid $100 per hour.
“MIS-ter Babcock works at Price-Peabody in the Computer Affairs Department,” she hissed. “MIS-ter Babcock told me that the Macintosh printouts look like a bunch of dots, and he therefore told me to buy this printer. I’m going to use this printer, and if you won’t help me do it, then I’ll find someone who can!”
If ever a gauntlet was thrown down, that was it. For the next nine months, in an effort to make the IBM printer work, I tried This and That Converto-Cable, So-and-So’s Adapter Software, and the Whatsihoosis Printer Driver. In the meantime, I endeavored to teach Mrs. C the basics. Two lessons on the Apple Guided Tour. Three on the Finder. Five on MacWrite.
Know what? The poor woman never did catch on. About the only thing about the Mac she really got was dragging something to the Trash Can. “That’s wonderful,” she said.
One day I came over with a new printer driver for her now very dusty daisy-wheel printer, which had not, as yet, printed so much as TESTING 123.
Mrs. C was ready for me.
“What is this? What do you take me for?! I met Arnold Teawitty at a function last week, and he told me I should have bought this… [consulting a handwritten slip of “WHILE YOU WERE OUT:” paper]… this… Imagination printer! He said I’m wasting my time with an IBM printer, and that I should have bought the Imagination printer! Why couldn’t you have said nine months ago, ‘Mrs. Cronkwitz, you should just sell this and get an Imagination printer?!”
Clutching the slip of paper, the faintly-penciled word “ImageWriter” protruding from under her pressure-paled thumb, Mrs. C. glared at me for an answer.
My mind raced. Should I remind her that I had been suggesting just such a transaction for nine months?
But in that moment, I came to realize what the Computer Virgin needs most of all. Mrs. C didn’t want instruction, and she didn’t want technical support. Heck, she didn’t even want a working printer.
She wanted reassurance.
“You’re right, Mrs. C. You’re absolutely right. I think Mr. Teawitty has an excellent solution, and we should proceed straightaway.”
And so we did.
Now, there’s nothing wrong with being a Computer Virgin. In fact, it may be difficult to believe, but all of us were computer virgins at one point.
And “intuitive” is a relative term, to be sure. It doesn’t shock me a bit to hear bewilderment expressed about Apple’s MultiFinder, MacroMaker and the Font/DA Mover. To a Mac Virgin, the manual may as well call them MiniShredder, ZeltroJotter and the Gonk/LK Steamer.
Quick! Distinguish the Zoom Box (huh?) from the Resize Box and the Clothes Box (what?). See that hard, rigid piece of plastic? That’s a floppy. To discard a file, drag it to the trash can. Of course actually, even then it’s not really gone–see? To really discard something, drag it to the trash and select Empty Trash. Of course actually, even THEN it’s not really gone… And the great thing about the Mac is there aren’t those weird IBM commands to memorize. OK, let’s eject the disk–just press the key combination Command-Shift 2…
Today, Mrs. C’s Mac-and-ImageWriter setup is fully operational. Yes, she’s still got 19.5 megs left on her 20-meg hard drive, and no, she still can’t type so much as a grocery list in MacWrite. But she’s been through the trials of Making it Work. She flips on the Mac now and then to take the Guided Tour. And she knows that at any moment she could send Christmas cards only to friends with last names P through Z who live in the 44120 zip code.
Mrs. Cronkwitz is no longer a Computer Virgin.
Comments are no longer being accepted.
dortress September 7, 2006 · 12:55 pm
Nice insight. What kills me though is: they’re still out there, in corporate America. I’ve been working in a computer customer support capacity for the better part of 10 years now and it never ceases to amaze me how many of the people I support fall into the Mrs.’ category. People who were ‘vetted for their skills – including computer. People for whom the basic operation of a computer and office applications are a requirement and neccessity of their job. How can this be when we’re almost 10 years into the computer being a ubiquitous part of daily life?????
Al September 7, 2006 · 1:39 pm
Actually David, what this does is make us realize how remarkable your writing was even when you were “fresh-faced.”
Jealously Yours,
Right On! September 7, 2006 · 1:47 pm
David, me lad, you and I have known each other almost since you wrote that, and our careers followed similar paths for a while. And as usual, you’re spot-on. Tech consulting has very little to do with tech, and never has. And that’s true at every level, not just in newbieland.
Hey . . . and your Blackberry Pearl video was without a doubt your best such work to date!
-Jeff Yablon
//www.pc-vip.com
Henry Wong September 7, 2006 · 3:00 pm
Thanks for reminding me that going back into the tech support business might not be worth the coin…
Jamie September 7, 2006 · 4:29 pm
I taught computer classes to high school teachers [way] back in the day. My personal Mrs. Cronkwitz-equivalent came to her first class one day and looked at the mouse.
And then picked it up, pointed it at the screen, and pushed the button repeatedly, as if she had a TV remote.
Russ Lemker September 7, 2006 · 6:47 pm
Fantastic! I worked for ComputerLand in 1987 and you nailed it. One of my co-workers summed it up, then, when he exclaimed, “Take my ulcer away for $25? My doctor couldn’t do that!” as he contemplated the loss of his fee to avoid another “Mrs. Cronkwitz” moment.
Thank you for the memories and the insight.
Meg September 7, 2006 · 7:15 pm
Maybe nothing to do with anything, but it has that “Back In The Day” feel.
Ad agency. Guy comes and says his computer doesn’t work. I’m ‘tech support,’ because I’m the one who finds computers most interesting. The rest of the agency is just screaming for 100mb hard drives to store their artwork.
I fuss and fuddle and finally yell at him for letting his children play in his office over the weekend, AGAIN. Finally I call professionals. For $65 of the company money, I learn that the monitor cord came loose.
In the home, among family and friends, I’m still Tech Support. I do a better job. I always check the cords first. I still push F8 to highlight, too.
And by the way, thanks, David. I enjoy your columns very much. — Regards.
James September 7, 2006 · 7:29 pm
But didn’t the ImageWriter make printouts that looked like a bunch of dots? Ohh … I guess that was the point of the article… didn’t matter what it printed – Mrs. C was just a hoot.
Always look forward to your articles. Thanks.
Lydia September 7, 2006 · 7:31 pm
How lucky that Mrs. C was. I can’t imagine having been that nice or understanding at 24. In fact, I don’t think I am at 44.
Ah good times, good times…
Andy September 7, 2006 · 9:03 pm
Nice story still. I belonged to the same user group and even wrote several stories for the Mac Street Journal, including a guide to “Creating Your Own Electronic Zine”, a quite positive review of Tex-Edit, and a story on “Online Worlds”, which summarized the cyber-thoughts of a MacFair ’95 panel. I also enjoyed firing up my Mac LC and hanging out on the group’s BBS and later contributed to its page on eWorld (an online service that someone once said was “like playing Myst — it’s beautiful, but there’s no one there.”) Those were fun days!
Lynn Yost September 7, 2006 · 9:50 pm
Ah, the good old days at the NYMUG Mac Street Journal in NYC! I’d forgotten this piece – still a good characterization of consulting, though. Read your column regularly. Warm regards, Lynn (former Editor, Mac Street Journal)
Mac Beach September 7, 2006 · 10:12 pm
What’s sad is that after all these years things haven’t improved much, if at all.
Yes there are a few devices that can be plugged in and “just work”. USB external hard drives fall into that category. But for reasons that will forever remain a mystery, most of the add-on gadgets at my local computer retailer require drivers and as a result may only work with particular operating systems, particular web browsers, and as actually happened to me, wipe out personal files during their installation process. “Ooops! We had no idea anyone would save thousands of pictures in a folder named Photos, really!”
When asked, I hang my head in shame and admit that I was a member of the computer profession. When the Ludites take over and line us all up against the wall, all I’ll say in my own defense was that I switched to Linux in the late nineties and have advised everyone else to avoid computers at all costs ever since. Maybe I’ll get a blindfold.
Nathanael September 7, 2006 · 11:42 pm
Wow! A whole 20 MB hard drive. I have a single music file that take up 25 MB.
Den Harris September 8, 2006 · 12:29 am
Bless you David Pogue. I’d forgotten how I loved my Mac in 1987 – back when you needed a bank loan to purchase the system with a printer. How far away I’ve traveled from Mac on the trip through the business world and Gate’s menagerie. I owe myself a Mac! Thank you.
jesse September 8, 2006 · 12:59 am
Wonderful, simply wonderful!! I’m working a temp job at a University IT help desk and my favorite people are the Professor Emeritus call in for help! Their passwords won’t work anymore because of security changes.
Poof! “Fluffy” “George” “MyMomLovesMe” won’t get them to their email anymore. The poor dears, so amazingly brave at ages =>70+ to take part in the cyber world albeit “only by email” are taken aback by this rejection.
The youngsters at the help desk, many of whom are less than 24, are impatient. But I, who am 56, I understand. We work together and “Flu.ffy.1″ makes it past the guardians, and we agree that this is a lot of broo-ha-ha. Tomorrow when I log in, I will think of this blog, and know that I’m doing it right! Thanks.
David Pogue September 8, 2006 · 1:53 am
Hey, I can’t believe how many of the old NYMUG crew have responded! Hi to Lynn (my one-time editor), Andy, Jeff–holy cow, we’re all still around and still computing! Must’ve been something in the water… :)
Elena-Beth Kaye September 8, 2006 · 5:56 am
Well, gosh, I have to chime in too! Just yesterday, while emcee-ing the MacValley user group meeting across the country in L.A., I mentioned the old days at NYMUG and how most of my initial learning happened there. Memories… The first time that we got to watch one of your demoes, we knew we had a find! How lucky we were to have you do your thing on stage every month, and now the good fortune gets shared with a whole bunch more folks. Yay! (It’s hard to believe how many years have passed in between — yikes!)
embee September 8, 2006 · 8:56 am
Hmmm. So when did I lose my computer virginity? I guess you COULD say when I was 10 years old in my parent’s basement at Chanukah. I had a C64 with TWO disk drives. Plus, a friend of mine gave me this program that let me copy a floppy diskette. I learned BASIC on that thing.
Or, maybe it was when I was 14, in my dad’s rec room. That was my first hard drive, 20 MB. I helped my dad organize all the files. I think my first real experience came when I accidentally deleted COMMAND.com and CONFIG.sys.
My dad was pissed that I “broke” the computer. Then, one of my friends brought me a boot disk. By the end of the summer, I had tweaked the AUTOEXEC.bat and CONFIG.sys files. At one point, I got the computer, a 286/16 running faster than my friend’s shiny new 386/32.
My dad quickly forgot about my “breaking” the computer because the file management I had done on the computer freed up enough space to install “World Class Leaderboard Golf” (“Looks like he hit the tree, Jim”) and a very risque computer game called “Leisure Suit Larry.”
I miss my TURBO button.
Bryce September 8, 2006 · 2:58 pm
Just imagination the mess Mrs C. had been in if she’d bought a PC instead of the Mac!
I say that as I remember playing with my PC back in ’87, with a dot-matrix printer, lining up the paper making sure it was near the top of the perforation, hacking the config.sys file for “fun”… so in 1990 I bought a Mac SE and an inkjet from HP – boy, what a difference! Printing “Test 123″ appeared exactly as it had on screen… wow! Now that was magic.
Thanks for the read David, it was very funny.
Bobbe September 8, 2006 · 3:49 pm
Remembering my early computing days: Late 90’s inherited a 286, no manual, just ”turn it on here, and type ”word”.” Never did learn how to properly close that program. Just used the ”power outage” method — pulled the plug.
A printer with a large supply of paper came with that computer and I printed out miles of the internal help files before putting the computer to sleep. The black screen with its flickering ”C:\” would not appear.
Days past before I found something in those ”help” pages. Was it hit the ”F8” key at start up? Whatever, my new toy was fixed.
Used this knowledge to test those ‘foreign-speaking’ salesmen while exploring the possibility of updating. If they offered my solution to the sleeping computer problem considered them knowledgeable. Otherwise they were just movers of inventory. That’s back when
DOS had a directory.
Those were the days that I approached the computer with sweaty palms. Always fearful that I would mess something up while exploring. And then the Internet entered my life with answers and solutions to some of my computing problems that no one in
my small community could solve.
Started computing in my late 50’s and firmly believe there’s no better mental exercise.
APR September 8, 2006 · 4:06 pm
I used to work for a news Web site, and would frequently get calls from the Mrs. Cronkwitzes of the world (or at least the region). Sometime around 2002, a fellow called me, angry because “we had only printed half the story.”
Half the story? “What do you mean, sir?”
“The story goes down the screen, and then it just ends…”
He couldn’t be saying what I thought he was saying. “OK, you’ll need to scroll down the screen to see the rest of it, sir…”
“Scroll?”
Sure enough. He’d never scrolled a browser. I explained in VERY specific detail how to do that, and finally communicated the idea of “grabbing” the scroll-bar with the mouse and “pulling” it downward.
When his ENTIRE SCREEN shifted upward, he literally hollered in fright. It unnerved him just like the first time you do that “switch user” thing in OSX and the whole environment rotates sickeningly around, like a big cube.
I hope he’s figured out how to right-click by now.
geekfx.blogspot.com September 9, 2006 · 12:06 am
I know someone who was given an email address over the phone. The mail she sent never reached though. She’s typed the address out as [name]attheratehotmaildotcom
Ivan Berger September 9, 2006 · 4:44 pm
Like you, I used to people with their VCRs and stereo systems. One day, an editor at a hi-fi magazine in Mass., asked me to set up a system for one of their music critics.
The system was fairly straightforward and easy to set up. But a week later, he called to say “You’ve gotta help me! The violins are on the right, not the left! I used to be a conductor, and I can’t stand that!”
As near as I could tell by tracing the wires, all was as it should be. But when I put the started the record he’d obligingly left on the turntable, the channels were reversed. I swapped two cables, and went home. But my phone was ringing when I got there: “The problem is back!” Suddenly, I understood: “Before, were the channels backward on anything besides the record you had on the turntable? No? Then I’ll fix it for everything else, but that record will always be reversed.”
A few days later, he called again: “Nothing works! The turntable doesn’t turn, nothing lights up!”
“And your cleaning woman was just there?”
“How did you know?”
Well, “I said, follow the extension cord to where it goes to the wall, pull out the sofa, and plug it back in.”
“That sounds too technical,” he whimpered. “Could you come and fix it?”
Rob September 11, 2006 · 6:40 am
Ah those were the days I could almost hear “All in the family theme song” on one of the many cable independent channels on Mrs C’s television because there was not enough media content to really fill the recent phenomenon of cable TV as well. We have come a long way but your writing was always rich and funny and this was one rerun worth reading again. Thanks for making me remember how glad I am that I got my tech virginity out of the way oh so many years ago and that I can now be dated by my knowledge of Font/DA mover and the Multifinder.
loadster September 12, 2006 · 9:34 am
Sorry Mrs Cronk, but you were the reason Mac couldn’t succeed for every desktop. It has nothing to do with virginity, creativity or advancing technology.
The reason you can’t teach old dogs new tricks is they’re brain-damaged. They’ve learned to survive with indelible patterns and cues. Virginity should not be derated and lumped in with stupid people that can’t be fixed. Virgin means fresh, new and ignorant. I envy that.
The early Mac world was full of enabling, efficiency and compatibility. The early PC world was full of dot-matrix, text-based, secretive, manipulating tron-heads resisting graphic-interfaces. Who was more like a virgin?
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A Revolution, or Just a Mouse?
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Home > News > Prescot Watch Factory Development Begins
Prescot Watch Factory Development Begins
By Prescot Online on Friday, April 10, 2015
Work has begun on the development of the former Prescot Watch Factory.
The site, on Albany Road, will house 70 new residential properties, including 54 extra-care apartments in the watch factory building itself.
Sixteen extra-care bungalows will be built elsewhere on the site during the current phase of development, due for completion in April 2016.
A later phase of construction will see another 62 homes added.
Christian Bury, managing director at Harbur Construction, said: “The one and two bedroom apartments will transform the historical site into a thriving community in an area where demand for this type of housing is high.
“The new homes are being built in keeping with the site’s rich heritage while providing modern living facilities to help elderly and disabled people live independently.”
Partners at Knowsley Housing Trust and Liverpool-based Iliad also emphasised the transformation would be in keeping with the area’s history.
“Prescot Watch Factory is of great significance to the historic fabric of Knowsley, with this Grade II listed building playing a key role in the industrial growth of the region,” said Iliad’s Ryan Cullen.
The original building was erected in 1889, when Prescot’s traditional watch- and clock-making industry was in decline.
The Lancashire Watch Company used newer American methods to compete with the industry worldwide, but ultimately lost to its rivals and closed down in 1910.
During World War One it became the PALS barracks, and it later housed Tinling’s printers.
Below: More artists’ impressions of the final development.
Albany RoaddevelopmentsfeaturedKHTLancashirelocal historyPals BarracksPrescot HistoryPrescot town centrePrescot Watch Factory
pauline foy
Tuesday, December 8, 2015 at 3:35 am
Hi.ism intrested in this home just making sure if kht have put my name diwn on waiting list as ism disabled with fibromylia struggling with it please let me know if Iam on waiting list thank you regards pauline foy
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"Where the wind blows" - Size 30X30/15X15 cm - Wall print - designed by the illustrator Izhar Cohen - Part of a limited edition collection.
PULP is proud to launch a limited edition collection by the artist Izhar Cohen - One of the most talented and prominent illustrators in Israel.
the new collection includes notebooks| postcards| prints
"Where the wind blows"
30X30/15X15 cm - 250 gr.
*frame is for display only.
Izhar Cohen - London | Paris | Florence | Tel Aviv
Izhar Cohen's & pulp new collection - London | Paris | Florence | Tel Aviv - as it's name - combines illustrations from all the years of him living in those cities - printed on notebooks and all sort of designed paper products from the house of PULP.
Izhar: "After years of creation, I'm stopping for a moment and sharing with PULP my enormous collection of illustrations"
Izhar Cohen is an artist, an illustrator, and a designer. His work has been published worldwide in leading newspapers and magazines - Such as the New York Times, The Guardian, Time Magazine, The Wall-street Journal, La Figaro, Yediot Aharonot and more. In addition, he is a renowned illustrator of books for children.
Born in Israel, 56 years old. Cohen studied at the Bezal'el Academy of Arts in Jerusalem and the Ecole des, Arts Decoratifs in Paris and Central Saint Martins in London.
For the last 25 years Izhar is living on the line of London - Paris - Florence & Tel Aviv. that affected his inspirations a lot - look for them in his prints and you'll understand the magic.
Cohen says, "My many years of work in different cultural environments have helped me transform my illustrations into an articulate instrument with an identifiable visual language that enables me to create original conceptual connections in the hope of arousing thought with the help of humor."
15*15 cm - $19.0030*30 cm - $25.00
"Tel Aviv City Night" - Size A5 - Wall print - designed by the illustrator Izhar Cohen - Part of new limited edition collection.
"Tel Aviv City Day" - Size A5 - Wall print - designed by the illustrator Izhar Cohen - Part of new limited edition collection.
"Chronotyps" - Size A5 - Wall print - designed by the illustrator Izhar Cohen - Part of new limited edition collection.
"The soul of the City" - Size 60X20 - Wall print - designed by the illustrator Izhar Cohen - Part of new limited edition collection.
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Pun Salad
(View: Movies)
Continuing in the December-January TV drought, we watched this 2016 movie, written and directed by Woody Allen. IMDB has it as 'Comedy | Drama | Romance', but it's one of those comedies where you don't laugh very much. (Scan through the IMDB quotes page if you want, all the gag lines are there.)
Also: the drama and romance depend on how much you care about what happens to these people, and the answer there is "not very much". The 2.5 stars are generous, awarded mostly because the movie is (warning: cliché coming up) a feast for the eyes. IMDB says it's the most expensive Woody Allen film made, and they went all out on the sets and costumes.
Also a feast for the eyes: Blake Lively. Whoa. Good move, Ryan Reynolds.
It's set in the 1930s. The main character is Bobby (Jesse Eisenberg), who's moving out to Hollywood from New York; his mom implores her brother, Hollywood exec Phil (Steve Carell), to use his connections to get Bobby a job. This happens, and Bobby happens to also find love with Vonnie (Kristen Stewart). Unfortunately, Vonnie is Uncle Phil's girlfriend. Forced to choose, Vonnie opts for getting hitched to Phil, breaking Bobby's heart. He moves back to NYC, uses his brother's mob connections to start a swanky nightclub. He meets Veronica (Blake Lively), she gets pregnant, they get hitched. But then Phil and Vonnie come to town…
Well, then some other stuff happens, then the movie ends.
Woody Allen himself does a voiceover narration. Jesse Eisenberg does a decent Woody Allen impression, which is apparently required for the main character in a Woody Allen movie these days.
Posted 2020-01-21 6:57 AM EST
This is the third entry in Rowan Atkinson's "Johnny English" series. Johnny is about halfway between James Bond and Mr. Bean.
As the movie opens, Johnny's been sidelined, off to a small school where he's ostensibly a geography teacher. But he actually spends most of his time teaching the kiddos spycraft: ninja techniques, disguise, weaponry.
Unfortunately, this is the best part of the movie.
An evil cyberhacker breaks into Britain's "MI7" computers, and outs all the current crop of spies. To investigate, the PM (Emma Thompson, pretty good) demands that an inactive agent be brought back to investigate. So Johnny's off to France to track down the hacker, when he runs into Ophelia Bhuletova (Olga Kurylenko, who was an actual Bond girl in Quantum of Solace). Friend or enemy?
So anyway, Johnny bumbles a lot, a considerable amount of physical comedy, some of the gags work better than others. Atkinson, it's revealed in a DVD interview, likes doing physical comedy. Fine, but know when to stop, OK?
Given the elements, you can write the script yourself.
This is a pretty good entry in the "Dumb People Committing Crimes" genre. At least I laughed all the way through. It is based on an actual $17 million heist, although considerable liberties were taken to make things funnier. Co-produced by Lorne Michaels, it's also a movie gig for a lot of ex-SNL cast members.
Zach Galifianakis (could equally well have been Will Forte) plays probably the dumbest guy, David Ghantt, a trusted employee of an armored car company. When slightly-smarter Steve (Owen Wilson) learns that David is smitten with his co-worker Kelly (Kristen Wiig), a plot is hatched. And it goes surprisingly well! David goes on the lam down to Mexico. Steve, with the lion's share of the loot, realizes that David is a loose end, and sends a hitman (Jason Sudekis) after him.
Also: Kate McKinnon as David's spacey fiancée; Leslie Jones as an FBI agent. Everybody's funny, and the movie is better than it probably deserves to be.
Pun Son and I trekked over to the icy wastes of Barrington to view 1917. After a good sleep, various bodily sphincters have finally unclenched. I understand there's an IMAX version; I probably wouldn't have survived that. Yes, it's intense.
IMDB raters have this as #41 on the list of best movies of all time. And (of course) it's been nominated for a Best Picture Oscar, and nine others.
Set in World War I's trenches, It's the story of two soldiers and their desperate mission to notify a remote regiment that their scheduled attack against a German force is doomed to failure. If they don't get through, 1600 of their countrymen will be slaughtered.
They proceed through different instantiations of hell. All impressively shot. I don't know about Best Picture, but the Oscar for Cinematography should be a lock. (And I say that without having watched the other nominees.)
Only one little quibble: would that have really been the best plan to save the regiment? Just send two random grunts to warn them in the nick of time? Especially since… well, I don't want to spoil anything.
As God is my witness, I thought this was gonna be funnier. I was deceived by the previews, which made it seem like kind of a slapstick hoot. And the IMDB has it as "Biography, Comedy, Drama".
To quote a (different) Brit queen: We were not amused.
Queen Anne is initially under the spell of manipulative Lady Sarah; she's finagled her into supporting a ruinous war with France (for a reason I missed, if it was provided). This goes along with punitive taxes on the populace, which they are pretty irked about.
Along comes Abigail, Sarah's cousin, who's trying to recover after a spell of degrading prostitution. She turns out to be equally as adept at winning the Queen's fancy, especially when she appeals to her, um, baser instincts.
To quote Bugs Bunny: of course you know, this means war.
Sarah and Abigail wage a genteel, and not-so-genteel war on each other. This is set against a backdrop of unending perversion (in this movie, everybody's pretty kinky and degenerate).
Nominated for 10 Oscars, and Olivia Colman won for Best Actress, playing Queen Anne.
Posted 2020-01-16 7:18 PM EST
Cary Grant and Katherine Hepburn! Directed by George Cukor! For what more could you ask?
And about ten minutes into it… "Did we see this before?" "It seems kind of familiar…"
I don't find it in my movie list, though. And I've been pretty diligent about keeping it complete. So it must have been pre-2004. But consumer note: I remember watching Bringing Up Baby; this one isn't super-memorable.
Anyway: Cary plays Johnny Case, who (as it happens) has just returned from Lake Placid, where he met the love of his life, Julia Seton (not Katherine Hepburn, Doris Nolan). To his eventual consternation, he discovers that, whoa, Julia's rich. As in falling-in-the-ditch rich! (I don't know what that means, but Mom used to say that.) Julia's dad, a scion of finance, is overbearing. Her brother's a drunkard. And sister Linda—ah, there's Katherine Hepburn—is "eccentric", meaning she's more fun than anyone else in the family.
There are some rough spots to overcome: Dad's skeptical, since Johnny's background is lower working class, for example. But he's a hard worker, put himself through Harvard, and has a talent for business. So eventually it's assumed he'll take his place in the Seton empire, and become heir to the throne.
But the plot-driving conflict is this: Johnny has different plans for his life. He wants to make a little money, then take off and have some fun. Then come back to work when the money runs out, then take off again. Rinse and repeat as necessary.
This is obviously unacceptable!
So yeah, the movie is mainly about Rich People Problems. How did this go over in 1938, anyway? Were people flocking to the theaters to watch Rich People Problems?
Or did people flock to the theater because they wanted to see how Cary Grant winds up with Katherine Hepburn? (Spoiler: he does.)
The Hitman's Bodyguard
IMDB records this movie's genres as "Action,Comedy,Thriller". It's rated R due to (according to the MPAA) " strong violence and language throughout". Salma Hayek is in it, and if you want to hear Salma talk dirty, this is your go-to flick.
Ryan Reynolds plays a private bodyguard specializing in escorting threatened individuals to safer places. He's at the top of that game… until he isn't, as a crooked Japanese businessman is picked off by a sniper shooting through the window of a private jet.
After some time passes, Ryan is still in the dumps about that, but he gets a shot at redemption when his ex-girlfriend recruits him to escort Samuel L. Jackson (the titular hitman) from London to the Hague, where he is to bear witness against murderous dictator Gary Oldman. And of course, Gary has a veritable army of mercenary thugs to deploy against Ryan and Sam. And there's an Interpol mole (Joaquim de Almeida, who might as well be wearing a "MOLE" sign taped to his back).
There is a lot of impressive, inventive, action and violence that must have cost a lot of money to film. Also a lot of wisecracking, profane, banter between Ryan and Sam. Gary Oldman is the only cast member who can be accused of acting.
Apparently it was successful enough to spawn a sequel, out later this year, The Hitman's Wife's Bodyguard, with Ryan, Sam, and Salma returning.
Posted 2020-01-07 11:37 AM EST
So was the world really clamoring for a star-studded movie about the relationship between Scribner's editor Max Perkins and writer Thomas Wolfe? Apparently not, as this movie wasn't widely released in the US, and didn't make much money.
Colin Firth plays Perkins, which explains why we got it. Mrs. Salad loooves Colin Firth. Jude Law is Wolfe. Nicole Kidman is Wolfe's, um, girlfriend (she's married to someone else). And Laura Linney is Mrs. Perkins. Guy Pearce has a meaty supporting role as F. Scott Fitzgerald, and there's also Dominic West as Ernest Hemingway. Everybody's pretty good, although the script suffers from biography-revealed-in-dialogue disease. ("So you're a best-selling author now, Tom.")
And the movie apparently strays from the facts in important ways. Arguably, a more factual take could have made a better flick.
And yeah, Colin Firth really does wear a hat in every scene right up until the end, when he doffs it while reading Wolfe's last letter to him. Kept waiting for someone to tell him to take it off.
Our first movie of 2020, and it kind of sucked. I liked the other "Cloverfield" movies just fine, but this one was kind of incoherent.
Also dull. Disclaimer: I did fall asleep on the futon for indeterminate periods while watching. The Pun Salad rules allow inclusion in the blog even for such occurrences.
The plot, as near as I can tell: in the future, Earth is running out of energy. Our only hope: the orbiting Cloverfield Station, which houses the developmental "Shepard particle accelerator"; if the international team of scientists and engineers aboard can get it to work, all will be well.
Unfortunately, it doesn't work. Instead their testing shifts them into a different parallel universe. And taken on board is a young lady who was on her version of Cloverfield Station in her universe. She materializes inside a wall, which means her body is riddled with space station wires and tubes. She recovers, though.
A bunch of stuff follows which disjointed, nonsensical, inexplicable, and (most of all) uninteresting.
The lead actress is named Gugu Mbatha-Raw. That's awesome. Also Ziyi Zhang from Crouching Tiger Hidden Dragon. Also awesome. Saved it from zero stars.
The Girl with All the Gifts
One last movie for 2019, watched while waiting for the ball to drop. It's pretty good, for a zombie movie. It appears not to have been widely released to US theaters for some reason.
I'd read the book on which it was based back in 2015, and… hey, I'll just steal a bit from what I said then, only minor spoilers:
Melanie is a smart kid in an unusual situation: she goes to school with her classmates, but that involves a couple of armed soldiers coming to get her in her cell. One holds a gun on her while the other puts her into a wheelchair with strong restraints on her arms, legs, and head. All indications are that the soldiers view her and her ilk with a mixture of fear and loathing. But she has a sympathetic teacher, Miss Justineau (Gemma Arterton, who played Strawberry Fields in Quantum of Solace!). And there's a very creepy lady scientist, Dr. Caldwell, played by Glenn Close. Pretty clearly she views the kids much like lab rats.
So she's in some sort of prison/lab. And all indications are that the outside world is … not well. The situation can't go on forever, and it doesn't.
This seems to be a big-budget movie, special effects are impressive. (According to Wikipedia (small spoiler) "Aerial views of a deserted London were filmed with drones in the abandoned Ukrainian town of Pripyat, which has been uninhabited since the 1986 Chernobyl disaster."
Posted 2019-12-31 10:00 PM EST
E-Mail: sand.paul@gmail.com
Disclaimers: Unquoted opinions expressed herein are solely those of the blogger.
Pun Salad is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for the blogger to earn fees by linking to Amazon.com and affiliated sites.
This blog is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
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Favorite Comments () Report
Milton is a hardened felon who has broken out of Hell, intent on finding the vicious cult who brutally murdered his daughter and kidnapped her baby. He joins forces with Piper, a sexy, tough-as-nails waitress with a 69 Charger, who’s also seeking redemption of her own. Caught in a deadly race against time, Milton has three days to avoid capture, avenge his daughter’s death, and save her baby before she’s mercilessly sacrificed by the cult.
Genre: Action, Crime, Fantasy, Thriller
Actors: Amber Heard, Billy Burke, Charlotte Ross, David Morse, Katy Mixon, Nicolas Cage, William Fichtner
Download Film Disini
Server Language Quality Links
Google Drive 1 Indonesia BLURAY Download Google Drive 2 Indonesia BLURAY Download Google Drive 3 Indonesia BLURAY Download Google Drive 4 Indonesia Download Subtitle Download
Hooked on the Game (2009)
After a stunning victory at a cyber sport tournament, the winning gamers are awarded CDs with a brand new game. After playing this game, each of them is affected with…
Genre: Action, Science Fiction
American Outlaws (2001)
When a Midwest town learns that a corrupt railroad baron has captured the deeds to their homesteads without their knowledge, a group of young ranchers join forces to take back…
Genre: Action, Western
Carriers (2009)
Four friends fleeing a viral pandemic soon learn they are more dangerous than any virus. A deadly virus has spread across the globe. Contagion is everywhere, no one is safe…
Genre: Action, Drama, Horror, Science Fiction, Thriller
The Medallion (2003)
A Hong Kong detective suffers a fatal accident involving a mysterious medallion and is transformed into an immortal warrior with superhuman powers.
Country: Hong Kong,USA
Genre: Action, Comedy, Fantasy, Thriller
Night at the Museum (2006)
Chaos reigns at the natural history museum when night watchman Larry Daley accidentally stirs up an ancient curse, awakening Attila the Hun, an army of gladiators, a Tyrannosaurus rex and…
Country: UK,USA
Based on the incredible true story of Jesse Owens, the legendary athletic superstar whose quest to become the greatest track and field athlete in history thrusts him onto the world…
Country: Canada,France,Germany
Star Wars: The Force Awakens (2015)
Genre: Action, Adventure, Fantasy, Science Fiction
Wanted by the mafia, a New York City bike messenger escapes into the world of parkour after meeting a beautiful stranger.
Vigilante Diaries (2016)
The Vigilante Diaries is a high octane action-adventure film featuring 90’s movie heroes, explosive action, and international espionage. The film revolves around a team of black-ops agents turned crime-fighters, led…
2 Guns (2013)
A DEA agent and an undercover Naval Intelligence officer who have been tasked with investigating one another find they have been set up by the mob — the very organization…
Kingdom of Heaven (2005)
After his wife dies, a blacksmith named Balian is thrust into royalty, political intrigue and bloody holy wars during the Crusades.
Country: Germany,Morocco,Spain,UK,USA
Genre: Action, Adventure, Drama, History, War
Infernal Affairs II (2003)
In this prequel to Mou gaan dou (2002), Chan Wing Yan has just become an undercover cop in the triads while Lau Kin Ming joins the police force. Both the…
Country: China,Hong Kong,Singapore
Trailer: Drive Angry (2011)
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Eyes on ‘Watch’
By PageSix.com Staff
May 4, 2012 | 4:00am
Jake Gyllenhaal REUTERS
Jake Gyllenhaal screened his buzzed-about upcoming movie “End of Watch” for Jay-Z at the Crosby Street Hotel on Wednesday. The rapper attended Gyllenhaal’s small friends-and-family screening of the Open Road Films movie, which comes out Sept. 28 as directed by “Training Day” writer David Ayer. Sources said Jay could be contributing a song to the project, which stars Gyllenhaal and Michael Pena as LAPD officers, with Anna Kendrick and America Ferrera. Producer John Lesher was also a guest. His next movie, “Blood Ties,” is shooting here with Clive Owen, Billy Crudup, Mila Kunis, Zoe Saldana, James Caan and Marion Cotillard.
Chris Harrison splits from wife
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MEET PARI
Conscious Fertility
The science behind ‘Pyramids’
by Pari Patri | Aug 29, 2018 | Manifestation, Meditation, pyramid, Spiritual | 0 comments
The Science Behind Pyramids
All the ancient civilizations, from the Pyramids of Giza to the towering Aztec and Mayan Pyramids of Central America have been using Pyramids for centuries.
The shape of the pyramid, which is a tetrahedron is considered as sacred geometry in the Universe. This shape is used to harness infinite source of energy as it creates a torsion field that generates high frequencies which amplify vibrational healing.
Extensive experiments have been conducted inside man-made pyramids. “Bovis” made a to-scale model of the Cheops Pyramid and placed it, like the original with the baselines aligned north-south and east-west. Inside the model, one-third of the way up, he placed a dead cat, it became mummified and thus, he concluded that the pyramid promoted rapid dehydration. Reports of this discovery attracted “Karl Drbal”, a radio engineer in Prague, who repeated similar experiments.
From then on, thousands of people had enhanced experiences when meditating beneath Pyramids, as its scientific properties focus harmonious energies while deflecting distracting ones. People have reported deeper relaxation, an enhanced sense of well-being and increased levels of awareness while meditating inside a Pyramid. They also experienced strong spiritual and psychic impressions like clarity in dreams, visions and increased memory recall. Changes in the meditator’s aura have been noted with Kirlian photography with auras becoming brighter and larger.
Experiments have shown copper to be the best metal for an open-frame meditation pyramid due to its natural electronic and bio-enhancing properties. However, pyramid structures of cardboard, wood or bamboo are also effective, if built to the same proportional dimensions as the “Great Pyramid” at Giza, in Egypt.
The sacred geometry behind a Pyramid is Nature’s gift to mankind. Other than spiritual benefits, pyramids are known to purify water, dehydrate food and flowers (thereby preserving them), promote healing of physical body from pain and injury and restore lustre to jewellery.
It is highly recommended to sit beneath a pyramid to improve one’s meditative experiences and to connect to one’s own Higher Self.
Patrick, G (2017) “Pyramid Power- The Science of Cosmic Energy.
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npr wait wait don’t tell me
Tag: npr wait wait don’t tell me
Tosh Torches Tiptoes!
May 4, 2012 March 13, 2017 Adam
Daniel Tosh talks about the movie classic “Tiptoes.” Even the Tosh knows a good bad movie when he’s force to see it. Tosh.0 If you’d rather listen to a review then watch it, we got it! Big shot TV writers Adam Felber (Real Time with Bill Maher) and Todd Levin (Conan) joins me talk about the little person show.Garry Oldman is wearing shoes on his knees to play a little person! Like “Dorf on Golf.” Need we say more? Ok, lets.. EMMY nominated writers Adam Felber and Todd Levin join…
blog"what's Happening?", adam felber, Bill Maher, can we say midget, comedy central, Conan, Daniel Tosh, dorf, dorf on golf, Emmys, Gary Oldman, golf, good bad movie, Internet, is the word midget wrong, Kate Beckinsale, kate beckinsale nude, kids, little people, little people getting drunk, Matthew McConaughey, matthew Mcconaughey dallas buyers club, matthew Mcconaughey oscar, matthew Mcconaughey oscar nom, matthew Mcconaughey oscar nomination, matthew Mcconaughey oscar win, midget, movies, npr, npr wait wait don't tell me, oral sex, Peter Dinklage, pop culture, pregnancy, reboot, review, SNl, Spoiler Alert, tim Conway, Tiptoes, Todd Levin, wait wait don't tell me, worst movie ever
Steve Agee & Todd Levin on “R.O.T.O.R.”
January 20, 2011 August 21, 2016 Adam
https://media.blubrry.com/proudlyresents/p/proudlyresents.com/media/prp022.mp3Podcast: Download | EmbedSubscribe: Android | Google Podcasts | RSS Steve Agee (“Guardians of the Galaxy 2”) and “Conan” writer Todd Levin are on to talk about the Robocop rip off “R.O.T.O.R.” Hear about: pointless plots, bottomless gaffs, a ‘roided out Tyne Daly with a gray mohawk, white guys in red face and Woody Allen robots. Plus Steve tells us how to get 1 million twitter followers and how having the ultimate dream job can be a nightmare. Host Adam Spiegelman (“Proudly Resents”) pitches his new sitcom! To listen go to…
Podcast, Recap"what's Happening?", adam felber, best buy, Bill Maher, can we say midget, cisco, comedy central, Conan, Daniel Tosh, dorf, dorf on golf, Emmys, Gary Oldman, germany, golf, good bad movie, guardians of the galaxy 2, guardians of the galaxy 2 steve agee, Internet, is the word midget wrong, Kate Beckinsale, kate beckinsale nude, kids, little people, little people getting drunk, Margaret Trigg, Matthew McConaughey, matthew Mcconaughey dallas buyers club, matthew Mcconaughey oscar, matthew Mcconaughey oscar nom, matthew Mcconaughey oscar nomination, matthew Mcconaughey oscar win, midget movies, national rental car, npr, npr wait wait don't tell me, oral sex, performance art, Peter Dinklage, pop culture, pregnancy, reboot, review, robocop, sarah silverman program, sitcom, SNl, Spoiler Alert, terminator, teve agge, tim Conway, Tiptoes, Todd Levin, tv, tv watchers, wait wait don't tell me, worst movie ever2 Comments
“Tiptoes” w/ @Toddlevin & @AdamFelber
August 27, 2010 March 16, 2016 Adam
https://media.blubrry.com/proudlyresents/p/proudlyresents.com/media/prp006.mp3Podcast: Download | EmbedSubscribe: Android | Google Podcasts | RSSGarry Oldman is wearing shoes on his knees to play a little person! Like “Dorf on Golf.” Need we say more? Ok, lets.. EMMY nominated writers Adam Felber and Todd Levin join non-nominated Adam Spiegelman to talk about “Tipoes,” Gary Oldman’s big career misstep, what jobs are recession proof, why Peter Dinklage is a jerk and the all white “What’s Happening.” Subscribe on itunes. UPDATE: Sadly, Adam, Brian and Todd lost to Colbert. You guys did a great job, all you…
Best of Adam Felber, Podcast, With Todd Levin"what's Happening?", adam felber, Bill Maher, can we say midget, comedy central, Conan, Daniel Tosh, dorf, dorf on golf, Emmys, Gary Oldman, golf, good bad movie, Internet, is the word midget wrong, Kate Beckinsale, kate beckinsale nude, kids, little people, little people getting drunk, Matthew McConaughey, matthew Mcconaughey dallas buyers club, matthew Mcconaughey oscar, matthew Mcconaughey oscar nom, matthew Mcconaughey oscar nomination, matthew Mcconaughey oscar win, midget movies, npr, npr wait wait don't tell me, oral sex, Peter Dinklage, pop culture, pregnancy, reboot, review, SNl, Spoiler Alert, tim Conway, Tiptoes, Todd Levin, wait wait don't tell me, worst movie ever1 Comment
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One-Man Business In Latrobe Crafts Championship Belts
By Dave Crawley June 22, 2017 at 7:37 pm
Filed Under:Andrew Lazarchik, Dave Crawley, Wildcat Championship Belts, WWE
LATROBE (KDKA) — From the hot dog eating contest on the Fourth of July to studio wrestling, you’ve seen his work on some of the world’s biggest stages.
At Coney Island last year, 70 hot dogs in ten minutes wins the annual Nathan’s chow down contest. Male and female championship belts resemble those of world wrestling entertainment.
In fact, all those belts are custom made by a home-based entrepreneur in Latrobe. Andrew Lazarchik’s one-man business, Wildcat Championship Belts, began 12 years ago.
“My parents would take me down to the Civic Arena. I saw Andre the Giant, Hulk Hogan, the Undertaker,” Lazarchik said.
“I used to make belts out of paper,” he added.
Working with World Wrestling Entertainment is a dream come true.
“It’s pretty cool. It’s pretty neat,” he said. “I’ll have a belt sitting here on the counter in my kitchen on a Thursday, and on Monday night, it’s on international television.”
Belts range from a basic $375 to $14,000 and up. Lazarchik’s business has broadened out to corporate awards, too.
“You know, salesman of the month, employee of the month type things, so that’s kind of the focus that I’m at right now,” Lazarchik said, “and the large majority of my business is corporate [belts] that don’t have anything to do with wrestling at all.”
Lazarchik’s dad once owned Strickler’s Drug Store in Latrobe, where the banana split was invented 113 years ago. Now, his son creates belts for the winner of the pie-eating contest at the annual banana split celebration.
He started making the Coney Island belts before his contract with WWE.
“The mustard yellow belt was named by ESPN Sports as one of the top coolest sports prizes out there, along with the Stanley Cup,” Lazarchik said.
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Dave Crawley
More from Dave Crawley
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Archive for the ‘Neutropenia’ Category
Neutrophil Serine Proteases in Disease and Therapeutic Considerations
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Larry H. Bernstein, MD, FCAP, Curator
LPBI
SERPINB1 Regulates the activity of the neutrophil proteases elastase, cathepsin G, proteinase-3, chymase,
chymotrypsin, and kallikrein-3. Belongs to the serpin family. Ov-serpin subfamily. Note: This description may
include information from UniProtKB.
Chromosomal Location of Human Ortholog: 6p25
Cellular Component: extracellular space; membrane; cytoplasm
Molecular Function: serine-type endopeptidase inhibitor activity
Reference #: P30740 (UniProtKB)
Alt. Names/Synonyms: anti-elastase; EI; ELANH2; ILEU; LEI; Leukocyte elastase inhibitor; M/NEI; MNEI; Monocyte/neutrophil elastase inhibitor; Peptidase inhibitor 2; PI-2; PI2; protease inhibitor 2 (anti-elastase), monocyte/neutrophil derived; serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 1; Serpin B1; serpin peptidase inhibitor, clade B (ovalbumin), member 1; SERPINB1
Gene Symbols: SERPINB1
Molecular weight: 42,742 Da
SERPIN PEPTIDASE INHIBITOR, CLADE B (OVALBUMIN), MEMBER 1; SERPINB1
Alternative titles; symbols
PROTEASE INHIBITOR 2, MONOCYTE/NEUTROPHIL DERIVED; ELANH2
ELASTASE INHIBITOR, MONOCYTE/NEUTROPHIL; EI
HGNC Approved Gene Symbol: SERPINB1
Cloning and Expression
Monocyte/neutrophil elastase inhibitor (EI) is a protein of approximately 42,000 Mr with serpin-like functional properties.
Remold-O’Donnell et al. (1992) cloned EI cDNA and identified 3 EI mRNA species of 1.5, 1.9, and 2.6 kb in monocyte-like cells
and no hybridizing mRNA in lymphoblastoid cells lacking detectable EI enzymatic activity. The cDNA open reading frame encoded
a 379-amino acid protein. Its sequence established EI as a member of the serpin superfamily. Sequence alignment indicated that
the reactive center P1 residue is cys-344, consistent with abrogation of elastase inhibitory activity by iodoacetamide and making
EI a naturally occurring cys-serpin.
In the course of studying 4 closely linked genes encoding members of the ovalbumin family of serine proteinase inhibitors
(Ov-serpins) located on 18q21.3, Schneider et al. (1995) investigated the mapping of elastase inhibitor. They prepared PCR
primer sets of the gene, and by using the NIGMS monochromosomal somatic cell hybrid panel, showed that the EI gene maps
to chromosome 6.
By amplifying DNA of a somatic cell hybrid panel, Evans et al. (1995) unambiguously localized ELANH2 to chromosome 6.
With the use of a panel of radiation and somatic cell hybrids specific for chromosome 6, they refined the localization to
the short arm telomeric of D6S89, F13A (134570), and D6S202 at 6pter-p24.
http://www.phosphosite.org/getImageAction.do?id=27292293
Evans, E., Cooley, J., Remold-O’Donnell, E. Characterization and chromosomal localization of ELANH2, the gene encoding human
monocyte/neutrophil elastase inhibitor. Genomics 28: 235-240, 1995. [PubMed: 8530031, related citations] [Full Text]
Remold-O’Donnell, E., Chin, J., Alberts, M. Sequence and molecular characterization of human monocyte/neutrophil elastase inhibitor.
Proc. Nat. Acad. Sci. 89: 5635-5639, 1992. [PubMed: 1376927, related citations][Full Text]
Schneider, S. S., Schick, C., Fish, K. E., Miller, E., Pena, J. C., Treter, S. D., Hui, S. M., Silverman, G. A. A serine proteinase inhibitor locus at
18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Nat. Acad. Sci. 92: 3147-3151, 1995.
[PubMed: 7724531,related citations] [Full Text]
Leukocyte elastase inhibitor (serpin B1) (IPR015557)
Short name: Serpin_B1
Serpin family (IPR000215)
Leukocyte elastase inhibitor is also known as serpin B1. Serpins (SERine Proteinase INhibitors) belong to MEROPS inhibitor family I4 (clan ID)
[PMID: 14705960].
Serpin B1 regulates the activity of neutrophil serine proteases such as elastase, cathepsin G and proteinase-3 and may play a regulatory role to
limit inflammatory damage due to proteases of cellular origin [PMID: 11747453]. It also functions as a potent intracellular inhibitor of granzyme
H [PMID: 23269243]. In mouse, four different homologues of human serpin B1 have been described [PMID: 12189154].
The neutrophil serine protease inhibitor SerpinB1 protects against inflammatory lung injury and morbidity in influenza virus infection
Dapeng Gong1,2, Charaf Benarafa1,2, Kevan L Hartshorn3 and Eileen Remold-O’Donnell1,2
J Immunol April 2009; 182(Meeting Abstract Supplement) 43.10
http://www.jimmunol.org/cgi/content/meeting_abstract/182/1_MeetingAbstracts/43.10
SerpinB1 is an efficient inhibitor of neutrophil serine proteases. SerpinB1-/- mice fail to clear bacterial lung infection with increased inflammation and neutrophil death. Here, we investigated the role of serpinB1 in influenza virus infection, where infiltrating neutrophils and monocytes facilitate virus clearance but can also cause tissue injury. Influenza virus (H3N2 A/Phil/82) infection caused greater and more protracted body weight loss in serpinB1-/- vs. WT mice (20% vs. 15%; nadir on day 4 vs. day 3). Increased morbidity was not associated with defective virus clearance. Cytokines (IFN, TNF, IL-17, IFN, G-CSF) and chemokines (MIP-1, KC, MIP-2) were increased in serpinB1-/- mice vs. WT on days 2-7 post-infection but not on day 1. In WT mice, histology indicated large infiltration of neutrophils peaking on day 1 and maximal airway injury on day 2 that resolved on day 3 coincident with the influx of monocytes/macrophages. In serpinB1-/- mice, neutrophils also peaked on day 1; epithelial injury was severe and sustained with accumulation of dead cells on day 2 and 3. Immunophenotyping of lung digests on day 2 and 3 showed delayed recruitment of monocytes, macrophages and DC in serpinB1-/- mice, but increase of activated CD4 (day 2-3) and CD8 (day 3) T cells. Our findings demonstrate that serpinB1 protects against morbidity and inflammatory lung injury associated with influenza infection.
The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosainfection
Charaf Benarafa 1 , 2 , Gregory P. Priebe 3 , 4 , and Eileen Remold-O’Donnell 1 , 2
JEM July 30, 2007; 204(8): 1901-1909 http://dx.doi.org:/10.1084/jem.20070494
Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa. On infection, wild-type (WT) and serpinb1-deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1−/− mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1-deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein–D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance inserpinb1−/− mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.
Neutrophils are the first and most abundant phagocytes mobilized to clear pathogenic bacteria during acute lung infection. Prominent among their antimicrobial weapons, neutrophils carry high concentrations of a unique set of serine proteases in their granules, including neu trophil elastase (NE), cathepsin G (CG), and proteinase-3. These neutrophil serine proteases (NSPs) are required to kill phagocytosed bacteria and fungi (1, 2). Indeed, neutrophils lacking NE fail to kill phagocytosed pathogens, and mice deficient for NE and/or CG have increased mortality after infection with pulmonary pathogens (3, 4). However, NSPs in the lung airspace can have a detrimental effect in severe inflammatory lung disease through degradation of host defense and matrix proteins (5–7). Thus, understanding of the mechanisms that regulate NSP actions during lung infections associated with neutrophilia will help identify strategies to balance host defense and prevent infection-induced tissue injury.
SERPINB1, also known as monocyte NE inhibitor (8), is an ancestral serpin super-family protein and one of the most efficient inhibitors of NE, CG, and proteinase-3 (9, 10). SERPINB1 is broadly expressed and is at particularly high levels in the cytoplasm of neutrophils (11, 12). SERPINB1 has been found complexed to neutro phil proteases in lung fluids of cystic fibrosis patients and in a baboon model of bronchopulmonary dysplasia (13, 14). Although these studies suggest a role for SERPINB1 in regulating NSP activity, it is unclear whether these complexes reflect an important physiological role for SERPINB1 in the lung air space.
To define the physiological importance of SERPINB1 in shaping the outcome of bacterial lung infection, we generated mice deficient for serpinb1 (serpinb1−/−) by targeted mutagenesis in embryonic stem (ES) cells (Fig. 1, A–C). Crossings of heterozygous mice produced WT (+/+), heterozygous (+/−), and KO (−/−) mice for serpinb1 at expected Mendelian ratios (25% +/+, 51% +/−, and 24% −/−; n = 225; Fig. 1 D), indicating no embryonic lethality. Bone marrow neutrophils of serpinb1−/− mice lacked expression of the protein, whereas heterozygous serpinb1+/− mice had reduced levels compared with WT mice (Fig. 1 E). Importantly, levels of the cognate neutrophil proteases NE and CG, measured as antigenic units, were not altered by deletion of serpinb1 (Fig. 1 F). When maintained in a specific pathogen-free environment, serpinb1−/− mice did not differ from WT littermates in growth, litter size, or life span (followed up to 12 mo), and no gross or histopathological defects were observed at necropsy in 8-wk-old mice.
6–8-wk-old animals were intranasally inoculated with the nonmucoid Pseudomonas aeruginosa strain PAO1. Using two infection doses (3 × 106 and 7 × 106 CFU/mouse),serpinb1−/− mice had a significantly lower survival probability and a shorter median survival time compared with WT mice (Fig. 2 A). Further groups of infected mice were used to evaluate bacterial clearance. At 6 h after infection, the bacteria were similarly restricted in mice of the two genotypes, suggesting that the serpinb1−/− mice have a normal initial response to infection. At 24 h, the median bacterial count in the lungs of serpinb1−/− mice was five logs higher than that of the WT mice (P < 0.001), and the infection had spread systemically in serpinb1−/− mice but not in WT mice, as shown by high median CFU counts in the spleen (Fig. 2 B). Histological examination at 24 h after infection revealed abundant neutrophil infiltration in the lungs of both WT and serpinb1−/− mice, and consistent with the bacteriological findings, numerous foci of bacterial colonies and large areas of alveolar exudates were found in serpinb1−/− mice only (Fig. 2 C). When challenged with the mucoid P. aeruginosa clinical strain PA M57-15 isolated from a cystic fibrosis patient, WT mice cleared >99.9% of the inoculum within 24 h, whereas serpinb1-deficient mice failed to clear the infection (Fig. 2 D). Thus, the NSP inhibitor serpinb1 is essential for maximal protection against pneumonia induced by mucoid and nonmucoid strains of P. aeruginosa.
Serpinb1−/− mice fail to clear P. aeruginosalung infection. (A) Kaplan-Meier survival curves of WT (+/+) and serpinb1-deficient (−/−) mice intranasally inoculated with nonmucoid P. aeruginosa strain PAO1. Increased mortality of serpinb1−/− mice was statistically significant (P = 0.03 at 3 × 106CFU/mouse; P < 0.0001 at 7 × 106CFU/mouse). (B) CFUs per milligram of lung (left) and splenic (right) tissue determined 6 and 24 h after inoculation with 3 × 106 CFUP. aeruginosa PAO1 in WT (+/+, filled circles) and serpinb1−/− (−/−, open circles) mice. Each symbol represents a value for an individual mouse. Differences between median values (horizontal lines) were analyzed by the Mann-Whitney U test. Data below the limit of detection (dotted line) are plotted as 0.5 CFU × dilution factor. (C) Lung sections stained with hematoxylin and eosin show bacterial colonies (arrowheads) and alveolar exudate in lungs of serpinb1−/− mice 24 h after infection with P. aeruginosa PAO1. Bars, 50 μm. (D) Total CFUs in the lung and spleen 24 h after inoculation with 2 × 108 CFU of the mucoid P. aeruginosa strain PA M57-15 in WT (+/+, filled circles) and serpinb1−/− (−/−, open circles) mice. Differences between median values (horizontal lines) were analyzed by the Mann-Whitney U test.
To verify specificity of the gene deletion, we tested whether delivering rSERPINB1 would correct the defective phenotype. Indeed, intranasal instillation of rSERPINB1 to serpinb1−/− mice at the time of inoculation significantly improved clearance of P. aeruginosa PAO1 from the lungs assessed at 24 h and reduced bacteremia compared with infectedserpinb1−/− mice that received PBS instead of the recombinant protein (Fig. S1 A, available at http://www.jem.org/cgi/content/full/jem.20070494/DC1). We have previously demonstrated that rSERPINB1 has no effect on the growth of P. aeruginosa in vitro (15) and does not induce bacterial aggrega tion (16). Also, rSERPINB1 mixed with PAO1 had no effect on adherence of the bacteria to human bronchial epithelial and corneal epithelial cell lines (unpublished data). Therefore, the improved bacterial clearance in treated serpinb1−/− mice is not related to a direct antibacterial role for rSERPINB1 but rather to reducing injury induced by excess neutrophil proteases. In addition, previous in vivo studies in WT rats showed that rSERPINB1 can protect against elastase-induced lung injury (17) and accelerate bacterial clearance two- to threefold in the Pseudomonas agar bead model (15).
Evidence of excess NSP action was examined in the lungs of infected serpinb1−/− mice by measuring surfactant protein–D (SP-D). SP-D, a multimeric collagenous C-type lectin produced by alveolar epithelial cells, is highly relevant as a host defense molecule, because it functions as an opsonin in microbial clearance (18) and acts on alveolar macrophages to regulate pro- and antiinflammatory cytokine production (19). SP-D is also relevant as an NSP target because it is degraded in vitro by trace levels of each of the NSPs (16, 20). SP-D levels in lung homogenates of WT and serpinb1−/− mice were similar 6 h after P. aeruginosa infection. At 24 h, SP-D levels were reduced in the lungs ofserpinb1−/− mice compared with WT mice, as indicated by immunoblots. A lower molecular mass band indicative of proteolytic degradation is also apparent (Fig. 3 A). Densitometry analysis of the 43-kD SP-D band relative to β-actin indicated that the reduction of SP-D level was statistically significant (+/+, 45 ± 6 [n = 8]; −/−, 10 ± 2 [n = 8]; P < 0.0001 according to the Student’s t test). Furthermore, rSERPINB1 treatment ofP. aeruginosa–infected serpinb1−/− mice partly prevented the degradation of SP-D in lung homogenates compared with nontreated mice (Fig. S1 B). As a further test of the impact of serpinb1 deletion on NSP activity, isolated neutrophils of serpinb1−/− mice were treated with LPS and FMLP and tested for their ability to cleave recombinant rat SP-D (rrSP-D) in vitro. The extent of rrSP-D cleavage by serpinb1−/− neutrophils was fourfold greater than by WT neutrophils, as determined by densitometry. The cleavage was specific for NSPs because it was abrogated by rSERPINB1 and diisopropyl fluorophosphate (Fig. 3 B). Collectively, these findings indicate a direct role for serpinb1 in regulating NSP activity released by neutrophils and in preserving SP-D, an important-host defense molecule.
Efficient clearance of P. aeruginosa infection requires an early cytokine and chemokine response coordinated by both resident alveolar macrophages and lung parenchymal cells (21, 22). The IL-8 homologue keratinocyte-derived chemokine (KC) and the cytokines TNF-α, IL-1β, and G-CSF were measured in cell-free bronchoalveolar (BAL) samples. Although the tested cytokines were undetectable in sham-infected mice of both genotypes (unpublished data), comparable induc tion of these cytokines was observed in BAL of WT and serpinb1−/− mice at 6 h after infection, demonstrating that there is no early defect in cytokine production in serpinb1−/− mice. At 24 h, levels of TNF-α, KC, and IL-1β were sustained or increased in serpinb1−/− mice and significantly higher than cytokine levels in WT mice. G-CSF levels at 24 h were elevated to a similar extent in BAL of WT and KO mice (Fig. 3 C). However, G-CSF levels were significantly higher in the serum of serpinb1−/− mice (WT, 336 ± 80 ng/ml; KO, 601 ± 13 ng/ml; n = 6 of each genotype; P < 0.01). In addition, serpinb1−/− mice that were treated at the time of infection with rSERPINB1 had cytokine levels in 24-h lung homogenates that were indistinguishable from those of infected WT mice (Fig. S1 C). The increased cytokine production in the lungs of infected serpinb1−/− mice may be caused by failed bacterial clearance but also by excess NSPs, which directly induce cytokine and neutrophil chemokine production in pulmonary parenchymal cells and alveolar macrophages (23, 24).
Neutrophil recruitment to the lungs was next examined as a pivotal event of the response to P. aeruginosa infection (25). Lung homogenates were assayed for the neutrophil-specific enzyme myeloperoxidase (MPO) to quantify marginating, interstitial, and alveolar neutrophils. Neutrophils in BAL fluid were directly counted as a measure of neutrophil accumulation in the alveolar and airway lumen. MPO in lung homo genates was undetectable in uninfected mice and was comparably increased in mice of both genotypes at 6 h, suggesting normal early serpinb1−/− neutrophil margination and migration into the interstitium. However, by 24 h after infection, MPO levels in lung homogenates remained high in WT mice but were significantly decreased in serpinb1−/− mice (Fig. 4 A). Importantly, the content of MPO per cell was the same for isolated neutrophils of WT andserpinb1−/− mice (+/+, 369 ± 33 mU/106 cells; −/−, 396 ± 27 mU/106 cells). The numbers of neutrophils in BAL were negligible in uninfected mice and were similarly increased in WT and serpinb1−/− mice at 6 h after infection. Neutrophil counts in BAL further increased at 24 h, but the mean BAL neutrophil numbers were significantly lower in serpinb1−/− mice compared with WT mice (Fig. 4 B). The evidence from the 6-h quantitation of MPO in homogenates and neutrophils in BAL strongly suggests that neutrophil recruitment is not defective in infected serpinb1−/− mice. Moreover, the high levels of cytokines and neutrophil chemoattractant KC in serpinb1−/− mice at 24 h (Fig. 3 C) also suggest that, potentially, more neutrophils should be recruited. Therefore, to examine neutrophil recruitment in serpinb1−/− mice, we used a noninfectious model in which neutrophils are mobilized to migrate to the lung after intranasal delivery of P. aeruginosa LPS. MPO levels in lung homogenate and neutrophil numbers in BAL were not statistically different in WT and serpinb1−/− mice 24 h after LPS instillation (Fig. 4, C and D). Furthermore, the number of circulating blood neutrophils and recruited peritoneal neutrophils after injection of sterile irritants glycogen and thioglycollate did not differ in WT and serpinb1−/− mice (unpublished data). Alveolar macrophage numbers were similar in uninfected mice of both genotypes (∼5 × 105 cells/mouse) and did not substantially change upon infection. Collectively, these findings show that neutrophil recruitment to the lungs in response to P. aeruginosa infection is not defective in serpinb1−/− mice, and therefore, the recovery of lower numbers of serpinb1−/− neutrophils at 24 h after infection suggests their decreased survival.
To examine the putative increased death of serpinb1−/− neutrophils in the lungs after P. aeruginosa infection, lung sections were analyzed by immunohistochemistry. Caspase-3–positive leukocytes were more relevant in the alveolar space of serpinb1−/− mice compared with WT mice at 24 h after infection, suggesting increased neutrophil apoptosis (Fig. 5 A). The positive cells were counted in 50 high power fields (hpf’s), and mean numbers of caspase-3–stained cells were increased in the lungs of serpinb1−/− mice (1.8 ± 0.2 cells/hpf) compared with WT mice (0.4 ± 0.1 cells/hpf; P < 0.0001). To characterize neutrophils in the alveoli and airways, neutrophils in BAL were identified in flow cytometry by forward scatter (FSC) and side scatter and were stained with annexin V (AnV) and propidium iodide (PI). At 24 h after infection, the proportion of late apoptotic/necrotic neutrophils (AnV+PI+) was increased at the expense of viable neutrophils (AnV−PI−) in the BAL of serpinb1−/− mice compared with WT mice (Fig. 5 B). Neutrophil fragments in BAL were also identified in flow cytometry by low FSC (FSClow) within the neutrophil population defined by the neutrophil marker Gr-1. The number of neutrophil fragments (FSClow, Gr-1+) relative to intact neutrophils was increased two- to threefold at 24 h after infection for serpinb1−/− compared with WT mice (Fig. 5 C). Moreover, free MPO in BAL supernatants was increased in serpinb1−/− mice compared with WT mice at 24 h after infection, indicating increased PMN lysis or degranulation (Fig. 5 D).
Finally, we questioned whether the enhanced death of serpinb1−/− pulmonary neutrophils was a primary effect of gene deletion or a secondary effect caused by, for example, bacteria or components of inflammation. To address this, neutrophils were collected using the noninfectious LPS recruitment model and were cultured in vitro to allow for spontaneous cell death. After 24 h, the percentages of apoptotic and necrotic neutrophils evaluated by microscopy were increased in serpinb1−/− neutrophils compared with WT neutrophils (Fig. 6, A–C). A similar increase in apoptotic cells was observed using AnV/PI staining and measurements of hypodiploid DNA (unpublished data). Moreover, live cell numbers from serpinb1−/− mice remaining in culture after 24 h were significantly decreased compared with WT mice (Fig. 6 D). The in vitro findings indicate that enhanced death of pulmonary neutrophils of infected serpinb1−/− mice is at least in part a cell-autonomous defect likely mediated by unchecked NSP actions.
In this paper, we have demonstrated that serpinb1, an intracellular serpin family member, regulates the innate immune response and protects the host during lung bacterial infection. Serpinb1 is among the most potent inhibitors of NSPs and is carried at high levels within neutrophils. Serpinb1-deficient mice fail to clear P. aeruginosa PAO1 lung infection and succumb from systemic bacterial spreading. The defective immune function in serpinb1−/− mice stems at least in part from an increased rate of neutrophil necrosis, reducing the number of phagocytes and leading to increased NSP activity in the lungs with proteolysis of SP-D. In addition, serpinb1-deficient mice also have impaired clearance of the mucoid clinical strain PA M57-15. Interestingly, mucoid strains of P. aeruginosa are cleared with a very high efficiency from the lungs of WT and cystic fibrosis transmembrane conductance regulator–deficient mice (26). The phenotype of serpinb1−/− mice reproduces major pathologic features of human pulmonary diseases characterized by excessive inflammation, massive neutrophil recruitment to the air space, and destruction of cellular and molecular protective mechanisms. Importantly, serpinb1 deficiency may be helpful as an alternative or additional model of the inflammatory lung pathology of cystic fibrosis.
The present study documents a key protective role for serpinb1 in regulating NSP actions in the lung. This role has previously been attributed to the NSP inhibitors α1-antitrypsin and secretory leukocyte protease inhibitor, which are found in the airway and alveolar lining fluid (27, 28). However, patients with α1-antitrypsin deficiency do not present with pulmonary infection secondary to innate immune defects despite increased NSP activity that leads to reduced lung elasticity and emphysema. Moreover, there is so far no evidence that deficiency in secretory leukocyte protease inhibitor results in failure to clear pulmonary infection. Because synthesis and storage of NSPs in granules is an event that exclusively takes place in bone marrow promyelocytes (29), the regulation of NSPs in the lung relies entirely on NSP inhibitors. Thus, the extent of the innate immune defect inserpinb1−/− mice and the normalization of bacterial clearance with topical rSERPINB1 treatment indicate that serpinb1 is required to regulate NSP activity in the airway fluids and that, during acute lung infection associated with high neutrophilic recruitment, there is insufficient compensation by other NSP inhibitors. The devastating effects of NSPs when released in the lungs by degranulating and necrotic neutrophils are well documented in human pulmonary diseases (5, 6, 30). Therefore, our findings clearly establish a physiological and nonredundant role for serpinb1 in regulating NSPs during pulmonary infection.
NSPs also cleave molecules involved in apoptotic cell clearance, including the surfactant protein SP-D and the phosphatidylserine receptor on macrophages (31, 32), thereby tipping the balance further toward a detrimental outcome. The increased numbers of leukocytes with active caspase-3 in the alveolar space of P. aeruginosa–infectedserpinb1−/− mice suggest that the removal of apoptotic cells may be inadequate during infection. SP-D has been shown to stimulate phagocytosis of P. aeruginosa by alveolar macrophages in vitro (33), and SP-D–deficient mice were found to have defective early (6-h) clearance of P. aeruginosa from the lung (34). Although the destruction of SP-D alone may not entirely account for the defective phenotype of serpinb1−/− mice, loss of SP-D likely diminishes bacterial clearance and removal of apop totic neutrophils.
Given that NSPs also mediate bacterial killing, why would NSP excess lead to a failed bacterial clearance? In the NE KO mice, the decreased killing activity of neutrophils is a direct consequence of the loss of the bactericidal activity of NE. The absence of an early bacterial clearance defect at 6 h after infection in serpinb1−/− mice suggests that there is initially normal bacterial killing. The current understanding is that the compartmentalization of the NSPs is crucial to the outcome of their actions: on the one hand, NSPs are protective when killing microbes within phagosomes, and on the other hand, extracellular NSPs destroy innate immune defense molecules such as lung collectins, immunoglobulins, and complement receptors. We have shown that the regulation of NSP activity is essential and that cytoplasmic serpinb1 provides this crucial shield. Neutrophils undergoing cell death gradually transition from apoptosis, characterized by a nonpermeable plasma membrane, to necrosis and lysis, where cellular and granule contents, including NSPs, are released. The increased pace of serpinb1−/− neutrophil cell death strongly suggests that unopposed NSPs may precipitate neutrophil demise and, therefore, reduce the neutrophil numbers leading to a late-onset innate immune defect. High levels of G-CSF, a prosurvival cytokine for neutrophils, also indicate that increased cell death is likely independent or downstream of G-CSF.
In conclusion, serpinb1 deficiency unleashes unbridled proteolytic activity during inflammation and thereby disables two critical components of the host response to bacterial infection, the neutrophil and the collectin SP-D. The phenotype of the infectedserpinb1-deficient mouse, characterized by a normal early antibacterial response that degenerates over time, highlights the delicate balance of protease–antiprotease systems that protect the host against its own defenses as well as invading microbes during infection-induced inflammation.
Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
K Kessenbrock,1 LFröhlich,2 M Sixt,3 …., A Belaaouaj,5 J Ring,6,7 M Ollert,6 R Fässler,3 and DE. Jenne1
J Clin Invest. 2008 Jul 1; 118(7): 2438–2447. http://dx.doi.org:/10.1172/JCI34694
Neutrophil granulocytes form the body’s first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex–mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents.
Neutrophils belong to the body’s first line of cellular defense and respond quickly to tissue injury and invading microorganisms (1). In a variety of human diseases, like autoimmune disorders, infections, or hypersensitivity reactions, the underlying pathogenic mechanism is the formation of antigen-antibody complexes, so-called immune complexes (ICs), which trigger an inflammatory response by inducing the infiltration of neutrophils (2). The subsequent stimulation of neutrophils by C3b-opsonized ICs results in the generation of ROS and the release of intracellularly stored proteases leading to tissue damage and inflammation (3). It is therefore important to identify the mechanisms that control the activation of infiltrating neutrophils.
Neutrophils abundantly express a unique set of neutrophil serine proteases (NSPs), namely cathepsin G (CG), proteinase 3 (PR3; encoded by Prtn3), and neutrophil elastase (NE; encoded by Ela2), which are stored in the cytoplasmic, azurophilic granules. PR3 and NE are closely related enzymes, with overlapping and potentially redundant substrate specificities different from those of CG. All 3 NSPs are implicated in antimicrobial defense by degrading engulfed microorganisms inside the phagolysosomes of neutrophils (4–8). Among many other functions ascribed to these enzymes, PR3 and NE were also suggested to play a fundamental role in granulocyte development in the bone marrow (9–11).
While the vast majority of the enzymes is stored intracellularly, minor quantities of PR3 and NE are externalized early during neutrophil activation and remain bound to the cell surface, where they are protected against protease inhibitors (12, 13). These membrane presented proteases were suggested to act as path clearers for neutrophil migration by degrading components of the extracellular matrix (14). This notion has been addressed in a number of studies, which yielded conflicting results (15–17). Thus, the role of PR3 and NE in leukocyte extravasation and interstitial migration still remains controversial.
Emerging data suggest that externalized NSPs can contribute to inflammatory processes in a more complex way than by simple proteolytic tissue degradation (18). For instance, recent observations using mice double-deficient for CG and NE indicate that pericellular CG enhances IC-mediated neutrophil activation and inflammation by modulating integrin clustering on the neutrophil cell surface (19, 20). Because to our knowledge no Prtn3–/– mice have previously been generated, the role of this NSP in inflammatory processes has not been deciphered. Moreover, NE-dependent functions that can be compensated by PR3 in Ela2–/–animals are still elusive.
One mechanism by which NSPs could upregulate the inflammatory response has recently been proposed. The ubiquitously expressed progranulin (PGRN) is a growth factor implicated in tissue regeneration, tumorigenesis, and inflammation (21–23). PGRN was previously shown to directly inhibit adhesion-dependent neutrophil activation by suppressing the production of ROS and the release of neutrophil proteases in vitro (23). This antiinflammatory activity was degraded by NE-mediated proteolysis of PGRN to granulin (GRN) peptides (23). In contrast, GRN peptides may enhance inflammation (23) and have been detected in neutrophil-rich peritoneal exudates (24). In short, recent studies proposed PGRN as a regulator of the innate immune response, but the factors that control PGRN function are still poorly defined and its relevance to inflammation needs to be elucidated in vivo.
In the present study, we generated double-deficient Prtn3–/–Ela2–/– mice to investigate the role of these highly similar serine proteases in noninfectious neutrophilic inflammation. We established that PR3 and NE are required for acute inflammation in response to subcutaneous IC formation. The proteases were found to be directly involved in early neutrophil activation events, because isolated Prtn3–/–Ela2–/– neutrophils were poorly activated by ICs in vitro. These defects in Prtn3–/–Ela2–/– mice were accompanied by accumulation of PGRN. We demonstrated that PGRN represents a potent inflammation-suppressing factor that is cleaved by both PR3 and NE. Our data delineate what we believe to be a previously unknown proinflammatory role for PR3 and NE, which is accomplished via the local inactivation of antiinflammatory PGRN.
Generation of Prtn3–/–Ela2–/– mice.
To analyze the role of PR3 and NE in neutrophilic inflammation, we generated a Prtn3–/–Ela2–/– mouse line by targeted gene disruption in embryonic stem cells (see Supplemental Figure 1; supplemental material available online with this article; doi: 10.1172/JCI34694DS1). Positive recombination of the Prtn3/Ela2locus was proven by Southern blotting of embryonic stem cell clones (Figure (Figure1A).1A). Prtn3–/–Ela2–/– mice showed no expression of mRNA for PR3 and NE in bone marrow cells, as assessed by RT-PCR (Figure (Figure1B).1B). The successful elimination of PR3 and NE was confirmed at the level of proteolytic activity in neutrophil lysates using a PR3/NE-specific chromogenic substrate (Supplemental Figure 3) as well as by casein zymography (Figure (Figure1C).1C). The substantially reduced casein degradation by heterozygous neutrophils indicates gene-dosage dependence of PR3/NE activities. Furthermore, PR3 and NE deficiency was proven by Western blotting using cell lysates from bone marrow–derived neutrophils, while other enzymes stored in azurophilic granula, such as CG and myeloperoxidase (MPO), were normally detected (Figure (Figure1D).1D). Crossing of heterozygous Prtn3+/–Ela2+/– mice resulted in regular offspring of WT, heterozygous, and homozygous genotype according to the Mendelian ratio. Despite the absence of 2 abundant serine proteases, and in contrast to expectations based on previous reports (9–11), we found unchanged neutrophil morphology (Figure (Figure1E)1E) and regular neutrophil populations in the peripheral blood of the mutant mice, the latter as assessed via flow cytometry to determine the differentiation markers CD11b and Gr-1 (Figure (Figure1F)1F) (25, 26). Moreover, Prtn3–/–Ela2–/– mice demonstrated normal percentages of the leukocyte subpopulations in the peripheral blood, as determined by the Diff-Quick staining protocol and by hemocytometric counting (Supplemental Figure 2, A and B). Hence, the proteases are not crucially involved in granulopoiesis, and ablating PR3 and NE in the germ line represents a valid approach to assess their biological significance in vivo.
Generation and characterization of Prtn3–/–Ela2–/– mice.
PR3 and NE are dispensable for neutrophil extravasation and interstitial migration.
To examine neutrophil infiltration into the perivascular tissue, we applied phorbol esters (croton oil) to the mouse ears. At 4 h after stimulation, we assessed the neutrophil distribution in relation to the extravascular basement membrane (EBM) by immunofluorescence microscopy of fixed whole-mount specimens (Figure (Figure2A).2A). We found that Prtn3–/–Ela2–/– neutrophils transmigrated into the interstitium without retention at the EBM (Figure (Figure2B),2B), resulting in quantitatively normal and widespread neutrophil influx compared with WT mice (Figure (Figure2C).2C). Moreover, we analyzed chemotactic migration of isolated neutrophils through a 3-dimensional collagen meshwork in vitro (Supplemental Video 1) and found unhampered chemotaxis toward a C5a gradient, based on the directionality (Figure (Figure2D)2D) and velocity (Figure (Figure2E)2E) of Prtn3–/–Ela2–/–neutrophils. These findings led us to conclude that PR3 and NE are not principally required for neutrophil extravasation or interstitial migration.
PR3 and NE are not principally required for neutrophil extravasation and interstitial migration.
Reduced inflammatory response to ICs in Prtn3–/–Ela2–/– mice.
The formation of ICs represents an important trigger of neutrophil-dependent inflammation in many human diseases (2). To determine the role of PR3 and NE in this context, we induced a classic model of subcutaneous IC-mediated inflammation, namely the reverse passive Arthus reaction (RPA) (27). At 4 h after RPA induction, we assessed the cellular inflammatory infiltrates by histology using H&E-stained skin sections (Figure (Figure3A).3A). Neutrophils, which were additionally identified by Gr-1 immunohistochemistry, made up the vast majority of all cellular infiltrates (Figure (Figure3A).3A). We found that neutrophil infiltration to the sites of IC formation was severely diminished in Prtn3–/–Ela2–/– mice. Indeed, histological quantification revealed significantly reduced neutrophil influx in Prtn3–/–Ela2–/– mice compared with WT mice, while Ela2–/– mice showed marginally reduced neutrophil counts (Figure (Figure3B).3B). These results indicate that PR3 and NE fulfill an important proinflammatory function during IC-mediated inflammation.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430496/bin/JCI0834694.f3.jpg
Impaired inflammatory response to locally formed ICs inPrtn3–/–Ela2–/– mice.
(A) Representative photomicrographs of inflamed skin sections 4 h after IC formation. Neutrophils were identified morphologically (polymorphic nucleus) in H&E stainings and by Gr-1 staining (red). The cellular infiltrates were located to the adipose tissue next to the panniculus carnosus muscle (asterisks) and were primarily composed of neutrophil granulocytes. Scale bars: 200 μm. (B) Neutrophil infiltrates in lesions from Prtn3–/–Ela2–/– mice were significantly diminished compared with Ela2–/– mice and WT mice. Neutrophil influx in Ela2–/–mice was slightly, but not significantly, diminished compared with WT mice. Results are mean ± SEM infiltrated neutrophils per HPF. *P < 0.05.
PR3 and NE enhance neutrophil activation by ICs in vitro.
Because PR3 and NE were required for the inflammatory response to IC (Figure (Figure3),3), but not to phorbol esters (Figure (Figure2),2), we considered the enzymes as enhancers of the neutrophil response to IC. We therefore assessed the oxidative burst using dihydrorhodamine as a readout for cellular activation of isolated, TNF-α–primed neutrophils in the presence of ICs in vitro. While both WT and Prtn3–/–Ela2–/– neutrophils showed a similar, approximately 20-min lag phase before the oxidative burst commenced, the ROS production over time was markedly reduced, by 30%–40%, in the absence of PR3 and NE (Figure (Figure4A).4A). In contrast, oxidative burst triggered by 25 nM PMA was not hindered in Prtn3–/–Ela2–/– neutrophils (Figure (Figure4B),4B), which indicated no general defect in producing ROS. We also performed a titration series ranging from 0.1 to 50 nM PMA and found no reduction in oxidative burst activity in Prtn3–/–Ela2–/– neutrophils at any PMA concentration used (Supplemental Figure 4). These data are consistent with our in vivo experiments showing that neutrophil influx to ICs was impaired (Figure (Figure3),3), whereas the inflammatory response to phorbol esters was normal (Figure (Figure2,2, A–C), in Prtn3–/–Ela2–/– mice. To compare neutrophil priming in WT and Prtn3–/–Ela2–/–neutrophils, we analyzed cell surface expression of CD11b after 30 min of incubation at various concentrations of TNF-α and found no difference (Supplemental Figure 5). Moreover, we observed normal neutrophil adhesion to IC-coated surfaces (Supplemental Figure 6A) and unaltered phagocytosis of opsonized, fluorescently labeled E. coli bacteria (Supplemental Figure 6, B and C) in the absence of both proteases. We therefore hypothesized that PR3 and NE enhance early events of adhesion-dependent neutrophil activation after TNF-α priming and binding of ICs. It is important to note that Ela2–/– neutrophils were previously shown to react normally in the same setup (20). Regarding the highly similar cleavage specificities of both proteases, we suggested that PR3 and NE complemented each other during the process of neutrophil activation and inflammation.
Impaired oxidative burst and PGRN degradation by IC-activatedPrtn3–/–Ela2–/– neutrophils.
Oxidative burst as the readout for neutrophil activation by ICs was measured over time. (A) While no difference was observed during the initial 20-min lag phase of the oxidative burst, Prtn3–/–Ela2–/– neutrophils exhibited diminished ROS production over time compared with WT neutrophils. (B) Bypassing receptor-mediated activation using 25 nM PMA restored the diminished oxidative burst of Prtn3–/–Ela2–/–neutrophils. Results are presented as normalized fluorescence in AU (relative to maximum fluorescence produced by WT cells). Data (mean ± SD) are representative of 3 independent experiments each conducted in triplicate. (C) Isolated mouse neutrophils were activated by ICs in vitro and tested for PGRN degradation by IB. In the cellular fraction, the PGRN (~80 kDa) signal was markedly increased in Prtn3–/–Ela2–/–cells compared with WT and Ela2–/– neutrophils. Intact PGRN was present in the supernatant (SN) of IC-activated Prtn3–/–Ela2–/–neutrophils only, not of WT or Ela2–/– cells. (D and E) Exogenous administration of 100 nM PGRN significantly reduced ROS production of neutrophils activated by ICs (D), but not when activated by PMA (E). Data (mean ± SD) are representative of 3 independent experiments each conducted in triplicate.
Antiinflammatory PGRN is degraded by PR3 and NE during IC-mediated neutrophil activation.
PGRN inhibits neutrophil activation by ICs in vitro.
Both PR3 and NE process PGRN in vitro.
PR3 and NE are major PGRN processing enzymes of neutrophils.
PGRN inhibits IC-mediated inflammation in vivo.
PGRN is a potent inhibitor of IC-stimulated inflammation in vivo.
PR3 and NE cleave PGRN during inflammation in vivo.
Finally, we aimed to demonstrate defective PGRN degradation in Prtn3–/–Ela2–/– mice during neutrophilic inflammation in vivo. For practical reasons, we harvested infiltrated neutrophils from the inflamed peritoneum 4 h after casein injection and subjected the lysates of these cells to anti-PGRN Western blot. Intact, inhibitory PGRN was detected in Prtn3–/–Ela2–/– neutrophils, but not in WT cells (Figure (Figure6D).6D). These data prove that neutrophilic inflammation is accompanied by proteolytic removal of antiinflammatory PGRN and that the process of PGRN degradation is essentially impaired in vivo in the absence of PR3 and NE.
Chronic inflammatory and autoimmune diseases are often perpetuated by continuous neutrophil infiltration and activation. According to the current view, the role of NSPs in these diseases is mainly associated with proteolytic tissue degradation after their release from activated or dying neutrophils. However, recent observations suggest that NSPs such as CG may contribute to noninfectious diseases in a more complex manner, namely as specific regulators of inflammation (18). Here, we demonstrate that PR3 and NE cooperatively fulfilled an important proinflammatory role during neutrophilic inflammation. PR3 and NE directly enhanced neutrophil activation by degrading oxidative burst–suppressing PGRN. These findings support the use of specific serine protease inhibitors as antiinflammatory agents.
Much attention has been paid to the degradation of extracellular matrix components by NSPs. We therefore expected that ablation of both PR3 and NE would cause impaired neutrophil extravasation and interstitial migration. Surprisingly, we found that the proteases were principally dispensable for these processes:Prtn3–/–Ela2–/– neutrophils migrated normally through a dense, 3-dimensional collagen matrix in vitro and demonstrated regular extravasation in vivo when phorbol esters were applied (Figure (Figure2).2). This finding is in agreement with recent reports that neutrophils preferentially and readily cross the EBM through regions of low matrix density in the absence of NE (28).
Conversely, we observed that PR3 and NE were required for the inflammatory response to locally formed ICs (Figure (Figure3).3). Even isolated Prtn3–/–Ela2–/– neutrophils were challenged in performing oxidative burst after IC stimulation in vitro (Figure (Figure4A),4A), showing that the proteases directly enhanced the activation of neutrophils also in the absence of extracellular matrix. However, when receptor-mediated signal transduction was bypassed by means of PMA, neutrophils from Prtn3–/–Ela2–/– mice performed normal oxidative burst (Figure (Figure4B),4B), indicating that the function of the phagocyte oxidase (phox) complex was not altered in the absence of PR3 and NE. These findings substantiate what we believe to be a novel paradigm: that all 3 serine proteases of azurophilic granules (CG, PR3, and NE), after their release in response to IC encounter, potentiate a positive autocrine feedback on neutrophil activation.
In contrast to CG, the highly related proteases PR3 and NE cooperate in the effacement of antiinflammatory PGRN, leading to enhanced neutrophil activation. Previous studies already demonstrated that PGRN is a potent inhibitor of the adhesion-dependent oxidative burst of neutrophils in vitro, which can be degraded by NE (23). Here, we showed that PR3 and NE play an equally important role in the regulation of PGRN function. Ela2–/– neutrophils were sufficiently able to degrade PGRN. Only in the absence of both PR3 and NE was PGRN degradation substantially impaired, resulting in the accumulation of antiinflammatory PGRN during neutrophil activation in vitro (Figure (Figure4C)4C) and neutrophilic inflammation in vivo (Figure (Figure6D).6D). Moreover, we provided in vivo evidence for the crucial role of PGRN as an inflammation-suppressing mediator, because administration of recombinant PGRN potently inhibited the neutrophil influx to sites of IC formation (Figure (Figure6,6, A–C). Hence, the cooperative degradation of PGRN by PR3 and NE is a decisive step for the establishment of neutrophilic inflammation.
The molecular mechanism of PGRN function is not yet completely understood, but it seems to interfere with integrin (CD11b/CD18) outside-in signaling by blocking the function of pyk2 and thus dampens adhesion-related oxidative burst even when added after the initial lag phase of oxidase activation (23). PGRN is produced by neutrophils and stored in highly mobile secretory granules (29). It was recently shown that PGRN can bind to heparan-sulfated proteoglycans (30), which are abundant components of the EBM and various cell surfaces, including those of neutrophils. Also, PR3 and NE are known to interact with heparan sulfates on the outer membrane of neutrophils, where the enzymes appear to be protected against protease inhibitors (12, 13, 31). These circumstantial observations support the notion that PGRN cleavage by PR3 and NE takes place at the pericellular microenvironment of the neutrophil cell surface.
Impaired outside-in signaling most likely reduced the oxidative burst in Prtn3–/–Ela2–/– neutrophils adhering to ICs. In support of this hypothesis, we excluded an altered response to TNF-α priming (Supplemental Figure 5) as well as reduced adhesion to immobilized ICs and defective endocytosis of serum-opsonized E. coli in Prtn3–/–Ela2–/– neutrophils (Supplemental Figure 6). MPO content and processing was also unchanged in Prtn3–/–Ela2–/– neutrophils (Figure (Figure1D);1D); hence, the previously discussed inhibitory effect of MPO on phox activity (32, 33) does not appear to be stronger in neutrophils lacking PR3 and NE. Because there was no difference in the lag phase of the oxidative burst, initial IC-triggered receptor activation was probably not affected by either PRGN or PR3/NE. Our concept is consistent with all these observations and takes into account that PGRN unfolds its suppressing effects in the second phase, when additional membrane receptors, endogenous PGRN, and some PR3/NE from highly mobile intracellular pools are translocated to the cell surface. The decline and cessation of ROS production suggested to us that outside-in signaling was not sustained and that active oxidase complexes were no longer replenished in the absence of PR3 and NE. Our present findings, however, do not allow us to exclude other potential mechanisms, such as accelerated disassembly of the active oxidase complex.
Proposed function of PR3 and NE in IC-mediated inflammation.
TNF-α–primed neutrophils extravasate from blood vessels, translocate PR3/NE to the cellular surface, and discharge PGRN to the pericellular environment (i). During transmigration of interstitial tissues (ii), neutrophil activation is initially suppressed by relatively high pericellular levels of antiinflammatory PGRN (green shading), which is also produced locally by keratinocytes and epithelial cells of the skin. Until IC depots are reached, neutrophil activation is inhibited by PGRN. Surface receptors (e.g., Mac-1) recognize ICs, which results in signal transduction (black dotted arrow) and activation of the phox. The molecular pathway of PGRN-mediated inhibition is not completely understood, but it may interfere with integrin signaling after IC encounter (green dotted line inside the cell). Adherence of neutrophils to ICs (iii) further increases pericellular PR3 and NE activity. PR3 and NE cooperatively degrade PGRN in the early stage of neutrophilic activation to facilitate optimal neutrophil activation (red shading), resulting in sustained integrin signaling (red arrow) and robust production of ROS by the phox system. Subsequently, neutrophils release ROS together with other proinflammatory mediators and chemotactic agents, thereby enhancing the recruitment of further neutrophils and establishing inflammation (iv). In the absence of PR3/NE, the switch from inflammation-suppressing (ii) to inflammation-enhancing (iii) conditions is substantially delayed, resulting in diminished inflammation in response to ICs (iv).
NSPs are strongly implicated as effector molecules in a large number of destructive diseases, such as emphysema or the autoimmune blistering skin disease bullous pemphigoid (14, 35–37). Normally, PR3/NE activity is tightly controlled by high plasma levels of α1-antitrypsin. This balance between proteases and protease inhibitors is disrupted in patients with genetic α1-antitrypsin deficiency, which represents a high risk factor for the development of emphysema and certain autoimmune disorders (38). The pathogenic effects of NSPs in these diseases have so far been associated with tissue destruction by the proteases after their release from dying neutrophils. Our findings showed that PR3 and NE were already involved in much earlier events of the inflammatory process, because the enzymes directly regulated cellular activation of infiltrating neutrophils by degrading inflammation-suppressing PGRN. This concept is further supported by previous studies showing increased inflammation in mice lacking serine protease inhibitors such as SERPINB1 or SLPI (39, 40). Blocking PR3/NE activity using specific inhibitors therefore represents a promising therapeutic strategy to treat chronic, noninfectious inflammation. Serine protease inhibitors as antiinflammatory agents can interfere with the disease process at 2 different stages, because they attenuate both early events of neutrophil activation and proteolytic tissue injury caused by released NSPs.
Editorial: Serine proteases, serpins, and neutropenia
David C. Dale
J Leuko Biol July 2011; 90(1): 3-4 http://dx.doi.org:/10.1189/jlb.1010592
Cyclic neutropenia and severe congenital neutropenia are autosomal-dominant diseases usually attributable to mutations in the gene for neutrophil elastase orELANE. Patients with these diseases are predisposed to recurrent and life-threatening infections [1]. Neutrophil elastase, the product of the ELANE gene, is a serine protease that is synthesized and packaged in the primary granules of neutrophils. These granules are formed at the promyelocytes stage of neutrophil development. Synthesis of mutant neutrophil elastase in promyelocytes triggers the unfolded protein response and a cascade of intracellular events, which culminates in death of neutrophil precursors through apoptosis [2]. This loss of cells causes the marrow abnormality often referred to as “maturation arrest” [3, 4].
Neutrophil elastase is one of the serine proteases normally inhibited by serpinB1. In this issue of JLB, Benarafa and coauthors [5] present their intriguing studies of serpinB1 expression in human myeloid cells and their extensive investigations ofSERPINB1−/− mice. They observed that serpinB1 expression parallels protease expression. The peak of serpinB1 expression occurs in promyelocytes. Benarafa et al. [5] found that SERPINB1−/− mice have a deficiency of postmitotic neutrophils in the bone marrow. This change was accompanied by an increase in the plasma levels of G-CSF. The decreased supply of marrow neutrophils reduced the number of neutrophils that could be mobilized to an inflammatory site. Using colony-forming cell assays, they determined that the early myeloid progenitor pool was intact. Separate assays showed that maturing myeloid cells were being lost through accelerated apoptosis of maturing neutrophils in the marrow. The authors concluded that serpinB1 is required for maintenance of a healthy reserve of marrow neutrophils and a normal acute immune response [5].
This paper provides new and fascinating insights for understanding the mechanism for neutropenia. It also suggests opportunities to investigate potential therapies for patients with neutropenia and prompts several questions. As inhibition of the activity of intracellular serine proteases is the only known function of serpinB1, the findings reported by Benarafa et al. [5] suggest that uninhibited serine proteases perturbed neutrophil production severely. The SERPINB1−/− mice used in their work have accelerated apoptosis of myeloid cells, a finding suggesting that uninhibited serine proteases or mutant neutrophil elastase perturb myelopoiesis by similar mechanisms. It is now important to determine whether the defect in the SERPINB1−/− mice is, indeed, attributable to uninhibited activity of normal neutrophil elastase, other neutrophil proteases, or another mechanism. ″Double-knockout″ studies in mice deficient in neutrophil elastase and serpinB1 might provide an answer.
This report provides evidence regarding the intracellular mechanisms for the apoptosis of myeloid cells and indicates that other studies are ongoing. The key antiapoptotic proteins, Mcl-1, Bcl-XL, and A1/Bfl-I, are apparently not involved. A more precise understanding of the mechanisms of cell death is important for development of targeted therapies for neutropenia. It is also important to discover whether only cells of the neutrophil lineage are involved or whether monocytes are also affected. In cyclic and congenital neutropenia, patients failed to produce neutrophils, but they can produce monocytes; in fact, they overproduce monocytes and have significantly elevated blood monocyte counts. Neutropenia with monocytosis is probably attributable to differences in the expression of ELANE in the two lineages. Benarafa et al. [5] reported that human bone marrow monocytes contain substantially less serpinB1 than marrow neutrophils, suggesting that the expression of serpinB1 and the serine proteases are closely coordinated.
This report shows the importance of the marrow neutrophil reserves in the normal response to infections. Compared with humans, healthy mice are always neutropenic, but they have a bigger marrow neutrophil reserve, and their mature neutrophils in the marrow and blood look like human band neutrophils. These differences are well known, but they are critical for considering the clinical inferences that can be made from this report. For example, although theSERPINB1−/− mice were not neutropenic, human SERPINB1−/− might cause neutropenia because of physiological differences between the species. If some but not all mutations in SERPINB1 cause neutropenia, we might gain a better understanding about how serpinB1 normally inhibits the neutrophil’s serine proteases.
We do not know if some or all of the mutant neutrophil elastases can be inhibited by serpinB1. We do not know whether cyclic or congenital neutropenia are attributable to defects in this interaction. However, we do know that there are chemical inhibitors of neutrophil elastase that can abrogate apoptosis of myeloid cells in a cellular model for congenital neutropenia [6]. It would be interesting to see if these chemical inhibitors can replace the natural inhibitor and normalize neutrophil production in the SERPINB1−/− mice. This would provide evidence to support use of chemical protease inhibitors as a treatment for cyclic and congenital neutropenia.
Concerns with the use of G-CSF for the treatment of cyclic and congenital neutropenia are how and why some of these patients are at risk of developing leukemia. Are the SERPINB1−/− mice with a hyperproliferative marrow and high G-CSF levels also at risk of developing myeloid leukemia?
This is a very provocative paper, and much will be learned from further studies of the SERPINB1−/− mice.
SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G
Mathias Baumann1,2, Christine T. N. Pham3, and Charaf Benarafa1
Blood May 9, 2013; 121(19) http://www.bloodjournal.org/content/121/19/3900
Serine protease inhibitor serpinB1 protects neutrophils by inhibition of their own azurophil granule protease cathepsin G.
Granule permeabilization in neutrophils leads to cathepsin G–mediated death upstream and independent of apoptotic caspases.
Bone marrow (BM) holds a large reserve of polymorphonuclear neutrophils (PMNs) that are rapidly mobilized to the circulation and tissues in response to danger signals. SerpinB1 is a potent inhibitor of neutrophil serine proteases neutrophil elastase (NE) and cathepsin G (CG). SerpinB1 deficiency (sB1−/−) results in a severe reduction of the BM PMN reserve and failure to clear bacterial infection. Using BM chimera, we found that serpinB1 deficiency in BM cells was necessary and sufficient to reproduce the BM neutropenia ofsB1−/− mice. Moreover, we showed that genetic deletion of CG, but not NE, fully rescued the BM neutropenia in sB1−/− mice. In mixed BM chimera and in vitro survival studies, we showed that CG modulates sB1−/− PMN survival through a cell-intrinsic pathway. In addition, membrane permeabilization by lysosomotropic agent L-leucyl-L-leucine methyl ester that allows cytosolic release of granule contents was sufficient to induce rapid PMN death through a CG-dependent pathway. CG-mediated PMN cytotoxicity was only partly blocked by caspase inhibition, suggesting that CG cleaves a distinct set of targets during apoptosis. In conclusion, we have unveiled a new cytotoxic function for the serine protease CG and showed that serpinB1 is critical for maintaining PMN survival by antagonizing intracellular CG activity.
Polymorphonuclear neutrophil (PMN) granulocytes are essential components of the innate immune response to infection. PMNs are relatively short-lived leukocytes that originate from hematopoietic stem cells in the bone marrow (BM) in a process called granulopoiesis. Granulopoiesis proceeds through a proliferative phase followed by a maturation phase. After maturation, the BM retains a large reserve of mature PMNs, which includes over 90% of the mature PMNs in the body while only a small proportion (1%-5%) is in the blood.1,2 Even in noninflammatory conditions, granulopoiesis is remarkable as >1011 PMNs are produced daily in an adult human, only to be disposed of, largely unused, a few hours later.3 There is evidence that the majority of PMNs produced never reach circulation and die within the BM.4 Congenital or acquired forms of neutropenia are associated with the highest risks of bacterial and fungal infection,5 indicating a strong evolutionary pressure to maintain granulopoiesis at high levels and sustain a large mobilizable pool of PMNs in the BM.
In steady state, PMNs die by apoptosis, a form of programmed cell death that allows for the safe disposal of aging PMNs and their potentially toxic cargo. Like in other cells, caspases participate in the initiation, amplification, and execution steps of apoptosis in PMNs.6,7 Interestingly, noncaspase cysteine proteases calpain and cathepsin D were reported to induce PMN apoptosis through activation of caspases.8⇓⇓–11 In addition, PMNs carry a unique set of serine proteases (neutrophil serine proteases [NSPs]) including elastase (NE), cathepsin G (CG), and proteinase-3 (PR3) stored active in primary granules. There is strong evidence for a role of NSPs in killing pathogens and inducing tissue injury when released extracellularly.12⇓–14 In contrast, the function of NSPs in PMN homeostasis and cell death remains elusive. In particular, no defects in granulopoiesis or PMN homeostasis have been reported in mice deficient in cathepsin G (CG−/−),15 neutrophil elastase (NE−/−),16,17 or dipeptidylpeptidase I (DPPI−/−), which lack active NSPs.18 We have recently shown that mice lacking the serine protease inhibitor serpinB1 (sB1−/−) have reduced PMN survival in the lungs following Pseudomonas infection and that these mice have a profound reduction in mature PMN numbers in the BM.19,20SerpinB1, also known as monocyte NE inhibitor, is expressed at high levels in the cytoplasm of PMNs and is one of the most potent inhibitors of NE, CG, and PR3.21,22 In this study, we tested the hypothesis that serpinB1 promotes PMN survival by inhibiting 1 or several NSPs, and we discovered a novel regulatory pathway in PMN homeostasis in vivo.
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Defective PMN reserve in BM chimera depends on serpinB1 deficiency in the hematopoietic compartment. Flow cytometry analysis of major BM leukocyte subsets of lethally irradiated mice was performed 8 to 10 weeks after BM transfer. (A) Irradiated WT (CD45.1) mice were transferred with WT (●) or sB1−/− (○) BM cells. (B) Irradiated WT (●) andsB1−/− (○) mice both CD45.2 were transferred with WT (CD45.1) BM cells. Each circle represents leukocyte numbers for 1 mouse and horizontal line indicates the median. Median subsets numbers were compared by the Mann-Whitney test (*P < .05; ***P < .001).
CG regulates neutrophil numbers in the BM
Because serpinB1 is an efficient inhibitor of NE, CG, and PR3, we then examined PMN numbers in mice deficient in 1 or several NSPs in combination with serpinB1 deletion. As expected, sB1−/− mice had significantly reduced numbers and percentage of mature PMNs in the BM compared with WT and heterozygous sB1+/− mice. In addition, PMN numbers were normal in mice deficient in either DPPI, NE, or CG (Figure 2A). DPPI is not inhibited by serpinB1 but is required for the activation of all NSPs, and no NSP activity is detectable in DPPI−/− mice.18,23 PMN counts in DPPI−/−.sB1−/− BM were significantly higher than in sB1−/− BM, suggesting that 1 or several NSPs contribute to the PMN survival defect. To examine the role of NSPs in this process, we crossed several NSP-deficient strains with sB1−/− mice. We found that NE.CG.sB1−/− mice had normal PMN numbers indicating that these NSPs play a key role in the defective phenotype of sB1−/− PMNs (Figure 2A). Furthermore, CG.sB1−/− mice showed normal PMN numbers whereasNE.sB1−/− mice retained the BM neutropenia phenotype indicating that CG, but not NE, plays a significant role in the death of sB1−/− PMNs (Figure 2A). In addition, the double-deficient NE.sB1−/− mice had significantly lower BM myelocyte numbers than sB1−/− mice while the myelocyte numbers in singly deficient NE−/− and sB1−/− BM were normal (Figure 2B). These results suggest that NE may promote myeloid cell proliferation, an activity that is revealed only when serpinB1 is absent. This complex interaction between sB1 and NE requires further investigation. On the other hand, B-cell and monocyte numbers and relative percentage in the BM were largely similar in all genotypes (supplemental Figure 2). Total numbers of blood leukocytes, erythrocytes, and platelets were normal in mice deficient in NSPs and/or serpinB1 (supplemental Figure 3). PMN numbers in blood were normal insB1−/− mice in steady state and combined deficiency of NSPs did not significantly alter these numbers (Figure 2C). Taken together, our results indicate that serpinB1 likely sustains the survival of postmitotic PMNs through its interaction with CG.
PMN and myelocyte numbers in BM and blood of mice deficient in NSPs and serpinB1.
CG-mediated PMN death proceeds independent of caspase activity
sB1−/− PMN death mediated by CG does not require caspase activity
Granule membrane permeabilization induces CG-mediated death in PMNs
To test whether granule disruption contributes to the serpinB1-regulated CG-dependent cell death, BM cells were treated with the lysosomotropic agent LLME. LLME accumulates in lysosomes where the acyl transferase activity of DPPI generates hydrophobic (Leu-Leu)n-OMe polymers that induce lysosomal membrane permeabilization (LMP) and cytotoxicity in granule-bearing cells such as cytotoxic T lymphocytes, NK cells, and myeloid cells.29,30
LMP induces CG-mediated death in PMNs
G-CSF therapy increases sB1−/− PMN numbers via enhanced granulopoiesis
G-CSF therapy is an effective long-term treatment in many cases of severe congenital neutropenia and it is also used to prevent chemotherapy-induced febrile neutropenia by enhancing PMN production. In addition, G-CSF delays neutrophil apoptosis by differentially regulating proapoptotic and antiapoptotic factors.10 To test whether G-CSF could rescue sB1−/− PMN survival defect, WT and sB1−/− mice were treated with therapeutic doses of G-CSF or saline for 5 days and BM and blood PMNs were analyzed 24 hours after the last injection. Total counts of myelocytes and PMNs were significantly increased in the BM of treated mice compared with their respective untreated genotype controls (Figure 6A-B). The increase in myelocyte numbers was identical in G-CSF–treated WT and sB1−/− mice, indicating that G-CSF–induced granulopoiesis proceeds normally in sB1−/−myeloid progenitors (Figure 6B).
In vivo G-CSF therapy increases PMN numbers in BM of sB1−/− mice.
SerpinB1 is a member of the clade B serpins, a subfamily composed of leaderless proteins with nucleocytoplasmic localization. Clade B serpins are often expressed in cells that also carry target proteases, which led to the hypothesis that intracellular serpins protect against misdirected granule proteases and/or protect bystander cells from released proteases.31 We previously reported that deficiency in serpinB1 is associated with reduced PMN survival in the BM and at inflammatory sites.19,20 The evidence presented here demonstrates that the cytoprotective function of serpinB1 in PMNs is based on the inhibition of granule protease CG. Deficiency in CG was sufficient to rescue the defect of sB1−/− mice as illustrated by normal PMN counts in the BM of double knockout CG.sB1−/− mice. We also showed that the protease-serpin interaction occurred within PMNs. Indeed, WT PMNs had a greater survival over sB1−/− PMNs in mixed BM chimera, whereas the survival of CG.sB1−/− PMNs was similar to WT PMNs after BM transfer. SerpinB1 is an ancestral clade B serpin with a conserved specificity determining reactive center loop in all vertebrates.32 Furthermore, human and mouse serpinB1 have the same specificity for chymotrypsin-like and elastase-like serine proteases.21,22 Likewise, human and mouse CG have identical substrate specificities and the phenotype of CG−/− murine PMN can be rescued by human CG.33 Therefore, it is highly likely that the antagonistic functions of CG and serpinB1 in cellular homeostasis observed in mice can be extended to other species.
Extracellular CG was previously reported to promote detachment-induced apoptosis (anoikis) in human and mouse cardiomyocytes.34 This activity is mediated through the shedding and transactivation of epidermal growth factor receptor and downregulation of focal adhesion signaling.35,36 In our study, exogenous human CG also induced PMN death in vitro but these effects were not enhanced in sB1−/− PMNs and the neutropenia associated with serpinB1 deficiency was principally cell intrinsic. How intracellular CG induces PMN death remains to be fully investigated. However, our studies provide some indications on the potential pathways. Like other NSPs, the expression of CG is transcriptionally restricted to the promyelocyte stage during PMN development and NSPs are then stored in active form in primary azurophil granules.37 Because serpinB1 is equally efficient at inhibiting NE, CG, and PR3, it was surprising that deletion of CG alone was sufficient to achieve a complete reversal of the PMN survival defect in CG.sB1−/− mice. A possible explanation would be that CG gains access to targets more readily than other granule proteases. There is evidence that binding to serglycin proteoglycans differs between NE and CG resulting in altered sorting of NE but not CG into granules of serglycin-deficient PMNs.38 Different interactions with granule matrix may thus contribute to differential release of CG from the granules compared with other NSPs. However, because sB1−/− PMNs have similar levels of CG and NE as WT PMNs20 and because LLME-induced granule permeabilization likely releases all granule contents equally, we favor an alternative interpretation where CG specifically targets essential cellular components that are not cleaved by the other serpinB1-inhibitable granule proteases. Upon granule permeabilization, we found that CG can induce cell death upstream of caspases as well as independent of caspases. CG was previously shown to activate caspase-7 in vitro and it functions at neutral pH, which is consistent with a physiological role in the nucleocytoplasmic environment.39 Cell death induced by lysosomal/granule membrane permeabilization has previously been linked to cysteine cathepsins in other cell types. However, these proteases appear to depend on caspase activation to trigger apoptosis and they function poorly at neutral pH, questioning their potential role as regulators of cell death.40 In contrast, CG-mediated cell death is not completely blocked by caspase inhibition, which is a property reminiscent of granzymes in cytotoxic T cells.41 In fact, CG is phylogenetically most closely related to serine proteases granzyme B and H.42 Granzymes have numerous nuclear, mitochondrial, and cytoplasmic target proteins leading to cell death41 and we anticipate that this may also be the case for CG.
G-CSF therapy is successfully used to treat most congenital and acquired neutropenia through increased granulopoiesis, mobilization from the BM, and increased survival of PMNs. Prosurvival effects of G-CSF include the upregulation of antiapoptotic Bcl-2 family members, which act upstream of the mitochondria and the activation of effector caspases. In sB1−/− mice, G-CSF levels in serum are fourfold higher than in WT mice in steady state and this is accompanied by an upregulation of the antiapoptotic Bcl-2 family member Mcl-1 in sB1−/− PMNs.19 Here, G-CSF therapy significantly increased granulopoiesis in both WT and sB1−/− mice. However, the PMN numbers in treated sB1−/− BM and blood were significantly lower than those of treated WT mice, indicating only a partial rescue of the survival defect. This is consistent with our findings that CG-mediated death can proceed independent of caspases and can thus bypass antiapoptotic effects mediated by G-CSF.
CG has largely been studied in association with antimicrobial and inflammatory functions due to its presence in PMNs.12⇓–14,49 In this context, we have previously shown that serpinB1 contributes to prevent increased mortality and morbidity associated with production of inflammatory cytokines upon infection with Pseudomonas aeruginosa and influenza A virus.20,50 In this study, we demonstrate that serpinB1 inhibition of the primary granule protease CG in PMNs is essential for PMN survival and this ultimately regulates PMN numbers in vivo. Our findings also extend the roles of CG from antimicrobial and immunoregulatory functions to a novel role in inducing cell death.
Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases
Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne and Francis Gauthier
Pharma Rev Dec 2010; 62(4):726-759 http://dx.doi.org:/10.1124/pr.110.002733
Polymorphonuclear neutrophils are the first cells recruited to inflammatory sites and form the earliest line of defense against invading microorganisms. Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules. They act in combination with reactive oxygen species to help degrade engulfed microorganisms inside phagolysosomes. These proteases are also externalized in an active form during neutrophil activation at inflammatory sites, thus contributing to the regulation of inflammatory and immune responses. As multifunctional proteases, they also play a regulatory role in noninfectious inflammatory diseases. Mutations in the ELA2/ELANE gene, encoding neutrophil elastase, are the cause of human congenital neutropenia. Neutrophil membrane-bound proteinase 3 serves as an autoantigen in Wegener granulomatosis, a systemic autoimmune vasculitis. All three proteases are affected by mutations of the gene (CTSC) encoding dipeptidyl peptidase I, a protease required for activation of their proform before storage in cytoplasmic granules. Mutations of CTSC cause Papillon-Lefèvre syndrome. Because of their roles in host defense and disease, elastase, proteinase 3, and cathepsin G are of interest as potential therapeutic targets. In this review, we describe the physicochemical functions of these proteases, toward a goal of better delineating their role in human diseases and identifying new therapeutic strategies based on the modulation of their bioavailability and activity. We also describe how nonhuman primate experimental models could assist with testing the efficacy of proposed therapeutic strategies.
Human polymorphonuclear neutrophils represent 35 to 75% of the population of circulating leukocytes and are the most abundant type of white blood cell in mammals (Borregaard et al., 2005). They are classified as granulocytes because of their intracytoplasmic granule content and are characterized by a multilobular nucleus. Neutrophils develop from pluripotent stem cells in the bone marrow and are released into the bloodstream where they reach a concentration of 1.5 to 5 × 109 cells/liter. Their half-life in the circulation is only on the order of a few hours. They play an essential role in innate immune defense against invading pathogens and are among the primary mediators of inflammatory response. During the acute phase of inflammation, neutrophils are the first inflammatory cells to leave the vasculature, where they migrate toward sites of inflammation, following a gradient of inflammatory stimuli. They are responsible for short-term phagocytosis during the initial stages of infection (Borregaard and Cowland, 1997; Hampton et al., 1998; Segal, 2005). Neutrophils use complementary oxidative and nonoxidative pathways to defend the host against invading pathogens (Kobayashi et al., 2005).
The three serine proteases neutrophil elastase (NE1), proteinase 3 (PR3), and cathepsin G (CG) are major components of neutrophil azurophilic granules and participate in the nonoxidative pathway of intracellular and extracellular pathogen destruction. These neutrophil serine proteases (NSPs) act intracellularly within phagolysosomes to digest phagocytized microorganisms in combination with microbicidal peptides and the membrane-associated NADPH oxidase system, which produces reactive oxygen metabolites (Segal, 2005). An additional extracellular antimicrobial mechanism, neutrophil extracellular traps (NET), has been described that is made of a web-like structure of DNA secreted by activated neutrophils (Papayannopoulos and Zychlinsky, 2009) (Fig. 1). NETs are composed of chromatin bound to positively charged molecules, such as histones and NSPs, and serve as physical barriers that kill pathogens extracellularly, thus preventing further spreading. NET-associated NSPs participate in pathogen killing by degrading bacterial virulence factors extracellularly (Brinkmann et al., 2004;Papayannopoulos and Zychlinsky, 2009).
http://pharmrev.aspetjournals.org/content/62/4/726/F1.small.gif
Polymorphonuclear neutrophil. Quiescent (A) and chemically activated (B) neutrophils purified from peripheral blood. C, PMA-activated neutrophils embedded within NET and neutrophil spreading on insoluble elastin.
In addition to their involvement in pathogen destruction and the regulation of proinflammatory processes, NSPs are also involved in a variety of inflammatory human conditions, including chronic lung diseases (chronic obstructive pulmonary disease, cystic fibrosis, acute lung injury, and acute respiratory distress syndrome) (Lee and Downey, 2001; Shapiro, 2002; Moraes et al., 2003; Owen, 2008b). In these disorders, accumulation and activation of neutrophils in the airways result in excessive secretion of active NSPs, thus causing lung matrix destruction and inflammation. NSPs are also involved in other human disorders as a consequence of gene mutations, altered cellular trafficking, or, for PR3, autoimmune disease. Mutations in the ELA2/ELANE gene encoding HNE are the cause of human cyclic neutropenia and severe congenital neutropenia (Horwitz et al., 1999, 2007). Neutrophil membrane-bound proteinase 3 (mPR3) is the major target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA), which are associated with Wegener granulomatosis (Jenne et al., 1990). All three proteases are affected by mutation of the gene (CTSC) encoding dipeptidyl peptidase I (DPPI), which activates several granular hematopoietic serine proteases (Pham and Ley, 1999; Adkison et al., 2002). Mutations of CTSC cause Papillon-Lefèvre syndrome and palmoplantar keratosis (Hart et al., 1999; Toomes et al., 1999).
Fully processed mature HNE, PR3, and CG isolated from azurophilic granules contain, respectively, 218 (Bode et al., 1986; Sinha et al., 1987), 222 (Campanelli et al., 1990b), and 235 (Salvesen et al., 1987; Hof et al., 1996) residues. They are present in several isoforms depending on their carbohydrate content, with apparent mass of 29 to 33 kDa upon SDS-polyacrylamide gel electrophoresis (Twumasi and Liener, 1977; Watorek et al., 1993). HNE and PR3 display two sites of N-glycosylation, whereas CG possesses only one. NSPs are stored mainly in neutrophil azurophilic granules, but HNE is also localized in the nuclear envelope, as revealed by immunostaining and electron microscopy (Clark et al., 1980;Benson et al., 2003), whereas PR3 is also found in secretory vesicles (Witko-Sarsat et al., 1999a). Upon neutrophil activation, granular HNE, PR3, and CG are secreted extracellularly, although some molecules nevertheless remain at the cell surface (Owen and Campbell, 1999; Owen, 2008a). The mechanism through which NSPs are sorted from the trans-Golgi network to the granules has not been completely defined, even though an intracellular proteoglycan, serglycin, has been identified as playing a role in elastase sorting and packaging into azurophilic granules (Niemann et al., 2007). Unlike HNE and CG, PR3 is constitutively expressed on the membranes of freshly isolated neutrophils (Csernok et al., 1990; Halbwachs-Mecarelli et al., 1995). Stimulation of neutrophils at inflammatory sites triggers intracytoplasmic granules to translocate to the phagosomes and plasma membrane, thereby liberating their contents. The first step of the translocation to the target membrane depends on cytoskeleton remodeling and microtubule assembly (Burgoyne and Morgan, 2003). This is followed by a second step of granule tethering and docking, which are dependent on the sequential intervention of SNARE proteins (Jog et al., 2007).
Exposure of neutrophils to cytokines (TNF-α), chemoattractants (platelet-activating factor, formyl-Met-Leu-Phe, or IL-8), or bacterial lipopolysaccharide leads to rapid granule translocation to the cell surface with secretion of HNE, PR3, and CG into the extracellular medium (Owen and Campbell, 1999). A fraction of secreted HNE, PR3, and CG is detected at the surface of activated neutrophils (Owen et al., 1995a, 1997; Campbell et al., 2000). Resting purified neutrophils from peripheral blood express variable amounts of PR3 on their surface. A bimodal, apparently genetically determined, distribution has been observed with two populations of quiescent neutrophils that express or do not express the protease at their surface (Halbwachs-Mecarelli et al., 1995; Schreiber et al., 2003). The percentage of mPR3-positive neutrophils ranges from 0 to 100% of the total neutrophil population within individuals. Furthermore, the percentage of mPR3-positive neutrophils remains stable over time and is not affected by neutrophil activation (Halbwachs-Mecarelli et al., 1995).
The mechanism through which HNE and CG are associated with the outer surface of the plasma membrane of neutrophils mainly involves electrostatic interactions with the sulfate groups of chondroitin sulfate- and heparan sulfate-containing proteoglycans (Campbell and Owen, 2007). These two proteases are released from neutrophil cell surfaces by high concentrations of salt (Owen et al., 1995b, 1997;Korkmaz et al., 2005a) and after treatment with chondroitinase ABC and heparinase (Campbell and Owen, 2007). Membrane PR3 is not solubilized by high salt concentrations, which means that its membrane association is not charge dependant (Witko-Sarsat et al., 1999a; Korkmaz et al., 2009). Unlike HNE and CG, PR3 bears at its surface a hydrophobic patch formed by residues Phe166, Ile217, Trp218, Leu223, and Phe224 that is involved in membrane binding (Goldmann et al., 1999; Hajjar et al., 2008) (Fig. 3B). Several membrane partners of PR3 have been identified, including CD16/FcγRIIIb (David et al., 2005; Fridlich et al., 2006), phospholipid scramblase-1, a myristoylated membrane protein with translocase activity present in lipid rafts (Kantari et al., 2007), CD11b/CD18 (David et al., 2003), and human neutrophil antigen NB1/CD177 (von Vietinghoff et al., 2007; Hu et al., 2009), a 58- to 64-kDa glycosyl-phosphatidylinositol anchored surface receptor belonging to the urokinase plasminogen activator receptor superfamily (Stroncek, 2007). NB1 shows a bimodal distribution that superimposes with that of PR3 on purified blood neutrophils (Bauer et al., 2007). Active, mature forms of PR3 but not pro-PR3 can bind to the surface of NB1-transfected human embryonic kidney 293 cells (von Vietinghoff et al., 2008) and Chinese hamster ovary cells (Korkmaz et al., 2008b). Interaction involves the hydrophobic patch of PR3 because specific amino acid substitutions disrupting this patch in the closely related gibbon PR3 prevent binding to NB1-transfected cells (Korkmaz et al., 2008b). Decreased interaction of pro-PR3 with NB1-transfected cells is explained by the topological changes affecting the activation domain containing the hydrophobic patch residues. Together, these results support the hydrophobic nature of PR3-membrane interaction.
Roles in Inflammatory Process Regulation
NSPs are abundantly secreted into the extracellular environment upon neutrophil activation at inflammatory sites. A fraction of the released proteases remain bound in an active form on the external surface of the plasma membrane so that both soluble and membrane-bound NSPs are able to proteolytically regulate the activities of a variety of chemokines, cytokines, growth factors, and cell surface receptors. Secreted proteases also activate lymphocytes and cleave apoptotic and adhesion molecules (Bank and Ansorge, 2001; Pham, 2006; Meyer-Hoffert, 2009). Thus, they retain pro- and anti-inflammatory activities, resulting in a modulation of the immune response at sites of inflammation.
Processing of Cytokines, Chemokines, and Growth Factors.
Processing and Activation of Cellular Receptors.
Induction of Apoptosis by Proteinase 3.
Physiological Inhibitors of Elastase, Proteinase 3, and Cathepsin G
During phagocytosis and neutrophil turnover, HNE, PR3, and CG are released into the extracellular space as active proteases. The proteolytic activity of HNE, PR3, and CG seems to be tightly regulated in the extracellular and pericellular space to avoid degradation of connective tissue proteins including elastin, collagen, and proteoglycans (Janoff, 1985). Protein inhibitors that belong to three main families, the serpins, the chelonianins, and the macroglobulins, ultimately control proteolytic activity of HNE, PR3, and CG activities. The individual contributions of these families depend on their tissue localization and that of their target proteases. The main characteristics of HNE, PR3, and CG physiological inhibitors are presented in Table 2.
Serine Protease Inhibitors
Serpins are the largest and most diverse family of protease inhibitors; more than 1000 members have been identified in human, plant, fungi, bacteria, archaea, and certain viruses (Silverman et al., 2001; Mangan et al., 2008). They share a similar highly conserved tertiary structure and similar molecular weight of approximately 50 kDa. Human serpins belong to the first nine clades (A–I) of the 16 that have been described based on phylogenic relationships (Irving et al., 2000; Silverman et al., 2001; Mangan et al., 2008). For historical reasons, α1-protease inhibitor (α1-PI) was assigned to the first clade. Clade B, also known as the ov-serpin clan because of the similarity of its members to ovalbumin (a protein that belongs to the serpin family but lacks inhibitory activity), is the second largest clan in humans, with 15 members identified so far. Ov-serpin clan members are generally located in the cytoplasm and, to a lesser extent, on the cell surface and nucleus (Remold-O’Donnell, 1993).
Serpins play important regulatory functions in intracellular and extracellular proteolytic events, including blood coagulation, complement activation, fibrinolysis, cell migration, angiogenesis, and apoptosis (Potempa et al., 1994). Serpin dysfunction is known to contribute to diseases such as emphysema, thrombosis, angioedema, and cancer (Carrell and Lomas, 1997; Lomas and Carrell, 2002). Most inhibitory serpins target trypsin-/chymotrypsin-like serine proteases, but some, termed “cross-class inhibitors,” have been shown to target cysteine proteases (Annand et al., 1999). The crystal structure of the prototype plasma inhibitor α1-PI revealed the archetype native serpin fold (Loebermann et al., 1984). All serpins typically have three β-sheets (termed A, B, and C) and eight or nine α-helices (hA–hI) arranged in a stressed configuration. The so-called reactive center loop (RCL) of inhibitory molecules determines specificity and forms the initial encounter complex with the target protease (Potempa et al., 1994; Silverman et al., 2001). Serpins inhibit proteases by a suicide substrate inhibition mechanism. The protease initially recognizes the serpin as a potential substrate using residues of the reactive center loop and cleaves it between P1 and P1′ This cleavage allows insertion of the cleaved RCL into the β-sheet A of the serpin, dragging the protease with it and moving it over 71 Å to the distal end of the serpin to form a 1:1 stoichiometric covalent inhibitory complex (Huntington et al., 2000). Such cleavage generates a ∼4-kDa C-terminal fragment that remains noncovalently bound to the cleaved serpin. Displacement of the covalently attached active site serine residue from its catalytic partner histidine explains the loss of catalytic function in the covalent complex. The distortion of the catalytic site structure prevents the release of the protease from the complex, and the structural disorder induces its proteolytic inactivation (Huntington et al., 2000). Covalent complex formation between serpin and serine proteases triggers a number of conformational changes, particularly in the activation domain loops of the bound protease (Dementiev et al., 2006).
Pathophysiology of Elastase, Proteinase 3 and Cathepsin G in Human Diseases
In many instances, the initiation and propagation of lung damage is a consequence of an exaggerated inappropriate inflammatory response, which includes the release of proteases and leukocyte-derived cytotoxic products (Owen, 2008b;Roghanian and Sallenave, 2008). Inflammation is a physiological protective response to injury or infection consisting of endothelial activation, leukocyte recruitment and activation, vasodilation, and increased vascular permeability. Although designed to curtail tissue injury and facilitate repair, the inflammatory response sometimes results in further injury and organ dysfunction. Inflammatory chronic lung diseases, chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, and cystic fibrosis are syndromes of severe pulmonary dysfunction resulting from a massive inflammatory response and affecting millions of people worldwide. The histological hallmark of these chronic inflammatory lung diseases is the accumulation of neutrophils in the microvasculature of the lung. Neutrophils are crucial to the innate immune response, and their activation leads to the release of multiple cytotoxic products, including reactive oxygen species and proteases (serine, cysteine, and metalloproteases). The physiological balance between proteases and antiproteases is required for the maintenance of the lung’s connective tissue, and an imbalance in favor of proteases results in lung injury (Umeki et al., 1988; Tetley, 1993). A number of studies in animal and cell culture models have demonstrated a contribution of HNE and related NSPs to the development of chronic inflammatory lung diseases. Available preclinical and clinical data suggest that inhibition of NSP in lung diseases suppresses or attenuates the contribution of NSP to pathogenesis (Chughtai and O’Riordan, 2004; Voynow et al., 2008; Quinn et al., 2010). HNE could also participate in fibrotic lung remodeling by playing a focused role in the conversion of latent transforming growth factor-β into its biologically active form (Chua and Laurent, 2006; Lungarella et al., 2008).
Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitides
ANCA-associated vasculitides encompasses a variety of diseases characterized by inflammation of blood vessels and by the presence of autoantibodies directed against neutrophil constituents. These autoantibodies are known as ANCAs (Kallenberg et al., 2006). In Wegener granulomatosis (WG), antibodies are mostly directed against PR3. WG is a relatively uncommon chronic inflammatory disorder first described in 1931 by Heinz Karl Ernst Klinger as a variant of polyarteritis nodosa (Klinger, 1931). In 1936, the German pathologist Friedrich Wegener described the disease as a distinct pathological entity (Wegener, 1936, 1939). WG is characterized by necrotizing granulomatous inflammation and vasculitis of small vessels and can affect any organ (Fauci and Wolff, 1973; Sarraf and Sneller, 2005). The most common sites of involvement are the upper and lower respiratory tract and the kidneys. WG affects approximately 1 in 20,000 people; it can occur in persons of any age but most often affects those aged 40 to 60 years (Walton, 1958; Cotch et al., 1996). Approximately 90% of patients have cold or sinusitis symptoms that fail to respond to the usual therapeutic measures and that last considerably longer than the usual upper respiratory tract infection. Lung involvement occurs in approximately 85% of the patients. Other symptoms include nasal membrane ulcerations and crusting, saddle-nose deformity, inflammation of the ear with hearing problems, inflammation of the eye with sight problems, and cough (with or without hemoptysis).
Hereditary Neutropenias
Neutropenia is a hematological disorder characterized by an abnormally low number of neutrophils (Horwitz et al., 2007). The normal neutrophil count fluctuates across human populations and within individual patients in response to infection but typically lies in the range of 1.5 to 5 × 109 cells/liter. Neutropenia is categorized as severe when the cell count falls below 0.5 × 109 cells/liter. Hence, patients with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening. Common causes of neutropenia include cancer chemotherapy, drug reactions, autoimmune diseases, and hereditary disorders (Berliner et al., 2004; Schwartzberg, 2006).
Papillon-Lefèvre Syndrome
New Strategies for Fighting Neutrophil Serine Protease-Related Human Diseases
Administration of therapeutic inhibitors to control unwanted proteolysis at inflammation sites has been tested as a therapy for a variety of inflammatory and infectious lung diseases (Chughtai and O’Riordan, 2004). Depending on the size and chemical nature of the inhibitors, they may be administered orally, intravenously, or by an aerosol route. Whatever the mode of administration, the access of therapeutic inhibitors to active proteases is often hampered by physicochemical constraints in the extravascular space and/or by the partitioning of proteases between soluble and solid phases.
NSPs were first recognized as protein-degrading enzymes but have now proven to be multifunctional components participating in a variety of pathophysiological processes. Thus, they appear as potential therapeutic targets for drugs that inhibit their active site or impair activation from their precursor. Overall, the available preclinical and clinical data suggest that inhibition of NSPs using therapeutic inhibitors would suppress or attenuate deleterious effects of inflammatory diseases, including lung diseases. Depending on the size and chemical nature of inhibitors, those may be administered orally, intravenously, or by aerosolization. But the results obtained until now have not been fully convincing because of the poor knowledge of the biological function of each protease, their spatiotemporal regulation during the course of the disease, the physicochemical constraints associated with inhibitor administration, or the use of animal models in which NSP regulation and specificity differ from those in human. Two different and complementary approaches may help bypass these putative problems. One is to target active proteases by inhibitors at the inflammatory site in animal models in which lung anatomy and physiology are close to those in human to allow in vitro and in vivo assays of human-directed drugs/inhibitors. The other is to prevent neutrophil accumulation at inflammatory sites by impairing production of proteolytically active NSPs using an inhibitor of their maturation protease, DPPI. Preventing neutrophil accumulation at the inflammatory sites by therapeutic inhibition of DPPI represents an original and novel approach, the exploration of which has just started (Méthot et al., 2008). Thus pharmacological inactivation of DPPI in human neutrophils could well reduce membrane binding of PR3 and, as a consequence, neutrophil priming by pathogenic auto-antibodies in WG. In addition, it has been recognized that the intracellular level of NSPs depends on their correct intracellular trafficking. In the future, pharmacological targeting of molecules specifically involved in the correct intracellular trafficking of each NSP could possibly regulate their production and activity, a feature that could be exploited as a therapeutic strategy for inflammatory diseases.
Granulocyte colony stimulating factor (G-CSF)
Posted in Hematopoiesis, Neutropenia, tagged G-CSF (garnulocyte colony stimulating factor) on October 10, 2015| Leave a Comment »
G-CSF (granulocyte colony stimulating factor)
http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/gcsf
G-CSF is a type of growth factor. Growth factors are proteins made in the body and some of them make the bone marrow produce blood cells. G-CSF makes the body produce white blood cells to reduce the risk of infection after some types of cancer treatment. It also makes some stem cells move from the bone marrow into the blood. Stem cells are the cells in the bone marrow from which red blood cells, white cells and platelets develop.
The full name for G-CSF is granulocyte colony stimulating factor.
There are different types, including
Lenograstim (Granocyte)
Filgrastim (Neupogen, Zarzio, Nivestim, Ratiograstim)
Long acting (pegylated) filgrastim (pegfilgrastim, Neulasta) and lipegfilgrastim (Longquex)
Pegylated G-CSF stays in the body for longer so you have treatment less often than with the other types of G-CSF.
You may have G-CSF
After chemotherapy
Before and after a stem cell transplant
G-CSF after chemotherapy
A common side effect of chemotherapy is a drop in the number of white blood cells, which leads to an increased risk of getting an infection. Most people’s white blood cells recover quickly after chemotherapy and they don’t need treatment with G-CSF. But with some types of chemotherapy, such as high dose treatment, it can take a long time for the number of white blood cells to rise again.
Having G-CSF treatment can make white blood cell levels go up faster. So if your white blood cell count doesn’t go up as it should you may have G-CSF treatment. With some types of chemotherapy you have G-CSF as a standard part of your treatment plan.
G-CSF before and after a stem cell transplant
You may have G-CSF as part of a stem cell transplant. Before the treatment you have G-CSF to stimulate the bone marrow to produce stem cells and release them into the blood. The stem cells are collected and then you have high dose chemotherapy.
The chemotherapy stops your bone marrow producing blood cells. So you have the stem cells back into your bloodstream. They go into the bone marrow and start making the different types of blood cells again.
You can have G-CSF either
As an injection just under your skin (subcutaneously)
As a drip into your bloodstream
You may have G-CSF as a drip into your bloodstream (intravenously). You can have it through a thin, short tube (a cannula) put into a vein in your arm each time you have treatment. Or you may have it through a central line, a portacath or aPICC line. These are long, plastic tubes that give the drugs directly into a large vein in your chest. You have the tube put in just before your course of treatment starts and it stays in place as long as you need it.
If you have G-CSF as an injection under the skin you have it daily for up to 14 days. You have regular blood tests to check your white blood cell count. If you are having it as part of a planned treatment you start at least a day after your chemotherapy and continue until the number of white blood cells called neutrophils is within the normal range.
If you are having pegylated G-CSF you only need to have one injection at least 24 hours after the end of the chemotherapy.
Common side effects
More than 10 in every 100 people have one or more of the side effects listed below.
Redness and irritation at the injection site
Feeling or being sick, but this is usually well controlled with anti sickness medicines
Bone pain happens in up to 4 out of 10 people (40%). It is caused by the bone marrow making blood cells. Paracetamol can help to control any pain
Diarrhoea – drink plenty of fluids. Tell your doctor or nurse if diarrhoea becomes severe, or continues for more than 3 days
Constipation – your doctor or nurse may give you laxatives to help prevent this but do tell them if you are constipated for more than 3 days
Liver changes that are very mild and unlikely to cause symptoms – the liver will almost certainly go back to normal when the treatment ends. You will have regular blood tests to check how well your liver is working
Posted in Anemia, Hematology, Hematopoiesis, Neutropenia, Neutrophilia, Platelet count disorder, tagged blood transfusions on October 10, 2015| Leave a Comment »
Larry H Bernstein, MD, FCAP, Curator
What Is a Blood Transfusion?
A blood transfusion is a safe, common procedure in which blood is given to you through an intravenous (IV) line in one of your blood vessels.
Blood transfusions are done to replace blood lost during surgery or due to a serious injury. A transfusion also may be done if your body can’t make blood properly because of an illness.
During a blood transfusion, a small needle is used to insert an IV line into one of your blood vessels. Through this line, you receive healthy blood. The procedure usually takes 1 to 4 hours, depending on how much blood you need.
Blood transfusions are very common. Each year, almost 5 million Americans need a blood transfusion. Most blood transfusions go well. Mild complications can occur. Very rarely, serious problems develop.
Blood is made up of various parts, including red blood cells, white blood cells, platelets (PLATE-lets), and plasma. Blood is transfused either as whole blood (with all its parts) or, more often, as individual parts.
Every person has one of the following blood types: A, B, AB, or O. Also, every person’s blood is either Rh-positive or Rh-negative. So, if you have type A blood, it’s either A positive or A negative.
The blood used in a transfusion must work with your blood type. If it doesn’t, antibodies (proteins) in your blood attack the new blood and make you sick.
Type O blood is safe for almost everyone. About 40 percent of the population has type O blood. People who have this blood type are called universal donors. Type O blood is used for emergencies when there’s no time to test a person’s blood type.
People who have type AB blood are called universal recipients. This means they can get any type of blood.
If you have Rh-positive blood, you can get Rh-positive or Rh-negative blood. But if you have Rh-negative blood, you should only get Rh-negative blood. Rh-negative blood is used for emergencies when there’s no time to test a person’s Rh type.
Blood banks collect, test, and store blood. They carefully screen all donated blood for possible infectious agents, such as viruses, that could make you sick. (For more information, see“What Are the Risks of a Blood Transfusion?”)
Blood bank staff also screen each blood donation to find out whether it’s type A, B, AB, or O and whether it’s Rh-positive or Rh-negative. Getting a blood type that doesn’t work with your own blood type will make you very sick. That’s why blood banks are very careful when they test the blood.
To prepare blood for a transfusion, some blood banks remove white blood cells. This process is called white cell or leukocyte (LU-ko-site) reduction. Although rare, some people are allergic to white blood cells in donated blood. Removing these cells makes allergic reactions less likely.
Not all transfusions use blood donated from a stranger. If you’re going to have surgery, you may need a blood transfusion because of blood loss during the operation. If it’s surgery that you’re able to schedule months in advance, your doctor may ask whether you would like to use your own blood, rather than donated blood.
Researchers are trying to find ways to make blood. There’s currently no man-made alternative to human blood. However, researchers have developed medicines that may help do the job of some blood parts.
For example, some people who have kidney problems can now take a medicine called erythropoietin that helps their bodies make more red blood cells. This means they may need fewer blood transfusions.
Surgeons try to reduce the amount of blood lost during surgery so that fewer patients need blood transfusions. Sometimes they can collect and reuse the blood for the patient.
https://www.nhlbi.nih.gov/health/health-topics/topics/bt
Your options may be limited by time and health factors, so it is important to begin carrying out your decision as soon as possible. For example, if friends or family members are donating blood for a patient (directed donors), their blood should be drawn several days prior to the anticipated need to allow adequate time for testing and labeling. The exact protocols are hospital and donor site specific.
The safest blood product is your own, so if a transfusion is likely, this is your lowest risk choice. Unfortunately this option is usually only practical when preparing for elective surgery. In most other instances the patient cannot donate their own blood due to the acute nature of the need for blood. Although you have the right to refuse a blood transfusion, this decision may have life-threatening consequences. If you are a parent deciding for your child, you as the parent or guardian must understand that in a life-threatening situation your doctors will act in your child’s best interest to insure your child’s health and wellbeing in accordance with standards of medical care regardless of religious beliefs. Please carefully review this material and decide with your doctor which option(s) you prefer, understanding that your doctor will always act in the best interest of his or her patient.
To assure a safe transfusion make sure your healthcare provider who starts the transfusion verifies your name and matches it to the blood that is going to be transfused. Besides your name, a second personal identifier usually used is your birthday. This assures the blood is given to the correct patient.
If during the transfusion you have symptoms of shortness of breath, itching,fever or chills or just not feeling well, alert the person transfusing the blood immediately.
Blood can be provided from two sources: autologous blood (using your own blood) or donor blood (using someone else’s blood).
Autologous blood (using your own blood)
Pre-operative donation: donating your own blood before surgery. The blood bank draws your blood and stores it until you need it during or after surgery. This option is only for non-emergency (elective) surgery. It has the advantage of eliminating or minimizing the need for someone else’s blood during and after surgery. The disadvantage is that it requires advanced planning which may delay surgery. Some medical conditions may prevent the pre-operative donation of blood products.
Intra-operative autologous transfusion: recycling your blood during surgery. Blood lost during surgery is filtered, and put back into your body during surgery. This can be done in emergency and elective surgeries. It has the advantage of eliminating or minimizing the need for someone else’s blood during surgery. Large amounts of blood can be recycled. This process cannot be used if cancer or infection is present.
Post-operative autologous transfusion: recycling your blood after surgery. Blood lost after surgery is collected, filtered and returned to your body. This can be done in emergency and elective surgeries. It has the advantage of eliminating or minimizing the need for someone else’s blood during surgery. This process can’t be used in patients where cancer or infection is present.
Hemodilution: donating your own blood during surgery. Immediately before surgery, some of your blood is taken and replaced with IV fluids. After surgery, your blood is filtered and returned to you. This is done only for elective surgeries. This process dilutes your own blood so you lose less concentrated blood during surgery. It has the advantage of eliminating or minimizing the need for someone else’s blood during surgery. The disadvantage of this process is that only a limited amount of blood can be removed, and certain medical conditions may prevent the use of this technique.
Apheresis: donating your own platelets and plasma. Before surgery, your platelets and plasma, which help stop bleeding, are withdrawn, filtered and returned to you when you need it later. This can be done only for elective surgeries. This process may eliminate the need for donor platelets and plasma, especially in high blood-loss procedures. The disadvantage of this process is that some medical conditions may prevent apheresis, and in actual practice it has limited applications.
http://www.medicinenet.com/blood_transfusion/article.htm
Diseases Requiring Blood Transfusion
Some illnesses cause your body to make too few platelets or clotting factors. You may need transfusions of just those blood components to make up for low levels.
Cancer may decrease your body’s production of red blood cells, white blood cells and platelets by impacting the organs that influence blood count, such as the kidneys, bone marrow and the spleen. Radiation and chemotherapy drugs also can decrease components of the blood. Blood transfusions may be used to counter such effects.
Other illness
Infection, liver failure or severe burns
If you experience an infection, liver failure or severe burns, you may need a transfusion of plasma. Plasma is the liquid part of blood.
People with blood diseases may receive transfusions of red blood cells, platelets or clotting factors.
Severe liver malfunction
If you have severe liver problems, you may receive a transfusion of albumin, a blood protein.
By Mayo Clinic Staff
Blood transfusions are generally considered to be safe. But they do carry some risk of complications. Complications may happen during the transfusion or not for weeks, months or even years afterward. They include the following:
Allergic reaction and hives
If you have an allergic reaction to the transfusion, you may experience hives and itching during the procedure or very soon after. This type of reaction is usually treated with antihistamines. Rarely, a more serious allergic reaction causes difficulty breathing, low blood pressure and nausea.
If you quickly develop a fever during the transfusion, you may be having a febrile transfusion reaction. Your doctor will stop the transfusion to do further tests before deciding whether to continue. A febrile reaction can also occur shortly after the transfusion. Fever may be accompanied by chills and shaking.
Acute immune hemolytic reaction
This is a very rare but serious transfusion reaction in which your body attacks the transfused red blood cells because the donor blood type is not a good match. In response, your immune system attacks the transfused red blood cells, which are viewed as foreign. These destroyed cells release a substance into your blood that harms your kidneys. This usually occurs during or right after a transfusion. Signs and symptoms include fever, nausea, chills, lower back or chest pain, and dark urine.
Lung injury
Transfusion-related acute lung injury (TRALI) is thought to occur due to antibodies or other biologic substances in the blood components. With TRALI, the lungs become damaged, making it difficult to breathe. Usually, TRALI occurs within one to six hours of the transfusion. People usually recover, especially when treated quickly. Most people who die after TRALI were very sick before the transfusion.
Bloodborne infections
Blood banks screen donors for risk factors and test donated blood to reduce the risk of transfusion-related infections. Infections related to blood transfusion still rarely may occur. It can take weeks or months after a blood transfusion to determine that you’ve been infected with a virus, bacterium or parasite.
The National Institutes of Health offers the following estimates for the risk of a blood donation carrying an infectious disease:
HIV — 1 in 2 million donations, which is lower than the risk of being killed by lightning
Hepatitis B — 1 in 205,000 donations
Hepatitis C — 1 in 2 million donations
Delayed hemolytic reaction
This type of reaction is similar to an acute immune hemolytic reaction, but it occurs much more slowly. Your body gradually attacks the donor red blood cells. It could take one to four weeks to notice a decrease in red blood cell levels.
Iron overload
If you receive multiple blood transfusions, you may end up with too much iron in your blood. Iron overload (hemochromatosis) can damage parts of your body, including the liver and the heart. You may receive iron chelation therapy, which uses medication to remove excess iron.
Graft-versus-host disease
Transfusion-associated graft-versus-host disease is a very rare condition in which transfused white blood cells attack the recipient’s bone marrow. This disease is usually fatal. It is more likely to affect people with severely weakened immune systems, such as those being treated for leukemia or lymphoma. Signs and symptoms include fever, rash, diarrhea and abnormal liver function test results. Irradiating the blood before transfusing it reduces the risk.
http://www.mayoclinic.org/tests-procedures/blood-transfusion/basics/risks/prc-20021256
Most of the donated blood collected by the American Red Cross is used for direct blood transfusions. Common types of blood transfusions including platelet, plasma and red blood cell transfusions.
A patient suffering from an iron deficiency or anemia, a condition where the body does not have enough red blood cells, may receive a Red Blood Cell Transfusion. This type of transfusion increases a patient’s hemoglobin and iron levels, while improving the amount of oxygen in the body.
Platelets are a component of blood that stops the body from bleeding. Often patients suffering from leukemia, or other types of cancer, have lower platelet counts as a side effect of their chemotherapy treatments. Patients who have illnesses that prevent the body from making enough platelets have to get regular transfusions to stay healthy.
Plasma is the liquid part of the body’s blood. It contains important proteins and other substances crucial to one’s overall health. Plasma transfusions are used for patients with liver failure, severe infections, and serious burns.
http://www.redcrossblood.org/learn-about-blood/blood-transfusions/types-of-blood-transfusions
Hematological Malignancy Diagnostics
Posted in Academic Publishing, Acute lymphocytic leukemia, Acute myelocytic leukemia, Anemia, BioIT: BioInformatics, Biomarkers & Medical Diagnostics, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, Cancer Screening, Cell Biology, Clinical & Translational, Clinical Diagnostics, Clinical Genomics, Curation, Curation methodology, Discovery process, Disease Biology, Experimental validation, Explanatory, Genetics & Pharmaceutical, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Hematology, Hematopoiesis, Lymphoma, Myelodysplasia, Myelofibrosis, Neutropenia, Neutrophilia, Platelet count disorder, tagged diagnostics, Flow cytometry, genomic analysis, hematological disorders on August 11, 2015| Leave a Comment »
Author and Curator: Larry H. Bernstein, MD, FCAP
2.4.3 Diagnostics
2.4.3.1 Computer-aided diagnostics
Back-to-Front Design
Robert Didner
Decision-making in the clinical setting
Didner, R Mar 1999 Amer Clin Lab
Mr. Didner is an Independent Consultant in Systems Analysis, Information Architecture (Informatics) Operations Research, and Human Factors Engineering (Cognitive Psychology), Decision Information Designs, 29 Skyline Dr., Morristown, NJ07960, U.S.A.; tel.: 973-455-0489; fax/e-mail: bdidner@hotmail.com
A common problem in the medical profession is the level of effort dedicated to administration and paperwork necessitated by various agencies, which contributes to the high cost of medical care. Costs would be reduced and accuracy improved if the clinical data could be captured directly at the point they are generated in a form suitable for transmission to insurers or machine transformable into other formats. Such a capability could also be used to improve the form and the structure of information presented to physicians and support a more comprehensive database linking clinical protocols to outcomes, with the prospect of improving clinical outcomes. Although the problem centers on the physician’s process of determining the diagnosis and treatment of patients and the timely and accurate recording of that process in the medical system, it substantially involves the pathologist and laboratorian, who interact significantly throughout the in-formation-gathering process. Each of the currently predominant ways of collecting information from diagnostic protocols has drawbacks. Using blank paper to collect free-form notes from the physician is not amenable to computerization; such free-form data are also poorly formulated, formatted, and organized for the clinical decision-making they support. The alternative of preprinted forms listing the possible tests, results, and other in-formation gathered during the diagnostic process facilitates the desired computerization, but the fixed sequence of tests and questions they present impede the physician from using an optimal decision-making sequence. This follows because:
People tend to make decisions and consider information in a step-by-step manner in which intermediate decisions are intermixed with data acquisition steps.
The sequence in which components of decisions are made may alter the decision outcome.
People tend to consider information in the sequence it is requested or displayed.
Since there is a separate optimum sequence of tests and questions for each cluster of history and presenting symptoms, there is no one sequence of tests and questions that can be optimal for all presenting clusters.
As additional data and test results are acquired, the optimal sequence of further testing and data acquisition changes, depending on the already acquired information.
Therefore, promoting an arbitrary sequence of information requests with preprinted forms may detract from outcomes by contributing to a non-optimal decision-making sequence. Unlike the decisions resulting from theoretical or normative processes, decisions made by humans are path dependent; that is, the out-come of a decision process may be different if the same components are considered in a different sequence.
This paper proposes a general approach to gathering data at their source in computer-based form so as to improve the expected outcomes. Such a means must be interactive and dynamic, so that at any point in the clinical process the patient’s presenting symptoms, history, and the data already collected are used to determine the next data or tests requested. That de-termination must derive from a decision-making strategy designed to produce outcomes with the greatest value and supported by appropriate data collection and display techniques. The strategy must be based on the knowledge of the possible outcomes at any given stage of testing and information gathering, coupled with a metric, or hierarchy of values for assessing the relative desirability of the possible outcomes.
A value hierarchy
The numbered list below illustrates a value hierarchy. In any particular instance, the higher-numbered values should only be considered once the lower- numbered values have been satisfied. Thus, a diagnostic sequence that is very time or cost efficient should only be considered if it does not increase the likelihood (relative to some other diagnostic sequence) that a life-threatening disorder may be missed, or that one of the diagnostic procedures may cause discomfort.
Minimize the likelihood that a treatable, life-threatening disorder is not treated.
Minimize the likelihood that a treatable, discomfort-causing disorder is not treated.
Minimize the likelihood that a risky procedure(treatment or diagnostic procedure) is inappropriately administered.
Minimize the likelihood that a discomfort-causing procedure is inappropriately administered.
Minimize the likelihood that a costly procedure is inappropriately administered.
Minimize the time of diagnosing and treating thepatient.8.Minimize the cost of diagnosing and treating the patient.
The above hierarchy is relative, not absolute; for many patients, a little bit of testing discomfort may be worth a lot of time. There are also some factors and graduations intentionally left out for expository simplicity (e.g., acute versus chronic disorders).This value hierarchy is based on a hypothetical patient. Clearly, the hierarchy of a health insurance carrier might be different, as might that of another patient (e.g., a geriatric patient). If the approach outlined herein were to be followed, a value hierarchy agreed to by a majority of stakeholders should be adopted.
Once the higher values are satisfied, the time and cost of diagnosis and treatment should be minimized. One way to do so would be to optimize the sequence in which tests are performed, so as to minimize the number, cost, and time of tests that need to be per-formed to reach a definitive decision regarding treatment. Such an optimum sequence could be constructed using Claude Shannon’s information theory.
According to this theory, the best next question to ask under any given situation (assuming the question has two possible outcomes) is that question that divides the possible outcomes into two equally likely sets. In the real world, all tests or questions are not equally valuable, costly, or time consuming; therefore, value(risk factors), cost, and time should be used as weighting factors to optimize the test sequence, but this is a complicating detail at this point.
A value scale
For dynamic computation of outcome values, the hierarchy could be converted into a weighted value scale so differing outcomes at more than one level of the hierarchy could be readily compared. An example of such a weighted value scale is Quality Adjusted Life Years (QALY).
Although QALY does not incorporate all of the factors in this example, it is a good conceptual starting place.
The display, request, decision-making relationship
For each clinical determination, the pertinent information should be gathered, organized, formatted, and formulated in a way that facilitates the accuracy, reliability, and efficiency with which that determination is made. A physician treating a patient with high cholesterol and blood pressure (BP), for example, may need to know whether or not the patient’s cholesterol and BP respond to weight changes to determine an appropriate treatment (e.g., weight control versus medication). This requires searching records for BP, certain blood chemicals (e.g., HDLs, LDLs, triglycerides, etc.), and weight from several
sources, then attempting to track them against each other over time. Manually reorganizing this clinical information each time it is used is extremely inefficient. More important, the current organization and formatting defies principles of human factors for optimally displaying information to enhance human information-processing characteristics, particularly for decision support.
While a discussion of human factors and cognitive psychology principles is beyond the scope of this paper, following are a few of the system design principles of concern:
Minimize the load on short-term memory.
Provide information pertinent to a given decision or component of a decision in a compact, contiguous space.
Take advantage of basic human perceptual and pat-tern recognition facilities.
Design the form of an information display to com-plement the decision-making task it supports.
F i g u re 1 shows fictitious, quasi-random data from a hypothetical patient with moderately elevated cholesterol. This one-page display pulls together all the pertinent data from six years of blood tests and related clinical measurements. At a glance, the physician’s innate pattern recognition, color, and shape perception facilities recognize the patient’s steadily increasing weight, cholesterol, BP, and triglycerides as well as the declining high-density lipoproteins. It would have taken considerably more time and effort to grasp this information from the raw data collection and blood test reports as they are currently presented in independent, tabular time slices.
Design the formulation of an information display to complement the decision-making task.
The physician may wish to know only the relationship between weight and cardiac risk factors rather than whether these measures are increasing or decreasing, or are within acceptable or marginal ranges. If so, Table 1 shows the correlations between weight and the other factors in a much more direct and simple way using the same data as in Figure 1. One can readily see the same conclusions about relations that were drawn from Figure 1.This type of abstract, symbolic display of derived information also makes it easier to spot relationships when the individual variables are bouncing up and down, unlike the more or less steady rise of most values in Figure 1. This increase in precision of relationship information is gained at the expense of other types of information (e.g., trends). To display information in an optimum form then, the system designer must know what the information demands of the task are at the point in the task when the display is to be used.
Present the sequence of information display clusters to complement an optimum decision-making strategy.
Just as a fixed sequence of gathering clinical, diagnostic information may lead to a far from optimum outcome, there exists an optimum sequence of testing, considering information, and gathering data that will lead to an optimum outcome (as defined by the value hierarchy) with a minimum of time and expense. The task of the information system designer, then, is to provide or request the right information, in the best form, at each stage of the procedure. For ex-ample, Figure 1 is suitable for the diagnostic phase since it shows the current state of the risk factors and their trends. Table 1, on the other hand, might be more appropriate in determining treatment, where there may be a choice of first trying a strict dietary treatment, or going straight to a combination of diet plus medication. The fact that Figure 1 and Table 1 have somewhat redundant information is not a problem, since they are intended to optimally provide information for different decision-making tasks. The critical need, at this point, is for a model of how to determine what information should be requested, what tests to order, what information to request and display, and in what form at each step of the decision-making process. Commitment to a collaborative relationship between physicians and laboratorians and other information providers would be an essential requirement for such an undertaking. The ideal diagnostic data-collection instrument is a flexible, computer-based device, such as a notebook computer or Personal Digital Assistant (PDA) sized device.
Barriers to interactive, computer-driven data collection at the source
As with any major change, it may be difficult to induce many physicians to change their behavior by interacting directly with a computer instead of with paper and pen. Unlike office workers, who have had to make this transition over the past three decades, most physicians’ livelihoods will not depend on converting to computer interaction. Therefore, the transition must be made attractive and the changes less onerous. Some suggestions follow:
Make the data collection a natural part of the clinical process.
Ensure that the user interface is extremely friendly, easy to learn, and easy to use.
Use a small, portable device.
Use the same device for collection and display of existing information (e.g., test results and his-tory).
Minimize the need for free-form written data entry (use check boxes, forms, etc.).
Allow the entry of notes in pen-based free-form (with the option of automated conversion of numeric data to machine-manipulable form).
Give the physicians a more direct benefit for collecting data, not just a means of helping a clerk at an HMO second-guess the physician’s judgment.
Improve administrative efficiency in the office.
Make the data collection complement the clinical decision-making process.
Improve information displays, leading to better outcomes.
Make better use of the physician’s time and mental effort.
The medical profession is facing a crisis of information. Gathering information is costing a typical practice more and more while fees are being restricted by third parties, and the process of gathering this in-formation may be detrimental to current outcomes. Gathered properly, in machine-manipulable form, these data could be reformatted so as to greatly improve their value immediately in the clinical setting by leading to decisions with better outcomes and, in the long run, by contributing to a clinical data warehouse that could greatly improve medical knowledge. The challenge is to create a mechanism for data collection that facilitates, hastens, and improves the outcomes of clinical activity while minimizing the inconvenience and resistance to change on the part of clinical practitioners. This paper is intended to provide a high-level overview of how this may be accomplished, and start a dialogue along these lines.
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Correlation of weight with other cardiac risk factors
Cholesterol 0.759384
HDL 0.53908
LDL 0.177297
BP-syst. 0.424728
BP-dia. 0.516167
Triglycerides 0.637817
Figure 1 Hypothetical patient data.
(not shown)
Realtime Clinical Expert Support
https://pharmaceuticalintelligence.com/2015/05/10/realtime-clinical-expert-support/
Regression: A richly textured method for comparison and classification of predictor variables
https://pharmaceuticalintelligence.com/2012/08/14/regression-a-richly-textured-method-for-comparison-and-classification-of-predictor-variables/
Converting Hematology Based Data into an Inferential Interpretation
Larry H. Bernstein, Gil David, James Rucinski and Ronald R. Coifman
In Hematology – Science and Practice
Lawrie CH, Ch 22. Pp541-552.
InTech Feb 2012, ISBN 978-953-51-0174-1
https://www.researchgate.net/profile/Larry_Bernstein/publication/221927033_Converting_Hematology_Based_Data_into_an_Inferential_Interpretation/links/0fcfd507f28c14c8a2000000.pdf
A model for Thalassemia Screening using Hematology Measurements
https://www.researchgate.net/profile/Larry_Bernstein/publication/258848064_A_model_for_Thalassemia_Screening_using_Hematology_Measurements/links/0c9605293c3048060b000000.pdf
2.4.3.2 A model for automated screening of thalassemia in hematology (math study).
Kneifati-Hayek J, Fleischman W, Bernstein LH, Riccioli A, Bellevue R.
Lab Hematol. 2007; 13(4):119-23. http://dx.doi.org:/10.1532/LH96.07003.
The results of 398 patient screens were collected. Data from the set were divided into training and validation subsets. The Mentzer ratio was determined through a receiver operating characteristic (ROC) curve on the first subset, and screened for thalassemia using the second subset. HgbA2 levels were used to confirm beta-thalassemia.
RESULTS: We determined the correct decision point of the Mentzer index to be a ratio of 20. Physicians can screen patients using this index before further evaluation for beta-thalassemia (P < .05).
CONCLUSION: The proposed method can be implemented by hospitals and laboratories to flag positive matches for further definitive evaluation, and will enable beta-thalassemia screening of a much larger population at little to no additional cost.
Measurement of granulocyte maturation may improve the early diagnosis of the septic state.
2.4.3.3 Bernstein LH, Rucinski J. Clin Chem Lab Med. 2011 Sep 21;49(12):2089-95.
http://dx.doi.org:/10.1515/CCLM.2011.688.
2.4.3.4 The automated malnutrition assessment.
David G, Bernstein LH, Coifman RR. Nutrition. 2013 Jan; 29(1):113-21.
http://dx.doi.org:/10.1016/j.nut.2012.04.017
2.4.3.5 Molecular Diagnostics
Genomic Analysis of Hematological Malignancies
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy that occurs in children. Although more than 90% of children with ALL now survive to adulthood, those with the rarest and high-risk forms of the disease continue to have poor prognoses. Through the Pediatric Cancer Genome Project (PCGP), investigators in the Hematological Malignancies Program are identifying the genetic aberrations that cause these aggressive forms of leukemias. Here we present two studies on the genetic bases of early T-cell precursor ALL and acute megakaryoblastic leukemia.
Early T-Cell Precursor ALL Is Characterized by Activating Mutations
The CBFA2T3-GLIS2Fusion Gene Defines an Aggressive Subtype of Acute Megakaryoblastic Leukemia in Children
Early T-cell precursor ALL (ETP-ALL), which comprises 15% of all pediatric T-cell leukemias, is an aggressive disease that is typically resistant to contemporary therapies. Children with ETP-ALL have a high rate of relapse and an extremely poor prognosis (i.e., 5-year survival is approximately 20%). The genetic basis of ETP-ALL has remained elusive. Although ETP-ALL is associated with a high burden of DNA copy number aberrations, none are consistently found or suggest a unifying genetic alteration that drives this disease.
Through the efforts of the PCGP, Jinghui Zhang, PhD (Computational Biology), James R. Downing, MD (Pathology), Charles G. Mullighan, MBBS(Hons), MSc, MD (Pathology), and colleagues analyzed the whole-genome sequences of leukemic cells and matched normal DNA from 12 pediatric patients with ETP-ALL. The identified genetic mutations were confirmed in a validation cohort of 52 ETP-ALL specimens and 42 non-ETP T-lineage ALLs (T-ALL).
In the journal Nature, the investigators reported that each ETP-ALL sample carried an average of 1140 sequence mutations and 12 structural variations. Of the structural variations, 51% were breakpoints in genes with well-established roles in hematopoiesis or leukemogenesis (e.g., MLH2,SUZ12, and RUNX1). Eighty-four percent of the structural variations either caused loss of function of the gene in question or resulted in the formation of a fusion gene such as ETV6-INO80D. The ETV6 gene, which encodes a protein that is essential for hematopoiesis, is frequently mutated in leukemia. Among the DNA samples sequenced in this study, ETV6 was altered in 33% of ETP-ALL but only 10% of T-ALL cases.
Next-generation sequencing in hematologic malignancies: what will be the dividends?
Jason D. Merker, Anton Valouev, and Jason Gotlib
Ther Adv Hematol. 2012 Dec; 3(6): 333–339.
http://dx.doi.org:/10.1177/2040620712458948
The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.
Leveraging cancer genome information in hematologic malignancies.
Rampal R1, Levine RL.
J Clin Oncol. 2013 May 20; 31(15):1885-92.
http://dx.doi.org:/10.1200/JCO.2013.48.7447
The use of candidate gene and genome-wide discovery studies in the last several years has led to an expansion of our knowledge of the spectrum of recurrent, somatic disease alleles, which contribute to the pathogenesis of hematologic malignancies. Notably, these studies have also begun to fundamentally change our ability to develop informative prognostic schema that inform outcome and therapeutic response, yielding substantive insights into mechanisms of hematopoietic transformation in different tissue compartments. Although these studies have already had important biologic and translational impact, significant challenges remain in systematically applying these findings to clinical decision making and in implementing new technologies for genetic analysis into clinical practice to inform real-time decision making. Here, we review recent major genetic advances in myeloid and lymphoid malignancies, the impact of these findings on prognostic models, our understanding of disease initiation and evolution, and the implication of genomic discoveries on clinical decision making. Finally, we discuss general concepts in genetic modeling and the current state-of-the-art technology used in genetic investigation.
p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies
E Wattel, C Preudhomme, B Hecquet, M Vanrumbeke, et AL.
Blood, (Nov 1), 1994; 84(9): pp 3148-3157
http://www.bloodjournal.org/content/bloodjournal/84/9/3148.full.pdf
We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < lo-‘). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P C lo-’). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil andlor CHOP andlor fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < IO-’). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.
Genomic approaches to hematologic malignancies
Benjamin L. Ebert and Todd R. Golub
Blood. 2004; 104:923-932
https://www.broadinstitute.org/mpr/publications/projects/genomics/Review%20Genomics%20of%20Heme%20Malig,%20Blood%202004.pdf
In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research.
2.4.3.6 Flow cytometry
Introduction to Flow Cytometry: Blood Cell Identification
Dana L. Van Laeys
https://www.labce.com/flow_cytometry.aspx
No other laboratory method provides as rapid and detailed analysis of cellular populations as flow cytometry, making it a valuable tool for diagnosis and management of several hematologic and immunologic diseases. Understanding this relevant methodology is important for any medical laboratory scientist.
Whether you have no previous experience with flow cytometry or just need a refresher, this course will help you to understand the basic principles, with the help of video tutorials and interactive case studies.
Basic principles include:
Immunophenotypic features of various types of hematologic cells
Labeling cellular elements with fluorochromes
Blood cell identification, specifically B and T lymphocyte identification and analysis
Cell sorting to isolate select cell population for further analysis
Analyzing and interpreting result reports and printouts
Hematological Malignancies, Table of Contents
Posted in Academic Publishing, Acute lymphocytic leukemia, Acute myelocytic leukemia, Curation, Curation methodology, Diagnostics and Lab Tests, Dialectic, Discovery process, Disease Biology, Evolutionary cognition, Explanatory, Gene Regulation, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Hematology, Hematopoiesis, Historical relevance, Lymphoma, Molecular Genetics & Pharmaceutical, Myelodysplasia, Myelofibrosis, Neutropenia, Neutrophilia, Platelet count disorder, Technology Advance Assessment of, tagged Chemotherapy, hematological malignancies, leukemias, lymphomas, table of contents on August 11, 2015| Leave a Comment »
Hematologic Malignancies , Table of Contents
Writer and Curator: Larry H. Bernstein, MD, FCAP
Hematologic Malignancies
Not excluding lymphomas [solid tumors]
The following series of articles are discussions of current identifications, classification, and treatments of leukemias, myelodysplastic syndromes and myelomas.
2.4 Hematological Malignancies
2.4.1 Ontogenesis of blood elements
Erythropoiesis
White blood cell series: myelopoiesis
Thrombocytogenesis
2.4.2 Classification of hematopoietic cancers
Primary Classification
Myelodysplastic syndromes
Chronic myeloproliferative disorders
Chronic myelogenous leukemia and related disorders
Myelofibrosis, including chronic idiopathic
Polycythemia, including polycythemia rubra vera
Thrombocytosis, including essential thrombocythemia
Chronic lymphoid leukemia and other lymphoid leukemias
Lymphomas
Lymphoproliferative disorders associated with immunodeficiency
Plasma Cell dyscrasias
Mast cell disease and Histiocytic neoplasms
Secondary Classification
Nuance – PathologyOutlines
Computer-aided diagnostics
The automated malnutrition assessment.
2.4.4 Treatment of hematopoietic cancers
2.4.4.1 Treatments for leukemia by type
2.4.4..2 Acute lymphocytic leukemias
2.4..4.3 Treatment of Acute Lymphoblastic Leukemia
2.4.5 Acute Myeloid Leukemia
New treatment approaches in acute myeloid leukemia: review of recent clinical studies
Current treatment of acute myeloid leukemia
2.4.6 Treatment for CML
4.2.7 Chronic Lymphocytic Leukemia
4.2.8 Lymphoma treatment
4.2.8.2 Chemotherapy
Total body irradiation (TBI)
Bone marrow (BM) transplantation
Autologous stem cell transplantation
Hematopoietic stem cell transplantation
G-CSF (granulocyte-colony stimulating factor)
Plasma exchange (plasmapheresis)
Platelet transfusions
Neonatal Pathophysiology
Posted in Amino acids, Anemia, Autism Spectrum Disorders, Behavioral Genetics, Best evidence, Biochemical pathways, Biological Networks, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Calcium Signaling, Cell Biology, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Child and Adolescent Psychiatry, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Congenital Heart DIsease, Curation, Cytoskeleton, Developmental biology, Diabetes Mellitus, Diagnostics and Lab Tests, Disease Biology, Embryology, Enzymes and isoenzymes, Explanatory, Fatty acids, Genetics & Pharmaceutical, Genome Biology, Health Economics and Outcomes Research, Hematology, Hematopoiesis, Historical relevance, Human Immune System in Health and in Disease, Inferential analysis, Innovations in Neurophysiology & Neuropsychology, Lipid metabolism, Liver & Digestive Diseases Research, Metabolism, Metabolomics, Microbiologial genetics, Molecular Genetics & Pharmaceutical, Mutant Gene Expression, Neurohumoral Transmission, Neurological Diseases, Neutropenia, Nitric Oxide in Health and Disease, Nutrition, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Placenta, Proteins, Proteomics, Regenerative Biology and Medicine, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Schizophrenia, Severe Autism, Signaling, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, Social Development, Stem Cells for Regenerative Medicine, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Translational Effectiveness, Translational Research, Translational Science, tagged acute and chronic gastroenteritis, Alzheimers Disease, bilirubin toxicity, Congenital Heart Disease, fetal hemoglobin, genetics, hemochromatosis, hemoglobinopathies, hemolytic diseases, inborn errors of metabolism, intestinal microbiome, neonatal intensive care, oxygen dissociation curve, oxygen saturation, prematurity, pulmonary bronchodysplasia, thalassemia, very low birthweight on February 22, 2015| Leave a Comment »
This curation deals with a large and specialized branch of medicine that grew since the mid 20th century in concert with the developments in genetics and as a result of a growing population, with large urban populations, increasing problems of premature deliveries. The problems of prematurity grew very preterm to very low birth weight babies with special problems. While there were nurseries, the need for intensive care nurseries became evident in the 1960s, and the need for perinatal care of pregnant mothers also grew as a result of metabolic problems of the mother, intrauterine positioning of the fetus, and increasing numbers of teen age pregnancies as well as nutritional problems of the mother. There was also a period when the manufacturers of nutritional products displaced the customary use of breast feeding, which was consequential. This discussion is quite comprehensive, as it involves a consideration of the heart, the lungs, the brain, and the liver, to a large extent, and also the kidneys and skeletal development.
It is possible to outline, with a proportionate emphasis based on frequency and severity, this as follows:
Genetic and metabolic diseases
Skeletal – bone and muscle
Hematological
Esophagus, stomach, and intestines
Gestation is the period of time between conception and birth when a baby grows and develops inside the mother’s womb. Because it’s impossible to know exactly when conception occurs, gestational age is measured from the first day of the mother’s last menstrual cycle to the current date. It is measured in weeks. A normal gestation lasts anywhere from 37 to 41 weeks.
Week 5 is the start of the “embryonic period.” This is when all the baby’s major systems and structures develop. The embryo’s cells multiply and start to take on specific functions. This is called differentiation. Blood cells, kidney cells, and nerve cells all develop. The embryo grows rapidly, and the baby’s external features begin to form.
Week 6-9: Brain forms into five different areas. Some cranial nerves are visible. Eyes and ears begin to form. Tissue grows that will the baby’s spine and other bones. Baby’s heart continues to grow and now beats at a regular rhythm. Blood pumps through the main vessels. Your baby’s brain continues to grow. The lungs start to form. Limbs look like paddles. Essential organs begin to grow.
Weeks 11-18: Limbs extended. Baby makes sucking motion. Movement of limbs. Liver and pancreas produce secretions. Muscle and bones developing.
Week 19-21: Baby can hear. Mom feels baby – and quickening.
http://www.nlm.nih.gov/medlineplus/ency/article/002398.htm
fetal-development
https://polination.files.wordpress.com/2014/02/abortion-new-research-into-fetal-development.jpg
Inherited Metabolic Disorders
The original cause of most genetic metabolic disorders is a gene mutation that occurred many, many generations ago. The gene mutation is passed along through the generations, ensuring its preservation.
Each inherited metabolic disorder is quite rare in the general population. Considered all together, inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns. In certain ethnic populations, such as Ashkenazi Jews (Jews of central and eastern European ancestry), the rate of inherited metabolic disorders is higher.
Hundreds of inherited metabolic disorders have been identified, and new ones continue to be discovered. Some of the more common and important genetic metabolic disorders include:
Lysosomal storage disorders : Lysosomes are spaces inside cells that break down waste products of metabolism. Various enzyme deficiencies inside lysosomes can result in buildup of toxic substances, causing metabolic disorders including:
Hurler syndrome (abnormal bone structure and developmental delay)
Niemann-Pick disease (babies develop liver enlargement, difficulty feeding, and nerve damage)
Tay-Sachs disease (progressive weakness in a months-old child, progressing to severe nerve damage; the child usually lives only until age 4 or 5)
Gauchers disease and others
Galactosemia: Impaired breakdown of the sugar galactose leads to jaundice, vomiting, and liver enlargement after breast or formula feeding by a newborn.
Maple syrup urine disease: Deficiency of an enzyme called BCKD causes buildup of amino acids in the body. Nerve damage results, and the urine smells like syrup.
Phenylketonuria (PKU): Deficiency of the enzyme PAH results in high levels of phenylalanine in the blood. Mental retardation results if the condition is not recognized.
Glycogen storage diseases: Problems with sugar storage lead to low blood sugar levels, muscle pain, and weakness.
Metal metabolism disorders: Levels of trace metals in the blood are controlled by special proteins. Inherited metabolic disorders can result in protein malfunction and toxic accumulation of metal in the body:
Wilson disease (toxic copper levels accumulate in the liver, brain, and other organs)
Hemochromatosis (the intestines absorb excessive iron, which builds up in the liver, pancreas, joints, and heart, causing damage)
Organic acidemias: methylmalonic acidemia and propionic acidemia.
Urea cycle disorders: ornithine transcarbamylase deficiency and citrullinemia
Hemoglobinopathies – thalassemias, sickle cell disease
Red cell enzyme disorders – glucose-6-phosphate dehydrogenase, pyruvate kinase
This list is by no means complete.
http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments
New variations in the galactose-1-phosphate uridyltransferase (GALT) gene
Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: Structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene
E Viggiano, A Marabotti, AP Burlina, C Cazzorla, MR D’Apice, et al.
Gene 559 (2015) 112–118
http://dx.doi.org/10.1016/j.gene.2015.01.013
Galactosemia (OMIM 230400) is a rare autosomal recessive inherited disorder caused by deficiency of galactose-1-phosphate uridyltransferase (GALT; OMIM 606999) activity. The incidence of galactosemia is 1 in 30,000–60,000, with a prevalence of 1 in 47,000 in the white population. Neonates with galactosemia can present acute symptoms, such as severe hepatic and renal failure, cataract and sepsis after milk introduction. Dietary restriction of galactose determines the clinical improvement in these patients. However, despite early diagnosis by neonatal screening and dietary treatment, a high percentage of patients develop long-term complications such as cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction.
With the benefit of early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30 years.
No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications.
A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of < 1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype–phenotype correlation in classical galactosemia and underlines the importance of molecular diagnostic testing prior to making any treatment.
Diagnosis and Management of Hereditary Hemochromatosis
Reena J. Salgia, Kimberly Brown
Clin Liver Dis 19 (2015) 187–198
http://dx.doi.org/10.1016/j.cld.2014.09.011
Hereditary hemochromatosis (HH) is a diagnosis most commonly made in patients with elevated iron indices (transferrin saturation and ferritin), and HFE genetic mutation testing showing C282Y homozygosity.
The HFE mutation is believed to result in clinical iron overload through altering hepcidin levels resulting in increased iron absorption.
The most common clinical complications of HH include cirrhosis, diabetes, nonischemic cardiomyopathy, and hepatocellular carcinoma.
Liver biopsy should be performed in patients with HH if the liver enzymes are elevated or serum ferritin is greater than 1000 mg/L. This is useful to determine the degree of iron overload and stage the fibrosis.
Treatment of HH with clinical iron overload involves a combination of phlebotomy and/or chelation therapy. Liver transplantation should be considered for patients with HH-related decompensated cirrhosis.
Health economic evaluation of plasma oxysterol screening in the diagnosis of Niemann–Pick Type C disease among intellectually disabled using discrete event simulation
CDM van Karnebeek, Tima Mohammadi, Nicole Tsaod, Graham Sinclair, et al.
Molecular Genetics and Metabolism 114 (2015) 226–232
http://dx.doi.org/10.1016/j.ymgme.2014.07.004
Background: Recently a less invasive method of screening and diagnosing Niemann–Pick C (NP-C) disease has emerged. This approach involves the use of a metabolic screening test (oxysterol assay) instead of the current practice of clinical assessment of patients suspected of NP-C (review of medical history, family history and clinical examination for the signs and symptoms). Our objective is to compare costs and outcomes of plasma oxysterol screening versus current practice in diagnosis of NP-C disease among intellectually disabled (ID) patients using decision-analytic methods.
Methods: A discrete event simulation model was conducted to follow ID patients through the diagnosis and treatment of NP-C, forecast the costs and effectiveness for a cohort of ID patients and compare the outcomes and costs in two different arms of the model: plasma oxysterol screening and routine diagnosis procedure (anno 2013) over 5 years of follow up. Data from published sources and clinical trials were used in simulation model. Unit costs and quality-adjusted life-years (QALYs) were discounted at a 3% annual rate in the base case analysis. Deterministic and probabilistic sensitivity analyses were conducted.
Results: The outcomes of the base case model showed that using plasma oxysterol screening for diagnosis of NP-C disease among ID patients is a dominant strategy. It would result in lower total cost and would slightly improve patients’ quality of life. The average amount of cost saving was $3642 CAD and the incremental QALYs per each individual ID patient in oxysterol screening arm versus current practice of diagnosis NP-C was 0.0022 QALYs. Results of sensitivity analysis demonstrated robustness of the outcomes over the wide range of changes in model inputs.
Conclusion: Whilst acknowledging the limitations of this study, we conclude that screening ID children and adolescents with oxysterol tests compared to current practice for the diagnosis of NP-C is a dominant strategy with clinical and economic benefits. The less costly, more sensitive and specific oxysterol test has potential to save costs to the healthcare system while improving patients’ quality of life and may be considered as a routine tool in the NP-C diagnosis armamentarium for ID. Further research is needed to elucidate its effectiveness in patients presenting characteristics other than ID in childhood and adolescence.
Neurological and Behavioral Disorders
Estrogen receptor signaling during vertebrate development
Maria Bondesson, Ruixin Hao, Chin-Yo Lin, Cecilia Williams, Jan-Åke Gustafsson
Biochimica et Biophysica Acta 1849 (2015) 142–151
http://dx.doi.org/10.1016/j.bbagrm.2014.06.005
Estrogen receptors are expressed and their cognate ligands produced in all vertebrates, indicative of important and conserved functions. Through evolution estrogen has been involved in controlling reproduction, affectingboth the development of reproductive organs and reproductive behavior. This review broadly describes the synthesis of estrogens and the expression patterns of aromatase and the estrogen receptors, in relation to estrogen functions in the developing fetus and child. We focus on the role of estrogens for the development of reproductive tissues, as well as non-reproductive effects on the developing brain. We collate data from human, rodent, bird and fish studies and highlight common and species-specific effects of estrogen signaling on fetal development. Morphological malformations originating from perturbed estrogen signaling in estrogen receptor and aromatase knockout mice are discussed, as well as the clinical manifestations of rare estrogen receptor alpha and aromatase gene mutations in humans. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
Memory function and hippocampal volumes in preterm born very-low-birth-weight (VLBW) young adults
Synne Aanes, Knut Jørgen Bjuland, Jon Skranes, Gro C.C. Løhaugen
NeuroImage 105 (2015) 76–83
http://dx.doi.org/10.1016/j.neuroimage.2014.10.023
The hippocampi are regarded as core structures for learning and memory functions, which is important for daily functioning and educational achievements. Previous studies have linked reduction in hippocampal volume to working memory problems in very low birth weight (VLBW; ≤1500 g) children and reduced general cognitive ability in VLBW adolescents. However, the relationship between memory function and hippocampal volume has not been described in VLBW subjects reaching adulthood. The aim of the study was to investigate memory function and hippocampal volume in VLBW young adults, both in relation to perinatal risk factors and compared to term born controls, and to look for structure–function relationships. Using Wechsler Memory Scale-III and MRI, we included 42 non-disabled VLBW and 61 control individuals at age 19–20 years, and related our findings to perinatal risk factors in the VLBW-group. The VLBW young adults achieved lower scores on several subtests of the Wechsler Memory Scale-III, resulting in lower results in the immediate memory indices (visual and auditory), the working memory index, and in the visual delayed and general memory delayed indices, but not in the auditory delayed and auditory recognition delayed indices. The VLBW group had smaller absolute and relative hippocampal volumes than the controls. In the VLBW group inferior memory function, especially for the working memory index, was related to smaller hippocampal volume, and both correlated with lower birth weight and more days in the neonatal intensive care unit (NICU). Our results may indicate a structural–functional relationship in the VLBW group due to aberrant hippocampal development and functioning after preterm birth.
The relation of infant attachment to attachment and cognitive and behavioural outcomes in early childhood
Yan-hua Ding, Xiu Xua, Zheng-yan Wang, Hui-rong Li, Wei-ping Wang
Early Human Development 90 (2014) 459–464
http://dx.doi.org/10.1016/j.earlhumdev.2014.06.004
Background: In China, research on the relation of mother–infant attachment to children’s development is scarce.
Aims: This study sought to investigate the relation of mother–infant attachment to attachment, cognitive and behavioral development in young children. Study design: This study used a longitudinal study design.
Subjects: The subjects included healthy infants (n=160) aged 12 to 18 months.
Outcome measures: Ainsworth’s “Strange Situation Procedure” was used to evaluate mother–infant attachment types. The attachment Q-set (AQS) was used to evaluate the attachment between young children and their mothers. The Bayley scale of infant development-second edition (BSID-II) was used to evaluate cognitive developmental level in early childhood. Achenbach’s child behavior checklist (CBCL) for 2- to 3-year-oldswas used to investigate behavioral problems.
Results: In total, 118 young children (73.8%) completed the follow-up; 89.7% of infants with secure attachment and 85.0% of infants with insecure attachment still demonstrated this type of attachment in early childhood (κ = 0.738, p b 0.05). Infants with insecure attachment collectively exhibited a significantly lower mental development index (MDI) in early childhood than did infants with secure attachment, especially the resistant type. In addition, resistant infants were reported to have greater social withdrawal, sleep problems and aggressive behavior in early childhood.
Conclusion: There is a high consistency in attachment development from infancy to early childhood. Secure mother–infant attachment predicts a better cognitive and behavioral outcome; whereas insecure attachment, especially the resistant attachment, may lead to a lower cognitive level and greater behavioral problems in early childhood.
representations of the HPA axis
representations of limbic stress-integrative pathways from the prefrontal cortex, amygdala and hippocampus
Fetal programming of schizophrenia: Select mechanisms
Monojit Debnatha, Ganesan Venkatasubramanian, Michael Berk
Neuroscience and Biobehavioral Reviews 49 (2015) 90–104
http://dx.doi.org/10.1016/j.neubiorev.2014.12.003
Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia.
NMDA receptor dysfunction in autism spectrum disorders
Eun-Jae Lee, Su Yeon Choi and Eunjoon Kim
Current Opinion in Pharmacology 2015, 20:8–13
http://dx.doi.org/10.1016/j.coph.2014.10.007
Autism spectrum disorders (ASDs) represent neurodevelopmental disorders characterized by two core symptoms;
(1) impaired social interaction and communication, and
(2) restricted and repetitive behaviors, interests, and activities.
ASDs affect ~ 1% of the population, and are considered to be highly genetic in nature. A large number (~600) of ASD-related genetic variations have been identified (sfari.org), and target gene functions are apparently quite diverse. However, some fall onto common pathways, including synaptic function and chromosome remodeling, suggesting that core mechanisms may exist.
Abnormalities and imbalances in neuronal excitatory and inhibitory synapses have been implicated in diverse neuropsychiatric disorders including autism spectrum disorders (ASDs). Increasing evidence indicates that dysfunction of NMDA receptors (NMDARs) at excitatory synapses is associated with ASDs. In support of this, human ASD-associated genetic variations are found in genes encoding NMDAR subunits. Pharmacological enhancement or suppression of NMDAR function ameliorates ASD symptoms in humans. Animal models of ASD display bidirectional NMDAR dysfunction, and correcting this deficit rescues ASD-like behaviors. These findings suggest that deviation of NMDAR function in either direction contributes to the development of ASDs, and that correcting NMDAR dysfunction has therapeutic potential for ASDs.
Among known synaptic proteins implicated in ASD are metabotropic glutamate receptors (mGluRs). Functional enhancement and suppression of mGluR5 are associated with fragile X syndrome and tuberous sclerosis, respectively, which share autism as a common phenotype. More recently, ionotropic glutamate receptors, namely NMDA receptors (NMDARs) and AMPA receptors (AMPARs), have also been implicated in ASDs. In this review, we will focus on NMDA receptors and summarize evidence supporting the hypothesis that NMDAR dysfunction contributes to ASDs, and, by extension, that correcting NMDAR dysfunction has therapeutic potential for ASDs. ASD-related human NMDAR genetic variants.
Chemokines roles within the hippocampus
IL-1 mediates stress-induced activation of the HPA axis
A systemic model of the beneficial role of immune processes in behavioral and neural plasticity
Three Classes of Glutamate Receptors
Clinical studies on ASDs have identified genetic variants of NMDAR subunit genes. Specifically, de novo mutations have been identified in the GRIN2B gene, encoding the GluN2B subunit. In addition, SNP analyses have linked both GRIN2A (GluN2A subunit) and GRIN2B with ASDs. Because assembled NMDARs contain four subunits, each with distinct properties, ASD-related GRIN2A/ GRIN2B variants likely alter the functional properties of NMDARs and/or NMDAR-dependent plasticity.
Pharmacological modulation of NMDAR function can improve ASD symptoms. D-cycloserine (DCS), an NMDAR agonist, significantly ameliorates social withdrawal and repetitive behavior in individuals with ASD. These results suggest that reduced NMDAR function may contribute to the development of ASDs in humans.
We can divide animal studies into two groups. The first group consists of animals in which NMDAR modulators were shown to normalize both NMDAR dysfunction and ASD-like behaviors, establishing strong association between NMDARs and ASD phenotypes (Fig.). In the second group, NMDAR modulators were shown to rescue ASD-like behaviors, but NMDAR dysfunction and its correction have not been demonstrated.
ASD models with data showing rescue of both NMDAR dysfunction and ASD like behaviors Mice lacking neuroligin-1, an excitatory postsynaptic adhesion molecule, show reduced NMDAR function in the hippocampus and striatum, as evidenced by a decrease in NMDA/AMPA ratio and long-term potentiation (LTP). Neuroligin-1 is thought to enhance synaptic NMDAR function, by directly interacting with and promoting synaptic localization of NMDARs.
Fig not shown.
Bidirectional NMDAR dysfunction in animal models of ASD. Animal models of ASD with bidirectional NMDAR dysfunction can be positioned on either side of an NMDAR function curve. Model animals were divided into two groups.
Group 1: NMDAR modulators normalize both NMDAR dysfunction and ASD-like behaviors (green).
Group 2: NMDAR modulators rescue ASD-like behaviors, but NMDAR dysfunction and its rescue have not been demonstrated (orange). Note that Group 2 animals are tentatively placed on the left-hand side of the slope based on the observed DCS rescue of their ASD-like phenotypes, but the directions of their NMDAR dysfunctions remain to be experimentally determined.
ASD models with data showing rescue of ASD-like behaviors but no demonstrated NMDAR dysfunction
Tbr1 is a transcriptional regulator, one of whose targets is the gene encoding the GluN2B subunit of NMDARs. Mice haploinsufficient for Tbr1 (Tbr1+/-) show structural abnormalities in the amygdala and limited GluN2B induction upon behavioral stimulation. Both systemic injection and local amygdalar infusion of DCS rescue social deficits and impaired associative memory in Tbr1+/- mice. However, reduced NMDAR function and its DCS-dependent correction have not been demonstrated.
Spatial working memory and attention skills are predicted by maternal stress during pregnancy
André Plamondon, Emis Akbari, Leslie Atkinson, Meir Steiner
Early Human Development 91 (2015) 23–29
Introduction: Experimental evidence in rodents shows that maternal stress during pregnancy (MSDP) negatively impacts spatial learning and memory in the offspring. We aim to investigate the association between MSDP (i.e., life events) and spatial working memory, as well as attention skills (attention shifting and attention focusing), in humans. The moderating roles of child sex, maternal anxiety during pregnancy and postnatal care are also investigated. Methods: Participants were 236mother–child dyads that were followed from the second trimester of pregnancy until 4 years postpartum. Measurements included questionnaires and independent observations.
Results: MSDP was negatively associated with attention shifting at 18monthswhen concurrent maternal anxiety was low. MSDP was associated with poorer spatial working memory at 4 years of age, but only for boys who experienced poorer postnatal care.
Conclusion: Consistent with results observed in rodents, MSDP was found to be associated with spatial working memory and attention skills. These results point to postnatal care and maternal anxiety during pregnancy as potential targets for interventions that aim to buffer children from the detrimental effects of MSDP.
Acute and massive bleeding from placenta previa and infants’ brain damage
Ken Furuta, Shuichi Tokunaga, Seishi Furukawa, Hiroshi Sameshima
Background: Among the causes of third trimester bleeding, the impact of placenta previa on cerebral palsy is not well known.
Aims: To clarify the effect ofmaternal bleeding fromplacenta previa on cerebral palsy, and in particular when and how it occurs.
Study design: A descriptive study.
Subjects: Sixty infants born to mothers with placenta previa in our regional population-based study of 160,000 deliveries from 1998 to 2012. Premature deliveries occurring atb26 weeks of gestation and placenta accrete were excluded.
Outcome measures: Prevalence of cystic periventricular leukomalacia (PVL) and cerebral palsy (CP).
Results: Five infants had PVL and 4 of these infants developed CP (1/40,000 deliveries). Acute and massive bleeding (>500 g) within 8 h) occurred at around 30–31 weeks of gestation, and was severe enough to deliver the fetus. None of the 5 infants with PVL underwent antenatal corticosteroid treatment, and 1 infant had mild neonatal hypocapnia with a PaCO2 < 25 mm Hg. However, none of the 5 PVL infants showed umbilical arterial academia with pH < 7.2, an abnormal fetal heart rate monitoring pattern, or neonatal hypotension.
Conclusions: Our descriptive study showed that acute and massive bleeding from placenta previa at around 30 weeks of gestation may be a risk factor for CP, and requires careful neonatal follow-up. The underlying process connecting massive placental bleeding and PVL requires further investigation.
Impact of bilirubin-induced neurologic dysfunction on neurodevelopmental outcomes
Courtney J. Wusthoff, Irene M. Loe
Seminars in Fetal & Neonatal Medicine 20 (2015) 52e57
http://dx.doi.org/10.1016/j.siny.2014.12.003
Extreme neonatal hyperbilirubinemia has long been known to cause the clinical syndrome of kernicterus, or chronic bilirubin encephalopathy (CBE). Kernicterus most usually is characterized by choreoathetoid cerebral palsy (CP), impaired upward gaze, and sensorineural hearing loss, whereas cognition is relatively spared. The chronic condition of kernicterus may be, but is not always, preceded in the acute stage by acute bilirubin encephalopathy (ABE). This acute neonatal condition is also due to hyperbilirubinemia, and is characterized by lethargy and abnormal behavior, evolving to frank neonatal encephalopathy, opisthotonus, and seizures. Less completely defined is the syndrome of bilirubin-induced neurologic dysfunction (BIND).
Bilirubin-induced neurologic dysfunction (BIND) is the constellation of neurologic sequelae following milder degrees of neonatal hyperbilirubinemia than are associated with kernicterus. Clinically, BIND may manifest after the neonatal period as developmental delay, cognitive impairment, disordered executive function, and behavioral and psychiatric disorders. However, there is controversy regarding the relative contribution of neonatal hyperbilirubinemia versus other risk factors to the development of later neurodevelopmental disorders in children with BIND. In this review, we focus on the empiric data from the past 25 years regarding neurodevelopmental outcomes and BIND, including specific effects on developmental delay, cognition, speech and language development, executive function, and the neurobehavioral disorders, such as attention deficit/hyperactivity disorder and autism.
As noted in a technical report by the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, “it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results”. As described above, this has certainly been the case in research to date. To clarify how hyperbilirubinemia influences neurodevelopmental outcome, more sophisticated consideration is needed both of how to assess bilirubin exposure leading to neurotoxicity, and of those comorbid conditions which may lower the threshold for brain injury.
For example, premature infants are known to be especially susceptible to bilirubin neurotoxicity, with kernicterus reported following TB levels far lower than the threshold expected in term neonates. Similarly, among extremely preterm neonates, BBC is proportional to gestational age, meaning that the most premature infants have the highest UB, even for similar TB levels. Thus, future studies must be adequately powered to examine preterm infants separately from term infants, and should consider not just peak TB, but also BBC, as independent variables in neonates with hyperbilirubinemia. Similarly, an analysis by the NICHD NRN found that, among ELBW infants, higher UB levels were associated with a higher risk of death or NDI. However, increased TB levels were only associated with death or NDI in unstable infants. Again, UB or BBC appeared to be more useful than TB.
Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?
Jon F. Watchko, Michael J. Painter, Ashok Panigrahy
Investigators have hypothesized a range of subcortical neuropathology in the genesis of bilirubin induced neurologic dysfunction (BIND). The current review builds on this speculation with a specific focus on the cerebellum and its connections in the development of the subtle neuromotor disabilities of BIND. The focus on the cerebellum derives from the following observations:
(i) the cerebellum is vulnerable to bilirubin-induced injury; perhaps the most vulnerable region within the central nervous system;
(ii) infants with cerebellar injury exhibit a neuromotor phenotype similar to BIND; and (iii) the cerebellum has extensive bidirectional circuitry projections to motor and non-motor regions of the brain-stem and cerebral cortex that impact a variety of neurobehaviors.
Future study using advanced magnetic resonance neuroimaging techniques have the potential to shed new insights into bilirubin’s effect on neural network topology via both structural and functional brain connectivity measurements.
Bilirubin-induced neurologic damage is most often thought of in terms of severe adverse neuromotor (dystonia with or without athetosis) and auditory (hearing impairment or deafness) sequelae. Observed together, they comprise the classic neurodevelopmental phenotype of chronic bilirubin encephalopathy or kernicterus, and may also be seen individually as motor or auditory predominant subtypes. These injuries reflect both a predilection of bilirubin toxicity for neurons (relative to glial cells) and the regional topography of bilirubin-induced neuronal damage characterized by prominent involvement of the globus pallidus, subthalamic nucleus, VIII cranial nerve, and cochlear nucleus.
It is also asserted that bilirubin neurotoxicity may be associated with other less severe neurodevelopmental disabilities, a condition termed “subtle kernicterus” or “bilirubin-induced neurologic dysfunction” (BIND). BIND is defined by a constellation of “subtle neurodevelopmental disabilities without the classical findings of kernicterus that, after careful evaluation and exclusion of other possible etiologies, appear to be due to bilirubin neurotoxicity”. These purportedly include:
(i) mild-to-moderate disorders of movement (e.g., incoordination, clumsiness, gait abnormalities, disturbances in static and dynamic balance, impaired fine motor skills, and ataxia); (ii) disturbances in muscle tone; and
(iii) altered sensorimotor integration. Isolated disturbances of central auditory processing are also included in the spectrum of BIND.
Cerebellar vulnerability to bilirubin-induced injury
Cerebellar injury phenotypes and BIND
Cerebellar projections
Transverse section of cerebellum and brainstem
Transverse section of cerebellum and brain-stem from a 34 gestational-week premature kernicteric infant formalin-fixed for two weeks. Yellow staining is evident in the cerebellar dentate nuclei (upper arrow) and vestibular nuclei at the pontomedullary junction (lower arrowhead). Photo is courtesy of Mahmdouha Ahdab-Barmada and reprinted with permission from Taylor-Francis Group (Ahdab Barmada M. The neuropathology of kernicterus: definitions and debate. In: Maisel MJ, Watchko JF editors. Neonatal jaundice. Amsterdam: Harwood Academic Publishers; 2000. p. 75e88
Whether cerebellar injury is primal or an integral part of disturbed neural circuitry in bilirubin-induced CNS damage is unclear. Movement disorders, however, are increasingly recognized to arise from abnormalities of neuronal circuitry rather than localized, circumscribed lesions. The cerebellum has extensive bidirectional circuitry projections to an array of brainstem nuclei and the cerebral cortex that modulate and refine motor activities. In this regard, the cerebellum is characteristically subdivided into three lobes based on neuroanatomic and phylogenetic criteria as well as by their primary afferent and efferent connections. They include:
(i) flocculonodular lobe (archicerebellum);
(ii) anterior lobe (paleocerebellum); and
(iii) posterior lobe (neocerebellum).
The archicerebellum, the oldest division phylogenically, receives extensive input from the vestibular system and is therefore also known as the vestibulocerebellum and is important for equilibrium control. The paleocerebellum, also a primitive region, receives extensive somatosensory input from the spinal cord, including the anterior and posterior spinocerebellar pathways that convey unconscious proprioception, and is therefore also known as the spinocerebellum. The neocerebellum is the most recently evolved region, receives most of the input from the cerebral cortex, and is thus termed the cerebrocerebellum. This area has greatly expanded in association with the extensive development of the cerebral cortex in mammals and especially primates. To cause serious longstanding dysfunction, cerebellar injury must typically involve the deep cerebellar nuclei and their projections.
Schematic of the bidirectional connectivity between the cerebellum and other
Schematic of the bidirectional connectivity between the cerebellum and other brain regions including the cerebral cortex. Most cerebro-cerebellar afferent projections pass through the basal (anterior or ventral) pontine nuclei and intermediate cerebellar peduncle, whereas most cerebello-cerebral efferent projections pass through the dentate and ventrolateral thalamic nuclei. DCN, deep cerebellar nuclei; RN, red nucleus; ATN, anterior thalamic nucleus; PFC, prefrontal cortex; MC, motor cortex; PC, parietal cortex; TC, temporal cortex; STN, subthalamic nucleus; APN, anterior pontine nuclei. Reprinted under the terms of the Creative Commons Attribution License from D’Angelo E, Casali S. Seeking a unified framework for cerebellar function and dysfunction: from circuit to cognition. Front Neural Circuits 2013; 6:116.
Given the vulnerability of the cerebellum to bilirubin-induced injury, cerebellar involvement should also be evident in classic kernicterus, contributing to neuromotor deficits observed therein. It is of interest, therefore, that cerebellar damage may play a role in the genesis of bilirubin-induced dystonia, a prominent neuromotor feature of chronic bilirubin encephalopathy in preterm and term neonates alike. This complex movement disorder is characterized by involuntary sustained muscle contractions that result in abnormal position and posture. Moreover, dystonia that is brief in duration results in chorea, and, if brief and repetitive, leads to athetosis ‒ conditions also classically observed in kernicterus. Recent evidence suggests that dystonic movements may depend on disruption of both basal ganglia and cerebellar neuronal networks, rather than isolated dysfunction of only one motor system.
Dystonia is also a prominent feature in Gunn rat pups and neonatal Ugt1‒/‒-deficient mice both robust models of kernicterus. The former is used as an experimental model of dystonia. Although these models show basal ganglia injury, the sine qua non of bilirubin-induced murine neuropathology is cerebellar damage and resultant cerebellar hypoplasia.
Studies are needed to define more precisely the motor network abnormalities in kernicterus and BIND. Magnetic resonance imaging (MRI) has been widely used in evaluating infants at risk for bilirubin-induced brain injury using conventional structural T1-and T2-weighted imaging. Infants with chronic bilirubin encephalopathy often demonstrate abnormal bilateral, symmetric, high-signal intensity on T2-weighted MRI of the globus pallidus and subthalamic nucleus, consistent with the neuropathology of kernicterus. Early postnatal MRI of at-risk infants, although frequently showing increased T1-signal in these regions, may give false-positive findings due to the presence of myelin in these structures.
Diffusion tensor imaging and tractography could be used to delineate long-term changes involving specific white matter pathways, further elucidating the neural basis of long-term disability in infants and children with chronic bilirubin encephalopathy and BIND. It will be equally valuable to use blood oxygen level-dependent (BOLD) “resting state” functional MRI to study intrinsic connectivity in order to identify vulnerable brain networks in neonates with kernicterus and BIND. Structural networks of the CNS (connectome) and functional network topology can be characterized in infants with kernicterus and BIND to determine disease-related pattern(s) with respect to both long- and short-range connectivity. These findings have the potential to shed novel insights into the pathogenesis of these disorders and their impact on complex anatomical connections and resultant functional deficits.
Audiologic impairment associated with bilirubin-induced neurologic damage
Cristen Olds, John S. Oghalai
Hyperbilirubinemia affects up to 84% of term and late preterm infants in the first week of life. The elevation of total serum/plasma bilirubin (TB) levels is generally mild, transitory, and, for most children, inconsequential. However, a subset of infants experiences lifelong neurological sequelae. Although the prevalence of classic kernicterus has fallen steadily in the USA in recent years, the incidence of jaundice in term and premature infants has increased, and kernicterus remains a significant problem in the global arena. Bilirubin-induced neurologic dysfunction (BIND) is a spectrum of neurological injury due to acute or sustained exposure of the central nervous system(CNS) to bilirubin. The BIND spectrum includes kernicterus, acute bilirubin encephalopathy, and isolated neural pathway dysfunction.
Animal studies have shown that unconjugated bilirubin passively diffuses across cell membranes and the blood‒brain barrier (BBB), and bilirubin not removed by organic anion efflux pumps accumulates within the cytoplasm and becomes toxic. Exposure of neurons to bilirubin results in increased oxidative stress and decreased neuronal proliferation and presynaptic neuro-degeneration at central glutaminergic synapses. Furthermore, bilirubin administration results in smaller spiral ganglion cell bodies, with decreased cellular density and selective loss of large cranial nerve VIII myelinated fibers. When exposed to bilirubin, neuronal supporting cells have been found to secrete inflammatory markers, which contribute to increased BBB permeability and bilirubin loading.
The jaundiced Gunn rat is the classic animal model of bilirubin toxicity. It is homozygous for a premature stop codon within the gene for UDP-glucuronosyltransferase family 1 (UGT1). The resultant gene product has reduced bilirubin-conjugating activity, leading to a state of hyperbilirubinemia. Studies with this rat model have led to the concept that impaired calcium homeostasis is an important mechanism of neuronal toxicity, with reduced expression of calcium-binding proteins in affected cells being a sensitive index of bilirubin-induced neurotoxicity. Similarly, application of bilirubin to cultured auditory neurons from brainstem cochlear nuclei results in hyperexcitability and excitotoxicity.
The auditory pathway and normal auditory brainstem response (ABR).
The auditory pathway and normal auditory brain-stem response (ABR). The ipsilateral (green) and contralateral (blue) auditory pathways are shown, with structures that are known to be affected by hyperbilirubinemia highlighted in red. Roman numerals in parentheses indicate corresponding waves in the normal human ABR (inset). Illustration adapted from the “Ear Anatomy” series by Robert Jackler and Christine Gralapp, with permission.
Bilirubin-induced neurologic dysfunction (BIND)
Vinod K. Bhutani, Ronald Wong
Seminars in Fetal & Neonatal Medicine 20 (2015) 1
Beyond the traditional recognized areas of fulminant injury to the globus pallidus as seen in infants with kernicterus, other vulnerable areas include the cerebellum, hippocampus, and subthalamic nuclear bodies as well as certain cranial nerves. The hippocampus is a brain region that is particularly affected by age related morphological changes. It is generally assumed that a loss in hippocampal volume results in functional deficits that contribute to age-related cognitive deficits. Lower grey matter volumes within the limbic-striato-thalamic circuitry are common to other etiological mechanisms of subtle neurologic injury. Lower grey matter volumes in the amygdala, caudate, frontal and medial gyrus are found in schizophrenia and in the putamen in autism. Thus, in terms of brain volumetrics, schizophrenia and autism spectrum disorders have a clear degree of overlap that may reflect shared etiological mechanisms. Overlap with injuries observed in infants with BIND raises the question about how these lesions are arrived at in the context of the impact of common etiologies.
Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health
Olena Babenko, Igor Kovalchuk, Gerlinde A.S. Metz
Neuroscience and Biobehavioral Reviews 48 (2015) 70–91
Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.
Sensitive time-windows for susceptibility in neurodevelopmental disorders
Rhiannon M. Meredith, Julia Dawitz and Ioannis Kramvis
Trends in Neurosciences, June 2012; 35(6): 335-344
http://dx.doi.org:/10.1016/j.tins.2012.03.005
Many neurodevelopmental disorders (NDDs) are characterized by age-dependent symptom onset and regression, particularly during early postnatal periods of life. The neurobiological mechanisms preceding and underlying these developmental cognitive and behavioral impairments are, however, not clearly understood. Recent evidence using animal models for monogenic NDDs demonstrates the existence of time-regulated windows of neuronal and synaptic impairments. We propose that these developmentally-dependent impairments can be unified into a key concept: namely, time-restricted windows for impaired synaptic phenotypes exist in NDDs, akin to critical periods during normal sensory development in the brain. Existence of sensitive time-windows has significant implications for our understanding of early brain development underlying NDDs and may indicate vulnerable periods when the brain is more susceptible to current therapeutic treatments.
Fig (not shown)
Misregulated mechanisms underlying spine morphology in NDDs. Several proteins implicated in monogenic NDDs (highlighted in red) are linked to the regulation of the synaptic cytoskeleton via F-actin through different Rho-mediated signaling pathways (highlighted in green). Mutations in OPHN1, TSC1/2, FMRP, p21-activated kinase (PAK) are directly linked to human NDDs of intellectual disability. For instance, point mutations in OPHN1 and a PAK isoform are linked to non-syndromic mental retardation, whereas mutations or altered expression of TSC1/2 and FMRP are linked to TSC and FXS, respectively. Cytoplasmic interacting protein (CYFIP) and LIM-domain kinase 1 (LIMK1) are known to interact with FMRP and PAK, respectively [105]. LIMK1 is one of many dysregulated proteins contributing to the NDD Williams syndrome. Mouse models are available for all highlighted (red) proteins and reveal specific synaptic and behavioral deficits. Local protein synthesis in synapses, dendrites and glia is also regulated by proteins such as TSC1/2 and the FMRP/CYFIP complex. Abbreviations: 4EBP, 4E binding protein; eIF4E, eukaryotic translation initiation factor 4E.
Sensitive time-windows, synaptic phenotypes and NDD gene targets. Sensitive time-windows exist in neural circuits, during which gene targets implicated in NDDs are normally expressed. Misregulation of these genes can affect multiple synaptic phenotypes during a restricted developmental period. The effect upon synaptic phenotypes is dependent upon the temporal expression of these NDD genes and their targets. (a) Expression outside a critical period of development will have no effect upon synaptic phenotypes. (b,c) A temporal expression pattern that overlaps with the onset (b) or closure (c) of a known critical period can alter the synaptic phenotype during that developmental time-window.
Outstanding questions
(1) Can treatment at early presymptomatic stages in animal models for NDDs prevent or ease the later synaptic, neuronal, and behavioral impairments?
(2) Are all sensory critical periods equally misregulated in mouse models for a specific NDD? Are there different susceptibilities for auditory, visual and somatosensory neurocircuits that reflect the degree of impairments observed in patients?
(3) If one critical period is missed or delayed during formation of a layer-specific connection in a network, does the network overcome this misregulated connectivity or plasticity window?
(4) In monogenic NDDs, does the severity of misregulating one particular time-window for synaptic establishment during development correlate with the importance of that gene for that synaptic circuit?
(5) Why do critical periods close in brain development?
(6) What underlies the regression of some altered synaptic phenotypes in Fmr1-KO mice?
(7) Can the concept of susceptible time-windows be applied to other NDDs, including schizophrenia and Tourette’s syndrome?
Cardiac output monitoring in newborns
Willem-Pieter de Boode
http://dx.doi.org:/10.1016/j.earlhumdev.2010.01.032
There is an increased interest in methods of objective cardiac output measurement in critically ill patients. Several techniques are available for measurement of cardiac output in children, although this remains very complex in newborns. Cardiac output monitoring could provide essential information to guide hemodynamic management. An overview is given of various methods of cardiac output monitoring with advantages and major limitations of each technology together with a short explanation of the basic principles.
Fick principle
According to the Fick principle the volume of blood flow in a given period equals the amount of substance entering the blood stream in the same period divided by the difference in concentrations of the substrate upstream respectively downstream to the point of entry in the circulation. This substance can be oxygen (O2-Fick) or carbon dioxide (CO2-FICK), so cardiac output can be calculated by dividing measured pulmonary oxygen uptake by the arteriovenous oxygen concentration difference. The direct O2-Fick method is regarded as gold standard in cardiac output monitoring in a research setting, despite its limitations. When the Fick principle is applied for carbon dioxide (CO2 Fick), the pulmonary carbon dioxide exchange is divided by the venoarterial CO2 concentration difference to calculate cardiac output.
In the modified CO2 Fick method pulmonary CO2 exchange is measured at the endotracheal tube. Measurement of total CO2 concentration in blood is more complex and simultaneous sampling of arterial and central venous blood is required. However, frequent blood sampling will result in an unacceptable blood loss in the neonatal population.
Blood flow can be calculated if the change in concentration of a known quantity of injected indicator is measured in time distal to the point of injection, so an indicator dilution curve can be obtained. Cardiac output can then be calculated with the use of the Stewart–Hamilton equation. Several indicators are used, such as indocyanine green, Evans blue and brilliant red in dye dilution, cold solutions in thermodilution, lithium in lithium dilution, and isotonic saline in ultrasound dilution.
Cardiovascular adaptation to extra uterine life
Alice Lawford, Robert MR Tulloh
Paediatrics And Child Health 2014; 25(1): 1-6.
The adaptation to extra uterine life is of interest because of its complexity and the ability to cause significant health concerns. In this article we describe the normal changes that occur and the commoner abnormalities that are due to failure of normal development and the effect of congenital cardiac disease. Abnormal development may occur as a result of problems with the mother, or with the fetus before birth. After birth it is essential to determine whether there is an underlying abnormality of the fetal pulmonary or cardiac development and to determine the best course of management of pulmonary hypertension or congenital cardiac disease. Causes of underdevelopment, maldevelopment and maladaptation are described as are the causes of critical congenital heart disease. The methods of diagnosis and management are described to allow the neonatologist to successfully manage such newborns.
Fetal vascular structures that exist to direct blood flow
Fetal structure Function
Arterial duct Connects pulmonary artery to the aorta and shunts blood right to left; diverting flow away from fetal lungs
Foramen ovale Opening between the two atria thatdirects blood flow returning to right
atrium through the septal wall into the left atrium bypassing lungs
Ductus venosus Receives oxygenated blood fromumbilical vein and directs it to the
inferior vena cava and right atrium
Umbilical arteries Carrying deoxygenated blood fromthe fetus to the placenta
Umbilical vein Carrying oxygenated blood from theplacenta to the fetus
Maternal causes of congenital heart disease
Maternal disorders rubella, SLE, diabetes mellitus
Maternal drug use Warfarin, alcohol
Chromosomal abnormality Down, Edward, Patau, Turner, William, Noonan
Fetal and Neonatal Circulation The fetal circulation is specifically adapted to efficiently exchange gases, nutrients, and wastes through placental circulation. Upon birth, the shunts (foramen ovale, ductus arteriosus, and ductus venosus) close and the placental circulation is disrupted, producing the series circulation of blood through the lungs, left atrium, left ventricle, systemic circulation, right heart, and back to the lungs.
Clinical monitoring of systemic hemodynamics in critically ill newborns
Circulatory failure is a major cause of mortality and morbidity in critically ill newborn infants. Since objective measurement of systemic blood flow remains very challenging, neonatal hemodynamics is usually assessed by the interpretation of various clinical and biochemical parameters. An overview is given about the predictive value of the most used indicators of circulatory failure, which are blood pressure, heart rate, urine output, capillary refill time, serum lactate concentration, central–peripheral temperature difference, pH, standard base excess, central venous oxygen saturation and color.
Key guidelines
➢ The clinical assessment of cardiac output by the interpretation of indirect parameters of systemic blood flow is inaccurate, irrespective of the level of experience of the clinician
➢ Using blood pressure to diagnose low systemic blood flow will consequently mean that too many patients will potentially be undertreated or overtreated, both with substantial risk of adverse effects and iatrogenic damage.
➢ Combining different clinical hemodynamic parameters enhances the predictive value in the detection of circulatory failure, although accuracy is still limited.
➢ Variation in time (trend monitoring) might possibly be more informative than individual, static values of clinical and biochemical parameters to evaluate the adequacy of neonatal circulation.
Monitoring oxygen saturation and heart rate in the early neonatal period
J.A. Dawson, C.J. Morley
Seminars in Fetal & Neonatal Medicine 15 (2010) 203e207
http://dx.doi.org:/10.1016/j.siny.2010.03.004
Pulse oximetry is commonly used to assist clinicians in assessment and management of newly born infants in the delivery room (DR). In many DRs, pulse oximetry is now the standard of care for managing high risk infants, enabling immediate and dynamic assessment of oxygenation and heart rate. However, there is little evidence that using pulse oximetry in the DR improves short and long term outcomes. We review the current literature on using pulse oximetry to measure oxygen saturation and heart rate and how to apply current evidence to management in the DR.
Practice points
Understand how SpO2 changes in the first minutes after birth.
Apply a sensor to an infant’s right wrist as soon as possible after birth.
Attach sensor to infant then to oximeter cable.
Use two second averaging and maximum sensitivity.
Using pulse oximetry assists clinicians:
Assess changes in HR in real time during transition.
Assess oxygenation and titrate the administration of oxygen to maintain oxygenation within the appropriate range for SpO2 during the first minutes after birth.
What are the appropriate centiles to target during the minutes after birth to prevent hypoxia and hyperoxia: 25th to 75th, or 10th to 90th, or just the 50th (median)?
Can the inspired oxygen be titrated against the SpO2 to keep the SpO2 in the ‘normal range’?
Does the use of centile charts in the DR for HR and oxygen saturation reduce the rate of hyperoxia when infants are treated with oxygen.
Does the use of pulse oximetry immediately after birth improve short term outcomes, e.g. efficacy of immediate respiratory support, intubation rates in the DR, percentage of inspired oxygen, rate of use of adrenalin or chest compressions, duration of hypoxia/hyperoxia and bradycardia.
Does the use of pulse oximetry in the DR improve short term respiratory and long term neurodevelopmental outcomes for preterm infants, e.g. rate of intubation, use of surfactant, and duration of ventilation, continuous positive airway pressure, or supplemental oxygen?
Can all modern pulse oximeters be used effectively in the DR or do some have a longer delay before giving an accurate signal and more movement artefact?
Would a longer averaging time result in more stable data?
Peripheral haemodynamics in newborns: Best practice guidelines
Michael Weindling, Fauzia Paize
Peripheral hemodynamics refers to blood flow, which determines oxygen and nutrient delivery to the tissues. Peripheral blood flow is affected by vascular resistance and blood pressure, which in turn varies with cardiac function. Arterial oxygen content depends on the blood hemoglobin concentration (Hb) and arterial pO2; tissue oxygen delivery depends on the position of the oxygen-dissociation curve, which is determined by temperature and the amount of adult or fetal hemoglobin. Methods available to study tissue perfusion include near-infrared spectroscopy, Doppler flowmetry, orthogonal polarization spectral imaging and the peripheral perfusion index. Cardiac function, blood gases, Hb, and peripheral temperature all affect blood flow and oxygen extraction. Blood pressure appears to be less important. Other factors likely to play a role are the administration of vasoactive medications and ventilation strategies, which affect blood gases and cardiac output by changing the intrathoracic pressure.
NIRS with partial venous occlusion to measure venous oxygen saturation
NIRS with partial venous occlusion to measure venous oxygen saturation. Taken from Yoxall and Weindling
Schematic representation of the biphasic relationship between oxygen delivery and oxygen consumption in tissue
Schematic representation of the biphasic relationship between oxygen delivery and oxygen consumption in tissue. (a) oxygen delivery (DO2). (b) As DO2 decreases, VO2 is dependent on DO2. The slope of the line indicates the FOE, which in this case is about 0.50. (c) The slope of the line indicates the FOE in the normal situation where oxygenation is DO2 independent, usually < 0.35
The oxygen-dissociation curve
Considerable information about the response of the peripheral circulation has been obtained using NIRS with venous occlusion. Although these measurements were validated against blood co-oximetry in human adults and infants, they can only be made intermittently by a trained operator and are thus not appropriate for general clinical use. Further research is needed to find other better measures of peripheral perfusion and oxygenation which may be easily and continuously monitored, and which could be useful in a clinical setting.
Peripheral oxygenation and management in the perinatal period
Michael Weindling
The mechanisms for the adequate provision of oxygen to the peripheral tissues are complex. They involve control of the microcirculation and peripheral blood flow, the position of the oxygen dissociation curve including the proportion of fetal and adult hemoglobin, blood gases and viscosity. Systemic blood pressure appears to have little effect, at least in the non-shocked state. The adequate delivery of oxygen (DO2) depends on consumption (VO2), which is variable. The balance between VO2 and DO2 is given by fractional oxygen extraction (FOE ¼ VO2/DO2). FOE varies from organ to organ and with levels of activity. Measurements of FOE for the whole body produce a range of about 0.15-0.33, i.e. the body consumes 15-33% of oxygen transported.
Biphasic relationship between oxygen delivery (DO2) and oxygen consumption (VO2) in tissue. Dotted lines show fractional oxygen extraction (FOE). ‘A’ indicates the normal situation when VO2 is independent ofDO2 and FOE is about 0.30. AsDO2 decreases in the direction of the arrow, VO2 remains independent of DO2 until the critical point is reached at ‘B’; in this illustration, FOE is about 0.50. The slope of the dotted line indicates the FOE (¼ VO2/DO2), which increases progressively as DO2 decreases.
Relationship between haemoglobin F fraction (HbF) and peripheral fractional oxygen extraction
(A)Relationship between haemoglobin F fraction (HbF) and peripheral fractional oxygen extraction in anaemic and control infants. (From Wardle et al.) (B) HbF synthesis and concentration. (From Bard and Widness.) (C) Oxygen dissociation curve.
Peripheral fractional oxygen extraction in babies
Peripheral fractional oxygen extraction in babies with asymptomatic or symptomatic anemia compared to controls. Bars represent the median for each group. (From Wardle et al.)
Peripheral tissue DO2 is complex: cardiac function, blood gases, Hb concentration and the proportion of HbF, and peripheral temperature all play a part in determining blood flow and oxygen extraction in the sick, preterm infant. Blood pressure appears to be less important.
Other factors likely to play a role are the administration of vasoactive medications and ventilation strategies, which affect blood gases and cardiac output by changing intrathoracic pressure.
Central blood pressure is a poor surrogate measurement for the adequacy of DO2 to the periphery. Direct measurement, using NIRS, laser Doppler flowmetry or other means, may give more useful information.
Reasons for total hemoglobin concentration (Hb) being a relatively poor indicator of the adequacy of the provision of oxygen to the tissues:
Hb is only indirectly related to red blood cell volume, which may be a better indicator of the body’s oxygen delivering capacity.
Hb-dependent oxygen availability depends on the position of the oxygen-hemoglobin dissociation curve.
An individual’s oxygen requirements vary with time and from organ to organ. This means that DO2 also needs to vary.
It is possible to compensate for a low Hb by increasing cardiac output and ventilation, and so the ability to compensate for anemia depends on an individual’s cardio-respiratory reserve as well as Hb.
The normal decrease of Hb during the first few weeks of life in both full-term and preterm babies usually occurs without symptoms or signs of anemia or clinical consequences.
The relationship between VO2 and DO2 is complex and various factors need to be taken into account, including the position of the oxygen dissociation curve, determined by the proportion of HbA and HbF, temperature and pH. Furthermore, diffusion of oxygen from capillaries to the cell depends on the oxygen tension gradient between erythrocytes and the mitochondria, which depends on microcirculatory conditions, e.g. capillary PO2, distance of the cell from the capillary (characterized by intercapillary distances) and the surface area of open capillaries. The latter can change rapidly, for example, in septic shock where arteriovenous shunting occurs associated with tissue hypoxia in spite of high DO2 and a low FOE.
Changes in local temperature deserve particular consideration. When the blood pressure is low, there may be peripheral vasoconstriction with decreased local perfusion and DO2. However, the fall in local tissue temperature would also be expected to be associated with a decreased metabolic rate and a consequent decrease in VO2. Thus a decreased DO2 may still be appropriate for tissue needs.
Accurate Measurements of Oxygen Saturation in Neonates: Paired Arterial and Venous Blood Analyses
Shyang-Yun Pamela K. Shiao
Newborn and Infant Nurs Rev, 2005; 5(4): 170–178
http://dx.doi.org:/10.1053/j.nainr.2005.09.001
Oxygen saturation (So2) measurements (functional measurement, So2; and fractional measurement, oxyhemoglobin [Hbo2]) and monitoring are commonly investigated as a method of assessing oxygenation in neonates. Differences exist between the So2 and Hbo2 when blood tests are performed, and clinical monitors indicate So2 values. Oxyhemoglobin will decrease with the increased levels of carbon monoxide hemoglobin (Hbco) and methemo-globin (MetHb), and it is the most accurate measurements of oxygen (O2) association of hemoglobin (Hb). Pulse oximeter (for pulse oximetry saturation [Spo2] measurement) is commonly used in neonates. However, it will not detect the changes of Hb variations in the blood for accurate So2 measurements. Thus, the measurements from clinical oximeters should be used with caution. In neonates, fetal hemoglobin (HbF) accounts for most of the circulating Hb in their blood. Fetal hemoglobin has a high O2 affinity, thus releases less O2 to the body tissues, presenting a left-shifted Hbo2 dissociation curve.5,6 To date, however, limited data are available with HbF correction, for accurate arterial and venous (AV) So2 measurements (arterial oxygen saturation [Sao2] and venous oxygen saturation [Svo2]) in neonates, using paired AV blood samples.
In a study of critically ill adult patients, increased pulmonary CO production and elevation in arterial Hbco but not venous Hbco were documented by inflammatory stimuli inducing pulmonary heme oxygenase–1. In normal adults, venous Hbco level might be slightly higher than or equal to arterial Hbco because of production of CO by enzyme heme oxygenase–2, which is predominantly produced in the liver and spleen. However, hypoxia or pulmonary inflammation could induce heme oxygenase–1 to increase endogenous CO, thus elevating pulmonary arterial and systemic arterial Hbco levels in adults. Both endogenous and exogenous CO can suppress proliferation of pulmonary smooth muscles, a significant consideration for the prevention of chronic lung diseases in newborns. Despite these considerations, a later study in healthy adults indicated that the AV differences in Hbco were from technical artifacts and perhaps from inadequate control of different instruments. Thus, further studies are needed to provide more definitive answers for the AV differences of Hbco for adults and neonates with acute and chronic lung diseases.
Methemoglobin is an indicator of Hb oxidation and is essential for accurate measurement of Hbo2, So2, and oxygenation status. No evidence exists to show the AV MetHb difference, although this difference was elucidated with the potential changes of MetHb with different O2 levels. Methemoglobin can be increased with nitric oxide (NO) therapy, used in respiratory distress syndrome (RDS) to reduce pulmonary hypertension and during heart surgery. Nitric oxide, in vitro, is an oxidant of Hb, with increased O2 during ischemia reperfusion. In hypoxemic conditions in vivo, nitrohemoglobin is a product generated by vessel responsiveness to nitrovasodilators. Nitro-hemoglobin can be spontaneously reversible in vivo, requiring no chemical agents or reductase. However, when O2 levels were increased experimentally in vitro following acidic conditions (pH 6.5) to simulate reperfusion conditions, MetHb levels were increased for the hemolysates (broken red cells). Nitrite-induced oxidation of Hb was associated with an increase in red blood cell membrane rigidity, thus contributing to Hb breakdown. A newer in vitro study of whole blood cells, however, concluded that MetHb formation is not dependent on increased O2 levels. Additional studies are needed to examine in vivo reperfusion of O2 and MetHb effects.
Purpose: The aim of this study was to examine the accuracy of arterial oxygen saturation (Sao2) and venous oxygen saturation (Svo2) with paired arterial and venous (AV) blood in relation to pulse oximetry saturation (Spo2) and oxyhemoglobin (Hbo2) with fetal hemoglobin determination, and their Hbo2 dissociation curves. Method: Twelve preterm neonates with gestational ages ranging from 27 to 34 weeks at birth, who had umbilical AV lines inserted, were investigated. Analyses were performed with 37 pairs of AV blood samples by using a blood volume safety protocol. Results: The mean differences between Sao2 and Svo2, and AV Hbo2 were both 6 percent (F6.9 and F6.7 percent, respectively), with higher Svo2 than those reported for adults. Biases were 2.1 – 0.49 for Sao2, 2.0 – 0.44 for Svo2, and 3.1 – 0.45 for Spo2, compared against Hbo2. With left-shifted Hbo2 dissociation curves in neonates, for the critical values of oxygen tension values between 50 and 75 millimeters of mercury, Hbo2 ranged from 92 to 93.4 percent; Sao2 ranged from 94.5 to 95.7 percent; and Spo2 ranged from 93.7 to 96.3 percent (compared to 85–94 percent in healthy adults). Conclusions: In neonates, both left-shifted Hbo2 dissociation curve and lower AV differences of oxygen saturation measurements indicated low flow of oxygen to the body tissues. These findings demonstrate the importance of accurate assessment of oxygenation statues in neonates.
In these neonates, the mean AV blood differences for both So2 and Hbo2 were about 6 percent, which was much lower than those reported for healthy adults (23 percent) for O2 supply and demand. In addition, with very high levels of HbF releasing less O2 to the body tissue, the results of blood analyses are worrisome for these critically ill neonates for low systemic oxygen states. O’Connor and Hall determined AV So2 in neonates without HbF determination. Much of the AV So2 difference is dependent on Svo2 measurement. The ranges of Svo2 spanned for 35 percent, and the ranges of Sao2 spanned 6 percent in these neonates. The greater intervals for Svo2 measurements contribute to greater sensitivity for the measurements (than Sao2 measurements) in responding to nursing care and changes of O2 demand. Thus, Svo2 measurement is essential for better assessment of oxygenation status in neonates.
The findings of this study on AV differences of So2 were limited with very small number of paired AV blood samples. However, critically ill neonates need accurate assessment of oxygenation status because of HbF, which releases less O2 to the tissues. Decreased differences of AV So2 measurements added further possibilities of lower flow of O2 to the body tissues and demonstrated the greater need to accurately assess the proper oxygenation in the neonates. The findings of this study continued to clarify the accuracy of So2 measurements for neonates. Additional studies are needed to examine So2 levels in neonates to further validate these findings by using larger sample sizes.
Neonatal ventilation strategies and long-term respiratory outcomes
Sandeep Shetty, Anne Greenough
Long-term respiratory morbidity is common, particularly in those born very prematurely and who have developed bronchopulmonary dysplasia (BPD), but it does occur in those without BPD and in infants born at term. A variety of neonatal strategies have been developed, all with short-term advantages, but meta-analyses of randomized controlled trials (RCTs) have demonstrated that only volume-targeted ventilation and prophylactic high-frequency oscillatory ventilation (HFOV) may reduce BPD. Few RCTs have incorporated long-term follow-up, but one has demonstrated that prophylactic HFOV improves respiratory and functional outcomes at school age, despite not reducing BPD. Results from other neonatal interventions have demonstrated that any impact on BPD may not translate into changes in long-term outcomes. All future neonatal ventilation RCTs should have long-term outcomes rather than BPD as their primary outcome if they are to impact on clinical practice.
A Model Analysis of Arterial Oxygen Desaturation during Apnea in Preterm Infants
Scott A. Sands, BA Edwards, VJ Kelly, MR Davidson, MH Wilkinson, PJ Berger
PLoS Comput Biol 5(12): e1000588
http://dx.doi.org:/10.1371/journal.pcbi.1000588
Rapid arterial O2 desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O2 desaturation during apnea (_SSaO2 ) is complicated by the non-linear O2 dissociation curve, falling pulmonary O2 uptake, and by the fact that O2 desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O2 consumption accelerates _SSaO2 throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar PO2 causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates _SSaO2 during stage 1, and finally, total blood O2 capacity (blood volume and hemoglobin content) alone determines _SSaO2 during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.
A novel approach to study oxidative stress in neonatal respiratory distress syndrome
Reena Negi, D Pande, K Karki, A Kumar, RS Khanna, HD Khanna
BBA Clinical 3 (2015) 65–69
http://dx.doi.org/10.1016/j.bbacli.2014.12.001
Oxidative stress is an imbalance between the systemic manifestation of reactive oxygen species and a biological system’s ability to readily detoxify the reactive intermediates or to repair the resulting damage. It is a physiological event in the fetal-to-neonatal transition, which is actually a great stress to the fetus. These physiological changes and processes greatly increase the production of free radicals, which must be controlled by the antioxidant defense system, the maturation of which follows the course of the gestation. This could lead to several functional alterations with important repercussions for the infants. Adequately mature and healthy infants are able to tolerate this drastic change in the oxygen concentration. A problem occurs when the intrauterine development is incomplete or abnormal. Preterm or intrauterine growth retarded (IUGR) and low birth weight neonates are typically of this kind. An oxidant/antioxidant imbalance in infants is implicated in the pathogenesis of the major complications of prematurity including respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), chronic lung disease, retinopathy of prematurity and intraventricular hemorrhage (IVH).
Background: Respiratory distress syndrome of the neonate (neonatal RDS) is still an important problem in treatment of preterm infants. It is accompanied by inflammatory processes with free radical generation and oxidative stress. The aim of study was to determine the role of oxidative stress in the development of neonatal RDS. Methods: Markers of oxidative stress and antioxidant activity in umbilical cord blood were studied in infants with neonatal respiratory distress syndrome with reference to healthy newborns. Results: Status of markers of oxidative stress (malondialdehyde, protein carbonyl and 8-hydroxy-2-deoxy guanosine) showed a significant increase with depleted levels of total antioxidant capacity in neonatal RDS when compared to healthy newborns. Conclusion: The study provides convincing evidence of oxidative damage and diminished antioxidant defenses in newborns with RDS. Neonatal RDS is characterized by damage of lipid, protein and DNA, which indicates the augmentation of oxidative stress. General significance: The identification of the potential biomarker of oxidative stress consists of a promising strategy to study the pathophysiology of neonatal RDS.
Neonatal respiratory distress syndrome represents the major lung complications of newborn babies. Preterm neonates suffer from respiratory distress syndrome (RDS) due to immature lungs and require assisted ventilation with high concentrations of oxygen. The pathogenesis of this disorder is based on the rapid formation of the oxygen reactive species, which surpasses the detoxification capacity of antioxidative defense system. The high chemical reactivity of free radical leads to damage to a variety of cellular macro molecules including proteins, lipids and nucleic acid. This results in cell injury and may induce respiratory cell death.
Malondialdehyde (MDA) is one of the final products of polyunsaturated fatty acids peroxidation. The present study showed increased concentration of MDA in neonates with respiratory disorders than that of control in consonance with the reported study.
Anemia, Apnea of Prematurity, and Blood Transfusions
Kelley Zagol, Douglas E. Lake, Brooke Vergales, Marion E. Moorman, et al
J Pediatr 2012;161:417-21
http://dx.doi.org:/10.1016/j.jpeds.2012.02.044
The etiology of apnea of prematurity is multifactorial; however, decreased oxygen carrying capacity may play a role. The respiratory neuronal network in neonates is immature, particularly in those born preterm, as demonstrated by their paradoxical response to hypoxemia. Although adults increase the minute ventilation in response to hypoxemia, newborns have a brief increase in ventilation followed by periodic breathing, respiratory depression, and occasionally cessation of respiratory effort. This phenomenon may be exacerbated by anemia in preterm newborns, where a decreased oxygen carrying capacity may result in decreased oxygen delivery to the central nervous system, a decreased efferent output of the respiratory neuronal network, and an increase in apnea.
Objective Compare the frequency and severity of apneic events in very low birth weight (VLBW) infants before and after blood transfusions using continuous electronic waveform analysis. Study design We continuously collected waveform, heart rate, and oxygen saturation data from patients in all 45 neonatal intensive care unit beds at the University of Virginia for 120 weeks. Central apneas were detected using continuous computer processing of chest impedance, electrocardiographic, and oximetry signals. Apnea was defined as respiratory pauses of >10, >20, and >30 seconds when accompanied by bradycardia (<100 beats per minute) and hypoxemia (<80% oxyhemoglobin saturation as detected by pulse oximetry). Times of packed red blood cell transfusions were determined from bedside charts. Two cohorts were analyzed. In the transfusion cohort, waveforms were analyzed for 3 days before and after the transfusion for all VLBW infants who received a blood transfusion while also breathing spontaneously. Mean apnea rates for the previous 12 hours were quantified and differences for 12 hours before and after transfusion were compared. In the hematocrit cohort, 1453 hematocrit values from all VLBW infants admitted and breathing spontaneously during the time period were retrieved, and the association of hematocrit and apnea in the next 12 hours was tested using logistic regression. Results Sixty-seven infants had 110 blood transfusions during times when complete monitoring data were available. Transfusion was associated with fewer computer-detected apneic events (P < .01). Probability of future apnea occurring within 12 hours increased with decreasing hematocrit values (P < .001). Conclusions Blood transfusions are associated with decreased apnea in VLBW infants, and apneas are less frequent at higher hematocrits.
Bronchopulmonary dysplasia: The earliest and perhaps the longest lasting obstructive lung disease in humans
Silvia Carraro, M Filippone, L Da Dalt, V Ferraro, M Maretti, S Bressan, et al.
Early Human Development 89 (2013) S3–S5
Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy, an umbrella term for a number of different diseases that evolve as a consequence of a neonatal respiratory disorder. BPD is defined as the need for supplemental oxygen for at least 28 days after birth, and its severity is graded according to the respiratory support required at 36 post-menstrual weeks.
BPD was initially described as a chronic respiratory disease occurring in premature infants exposed to mechanical ventilation and oxygen supplementation. This respiratory disease (later named “old BPD”) occurred in relatively large premature newborn and, from a pathological standpoint, it was characterized by intense airway inflammation, disruption of normal pulmonary structures and lung fibrosis.
Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.
We have a limited understanding of the presence and nature of pathological mechanisms in the lung of BPD survivors. The possible role of asthma-like inflammation has been investigated because BPD subjects often present with recurrent wheezing and other symptoms resembling asthma during their childhood and adolescence. But BPD subjects have normal or lower than normal exhaled nitric oxide levels and exhaled air temperatures, whereas they are higher than normal in asthmatic patients.
Of all obstructive lung diseases in humans, BPD has the earliest onset and is possibly the longest lasting. Given its frequent association with other conditions related to preterm birth (e.g. growth retardation, pulmonary hypertension, neurodevelopmental delay, hearing defects, and retinopathy of prematurity), it often warrants a multidisciplinary management.
Effects of Sustained Lung Inflation, a lung recruitment maneuver in primary acute respiratory distress syndrome, in respiratory and cerebral outcomes in preterm infants
Chiara Grasso, Pietro Sciacca, Valentina Giacchi, Caterina Carpinato, et al.
Background: Sustained Lung Inflation (SLI) is a maneuver of lung recruitment in preterm newborns at birth that can facilitate the achieving of larger inflation volumes, leading to the clearance of lung fluid and formation of functional residual capacity (FRC). Aim: To investigate if Sustained Lung Inflation (SLI) reduces the need of invasive procedures and iatrogenic risks. Study design: 78 newborns (gestational age ≤ 34 weeks, weighing ≤ 2000 g) who didn’t breathe adequately at birth and needed to receive SLI in addition to other resuscitation maneuvers (2010 guidelines). Subjects: 78 preterm infants born one after the other in our department of Neonatology of Catania University from 2010 to 2012. Outcome measures: The need of intubation and surfactant, the ventilation required, radiological signs, the incidence of intraventricular hemorrhage (IVH), periventricular leukomalacia, retinopathy in prematurity from III to IV plus grades, bronchopulmonary dysplasia, patent ductus arteriosus, pneumothorax and necrotizing enterocolitis. Results: In the SLI group infants needed less intubation in the delivery room (6% vs 21%; p b 0.01), less invasive mechanical ventilation (14% vs 55%; p ≤ 0.001) and shorter duration of ventilation (9.1 days vs 13.8 days; p ≤ 0.001). There wasn’t any difference for nasal continuous positive airway pressure (82% vs 77%; p = 0.43); but there was less surfactant administration (54% vs 85%; p ≤ 0.001) and more infants received INSURE (40% vs 29%; p=0.17). We didn’t found any differences in the outcomes, except for more mild intraventricular hemorrhage in the SLI group (23% vs 14%; p = 0.15; OR= 1.83). Conclusion: SLI is easier to perform even with a single operator, it reduces the necessity of more complicated maneuvers and surfactant without statistically evident adverse effects.
Long-term respiratory consequences of premature birth at less than 32 weeks of gestation
Anne Greenough
Early Human Development 89 (2013) S25–S27
Chronic respiratory morbidity is a common adverse outcome of very premature birth, particularly in infants who had developed bronchopulmonary dysplasia (BPD). Prematurely born infants who had BPD may require supplementary oxygen at home for many months and affected infants have increased healthcare utilization until school age. Chest radiograph abnormalities are common; computed tomography of the chest gives predictive information in children with ongoing respiratory problems. Readmission to hospital is common, particularly for those who have BPD and suffer respiratory syncytial virus lower respiratory infections (RSV LRTIs). Recurrent respiratory symptoms requiring treatment are common and are associated with evidence of airways obstruction and gas trapping. Pulmonary function improves with increasing age, but children with BPD may have ongoing airflow limitation. Lung function abnormalities may be more severe in those who had RSV LRTIs, although this may partly be explained by worse premorbid lung function. Worryingly, lung function may deteriorate during the first year. Longitudinal studies are required to determine if there is catch up growth.
Long-term pulmonary outcomes of patients with bronchopulmonary dysplasia
Anita Bhandari and Sharon McGrath-Morrow
Seminars in Perinatology 37 (2013)132–137
http://dx.doi.org/10.1053/j.semperi.2013.01.010
Bronchopulmonary dysplasia (BPD) is the commonest cause of chronic lung disease in infancy. The incidence of BPD has remained unchanged despite many advances in neonatal care. BPD starts in the neonatal period but its effects can persist long term. Premature infants with BPD have a greater incidence of hospitalization, and continue to have a greater respiratory morbidity and need for respiratory medications, compared to those without BPD. Lung function abnormalities, especially small airway abnormalities, often persist. Even in the absence of clinical symptoms, BPD survivors have persistent radiological abnormalities and presence of emphysema has been reported on chest computed tomography scans. Concern regarding their exercise tolerance remains. Long-term effects of BPD are still unknown, but given reports of a more rapid decline in lung function and their susceptibility to develop chronic obstructive pulmonary disease phenotype with aging, it is imperative that lung function of survivors of BPD be closely monitored.
Prediction of neonatal respiratory distress syndrome in term pregnancies by assessment of fetal lung volume and pulmonary artery resistance index
Mohamed Laban, GM Mansour, MSE Elsafty, AS Hassanin, SS EzzElarab
International Journal of Gynecology and Obstetrics 128 (2015) 246–250
http://dx.doi.org/10.1016/j.ijgo.2014.09.018
Objective: To develop reference cutoff values for mean fetal lung volume (FLV) and pulmonary artery resistance index (PA-RI) for prediction of neonatal respiratory distress syndrome (RDS) in low-risk term pregnancies. Methods: As part of a cross-sectional study, women aged 20–35 years were enrolled and admitted to a tertiary hospital in Cairo, Egypt, for elective repeat cesarean at 37–40 weeks of pregnancy between January 1, 2012, and July 31, 2013. FLV was calculated by virtual organ computer-aided analysis, and PA-RI was measured by Doppler ultrasonography before delivery. Results: A total of 80 women were enrolled. Neonatal RDS developed in 11 (13.8%) of the 80 newborns. Compared with neonates with RDS, healthy neonates had significantly higher FLVs (P b 0.001) and lower PA-RIs (P b 0.001). Neonatal RDS is less likely with FLV of at least 32 cm3 or PA-RI less than or equal to 0.74. Combining these two measures improved the accuracy of prediction. Conclusion: The use of either FLV or PA-RI predicted neonatal RDS. The predictive value increased when these two measures were combined
Pulmonary surfactant – a front line of lung host defense, 2003 JCI0318650.f2
Pulmonary hypertension in bronchopulmonary dysplasia
Sara K.Berkelhamer, Karen K.Mestan, and Robin H. Steinhorn
Pulmonary hypertension (PH) is a common complication of neonatal respiratory diseases, including bronchopulmonary dysplasia (BPD), and recent studies have increased aware- ness that PH worsens the clinical course, morbidity and mortality of BPD. Recent evidence indicates that up to 18% of all extremely low-birth-weight infants will develop some degree of PH during their hospitalization, and the incidence rises to 25–40% of the infants with established BPD. Risk factors are not yet well understood, but new evidence shows that fetal growth restriction is a significant predictor of PH. Echocardiography remains the primary method for evaluation of BPD-associated PH, and the development of standardized screening timelines and techniques for identification of infants with BPD-associated PH remains an important ongoing topic of investigation. The use of pulmonary vasodilator medications, such as nitric oxide, sildenafil, and others, in the BPD population is steadily growing, but additional studies are needed regarding their long-term safety and efficacy.
An update on pharmacologic approaches to bronchopulmonary dysplasia
Sailaja Ghanta, Kristen Tropea Leeman, and Helen Christou
Bronchopulmonary dysplasia (BPD) is the most prevalent long-term morbidity in surviving extremely preterm infants and is linked to increased risk of reactive airways disease, pulmonary hypertension, post-neonatal mortality, and adverse neurodevelopmental outcomes. BPD affects approximately 20% of premature newborns, and up to 60% of premature infants born before completing 26 weeks of gestation. It is characterized by the need for assisted ventilation and/or supplemental oxygen at 36 weeks postmenstrual age. Approaches to prevention and treatment of BPD have evolved with improved understanding of its pathogenesis. This review will focus on recent advancements and detail current research in pharmacotherapy for BPD. The evidence for both current and potential future experimental therapies will be reviewed in detail. As our understanding of the complex and multifactorial pathophysiology of BPD changes, research into these current and future approaches must continue to evolve.
Methylxanthines
Diuretics and bronchodilators
Macrolide antibiotics
Recombinant human Clara cell 10-kilodalton protein(rhCC10)
Leukotriene receptor antagonist
Pulmonary vasodilators
Skeletal and Muscle
Skeletal Stem Cells in Space and Time
Moustapha Kassem and Paolo Bianco
Cell Jan 15, 2015; 160: 17-19
http://dx.doi.org/10.1016/j.cell.2014.12.034
The nature, biological characteristics, and contribution to organ physiology of skeletal stem cells are not completely determined. Chan et al. and Worthley et al. demonstrate that a stem cell for skeletal tissues, and a system of more restricted, downstream progenitors, can be identified in mice and demonstrate its role in skeletal tissue maintenance and regeneration.
The groundbreaking concept that bone, cartilage, marrow adipocytes, and hematopoiesis-supporting stroma could originate from a common progenitor and putative stem cell was surprising at the time when it was formulated (Owen and Friedenstein, 1988). The putative stem cell, nonhematopoietic in nature, would be found in the postnatal bone marrow stroma, generate tissues previously thought of as foreign to each other, and support the turnover of tissues and organs that self-renew at a much slower rate compared to other tissues associated with stem cells (blood, epithelia). This concept also connected bone and bone marrow as parts of a single-organ system, implying their functional interplay. For many years, the evidence underpinning the concept has been incomplete.
While multipotency of stromal progenitors has been demonstrated by in vivo transplantation experiments, self-renewal, the defining property of a stem cell, has not been easily demonstrated until recently in humans (Sacchetti et al., 2007) and mice (Mendez-Ferrer et al., 2010). Meanwhile, a confusing and plethoric terminology has been introduced into the literature, which diverted and confounded the search for a skeletal stem cell and its physiological significance (Bianco et al., 2013).
Two studies in this issue of Cell (Chan et al., 2015; Worthley et al., 2015), using a combination of rigorous single-cell analyses and lineage tracing technologies, mark significant steps toward rectifying the course of skeletal stem cell discovery by making several important points, within and beyond skeletal physiology.
First, a stem cell for skeletal tissues, and a system of more restricted, downstream progenitors can in fact be identified and linked to defined phenotype(s) in the mouse. The system is framed conceptually, and approached experimentally, similar to the hematopoietic system.
Second, based on its assayable functions and potential, the stem cell at the top of the hierarchy is defined as a skeletal stem cell (SSC). As noted earlier (Sacchetti et al., 2007) (Bianco et al., 2013), this term clarifies, well beyond semantics, that the range of tissues that the self-renewing stromal progenitor (originally referred to as an ‘‘osteogenic’’ or ‘‘stromal’’ stem cell) (Owen and Friedenstein, 1988) can actually generate in vivo, overlaps with the range of tissues that make up the skeleton.
Third, these cells are spatially restricted, local residents of the bone/bone marrow organ. The systemic circulation is not a sizable contributor to their recruitment to locally deployed functions.
Fourth, a native skeletogenic potential is inherent to the system of progenitor/ stem cells found in the skeleton, and internally regulated by bone morphogenetic protein (BMP) signaling. This is reflected in the expression of regulators and antagonists of BMP signaling within the system, highlighting potential feedback mechanisms modulating expansion or quiescence of specific cell compartments.
Fifth, in cells isolated from other tissues, an assayable skeletogenic potential is not inherent: it can only be induced de novo by BMP reprogramming. These two studies (Chan et al., 2015, Worthley et al., 2015) corroborate the classical concept of ‘‘determined’’ and ‘‘inducible’’ skeletal progenitors (Owen and Friedenstein, 1988): the former residing in the skeleton, the latter found in nonskeletal tissues; the former capable of generating skeletal tissues, in vivo and spontaneously, the latter requiring reprogramming signals in order to acquire a skeletogenic capacity; the former operating in physiological bone formation, the latter in unwanted, ectopic bone formation in diseases such as fibrodysplasia ossificans progressiva.
To optimize our ability to obtain specific skeletal tissues for medical application, the study by Chan et al. offers a glimpse of another facet of the biology of SSC lineages and progenitors. Chan et al. show that a homogeneous cell population inherently committed to chondrogenesis can alter its output to generate bone if cotransplanted with multipotent progenitors. Conversely, osteogenic cells can be shifted to a chondrogenic fate by blockade of vascular endothelial growth factor receptor, consistent with the avascular and hypoxic milieu of cartilage. This has two important implications:
commitment is flexible in the system;
the choir is as important as the soloist and can modulate the solo tune.
Reversibility and population behavior thus emerge as two features that may be characteristic, albeit not unique, of the stromal system, resonating with conceptually comparable evidence in the human system.
The two studies by Chan et al. and Worthely et al. emphasize the relevance not only of their new data, but also of a proper concept of a skeletal stem cell per se, for proper clinical use. Confusion arising from improper conceptualization of skeletal stem cells has markedly limited clinical development of skeletal stem cell biology.
Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential
Daniel L. Worthley, Michael Churchill, Jocelyn T. Compton, Yagnesh Tailor, et al.
Cell, Jan 15, 2015; 160: 269–284
The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).
Identification and Specification of the Mouse Skeletal Stem Cell
Charles K.F. Chan, Eun Young Seo, James Y. Chen, David Lo, A McArdle, et al.
How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.
Bone mesenchymal development
The bone-remodeling cycle
Nuclear receptor modulation – Role of coregulators in selective estrogen receptor modulator (SERM) actions
Qin Feng, Bert W. O’Malley
Steroids 90 (2014) 39–43
http://dx.doi.org/10.1016/j.steroids.2014.06.008
Selective estrogen receptor modulators (SERMs) are a class of small-molecule chemical compounds that bind to estrogen receptor (ER) ligand binding domain (LBD) with high affinity and selectively modulate ER transcriptional activity in a cell- and tissue-dependent manner. The prototype of SERMs is tamoxifen, which has agonist activity in bone, but has antagonist activity in breast. Tamoxifen can reduce the risk of breast cancer and, at same time, prevent osteoporosis in postmenopausal women. Tamoxifen is widely prescribed for treatment and prevention of breast cancer. Mechanistically the activity of SERMs is determined by the selective recruitment of coactivators and corepressors in different cell types and tissues. Therefore, understanding the coregulator function is the key to understanding the tissue selective activity of SERMs.
Hematopoietic Stem Cell Arrival Triggers Dynamic Remodeling of the Perivascular Niche
Owen J. Tamplin, Ellen M. Durand, Logan A. Carr, Sarah J. Childs, et al.
Hematopoietic stem and progenitor cells (HSPCs) can reconstitute and sustain the entire blood system. We generated a highly specific transgenic reporter of HSPCs in zebrafish. This allowed us to perform high resolution live imaging on endogenous HSPCs not currently possible in mammalian bone marrow. Using this system, we have uncovered distinct interactions between single HSPCs and their niche. When an HSPC arrives in the perivascular niche, a group of endothelial cells remodel to form a surrounding pocket. This structure appears conserved in mouse fetal liver. Correlative light and electron microscopy revealed that endothelial cells surround a single HSPC attached to a single mesenchymal stromal cell. Live imaging showed that mesenchymal stromal cells anchor HSPCs and orient their divisions. A chemical genetic screen found that the compound lycorine promotes HSPC-niche interactions during development and ultimately expands the stem cell pool into adulthood. Our studies provide evidence for dynamic niche interactions upon stem cell colonization.
Neonatal anemia
Sanjay Aher, Kedar Malwatkar, Sandeep Kadam
Seminars in Fetal & Neonatal Medicine (2008) 13, 239e247
Neonatal anemia and the need for red blood cell (RBC) transfusions are very common in neonatal intensive care units. Neonatal anemia can be due to blood loss, decreased RBC production, or increased destruction of erythrocytes. Physiologic anemia of the newborn and anemia of prematurity are the two most common causes of anemia in neonates. Phlebotomy losses result in much of the anemia seen in extremely low birthweight infants (ELBW). Accepting a lower threshold level for transfusion in ELBW infants can prevent these infants being exposed to multiple donors.
Management of anemia in the newborn
Naomi L.C. Luban
Early Human Development (2008) 84, 493–498
Red blood cell (RBC) transfusions are administered to neonates and premature infants using poorly defined indications that may result in unintentional adverse consequences. Blood products are often manipulated to limit potential adverse events, and meet the unique needs of neonates with specific diagnoses. Selection of RBCs for small volume (5–20 mL/kg) transfusions and for massive transfusion, defined as extracorporeal bypass and exchange transfusions, are of particular concern to neonatologists. Mechanisms and therapeutic treatments to avoid transfusion are another area of significant investigation. RBCs collected in anticoagulant additive solutions and administered in small aliquots to neonates over the shelf life of the product can decrease donor exposure and has supplanted the use of fresh RBCs where each transfusion resulted in a donor exposure. The safety of this practice has been documented and procedures established to aid transfusion services in ensuring that these products are available. Less well established are the indications for transfusion in this population; hemoglobin or hematocrit alone are insufficient indications unless clinical criteria (e.g. oxygen desaturation, apnea and bradycardia, poor weight gain) also augment the justification to transfuse. Comorbidities increase oxygen consumption demands in these infants and include bronchopulmonary dysplasia, rapid growth and cardiac dysfunction. Noninvasive methods or assays have been developed to measure tissue oxygenation; however, a true measure of peripheral oxygen offloading is needed to improve transfusion practice and determine the value of recombinant products that stimulate erythropoiesis. The development of such noninvasive methods is especially important since randomized, controlled clinical trials to support specific practices are often lacking, due at least in part, to the difficulty of performing such studies in tiny infants.
The Effect of Blood Transfusion on the Hemoglobin Oxygen Dissociation Curve of Very Early Preterm Infants During the First Week of Life
Virginie De HaUeux, Anita Truttmann, Carmen Gagnon, and Harry Bard
Seminars in Perinatology, 2002; 26(6): 411-415
http://dx.doi.org:/10.1053/sper.2002.37313
This study was conducted during the first week of life to determine the changes in Ps0 (PO2 required to achieve a saturation of 50% at pH 7.4 and 37~ and the proportions of fetal hemoglobin (I-IbF) and adult hemoglobin (HbA) prior to and after transfusion in very early preterm infants. Eleven infants with a gestational age <–27 weeks have been included in study. The hemoglobin dissociation curve and the Ps0 was determined by Hemox-analyser. Liquid chromatography was also performed to determine the proportions of HbF and HbA. The mean gestational age of the 11 infants was 25.1 weeks (-+1 weeks) and their mean birth weight was 736 g (-+125 g). They received 26.9 mL/kg of packed red cells. The mean Ps0 prior and after transfusion was 18.5 +- 0.8 and 21.0 + 1 mm Hg (P = .0003) while the mean percentage of HbF was 92.9 -+ 1.1 and 42.6 -+ 5.7%, respectively. The data of this study show a decrease of hemoglobin oxygen affinity as a result of blood transfusion in very early preterm infants prone to O 2 toxicity. The shift in HbO 2 curve after transfusion should be taken into consideration when oxygen therapy is being regulated for these infants.
Effect of neonatal hemoglobin concentration on long-term outcome of infants affected by fetomaternal hemorrhage
Mizuho Kadooka, H Katob, A Kato, S Ibara, H Minakami, Yuko Maruyama
Background: Fetomaternal hemorrhage (FMH) can cause severe morbidity. However, perinatal risk factors for long-term poor outcome due to FMH have not been extensively studied. Aims: To determine which FMH infants are likely to have neurological sequelae.
Study design: A single-center retrospective observational study. Perinatal factors, including demographic characteristics, Kleihauer–Betke test, blood gas analysis, and neonatal blood hemoglobin concentration ([Hb]), were analyzed in association with long-term outcomes.
Subjects: All 18 neonates referred to a Neonatal Intensive Care Unit of Kagoshima City Hospital and diagnosed with FMH during a 15-year study period. All had a neonatal [Hb] b7.5 g/dL and 15 of 17 neonates tested had Kleihauer–Betke test result N4.0%.
Outcome measures: Poor long-term outcome was defined as any of the following determined at 12 month old or more: cerebral palsy, mental retardation, attention deficit/hyperactivity disorder, and epilepsy.
Results: Nine of the 18 neonates exhibited poor outcomes. Among demographic characteristics and blood variables compared between two groups with poor and favorable outcomes, significant differences were observed in [Hb] (3.6 ± 1.4 vs. 5.4 ± 1.1 g/dL, P = 0.01), pH (7.09 ± 0.11 vs. 7.25 ± 0.13, P = 0.02) and base deficits (17.5 ± 5.4 vs. 10.4 ± 6.0 mmol/L, P = 0.02) in neonatal blood, and a number of infants with [Hb] ≤ 4.5 g/dL (78%[7/9] vs. 22%[2/9], P= 0.03), respectively. The base deficit in neonatal arterial blood increased significantly with decreasing neonatal [Hb].
Conclusions: Severe anemia causing severe base deficit is associated with neurological sequelae in FMH infants
Clinical and hematological presentation among Indian patients with common hemoglobin variants
Khushnooma Italia, Dipti Upadhye, Pooja Dabke, Harshada Kangane, et al.
Clinica Chimica Acta 431 (2014) 46–51
http://dx.doi.org/10.1016/j.cca.2014.01.028
Background: Co-inheritance of structural hemoglobin variants like HbS, HbD Punjab and HbE can lead to a variable clinical presentation and only few cases have been described so far in the Indian population.
Methods: We present the varied clinical and hematological presentation of 22 cases (HbSD Punjab disease-15, HbSE disease-4, HbD Punjab E disease-3) referred to us for diagnosis.
Results: Two of the 15 HbSDPunjab disease patients had moderate crisis, one presented with mild hemolytic anemia; however, the other 12 patients had a severe clinical presentation with frequent blood transfusion requirements, vaso occlusive crisis, avascular necrosis of the femur and febrile illness. The 4 HbSE disease patients had a mild to moderate presentation. Two of the 3 HbD Punjab E patients were asymptomatic with one patient’s sibling having a mild presentation. The hemoglobin levels of the HbSD Punjab disease patients ranged from 2.3 to 8.5 g/dl and MCV from 76.3 to 111.6 fl. The hemoglobin levels of the HbD Punjab E and HbSE patients ranged from 10.8 to 11.9 and 9.8 to 10.0 g/dl whereas MCV ranged from 67.1 to 78.2 and 74.5 to 76.0 fl respectively.
Conclusions: HbSD Punjab disease patients should be identified during newborn screening programs and managed in a way similar to sickle cell disease. Couple at risk of having HbSD Punjab disease children may be given the option of prenatal diagnosis in subsequent pregnancies.
Sickle cell anemia is the most common hemoglobinopathy seen across the world. It is caused by a point mutation in the 6th codon of the beta (β) globin gene leading to the substitution of the amino acid glutamic acid to valine. The sickle gene is frequently seen in Africa, some Mediterranean countries, India, Middle East—Saudi Arabia and North America. In India the prevalence of hemoglobin S (HbS) carriers varies from 2 to 40% among different population groups and HbS is mainly seen among the scheduled tribe, scheduled caste and other backward class populations in the western, central and parts of eastern and southern India. Sickle cell anemia has a variable clinical presentation in India with the most severe clinical presentation seen in central India whereas patients in the western region show a mild to moderate clinical presentation.
Hemoglobin D Punjab (HbD Punjab) (also known as HbD Los-Angeles, HbD Portugal, HbD North Carolina, D Oak Ridge and D Chicago) is another hemoglobin variant due to a point mutation in codon 121 of the β globin gene resulting in the substitution of the amino acid glutamic acid to glycine. It is a widely distributed hemoglobin with a relatively low prevalence of 0.86% in the Indo-Pak subcontinent, 1–3% in north-western India, 1–3% in the Black population in the Caribbean and North America and has also been reported among the English. It accounts for 55.6% of all the Hb variants seen in the Xenjiang province of China.
Hemoglobin E (HbE) is the most common abnormal hemoglobin in Southeast Asia. In India, the frequency ranges from 4% to 51% in the north eastern region and 3% to 4% in West Bengal in the east. The HbE mutation (β26 GAG→AAG) creates an alternative splice site and the βE chain is insufficiently synthesized, hence the phenotype of this disorder is that of a mild form of β thalassemia.
Though these 3 structural variants are prevalent in different regions of India, their interaction is increasingly seen in all states of the country due to migration of people to different regions for a better livelihood. There are very few reports on interaction of these commonly seen Hb variants and the phenotypic–genotypic presentation of these cases is important for genetic counseling and management.
HbF of patients with HbSD Punjab disease with variable clinical severity. The HbF values of 4 patients are not included as they were post blood transfusion
The genotypes of the patients were confirmed by restriction enzyme digestion and ARMS (Fig). Patients 1 to 15 were characterized as compound heterozygous for HbS and HbD Punjab whereas patients 16 to 19 were characterized as compound heterozygous for HbS and HbE. Patient nos. 20 to 22 were characterized as compound heterozygous for HbE and HbD Punjab.
Molecular characterization of HbS and HbDPunjab by restriction enzyme digestion and of HbE by ARMS.
The 3 common β globin gene variants of hemoglobin, HbS, HbE and HbD Punjab are commonly seen in India, with HbS having a high prevalence in the central belt and some parts of western, eastern and southern India, HbE in the eastern and north eastern region whereas HbD is mostly seen in the north western part of India. These hemoglobin variants have been reported in different population groups. However, with migration and intermixing of the different populations from different geographic regions, occasional cases of HbSD Punjab and HbSE are being reported. There are several HbD variants like HbD Punjab, HbD Iran, HbD Ibadan. However, of these only HbD Punjab interacts with HbS to form a clinically significant condition as the glutamine residue facilitates polymerization of HbS. HbD Iran and HbD Ibadan are non-interacting and produce benign conditions like the sickle cell trait. The first case of HbSD Punjab disease was a brother and sister considered to have atypical sickle cell disease in 1934. This family was further reinvestigated and reported as the first case of HbD Los Angeles which has the same mutation as the HbD Punjab. Serjeant et al. reported HbD Punjab in an English parent in 6 out of 11 HbSD-Punjab disease cases. This has been suggested to be due to the stationing of nearly 50,000 British troops on the Indian continent for a period of 200 y and the introduction into Britain of their Anglo-Indian children.
HbSD Punjab disease shows a similar pattern to HbS homozygous on alkaline hemoglobin electrophoresis but can be differentiated on acid agar gel electrophoresis and on HPLC. In HbSD Punjab disease cases, the peripheral blood films show anisocytosis, poikilocytosis, target cells and irreversibly sickled cells. Values of HbF and HbA2 are similar to those in sickle homozygous cases. HbSD Punjab disease is characterized by a moderately severe hemolytic anemia.
Twenty-one cases of HbSDPunjab were reported by Serjeant of which 16 were reported by different workers among patients originating from Caucasian, Spanish, Australian, Irish, English, Portuguese, Black, American, Venezuelan, Caribbean, Mexican, Turkish and Jamaican backgrounds. Yavarian et al. 2009 reported a multi centric origin of HbD Punjab which in combination with HbS results in sickle cell disease. Patel et al. 2010 have also reported 12 cases of HbSD Punjab from the Orissa state of eastern India. Majority of these cases were symptomatic, presenting with chronic hemolytic anemia and frequent painful crises.
HbF levels >20% were seen in 4 out of our 11 clinically severe patients of HbSD-Punjab disease with the mean HbF levels of 16.8% in 8 clinically severe patients, while 3 clinically severe patients were post transfused. However, the 3 patients with a mild to moderate clinical presentation showed a mean HbF level of 8.6%. This is in contrast to the relatively milder clinical presentation associated with high HbF seen in patients with sickle cell anemia. This was also reported by Adekile et al. 2010 in 5 cases of HbS-DLos Angeles where high HbF did not ameliorate the severe clinical presentation seen in these patients.
These 15 cases of HbSDPunjab disease give us an overall idea of the severe clinical presentation of the disease in different regions of India. However the HbDPunjabE cases were milder or asymptomatic and the HbSE cases were moderately symptomatic. Since most of the cases of HbSDPunjab disease were clinically severe, it is important to pick up these cases during newborn screening and enroll them into a comprehensive care program with the other sickle cell disease patients with introduction of therapeutic interventions such as penicillin prophylaxis if required and pneumococcal immunization. In fact, 2 of our cases (No. 6 and 7) were identified during newborn screening for sickle cell disorders. The parents can be given information on home care and educated to detect symptoms that may lead to serious medical emergencies. The parents of these patients as well as the couples who are at risk of having a child with HbSDPunjab disease could also be counseled about the option of prenatal diagnosis in subsequent pregnancies. It is thus important to document the clinical and hematological presentation of compound heterozygotes with these common β globin chain variants.
Common Hematologic Problems in the Newborn Nursery
Jon F. Watchko
Pediatr Clin N Am – (2015) xxx-xxx
http://dx.doi.org/10.1016/j.pcl.2014.11.011
Common RBC disorders include hemolytic disease of the newborn, anemia, and polycythemia. Another clinically relevant hematologic issue in neonates to be covered herein is thrombocytopenia. Disorders of white blood cells will not be reviewed.
(1) Early clinical jaundice or rapidly developing hyperbilirubinemia are often signs of hemolysis, the differential diagnosis of which commonly includes immune-mediated disorders, red-cell enzyme deficiencies, and red-cell membrane defects.
(2) Knowledge of the maternal blood type and antibody screen is critical in identifying non-ABO alloantibodies in the maternal serum that may pose a risk for severe hemolytic disease in the newborn.
(3) Moderate to severe thrombocytopenia in an otherwise well-appearing newborn strongly suggests immune-mediated (alloimmune or autoimmune) thrombocytopenia.
Hemolytic conditions in the neonate
1. Immune-mediated (positive direct Coombs test) a. Rhesus blood group: Anti-D, -c, -C, -e, -E, CW, and several others
b. Non-Rhesus blood groups: Kell, Duffy, Kidd, Xg, Lewis, MNS, and others
c. ABO blood group: Anti-A, -B
2. Red blood cell (RBC) enzyme defects
a. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
b. Pyruvate kinase deficiency
c. Others
3. RBC membrane defects
a. Hereditary spherocytosis
b. Elliptocytosis
c. Stomatocytosis
d. Pyknocytosis
e. Others
4. Hemoglobinopathies
a. alpha-thalassemia
b. gamma-thalassemia
Standard maternal antibody screeningAlloantibody Blood Group
D, C, c, E, e, f, CW, V Rhesus
K, k, Kpa, Jsa Kell
Fya, Fyb Duffy
Jka, Jkb Kidd
Xga Xg
Lea, Leb Lewis
S, s, M, N MNS
P1 P
Lub Lutheran
Non-ABO alloantibodies reported to cause moderate to severe hemolytic disease of the newbornWithin Rh system: Anti-D, -c, -C, -Cw, -Cx, -e, -E, -Ew, -ce, -Ces, -Rh29, -Rh32, -Rh42, -f, -G, -Goa, -Bea, -Evans, -Rh17, -Hro, -Hr, -Tar, -Sec, -JAL, -STEM
Outside Rh system: Anti-LW, -K, -k, -Kpa, -Kpb, -Jka, -Jsa, -Jsb, -Ku, -K11, -K22, -Fya, -M, -N, -S, -s, -U, -PP1 pk, -Dib, -Far, -MUT, -En3, -Hut, -Hil, -Vel, -MAM, -JONES, -HJK, -REIT
Red Blood Cell Enzymopathies
G6PD9 and pyruvate kinase (PK) deficiency are the 2 most common red-cell enzyme disorders associated with marked neonatal hyperbilirubinemia. Of these, G6PD deficiency is the more frequently encountered and it remains an important cause of kernicterus worldwide, including the United States, Canada, and the United Kingdom, the prevalence in Western countries a reflection in part of immigration patterns and intermarriage. The risk of kernicterus in G6PD deficiency also relates to the potential for unexpected rapidly developing extreme hyperbilirubinemia in this disorder associated with acute severe hemolysis.
Red Blood Cell Membrane Defects
Establishing a diagnosis of RBC membrane defects is classically based on the development of Coombs-negative hyperbilirubinemia, a positive family history, and abnormal RBC smear, albeit it is often difficult because newborns normally exhibit a marked variation in red-cell membrane size and shape. Spherocytes, however, are not often seen on RBC smears of hematologically normal newborns and this morphologic abnormality, when prominent, may yield a diagnosis of hereditary spherocytosis (HS) in the immediate neonatal period. Given that approximately 75% of families affected with hereditary spherocytosis manifest an autosomal dominant phenotype, a positive family history can often be elicited and provide further support for this diagnosis. More recently, Christensen and Henry highlighted the use of an elevated mean corpuscular hemoglobin concentration (MCHC) (>36.0 g/dL) and/or elevated ratio of MCHC to mean corpuscular volume, the latter they term the “neonatal HS index” (>0.36, likely >0.40) as screening tools for HS. An index of greater than 0.36 had 97% sensitivity, greater than 99% specificity, and greater than 99% negative predictive value for identifying HS in neonates. Christensen and colleagues also provided a concise update of morphologic RBC features that may be helpful in diagnosing this and other underlying hemolytic conditions in newborns.
The diagnosis of HS can be confirmed using the incubated osmotic fragility test when coupled with fetal red-cell controls or eosin-5-maleimide flow cytometry. One must rule out symptomatic ABO hemolytic disease by performing a direct Coombs test, as infants so affected also may manifest prominent micro-spherocytosis. Moreover, HS and symptomatic ABO hemolytic disease can occur in the same infant and result in severe hyperbilirubinemia and anemia. Of other red-cell membrane defects, only hereditary elliptocytosis, stomato-cytosis, and infantile pyknocytosis have been reported to exhibit significant hemolysis in the newborn period. Hereditary elliptocytosis and stomatocytosis are both rare. Infantile pyknocytosis, a transient red-cell membrane abnormality manifesting itself during the first few months of life, is more common.
Risk factors for bilirubin neurotoxicityIsoimmune hemolytic disease
G6PD deficiency
Albumin less than 3.0 g/dL
Data from Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant > or 535 weeks’ gestation: an update with clarifications. Pediatrics 2009; 124:1193–8.
Polycythemia
Polycythemia (venous hematocrit 65%) in seen in infants across a range of conditions associated with active erythropoiesis or passive transfusion.76,77 They include, among others, placental insufficiency, the infant of a diabetic mother, recipient in twin-twin transfusion syndrome, and several aneuploidies, including trisomy. The clinical concern related to polycythemia is the risk for microcirculatory complications of hyperviscosity. However, determining which polycythemic infants are hyperviscous and when to intervene is a challenge.
Metabolic disorders presenting as liver disease
Germaine Pierre, Efstathia Chronopoulou
Paediatrics and Child Health 2013; 23(12): 509-514
The liver is a highly metabolically active organ and many inherited metabolic disorders have hepatic manifestations. The clinical presentation in these patients cannot usually be distinguished from liver disease due to acquired causes like infection, drugs or hematological disorders. Manifestations include acute and chronic liver failure, cholestasis and hepatomegaly. Metabolic causes of acute liver failure in childhood can be as high as 35%. Certain disorders like citrin deficiency and Niemann-Pick C disease may present in infancy with self-limiting cholestasis before presenting in later childhood or adulthood with irreversible disease. This article reviews important details from the history and clinical examination when evaluating the pediatric patient with suspected metabolic disease, the specialist and genetic tests when investigating, and also discusses specific disorders, their clinical course and treatment. The role of liver transplantation is also briefly discussed. Increased awareness of this group of disorders is important as in many cases, early diagnosis leads to early intervention with improved outcome. Diagnosis also allows genetic counselling and future family planning.
Adult liver disorders caused by inborn errors of metabolism: Review and update
Sirisak Chanprasert, Fernando Scaglia
Molecular Genetics and Metabolism 114 (2015) 1–10
Inborn errors of metabolism (IEMs) are a group of genetic diseases that have protean clinical manifestations and can involve several organ systems. The age of onset is highly variable but IEMs afflict mostly the pediatric population. However, in the past decades, the advancement in management and new therapeutic approaches have led to the improvement in IEM patient care. As a result, many patients with IEMs are surviving into adulthood and developing their own set of complications. In addition, some IEMs will present in adulthood. It is important for internists to have the knowledge and be familiar with these conditions because it is predicted that more and more adult patients with IEMs will need continuity of care in the near future. The review will focus on Wilson disease, alpha-1 antitrypsin deficiency, citrin deficiency, and HFE-associated hemochromatosis which are typically found in the adult population. Clinical manifestations and pathophysiology, particularly those that relate to hepatic disease as well as diagnosis and management will be discussed in detail.
Inborn errors of metabolism (IEMs) are a group of genetic diseases characterized by abnormal processing of biochemical reactions, resulting in accumulation of toxic substances that could interfere with normal organ functions, and failure to synthesize essential compounds. IEMs are individually rare, but collectively numerous. The clinical presentations cover a broad spectrum and can involve almost any organ system. The age of onset is highly variable but IEMs afflict mostly the pediatric population.
Wilson disease is an autosomal recessive genetic disorder of copper metabolism. It is characterized by an abnormal accumulation of inorganic copper in various tissues, most notably in the liver and the brain, especially in the basal ganglia. The disease was first described in 1912 by Kinnier Wilson, and affects between 1 in 30,000 and 1 in 100,000 individuals. Clinical features are variable and depend on the extent and the severity of copper deposition. Typically, patients tend to develop hepatic disease at a younger age than the neuropsychiatric manifestations. Individuals withWilson disease eventually succumb to complications of end stage liver disease or become debilitated from neurological problems, if they are left untreated.
The clinical presentations of Wilson disease are varied affecting many organ systems. However, the overwhelming majority of cases display hepatic and neurologic symptoms. In general, patients with hepatic disease present between the first and second decades of life although patients as young as 3 years old or over 50 years old have also been reported. The most common modes of presentations are acute self-limited hepatitis and chronic active hepatitis that are indistinguishable from other hepatic disorders although liver aminotransferases are generally much lower than in autoimmune or viral hepatitis. Acute fulminant hepatic failure is less common but is observed in approximately 3% of all cases of acute liver failure. Symptoms of acute liver failure include jaundice, coagulopathy, and hepatic encephalopathy. Cirrhosis can develop over time and may be clinically silent. Hepatocellular carcinoma (HCC) is rarely associated with Wilson disease, but may occur in the setting of cirrhosis and chronic inflammation.
Copper is an essential element, and is required for the proper functioning of various proteins and enzymes. The total body content of copper in a healthy adult individual is approximately 70–100 mg, while the daily requirements are estimated to be between 1 and 5 mg. Absorption occurs in the small intestine. Copper is taken up to the hepatocytes via the copper transporter hTR1. Once inside the cell, copper is bound to various proteins including metallothionein and glutathione, however, it is the metal chaperone, ATOX1 that helps direct copper to the ATP7B protein for intracellular transport and excretion. At the steady state, copper will be bound to ATP7B and is then incorporated to ceruloplasmin and secreted into the systemic circulation. When the cellular copper concentration arises, ATP7B protein will be redistributed from the trans-Golgi network to the prelysosomal vesicles facilitating copper excretion into the bile. The molecular defects in ATP7B lead to a reduction of copper excretion. Excess copper is accumulated in the liver causing tissue injury. The rate of accumulation of copper varies among individuals, and it may depend on other factors such as alcohol consumption, or viral hepatitis infections. If the liver damage is not severe, patients will accumulate copper in various tissues including the brain, the kidney, the eyes, and the musculoskeletal system leading to clinical disease. A failure of copper to incorporate into ceruloplasmin leads to secretion of the unsteady protein that has a shorter half-life, resulting in the reduced concentrations of ceruloplasmin seen in most patients with Wilson disease.
Wilson disease used to be a progressive fatal condition during the first half of the 20th century because there was no effective treatment available at that time. Penicillamine was the first pharmacologic agent introduced in 1956 for treating this condition. Penicillamine is a sulfhydryl-bearing amino acid cysteine doubly substituted with methyl groups. This drug acts as a chelating agent that promotes the urinary excretion of copper. It is rapidly absorbed in the gastrointestinal track, and over 80% of circulating penicillamine is excreted via the kidneys. Although it is very effective, approximately 10%–50% of Wilson disease patients with neuropsychiatric presentations may experience worsening of their symptoms, and often times the worsening symptoms may not be reversible.
Alpha1-antitrypsin deficiency
Alpha1-antitrypsin deficiency (AATD) is one of the most common genetic liver diseases in children and adults, affecting 1 in 2000 to 1 in 3000 live births worldwide. It is transmitted in an autosomal co-dominant fashion with variable expressivity. Alpha1 antitrypsin (A1AT) is a member of the serine protease inhibitor (SERPIN) family. Its function is to counteract the proteolytic effect of neutrophil elastase and other neutrophil proteases. Mutations in the SERPINA1, the gene encoding A1AT, result in changes in the protein structure with the PiZZ phenotype being the most common cause of liver and lung disease-associated AATDs. Although, it classically causes early onset chronic obstructive pulmonary disease (COPD) in adults, liver disease characterized by chronic inflammation, hepatic fibrosis, and cirrhosis is not uncommon in the adult population. Decreased plasma concentration of A1AT predisposes lung tissue to be more susceptible to injury from protease enzymes. However, the underlying mechanism of liver injury is different, and is believed to be caused by accumulation of polymerized mutant A1AT in the hepatocyte endoplasmic reticulum (ER). Currently, there is no specific treatment for liver disease-associated AATD, but A1AT augmentation therapy is available for patients affected with pulmonary involvement.
A1AT is a single-chain, 52-kDa polypeptide of approximately 394 amino acids [56]. It is synthesized in the liver, circulates in the plasma, and functions as an inhibitor of neutrophil elastase and other proteases such as cathepsin G, and proteinase 3. A1AT has a globular shape composed of two central β sheets surrounded by a small β sheet and nine α helices. The pathophysiology underlying liver disease is thought to be a toxic gain-of-function mutation associated with the PiZZ phenotypes. This hypothesis has been supported by the fact that null alleles which produce no detectable plasma A1AT, are not associated with liver disease. In addition, the transgenic mouse model of AATD PiZZ developed periodic acid-Schiff-positive diastase-resistant intrahepatic globule early in life similar to AATD patients. The PiZZ phenotype results in the blockade of the final processing of A1AT in the liver, as only 15% of the A1AT reaches the circulation whereas 85% of non-secreted protein is accumulated in the hepatocytes.
Citrin deficiency
Citrin deficiency is a relatively newly-defined autosomal recessive disease. It encompasses two different sub-groups of patients, neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult onset citrullinemia type 2 (CTLN 2).
AGC2 exports aspartate out of the mitochondrial matrix in exchange for glutamate and a proton. Thus, this protein has an important role in ureagenesis and gluconeogenesis. In CTLN2, a defect in this protein is believed to limit the supply of aspartate for the formation of argininosuccinate in the cytosol resulting in impairment of ureagenesis. Interestingly, the mouse model of citrin deficiency (Ctrn−/−) fails to develop symptoms of CTLN2 suggesting that the mitochondrial aspartate is not the only source of ureagenesis. However, it should be noted that the rodent liver expresses higher glycerol-phosphate shuttle activity than the human counterpart. With the intact glycerol-phosphate dehydrogenase, it can compensate for the deficiency of AGC2, as demonstrated by the AGC2 and glycerol-phosphate dehydrogenase double knock-out mice that exhibit similar features to those observed in human CTLN2.
HFE-associated hemochromatosis
HFE-associated hemochromatosis is an inborn error of iron metabolism characterized by excessive iron storage resulting in tissue and organ damage. It is the most common autosomal recessive disorder in the Caucasian population, affecting 0.3%–0.5% of individuals of Northern European descent. The term “hemochromatosis” was coined in 1889 by the German pathologist Friedrich Daniel Von Recklinghausen, who described it as bronze stain of organs caused by a blood borne pigment.
The classic clinical triad of cirrhosis, diabetes, and bronze skin pigmentation is rarely observed nowadays given the early recognition, diagnosis, and treatment of this condition. The most common presenting symptoms are nonspecific including weakness, lethargy, and arthralgia.
The liver is a major site of iron storage in healthy individuals and as such it is the organ that is universally affected in HFE-associated hemochromatosis. Elevation of liver aminotransferases indicative of hepatocyte injury is the most common mode of presentation and it can be indistinguishable from other causes of hepatitis. Approximately 15%–40% of patients with HFE-associated hemochromatosis have other liver conditions, including chronic viral hepatitis B or C infection, nonalcoholic fatty liver disease, and alcoholic liver disease.
The liver in haemochromatosis
Rune J. Ulvik
Journal of Trace Elements in Medicine and Biology xxx (2014) xxx–xxx
http://dx.doi.org/10.1016/j.jtemb.2014.08.005
The review deals with genetic, regulatory and clinical aspects of iron homeostasis and hereditary hemochromatosis. Hemochromatosis was first described in the second half of the 19th century as a clinical entity characterized by excessive iron overload in the liver. Later, increased absorption of iron from the diet was identified as the pathophysiological hallmark. In the 1970s genetic evidence emerged supporting the apparent inheritable feature of the disease. And finally in 1996 a new “hemochromato-sis gene” called HFE was described which was mutated in about 85% of the patients. From the year2000 onward remarkable progress was made in revealing the complex molecular regulation of iron trafficking in the human body and its disturbance in hemochromatosis. The discovery of hepcidin and ferroportin and their interaction in regulating the release of iron from enterocytes and macrophages to plasma were important milestones. The discovery of new, rare variants of non-HFE-hemochromatosis was explained by mutations in the multicomponent signal transduction pathway controlling hepcidin transcription. Inhibited transcription induced by the altered function of mutated gene products, results in low plasma levels of hepcidin which facilitate entry of iron from enterocytes into plasma. In time this leads to progressive accumulation of iron and subsequently development of disease in the liver and other parenchymatous organs. Being the major site of excess iron storage and hepcidin synthesis the liver is a cornerstone in maintaining normal systemic iron homeostasis. Its central pathophysiological role in HFE-hemochromatosis with downgraded hepcidin synthesis, was recently shown by the finding that liver transplantation normalized the hepcidin levels in plasma and there was no sign of iron accumulation in the new liver.
Decoding the enigma of necrotizing enterocolitis in premature infants
Roberto Murgas Torrazza, Nan Li, Josef Neu
Pathophysiology 21 (2014) 21–27
http://dx.doi.org/10.1016/j.pathophys.2013.11.011
Necrotizing enterocolitis (NEC) is an enigmatic disease that affects primarily premature infants. It often occurs suddenly and when it occurs, treatment attempts at treatment often fail and results in death. If the infant survives, there is a significant risk of long term sequelae including neurodevelopmental delays. The pathophysiology of NEC is poorly understood and thus prevention has been difficult. In this review, we will provide an overview of why progress may be slow in our understanding of this disease, provide a brief review diagnosis, treatment and some of the current concepts about the pathophysiology of this disease.
Necrotizing enterocolitis (NEC) has been reported since special care units began to house preterm infants .With the advent of modern neonatal intensive care approximately 40 years ago, the occurrence and recognition of the disease markedly increased. It is currently the most common and deadly gastro-intestinal illness seen in preterm infants. Despite major efforts to better understand, treat and prevent this devastating disease, little if any progress has been made during these 4 decades. Underlying this lack of progress is the fact that what is termed “NEC” is likely more than one disease, or mimicked by other diseases, each with a different etiopathogenesis.
Human gut microbiome
Term or near term infants with “NEC” when compared to matched controls usually have occurrence of their disease in the first week after birth, have a significantly higher frequency of prolonged rupture of membranes, chorio-amnionitis, Apgar score <7 at 1 and 5 min, respiratory problems, congenital heart disease, hypoglycemia, and exchange transfusions. When a “NEC” like illness presents in term or near term infants, it should be noted that these are likely to be distinct in pathogenesis than the most common form of NEC and should be differentiated as such.
The infants who suffer primary ischemic necrosis are term or near term infants (although this can occur in preterms) who have concomitant congenital heart disease, often related to poor left ventricular output or obstruction. Other factors that have been associated with primary ischemia are maternal cocaine use, hyperviscosity caused by polycythemia or a severe antecedent hypoxic–ischemic event. Whether the dis-ease entity that results from this should be termed NEC can be debated on historical grounds, but the etiology is clearly different from the NEC seen in most preterm infants.
The pathogenesis of NEC is uncertain, and the etiology seems to be multifactorial. The “classic” form of NEC is highly associated with prematurity; intestinal barrier immaturity, immature immune response, and an immature regulation of intestinal blood flow (Fig.). Although genetics appears to play a role, the environment, especially a dysbiotic intestinal microbiota acting in concert with host immaturities predisposes the preterm infant to disruption of the intestinal epithelia, increased permeability of tight junctions, and release of inflammatory mediators that leads to intestinal mucosa injury and therefore development of necrotizing enterocolitis.
NEC is a multifactorial disease
What causes NEC? NEC is a multifactorial disease with an interaction of several etiophathologies
It is clear from this review that there are several entities that have been described as NEC. What is also clear is that despite having some overlap in the final parts of the pathophysiologic cascade that lead to necrosis, the disease that is most commonly seen in the preterm infant is likely to have an origin that differs markedly from that seen in term infants with congenital heart disease or severe hypoxic–ischemic injury. Thus, epidemiologic studies will need to differentiate these entities, if the aim is to dissect common features that are most highly associated with development of the disease. At this juncture, we areleft with more of a population based preventative approach, where the use of human milk, evidence based feeding guide-lines, considerations for microbial therapy once these are proved safe and effective and approved as such by regulatory authorities, and perhaps even measures that prevent prematurity will have a major impact on this devastating disease.
Influenced by the microbiota, intestinal epithelial cells (IECs) elaborate cytokines
Influenced by the microbiota, intestinal epithelial cells (IECs) elaborate cytokines, including thymic stromal lymphoprotein (TSLP), transforming growthfactor (TGF), and interleukin-10 (IL-10), that can influence pro-inflammatory cytokine production by dendritic cells (DC) and macrophages present in the laminapropria (GALT) and Peyer’s patches. Signals from commensal organisms may influence tissue-specific functions, resulting in T-cell expansion and regulation of the numbers of Th-1,
Th-2, and Th-3 cells. Also modulated by the microbiota, other IEC derived factors, including APRIL (a proliferation-inducing ligand),B-cell activating factor (BAFF), secretory leukocyte peptidase inhibitor (SLPI), prostaglandin E2(PGE2), and other metabolites, directly regulate functions ofboth antigen presenting cells and lymphocytes in the intestinal ecosystem. NK: natural killer cell; LN: lymph node; DC: dendritic cells.Modified from R. Sharma, C. Young, M. Mshvildadze, J. Neu, Intestinal microbiota does it play a role in diseases of the neonate? NeoReviews 10 (4) (2009)e166, with permission
Cross-talk between monocyte.macrophage cells and T.NK lymphocytes
Current Issues in the Management of Necrotizing Enterocolitis
Marion C. W. Henry and R. Lawrence Moss
http://dx.doi.org:/10.1053/j.semperi.2004.03.010
Necrotizing enterocolitis is almost exclusively a disease of prematurity, with 90% of all cases occurring in premature infants and 90% of those infants weighing less than 2000 g. Prematurity is the only risk factor for necrotizing enterocolitis consistently identified in case control studies and the disease is rare in countries where prematurity is uncommon such as Japan and Sweden. When necrotizing enterocolitis does occur in full-term infants, it appears to by a somewhat different disease, typically associated with some predisposing condition.
NEC occurs in one to three in 1,000 live births and most commonly affects babies born between 30-32 weeks. It is most often diagnosed during the second week of life and occurs more often in previously fed infants. The mortality from NEC has been cited as 10% to 50% of all NEC cases. Surgical mortality has decreased over the last several decades from 70% to between 20 and 50%. The incremental cost per case of acute hospital care is estimated at $74 to 186 thousand compared to age matched controls, not including additional costs of long term care for the infants’ with lifelong morbidity. Survivors may develop short bowel syndrome, recurrent bouts of catheter-related sepsis, malabsorption, malnutrition, and TPN induced liver failure.
Although extensive research concerning the pathophysiology of necrotizing enterocolitis has occurred, a complete understanding has not been fully elucidated. The classic histologic finding is coagulation necrosis; present in over 90% of specimens. This finding suggests the importance of ischemia in the pathogenesis of NEC. Inflammation and bacterial overgrowth also are present. These findings support the assumptions by Kosloske that NEC occurs by the interaction of 3 events:
intestinal ischemia,
colonization by pathogenic bacteria and
excess protein substrate in the intestinal lumen.
Additionally, the immunologic immaturity of the neonatal gut has been implicated in the development of NEC. Reparative tissue changes including epithelial regeneration, formation of granulation tissue and fibrosis, and mixed areas of acute and chronic inflammatory changes suggest that the pathogenesis of NEC may involve a chronic process of injury and repair.
Premature newborns born prior to the 32nd week of gestational age may have compromised intestinal peristalsis and decreased motility. These motility problems may lead to poor clearance of bacteria, and subsequent bacterial overgrowth. Premature infants also have an immature intestinal tract in terms of immunologic immunity.
There are fewer functional B lymphocytes present and the ability to produce sufficient secretory IgA is reduced. Pepsin, gastric acid and mucus are also not produced as well in prematurity. All of these factors may contribute to the limited proliferation of intestinal flora and the decreased binding of these flora to mucosal cells (Fig).
Role of nitric oxide in the pathogenesis of NEC
Role of nitric oxide in the pathogenesis of NEC.
Characteristics of the immature gut leading to increased risk of necrotizing enterocolitis
Characteristics of the immature gut leading to increased risk of necrotizing enterocolitis.
As understanding of the pathophysiology of necrotizing enterocolitis continues to evolve, a unifying concept is emerging. Initially, there is likely a subclinical insult leading to NEC. This may arise from a brief episode of hypoxia or infection. With colonization of the intestines, bacteria bind to the injured mucosa eliciting an inflammatory response which leads to further inflammation.
Intestinal Microbiota Development in Preterm Neonates and Effect of Perinatal Antibiotics
Silvia Arboleya, Borja Sanchez,, Christian Milani, Sabrina Duranti, et al.
Pediatr 2014;-:—). http://dx.doi.org/10.1016/j.jpeds.2014.09.041
Objectives Assess the establishment of the intestinal microbiota in very low birth-weight preterm infants and to evaluate the impact of perinatal factors, such as delivery mode and perinatal antibiotics.
Study design We used 16S ribosomal RNA gene sequence-based microbiota analysis and quantitative polymerase chain reaction to evaluate the establishment of the intestinal microbiota. We also evaluated factors affecting the microbiota, during the first 3 months of life in preterm infants (n = 27) compared with full-term babies (n = 13).
Results Immaturity affects the microbiota as indicated by a reduced percentage of the family Bacteroidaceae during the first months of life and by a higher initial percentage of Lactobacillaceae in preterm infants compared with full term infants. Perinatal antibiotics, including intrapartum antimicrobial prophylaxis, affects the gut microbiota, as indicated by increased Enterobacteriaceae family organisms in the infants.
Conclusions Prematurity and perinatal antibiotic administration strongly affect the initial establishment of microbiota with potential consequences for later health.
Ischemia and necrotizing enterocolitis: where, when, and how
Philip T. Nowicki
Seminars in Pediatric Surgery (2005) 14, 152-158
http://dx.doi.org:/10.1053/j.sempedsurg.2005.05.003
While it is accepted that ischemia contributes to the pathogenesis of necrotizing enterocolitis (NEC), three important questions regarding this role subsist. First, where within the intestinal circulation does the vascular pathophysiology occur? It is most likely that this event begins within the intramural microcirculation, particularly the small arteries that pierce the gut wall and the submucosal arteriolar plexus insofar as these represent the principal sites of resistance regulation in the gut. Mucosal damage might also disrupt the integrity or function of downstream villous arterioles leading to damage thereto; thereafter, noxious stimuli might ascend into the submucosal vessels via downstream venules and lymphatics. Second, when during the course of pathogenesis does ischemia occur? Ischemia is unlikely to the sole initiating factor of NEC; instead, it is more likely that ischemia is triggered by other events, such as inflammation at the mucosal surface. In this context, it is likely that ischemia plays a secondary, albeit critical role in disease extension. Third, how does the ischemia occur? Regulation of vascular resistance within newborn intestine is principally determined by a balance between the endothelial production of the vasoconstrictor peptide endothelin-1 (ET-1) and endothelial production of the vasodilator free radical nitric oxide (NO). Under normal conditions, the balance heavily favors NO-induced vasodilation, leading to a low resting resistance and high rate of flow. However, factors that disrupt endothelial cell function, eg, ischemia-reperfusion, sustained low-flow perfusion, or proinflammatory mediators, alter the ET-1:NO balance in favor of constriction. The unique ET-1–NO interaction thereafter might facilitate rapid extension of this constriction, generating a viscous cascade wherein ischemia rapidly extends into larger portions of the intestine.
Schematic representation of the intestinal microcirculation
Schematic representation of the intestinal microcirculation. Small mesenteric arteries pierce the muscularis layers and terminate in the submucosa where they give rise to 1A (1st order) arterioles. 2A (2nd order) arterioles arise from the 1A. Although not shown here, these 2A arterioles connect merge with several 1A arterioles, thus generating an arteriolar plexus, or manifold that serves to pressurize the terminal downstream microvasculature. 3A (3rd order) arterioles arise from the 2A and proceed to the mucosa, giving off a 4A branch just before descent into the mucosa. This 4A vessel travels to the muscularis layers. Each 3A vessel becomes the single arteriole perfusing each villus.
Collectively, these studies indicate that disruption of endothelial cell function has the potential to disrupt the normal balance between NO and ET-1 within the newborn intestinal circulation, and that such an event can generate significant ischemia. In this context, it is important to note that NO and ET-1 each regulate the expression and activity of the other. An increased [NO] within the microvascular environment reduces ET-1 expression and compromises ligand binding to the ETA receptor (thus decreasing its contractile efficacy), while ET-1 compromises eNOS expression. Thus, factors that upset the balance between NO and ET-1 will have an immediate and direct effect on vascular tone, but also exert an additional indirect effect by extenuating the disruption of balance between these two factors.
It is not difficult to construct a hypothesis that links the perturbations of I/R and sustained low-flow perfusion with an initial inflammatory insult. Initiation of an inflammatory process at the mucosal–luminal interface could have a direct impact on villus and mucosal 3A arterioles, damaging arteriolar integrity and disrupting villus hemodynamics. Ascent of proinflammatory mediators to the submucosal 1A–2A arteriolar plexus could occur via draining venules and lymphatics, generating damage to vascular effector systems therein; these mediators might include cytokines and platelet activating factor, as these elements have been recovered from human infants with NEC. This event, coupled with a generalized loss of 3A flow throughout a large portion of the mucosal surface, could compromise flow rate within the submucosal arteriolar plexus.
Necrotizing enterocolitis: An update
Loren Berman, R. Lawrence Moss
Necrotizing enterocolitis (NEC) is a leading cause of death among patients in the neonatal intensive care unit, carrying a mortality rate of 15e30%. Its pathogenesis is multifactorial and involves an over reactive response of the immune system to an insult. This leads to increased intestinal permeability, bacterial translocation, and sepsis. There are many inflammatory mediators involved in this process, but thus far none has been shown to be a suitable target for preventive or therapeutic measures. NEC usually occurs in the second week of life after the initiation of enteral feeds, and the diagnosis is made based on physical examination findings, laboratory studies, and abdominal radiographs. Neonates with NEC are followed with serial abdominal examinations and radiographs, and may require surgery or primary peritoneal drainage for perforation or necrosis. Many survivors are plagued with long term complications including short bowel syndrome, abnormal growth, and neurodevelopmental delay. Several evidence-based strategies exist that may decrease the incidence of NEC including promotion of human breast milk feeding, careful feeding advancement, and prophylactic probiotic administration in at-risk patients. Prevention is likely to have the greatest impact on decreasing mortality and morbidity related to NEC, as little progress has been made with regard to improving outcomes for neonates once the disease process is underway.
Primary immunodeficiencies: A rapidly evolving story
Nima Parvaneh, Jean-Laurent Casanova, LD Notarangelo, ME Conley
J Allergy Clin Immunol 2013;131:314-23.
http://dx.doi.org/10.1016/j.jaci.2012.11.051
The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the biology of the immune response. New achievements in this field have been possible in light of collaborative studies; attention paid to new phenotypes, infectious and otherwise; improved immunologic techniques; and use of exome sequencing technology. The International Union of Immunological Societies Expert Committee on PIDs recently reported on the updated classification of PIDs. However, new PIDs are being discovered at an ever-increasing rate. A series of 19 novel primary defects of immunity that have been discovered after release of the International Union of Immunological Societies report are discussed here. These new findings highlight the molecular pathways that are associated with clinical phenotypes and suggest potential therapies for affected patients.
Combined Immunodeficiencies
T-cell receptor a gene mutation: T-cell receptor ab1 T-cell depletion
T cells comprise 2 distinct lineages that express either ab or gd T-cell receptor (TCR) complexes that perform different tasks in immune responses. During T-cell maturation, the precise order and efficacy of TCR gene rearrangements determine the fate of the cells. Productive β-chain gene rearrangement produces a pre-TCR on the cell surface in association with pre-Tα invariant peptide (β-selection). Pre-TCR signals promote α-chain recombination and transition to a double-positive stage (CD41CD81). This is the prerequisite for central tolerance achieved through positive and negative selection of thymocytes.
Ras homolog gene family member H deficiency: Loss of naive T cells and persistent human papilloma virus infections
MST1 deficiency: Loss of naive T cells
New insight into the role of MST1 as a critical regulator of T-cell homing and function was provided by the characterization of 8 patients from 4 unrelated families who had homozygous nonsense mutations in STK4, the gene encoding MST1. MST1 was originally identified as an ubiquitously expressed kinase with structural homology to yeast Ste. MST1 is the mammalian homolog of the Drosophila Hippo protein, controlling cell growth, apoptosis, and tumorigenesis. It has both proapoptotic and antiapoptotic functions.
Lymphocyte-specific protein tyrosine kinase deficiency: T-cell deficiency with CD41 lymphopenia
Defects in pre-TCR– and TCR-mediated signaling lead to aberrant T-cell development and function (Fig). One of the earliest biochemical events occurring after engagement of the (pre)-TCR is the activation of lymphocyte-specific protein tyrosine kinase (LCK), a member of the SRC family of protein tyrosine kinases. This kinase then phosphorylates immunoreceptor tyrosine-based activation motifs of intracellular domains of CD3 subunits. Phosphorylated immunoreceptor tyrosine-based activation motifs recruit z-chain associated protein kinase of 70 kDa, which, after being phosphorylated by LCK, is responsible for activation of critical downstream events. Major consequences include activation of the membrane-associated enzyme phospholipase Cg1, activation of the mitogen-activated protein kinase, nuclear translocation of nuclear factor kB (NFkB), and Ca21/Mg21 mobilization. Through these pathways, LCK controls T-cell development and activation. In mice lacking LCK, T-cell development in the thymus is profoundly blocked at an early double-negative stage.
TCR signaling
TCR signaling. Multiple signal transduction pathways are stimulated through the TCR. These pathways collectively activate transcription factors that organize T-cell survival, proliferation, differentiation, homeostasis, and migration. Mutant molecules in patients with TCR-related defects are indicated in red.
Uncoordinated 119 deficiency: Idiopathic CD41 lymphopenia
Idiopathic CD41 lymphopenia (ICL) is a very heterogeneous clinical entity that is defined, by default, by persistent CD41 T-cell lymphopenia (<300 cells/mL or <20% of total T cells) in the absence of HIV infection or any other known cause of immunodeficiency.
Well-Defined Syndromes with Immunodeficiency
Wiskott-Aldrich syndrome protein–interacting protein deficiency: Wiskott-Aldrich syndrome-like phenotype
In hematopoietic cells Wiskott-Aldrich syndrome protein (WASP) is stabilized through forming a complex with WASP interacting protein (WIP).
Phospholipase Cg2 gain-of-function mutations: Cold urticaria, immunodeficiency, and autoimmunity/autoinflammatory
This is a unique phenotype, sharing features of antibody deficiency, autoinflammatory diseases, and immune dysregulatory disorders, making its classification difficult. Two recent studies validated the pleiotropy of genetic alterations in the same gene.
Predominantly Antibody Defects
Defect in the p85a subunit of phosphoinositide 3-kinase: Agammaglobulinemia and absent B cells
CD21 deficiency: Hypogammaglobulinemia
LPS-responsive beige-like anchor deficiency:
Hypogammaglobulinemia with autoimmunity and
early colitis
Defects Of Immune Dysregulation
Pallidin deficiency: Hermansky-Pudlak syndrome type 9
CD27 deficiency: Immune dysregulation and
persistent EBV infection
Congenital Defects Of Phagocyte Number, Function, Or Both
Interferon-stimulated gene 15 deficiency: Mendelian susceptibility to mycobacterial diseases
Defects In Innate Immunity
NKX2-5 deficiency: Isolated congenital asplenia
Toll/IL-1 receptor domain–containing adaptor inducing IFN-b and TANK-binding kinase 1 deficiencies: Herpes simplex encephalitis
Minichromosome maintenance complex component 4 deficiency: NK cell deficiency associated with growth retardation and adrenal insufficiency
Autoinflammatory Disorders
A disintegrin and metalloproteinase 17 deficiency: Inflammatory skin and bowel disease
Cross-talk between monocyte/macrophage cells and T/NK lymphocytes. Genes in the IL-12/IFN-g pathway are particularly important for protection against mycobacterial disease. IRF8 is an IFN-g–inducible transcription factor required for the induction of various target genes, including IL-12. The NF-kB essential modulator (NEMO) mutations in the LZ domain impair CD40-NEMO–dependent pathways. Some gp91phox mutations specifically abolish the respiratory burst in monocyte-derived macrophages. ISG15 is secreted by neutrophils and potentiates IFN-g production by NK/T cells. Genetic defects that preclude monocyte development (eg, GATA2) can also predispose to mycobacterial infections (not shown). Mutant molecules in patients with unusual susceptibility to infection are indicated in red.
The field of PIDs is advancing at full speed in 2 directions. New genetic causes of known PIDs are being discovered (eg, CD21 and TRIF). Moreover, new phenotypes qualify as PIDs with the identification of a first genetic cause (eg, generalized pustular psoriasis). Recent findings contribute fundamental knowledge about immune system biology and its perturbation in disease. They are also of considerable clinical benefit for the patients and their families. A priority is to further translate these new discoveries into improved diagnostic methods and more effective therapeutic strategies, promoting the well-being of patients with PIDs.
Primary immunodeficiencies
Luigi D. Notarangelo
J Allergy Clin Immunol 2010; 125(2): S182-194
http://dx.doi.org:/10.1016/j.jaci.2009.07.053
In the last years, advances in molecular genetics and immunology have resulted in the identification of a growing number of genes causing primary immunodeficiencies (PIDs) in human subjects and a better understanding of the pathophysiology of these disorders. Characterization of the molecular mechanisms of PIDs has also facilitated the development of novel diagnostic assays based on analysis of the expression of the protein encoded by the PID-specific gene. Pilot newborn screening programs for the identification of infants with severe combined immunodeficiency have been initiated. Finally, significant advances have been made in the treatment of PIDs based on the use of subcutaneous immunoglobulins, hematopoietic cell transplantation from unrelated donors and cord blood, and gene therapy. In this review we will discuss the pathogenesis, diagnosis, and treatment of PIDs, with special attention to recent advances in the field.
Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker
Posted in Anemia, Best evidence, Diabetes Mellitus, Folate and B12, Frontiers in Cardiology and Cardiovascular Disorders, Hematology, Hematopoiesis, Inferential analysis, Iron deficiency, Myelodysplasia, Myelofibrosis, Myocardial metabolism, Myocardial ischemia, Myocardial adenine nucleotide metabolism, Nephrology, Neutropenia, Neutrophilia, Nutrition, Pharmacotherapy of Cardiovascular Disease, Platelet count disorder, Translational Effectiveness, Translational Science, tagged Aviva Lev-Ari, BNP, CAD, CHF, comorbidities - type 2 DM, Ejection Fraction, Erythropoietin, erythropoietin (EPO), Heart Failure, Hypertension, IV Iron (Fe), Journal of the American College of Cardiology, Larry H. Bernstein, myocardial infarction, N-terminal prohormone of brain natriuretic peptide on December 10, 2013| 4 Comments »
Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP
Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP
Article Architecture Curator: Aviva Lev-Ari, PhD, RN
This article presents Advances in the Treatment using Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe) for IMPROVEMENT of Severe and Resistant Congestive Heart Failure and its resultant Anemia. The Leading Biomarker for Congestive Heart Failure is an Independent Predictor identified as an Elevated N-terminal proBNP.
FIRST ARTICLE
Anemia as an Independent Predictor of Elevated N-terminal proBNP
Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3, LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6, John F. Heitner, MD, FACC7
1Cardiology Fellow, 2 Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology, Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY
(Unpublished manuscript) Poster Presentation
SECOND ARTICLE
The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study
Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa
J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7
http://content.onlinejacc.org/article.aspx?articleid=1127229
THIRD ARTICLE
The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations
Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa
This THREE article sequence is related by investigations occurring by me, a very skilled cardiologist and his resident, and my premedical student at New York Methodist Hospital-Weill Cornell, in Brooklyn, NY, while a study had earlier been done applying the concordant discovery, which the team in Israel had though was knowledge neglected. There certainly was no interest in the problem of the effect of anemia on the patient with severe congestive heart failure, even though erythropoietin was used widely in patients with end-stage renal disease requiring dialysis, and also for patients with myelofibrosis. The high cost of EPO was only one factor, the other being a guideline to maintain the Hb concentration at or near 11 g/dl – not higher. In the first article, the authors sought to determine whether the amino terminal pro– brain type natriuretic peptide (NT-pro BNP) is affected by anemia, and to determine that they excluded all patients who had renal insufficiency and/or CHF, since these were associated with elevated NT-proBNP. It was already well established that this pro-peptide is secreted by the heart with the action as a urinary sodium retention hormone on the kidney nephron, the result being an increase in blood volume. Perhaps the adaptation would lead to increased stroke volume from increased venous return, but that is not conjectured. However, at equilibrium, one would expect there to be increased red cell production to maintain the cell to plasma volume ratio, thereby, resulting in adequate oxygen exchange to the tissues. Whether that is always possible is uncertain because any reduction in the number of functioning nephrons would make the kidney not fully responsive at the Na+ exchange level, and the NT-pro BNP would rise. This introduces complexity into the investigation, requiring a removal of confounders to establish the effect of anemia.
The other two articles are related studies by the same group in Israel. They surmised that there was evidence that was being ignored as to the effect of anemia, and the treatment of anemia was essential in addition to other treatments. They carried out a randomized trial to determine just that, a benefit to treating the anemia. But they also conjectured that an anemia with a Hb concentration below 12 g/dl has an deleterious effect on the targeted population. Treatment by intermittent transfusions could potentially provide the added oxygen-carrying capacity, but the fractionation of blood, the potential for transfusion-transmitted disease and transfusion-reactions, combined with the need for the blood for traumatic blood loss made EPO a more favorable alternative to packed RBCs. The proof-of-concept is told below. Patients randomized to receive EPO at a lower than standard dose + iron did better.
In this article, Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker we provides a summary of three articles on the topic and we shading new light on the role that Anemia Hb < 12 g% plays as a Biomarker for CHF and for
prediction of elevated BNP, known as an indicator for the following Clinical Uses:
Clinical Use
Rule out congestive heart failure (CHF) in symptomatic individuals
Determine prognosis in individuals with CHF or other cardiac disease
Maximize therapy in individuals with heart failure by the use of Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe)
Evaluation of BNP and NT-proBNP Clinical Performance
Study Sensitivity(%) Specificity(%) PPV(%) NPV(%)
Diagnose impaired LVEF3
BNP 73 77 70 79
NT-proBNP 70 73 61 80
Diagnose LV systolic dysfunction after MI2
Diagnose LV systolic dysfunction after MI12
BNP 94 40 NG 96
NT-proBNP 94 37 NG 96
Prognosis in newly diagnosed heart failure patients: prediction of mortality/survival1
Prognosis post myocardial infarction: prediction of mortality2
Prognosis post myocardial infarction: prediction of heart failure2
PPV, positive predictive value; NPV, negative predictive value; LVEF, left ventricular ejection fraction; NG, not given.
Reference Range
BNP: < 100 pg/mL13
proBNP, N-terminal: ≤ 300 pg/mL
The NT-proBNP reference range is based on EDTA plasma. Other sample types will produce higher values.
Interpretive Information
Symptomatic patients who present with a BNP or NT-proBNP level within the normal reference range are highly unlikely to have CHF. Conversely, an elevated baseline level indicates the need for further cardiac assessment and indicates the patient is at increased risk for future heart failure and mortality.BNP levels increase with age in the general population, with the highest concentrations seen in those greater than 75 years of age.14 Heart failure is unlikely in individuals with a BNP level <100 pg/mL and proBNP level ≤300 pg/mL. Heart failure is very likely in individuals with a BNP level >500 pg/mL and proBNP level ≥450 pg/mL who are <50 years of age, or ≥900 pg/mL for patients ≥50 years of age. Patients in between are either hypertensive or have mild ischemic or valvular disease and should be observed closely.15BNP is increased in CHF, left ventricular hypertrophy, acute myocardial infarction, atrial fibrillation, cardiac amyloidosis, and essential hypertension. Elevations are also observed in right ventricular dysfunction, pulmonary hypertension, acute lung injury, subarachnoid hemorrhage, hypervolemic states, chronic renal failure, and cirrhosis.NT-proBNP levels are increased in CHF, left ventricular dysfunction, myocardial infarction, valvular disease, hypertensive pregnancy, and renal failure, even after hemodialysis.Although levels of BNP and NT-proBNP are similar in normal individuals, NT-proBNP levels are substantially greater than BNP levels in patients with cardiac disease due to increased stability (half-life) of NT-proBNP in circulation. Thus, results from the two tests are not interchangeable.
Cowie MR and Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis. 2002;44:293-321.
Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998:97:1921-1929.
Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta. 2001;310:193-197.
McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351:9-13.
Mukoyama Y, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans: Evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest. 1991;87:1402-1412.
Hunt PJ, Richards AM, Nicholls MG, et al. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 1997;47:287-296.
Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440-444.
Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. Am J Med. 1992;92:29-34.
Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23:921-927.
Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40:437-445.
Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
Pfister R, Scholz M, Wielckens K, et al. The value of natriuretic peptides NT-pro-BNP and BNP for the assessment of left-ventricular volume and function. A prospective study of 150 patients.Dtsch Med Wochenschr. 2002;127:2605-2609.
Siemens ADVIA Centaur® BNP directional insert; 2003.
Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976-982.
Weber M, Hamm C. Role of B-type natriuretic peptid (BNP) and NT-proBNP in clinical routine.Heart. 2006;92:843-849.
B-type Natriuretic Peptide and proBNP, N-terminal
http://www.questdiagnostics.com/testcenter/testguide.action?dc=TS_BNP_proBNP
(Unpublished manuscript) Poster Presentation:
Anemia as an Independent Predictor of Elevated N-Terminal proBNP Levels in
Patients without Evidence of Heart Failure and Normal Renal Function.
Haq SA, Alam ME, Bernstein L, Banko LB, Saul BI, Lee LY, Sacchi TJ, Heitner JF.
Table 1. Patient Characteristics
Variable No Anemia(n=138) Anemia(n=80)
Median Age (years) 63 76
Men (%) 35 33
Creatinine (mg/dl) 0.96 1.04
Hemoglobin (g/dl) 13.7 10.2
LVEF (%) 67 63
Median NT-proBNP (pg/ml) 321.6 1896.0
A series of slide showing the determination of the representation of normal NT-proBNP range
after removal of patient confounders.
N-terminal proBNP (NT-proBNP) has emerged as a primary tool for diagnosing congestive heart failure (CHF). Studies have shown that the level of
NT-proBNP is affected by renal insufficiency (RI) and age, independent of the diagnosis of CHF.
There is some suggestion from recent studies that
anemia may also independently affect NT-proBNP levels.
To assess the affect of anemia on NT-proBNP independent of CHF, RI, and age.
We evaluated 746 consecutive patients presenting to the Emergency Department (ED) with shortness of breath and underwent evaluation with serum NT-proBNP.
All patients underwent a trans-thoracic echocardiogram (TTE) and clinical evaluation for CHF. Patients were included in this study if they had a normal TTE (normal systolic function, mitral inflow pattern and left ventricular (LV) wall thickness) and no evidence of CHF based on clinical evaluation. Patients were excluded if they had RI (creatinine > 2 mg/dl) or a diagnosis of sepsis. Anemia was defined using the World Health Organization (W.H.O.) definition of
hemoglobin (hgb) < 13 g/dl for males and hgb < 12 g/dl for females.
Of the 746 consecutive patients, 218 patients (138 anemia, 80 no anemia) met the inclusion criteria. There was a markedly significant difference between
NT- proBNP levels based on the W.H.O. diagnosis of anemia.
Patients with anemia had a
mean NT- proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p=0.0001).
There was a markedly
significant difference in patients who had a hgb > 12 (median 295 pg/ml) when compared to
both patients with an hgb of 10.0 to 11.9 (median 2,102 pg/ml; p = 0.0001) and
those with a hgb < 10 (median 2,131 pg/ml; p = 0.001).
Linear regression analysis comparing hgb with log NT-proBNP was statistically significant (r = 0.395; p = 0.0001). MANOVA demonstrated that
elevated NT- proBNP levels in patients with anemia was independent of age.
This study shows that NT-proBNP is associated with anemia independent of CHF, renal insufficiency, sepsis or age.
B-type natriuretic peptide (BNP) is secreted from the myocardium in response to myocyte stretch. 1-2 BNP is released from the myocytes as a 76 aminoacid N-terminal fragment (NT-proBNP) and a 32-amino acid active hormone (BNP). 3 These peptides have emerged as a primary non-invasive modality for the diagnosis of congestive heart failure (CHF). 4- 7 In addition, these peptides have demonstrated prognostic significance in patients with invasive modality for the diagnosis of
congestive heart failure (CHF). 4- 7
heart failure 8-9,
stable coronary artery disease 10, and
in patients with acute coronary syndromes. 11-14
Studies have shown that the level of NT- proBNP is affected by
age and renal insufficiency (RI) independent of the diagnosis of CHF. 15,16
There is some suggestion from the literature that
anemia may also independently affect NT-proBNP levels. 17-20
Willis et al. demonstrated in a cohort of 209 patients without heart failure that anemia was associated with an elevated NT- proBNP. 17 Similarly, in 217 patients undergoing cardiac catheterization, blood samples were drawn from the descending aorta prior to contrast ventriculography for BNP measurements and
anemia was found to be an independent predictor of plasma BNP levels. 18
The objective of this study is to assess the effect of anemia on NT-proBNP independent of CHF, sepsis, age or renal insufficiency.
Patient population
The study population consisted of 746 consecutive patients presenting to the emergency room who underwent NT-proBNP evaluation for the evaluation of dyspnea. Transthoracic echocardiogram (TTE) was available on 595 patients. Patients were included in this study if they had a normal TTE, which was defined as normal systolic function (left ventricular ejection fraction [LVEF] > 45%), normal mitral inflow pattern and normal LV wall thickness. CHF was excluded based on thorough clinical evaluation by the emergency department attending and the attending medical physician. Patients with disease states that may affect the NT- proBNP levels were also excluded:
left ventricular systolic dysfunction (LVEF < 45%),
renal insufficiency defined as a creatinine > 2 mg/dl and
sepsis (defined as positive blood cultures with two or more of the following systemic inflammatory response syndrome (SIRS) criteria: heart rate > 90 beats per minute;
body temperature < 36 (96.8 °F) or > 38 °C (100.4 °F);
hyperventilation (high respiratory rate) > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg;
white blood cell count < 4000 cells/mm3 or > 12000 cells/mm³ (< 4 x 109 or > 12 x 109 cells/L), or greater than 10% band forms (immature white blood cells). 21
The study population was then divided into two groups, anemic and non- anemic. Anemia was defined using the world health organization (W.H.O.) definition of hemoglobin (hgb) < 13 g/dl for males and < 12 g/dl for females.The data was also analyzed by dividing the patients into three groups based on hgb levels i.e. hgb > 12, hgb 10 to 11.9 and hgb < 10.
Baseline patient data
Patient’s baseline data including age, gender, ethnicity, hemoglobin (hgb), hematocrit (hct), creatinine, NT- proBNP were recorded from the electronic medical record system in our institution. Chemistry results were performed on the Roche Modular System (Indianapolis, IN), with the NT- proBNP done by chemiluminescence assay. The hemogram was performed on the Beckman Coulter GenS. All TTE’s were performed on Sonos 5500 machine. TTE data collected included LVEF, mitral inflow pattern and LV wall thickness assessment.
The results are reported in the means with p < 0.05 as the measure of significance for difference between means. Independent Student’s t-tests were done comparing NT proBNP and anemia. Univariate ANOVAs and multivariate ANOVA (MANOVA) with post hoc tests using the Bonferroni method were used to compare NT- proBNP levels with varying ranges of hgb and age using SPSS 13.0 (SPSS, Chicago, IL). A linear regression analysis was performed using SYSTAT. Calculations included Wilks’Lamda, Pillai trace and Hotelling-Lawley trace. A GOLDMineR® plot was constructed to estimate the effects of age and anemia on NT- proBNP levels. The GOLDMineR® effects plot displays the odds-ratios for predicted NT-proBNP elevation versus the predictor values. Unlike the logistic regression, the ordinal regression, which the plot is derived from, can have polychotomous as well as dichotomous values, as is the case for NT-proBNP.
Of the 746 consecutive patients, 218 patients met the inclusion criteria (fig 1). Baseline characteristics of patients are listed in table 1. The median age for anemic patients was 76 years and 63 years for patients without anemia. One third of patients in both groups were men. The mean hemoglobin for
anemic patients was 10.2 g/dl as compared to 13.7 g/dl for non-anemic patients.
The mean LVEF of patients with anemia was 64% as compared to 67% for non-anemic patients.
Based on the WHO definition of anemia, 138 patients were determined to be anemic while 80 patients were diagnosed as non-anemic. There was a markedly significant difference between NT-proBNP levels based on the WHO diagnosis of anemia.
mean NT-proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p = 0.0001).
Of the 218 patients in the study, 55 patients had a hgb of < 10 g/dl. Analysis using
hgb < 10 g/dl for anemia demonstrated a statistically significant difference in the NT-proBNP values.
Patients with a hgb < 10 g/dl had a mean NT- proBNP of 5,130 pg/ml
compared to 2,882 pg/ml in patients with a hgb of > 10 g/dl (p = 0.01)
The groups were also divided into three separate categories of hgb for subset analysis:
hgb > 12 g/dl,
hgb 10 to 11.9 g/dl and
hgb < 10 g/dl.
There was a markedly significant difference in
the NT- ProBNP levels of patients who had a hgb > 12 g/dl (median 295 pg/ml) when
compared to those with a hgb range of 10.0 g/dl to 11.9 g/dl (median 2,102 pg/ml) (p = 0.0001),
and also a significant difference in
NT- proBNP levels of patients with a hgb > 12 g/dl (median 295 pg/ml) when
compared to a hgb of < 10 g/dl (median 2,131 pg/ml) (p = 0.001).
However, there was no statistically significant difference in NT-proBNP levels of patients with hgb 10 g/dl to 11.9 g/dl
when compared to those with a hgb of < 10 g/dl (p = 1.0).
A scatter plot comparing hgb with log NT-proBNP and fitting of a line to the data by ordinary least squares regression was significant (p = 0.0001) and demonstrated
a correlation between anemia and NT-proBNP levels (r = 0.395) (fig. 2).
MANOVA demonstrated that elevated NT- proBNP levels in patients with anemia was independent of age (Wilks’ Lambda [p = 0.0001]). In addition, using GOLDMineR® plots (figure 3a and 3b) with a combination of age and hb scaled as predictors of elevated NT-proBNP,
both age and hgb were required as independent predictors.
What about the effect of anemia? The GOLDminer analysis of ordinal regression was carried out in a database from which renal insufficiency and CHF were removed. The anemia would appear to have an independent effect on renal insufficiency. Figure 4 is a boxplot comparison of NT – proBNP, the age normalized function NKLog (NT- proBNP)/eGFR formed from taking 1000*Log(NT- proBNP) divided by the MDRD at eGFR exceeding 60 ml/min/m2 and exceeding 30 ml/min/m2. The transformed variable substantially makes the test independent of age and renal function. The boxplot shows the medians, 97.5, 75, 25 and 2.5 percentiles. There appears to be no significance in the NKLog(NT pro-BNP)/MDRD plot. Table II compares the NT-proBNP by WHO criteria at eGFR 45, 60 and 75 ml/mln/m2 using the t-test with unequal variance assumed, and the Kolmogorov-Smirnov test for nonparametric measures of significance. The significance at 60 ml/min/m2 is marginal and nonexistent at 75 ml/min/m2. This suggests that the contribution from renal function at above 60 ml/min2 can be ignored. This is consistent with the findings using the smaller, trimmed database, but there is an interaction between
anemia, and
eGFR at levels below 60 ml/min/m2
The findings in this study indicate that
anemia was associated with elevated NT-proBNP levels independent of CHF, renal insufficiency, sepsis or age.
These findings have been demonstrated with NT-proBNP in only one previous study. Wallis et al. demonstrated that after adjusting for age, sex, BMI, GFR, LVH and valvular disease;
only age,
valvular disease and
low hemoglobin
were significantly associated with increased NT-proBNP. 18.
In our study, CHF was excluded based on both a normal TTE and a thorough clinical evaluation. In the only other study directly looking at NT- proBNP levels in anemic patients without heart failure
only 25% of patients had TTEs, with one patient having an LVEF of 40%. 17
BNP, the active molecule released after cleavage along with NT- proBNP, has also been studied in relation to blood hemoglobin levels. 18 In 263 patients undergoing cardiac catheterization blood samples were drawn from the descending aorta prior to contrast ventriculography to determine the value of BNP. Anemia was present in 217 patients. Multivariate linear regression model adjusting for
age,
body mass index,
history of myocardial infarction,
estimated creatinine clearance, and
LVEF
found hgb to be an independent predictor of BNP levels.
In our study, patients with anemia were slightly older than those without anemia. However, both MANOVA and GOLDMineR® plot demonstrated that
elevated NT-proBNP levels in patients with anemia was independent of age.
Other studies have found that BNP is dependent on renal insufficiency and age. Raymond et al. randomly selected patients to complete questionnaires regarding CHF and
then underwent pulse and blood pressure measurements,
electrocardiogram (ECG),
echocardiography and
blood sampling. 15
A total of 672 subjects were screened and 130 were determined to be normal, defined as
no CHF or ischemic heart disease,
normal LVEF,
no hypertension,
diabetes mellitus,
lung disease, and
not on any cardiovascular drugs.
They found
older age,
increasing dyspnea,
high plasma creatinine and a
LVEF < 45%
to be independently associated with an elevated NT-proBNP plasma level by multiple linear regression analysis. In another study, McCullough et al. evaluated the patients from the Breathing Not Properly Multinational Study
looking at the relationship between BNP and renal function in CHF. 16
Patients were excluded if they were on hemodialysis or had a estimated glomerular filteration rate (eGFR) of < 15 ml/min. They found that the BNP levels correlated significantly with the eGFR, especially in patients without CHF, suggesting
chronic increased blood volume and
increased left ventricular wall tension as a possible cause. 16
Our study was designed to exclude patients with known diseases such as CHF and renal insufficiency in order to demonstrate
the independent effect of anemia on elevated NT-proBNP levels.
The mechanism for elevated NT-proBNP levels in patients with anemia is unknown. Some possible mechanisms that have been reported in the literature include
hemodilution secondary to fluid retention in patients with CHF 18,
decreased oxygen carrying capacity with accompanying tissue hypoxia which
stimulates the cardio-renal compensatory mechanism leading to increased release of NT-proBNP. 17
The findings from our study suggest that
NT-proBNP values should not be interpreted in isolation of hemoglobin levels and
should be integrated with other important clinical findings for the diagnosis of CHF.
Further studies are warranted
to assess the relationship between anemia and plasma natriuretic peptides, and
possibly modify the NT-proBNP cutoff points for diagnosing acutely decompensated CHF in patients with anemia.
This study shows that elevated NT-proBNP levels are associated with anemia independent of
CHF,
renal insufficiency,
sepsis and
NT-proBNP levels should be interpreted with caution in patients who have anemia.
1. Brunea BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria.Am J Physiol 1997; 273:H2678-86.
2. Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circ 2000; 102:3074-79.
3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362:316-22.
4. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent care setting. J Am Coll Cardiol 2001; 37:379-85.
5. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of rapid natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea.
J Am Coll Cardiol 2003; 39:202-09.
6. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347:161-67.
7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005; 95:948-954.
8. Tsutamoto T, Wada A, Meada K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction.
Circulation 1997; 96(2): 509-16.
9. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HEFT). Circulation 2003; 107:1278-1283.
10. Omland T, Richards AM, Wergeland R and Vik-Mo H. B-type natriuretic peptide and long term survival in patients with stable coronary artery disease.
Am J Cardiol 2005; 95:24-28.
11. Omland T, Aakvaag A, Bonarjee VV. et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic dysfunction and long term prognosis after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.
Circulation 1996; 93:1963-1969.
12. de Lemos JA, Morrow DA, Bently JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345:1014-1021.
13. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003; 107:2786-2792.
14. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein and B-type natriuretic peptide.
Circulation 2002; 105:1760-1763.
15. Raymond I, Groenning BA, Hildebrandt PR, Nilsson JC, Baumann M, Trawinski J, Pedersen F. The influence of age, sex andother variables on the plasma level of N-terminal pro brain natriureticpeptide in a large sample of the general population. Heart 2003; 89:745-751.
16. McCollough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, et al. B-type natriuretic peptide and renal function in the diagnosis of heartfailure: an analysis from the Breathing Not Properly Multinational Study.
Am J Kidney Dis 2003; 41:571-579.
17. Willis MS, Lee ES, Grenache DG. Effect of anemia on plasma concentrations of NT-proBNP.
Clinica Chim Acta 2005; 358:175-181.
18. Wold Knudsen C, Vik-Mo H, Omland T. Blood hemoglobin is an independent predictor of B-type natriuretic peptide.
Clin Sci 2005; 109:69-74.
19. Tsuji H, Nishino N, Kimura Y, Yamada K, Nukui M, et al. Haemoglobin level influences plasma brain natriuretic peptide concentration. Acta Cardiol 2004;59:527-31.
20. Wu AH, Omland T, Wold KC, McCord J, Nowak RM, et al. Relationship of B-type natriuretic peptide and anemia in patients withand without heart failure: A substudy from the Breathing Not Properly(BNP) Multinational Study.
Am J Hematol 2005; 80:174-80.
22. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al. Definitions for sepsis and organ failure and guidelines for theuse of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101(6):1644-55.
Table Legends
Table I. Clinical characteristics of the study population
Table II. Comparison of NT- proBNP means under WHO criteria at different GFR
Table I
Variable No Anemia(n=80) Anemia(n=138)
Men (%) 27 (34) 47 (34)
Women (%) 53 (66) 91 (66)
Weight (kg) 82.9 80.1
Chest Pain 21 (26) 3 (2)
Hematocrit (%) 40.5 30.5
Mean Corpuscular Volume 97 87
Median NT-proBNP (pg/ml) 321 1896
HTN (%) 12 (15) 51 (37)
Prior MI (%) 11 (14) 5 (4)
ACS (%) 16 (20) 3 (2)
CAD (%) 2 (1) 3 (2)
DM (%) 18 (22) 11 (8)
Clopidogrel 58 (72) 15 (11)
Beta Blockers 68 (85) 27 (20)
Ace Inhibitors 45 (56) 18 (13)
Statins 57 (71) 17 (12)
Calcium Channel Blocker 17 (21) 8 (6)
HTN: Hypertension CAD: Coronary Artery Disease
MI: Myocardial Infarction DM: Diabetes Mellitus
ACS: Acute Coronary Syndrome LVEF: Left Ventricular Ejection Fraction
Table II
GFR WHO Mean P (F) N NPar
> 45 0 3267 0.022 (4.33) 661
> 60* 0 2593 0.031 (5.11) 456 0.018
> 60r 0 786 0.203 (3.63) 303 0.08
> 75 0 2773 > 0.80 320 0.043
*AF, valve disease and elevated troponin T included
r AF, valve disease and elevated troponin T removed
FIGURE LEGENDS
FIGURE 1. Study population flow chart. (see poster)
FIGURE 2. Relationship between proBNP and hemoglobin. (see above)
FIGURE 3. NT-proBNP levels in relation to anemia (see above)
Table based on LatentGOLD Statistical Innovations, Inc., Belmont, MA., 2000: Jeroen Vermunt & Jay Magidson)
4-Cluster Model
Number of cases 408
Number of parameters (Npar) 24
Chi-squared Statistics
Degrees of freedom (df) 71 p-value
L-squared (L²) 80.2033 0.21
X-squared 80.8313 0.20
Cressie-Read 76.6761 0.30
BIC (based on L²) -346.5966
AIC3 (based on L²) -132.7967
CAIC (based on L²) -417.5966
Model for Clusters
Intercept Cluster1 Cluster2 Cluster3 Cluster4 Wald p-value
————– 0.1544 0.1434 0.0115 -0.3093 1.1981 0.75
Cluster Size 0.2870 0.2838 0.2487 0.1805
(across)
LogNTpr
< 1.5 0.0843 0.2457 0.0006 0.0084
1.6-2.5 0.6179 0.6458 0.0709 0.2809
> 3.5 0.0130 0.0018 0.3966 0.1224
MDRD
> 90 0.1341 0.7919 0.0063 0.6106
61-90 0.6019 0.2040 0.1633 0.3713
< 41 0.0542 0.0001 0.4987 0.0006
under 51 0.0668 0.5646 0.0568 0.0954
over 70 0.5870 0.0752 0.6161 0.5166
No anemia 0.7518 0.6556 0.2041 0.0998
Anemia 0.2482 0.3444 0.7959 0.9002
——— Cluster1 Cluster2 Cluster3 Cluster4
Overall 0.2870 0.2838 0.2487 0.1805
(down)
LogNTpro
This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.
Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.
Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV)
who had a left ventricular ejection fraction (LVEF) of 40% despite maximally tolerated doses of CHF medications and
whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups.
Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.
Over a mean of 8.2 +/- 2.6 months,
four patients in Group B and none in Group A died of CHF-related illnesses.
The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B.
The LVEF increased by 5.5% in A and decreased by 5.4% in B.
The serum creatinine did not change in A and increased by 28.6% in B.
The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B.
The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.
When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen,
associated with less hospitalization and renal impairment and less need for diuretics. (J Am Coll Cardiol 2001;37:1775– 80)
Anemia of any cause is known to be capable of causing congestive heart failure (CHF) (1). In patients hospitalized with CHF the
mean hemoglobin (Hb) is about 12 g% (2,3),
which is considered the lower limit of normal in adults (4). Thus, anemia appears to be
common in CHF. Recently, in 142 patients in our special CHF outpatient clinic, we found that
as the CHF worsened, the mean Hb concentration decreased, from 13.7 g% in mild CHF (New York Heart Association [NYHA] class I) to 10.9 g% in severe CHF (NYHA 4), and
the prevalence of a Hb 12 g% increased from 9.1% in patients with NYHA 1 to 79.1% in those with NYHA 4 (5).
The Framingham Study has shown that anemia is an
independent risk factor for the production of CHF (6).
Despite this association of CHF with anemia,
its role is not mentioned in the 1999 U.S. guidelines for the diagnosis and treatment of CHF (7), and
many studies consider anemia to be only a rare contributing cause of hospitalization for CHF (8,9).
Recently, we performed a study in which the anemia of severe CHF that was resistant to maximally tolerated doses of standard medications
was corrected with a combination of subcutaneous (sc) erythropoietin (EPO) and intravenous iron (IV Fe) (5).
We have found this combination to be safe, effective and additive
in the correction of the anemia of chronic renal failure (CRF) in both
the predialysis period (10) and the dialysis period (11).
The IV Fe appears to be more effective than oral iron (12,13). In our previous study of CHF patients (5), the treatment resulted in
improved cardiac function,
improved NYHA functional class,
increased glomerular filtration rate,
a marked reduction in the need for diuretics and
a 92% reduction in the hospitalization rate
compared with a similar time period before the intervention. In the light of these positive results, a prospective randomized study was undertaken
to determine the effects of the correction of anemia in severe symptomatic CHF resistant to maximally tolerated CHF medication.
Abbreviations and Acronyms
CABG coronary artery bypass graft
CHF congestive heart failure
CRF chronic renal failure
EPO erythropoietin
%Fe Sat percent iron saturation
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IU international units
IV intravenous
LVEF left ventricular ejection fraction
NYHA New York Heart Association
PA pulmonary artery
sc subcutaneous
SOLVD Studies Of Left Ventricular Dysfunction
Patients.Thirty-two patients with CHF were studied. Before the study, the patients were treated for least six months in the CHF clinic with
maximally tolerated doses of angiotensin-converting enzyme inhibitors, the beta-blockers bisoprolol or carvedilol, aldospirone, long-acting nitrates, digoxin and oral and intravenous (IV) furosemide.
In some patients these agents could not be given because of contraindications and in others they had to be stopped because of side effects. Despite this maximal treatment
the patients still had severe CHF (NYHA classIII), with fatigue and/or shortness of breath on even mild exertion or at rest. All had levels of
Hb in the range of 10 to 11.5 g% on at least three consecutive visits over a three-week period.
All had a LVEF of 40%.
Secondary causes of anemia including hypothyroidism, and folic acid and vitamin B12 deficiency were ruled out and
there was no clinical evidence of gastrointestinal bleeding.
The patients were randomized consecutively into two groups:
Group A, 16 patients, was treated with sc EPO and IV Fe to achieve a target Hb of at least 12.5 g%.
Group B, 16 patients, did not receive the EPO and IV Fe.
Treatment protocol for correction of anemia.
All patients in Group A received the combination of sc EPO and IV Fe. The EPO was given once a week at a starting dose of 4,000 international units (IU) per week and
the dose was increased to two or three times a week or decreased to once every few weeks as necessary
to achieve and maintain a target Hb of 12.5 g%.
The IV Fe (Venofer-Vifor International, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every two weeks
until the serum ferritin reached 400 g/l or
the %Fe saturation (%Fe Sat is serum iron/total iron binding capacity 100) reached 40% or
the Hb reached 12.5g%.
The IV Fe was then given at longer intervals as needed to maintain these levels.
Visits to the clinic were at two- to three week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before then,
potassium and ferritin and %Fe Sat were performed on every visit.
blood pressure was measured by an electronic device on every visit.
LVEF was measured initially and at four- to six-month intervals by MUGA radioisotope ventriculography.
This technique measures
the amount of blood in the ventricle at the end of systole and at the end of diastole, thus giving
a very accurate assessment of the ejection fraction.
It has been shown to be an accurate and reproducible method of measuring the ejection fraction (14). Hospital records were reviewed at the end of the intervention period to compare
the number of days hospitalized during the study with
the number of days hospitalized during a similar period
when the patients were treated in the CHF clinic before the initial randomization and entry into the study.
Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study. The mean follow-up for patients was 8.2 +/- 2.7 months (range 5 to 12 months). The study was done with the approval of the local ethics committee.Statistical analysis.
An analysis of variance with repeated measures (over time) was performed to compare the two study groups (control vs. treatment) and
to assess time trend and the interactions between the two factors.
A separate analysis was carried out for each of the outcome parameters.
The Mann-Whitney test was used to compare the change in NYHA class between two groups.
All the statistical analysis was performed by SPSS (version 10).
The mean age in Group A (EPO and Fe) was 75.3 +/- 14.6 years and in group B was 72.2 +/- 9.9 years. There were 11 and 12 men in Groups A and B, respectively.
Before the study the two groups were similar in
cardiac function,
comorbidities,
laboratory investigations and
(Tables 1, 2 and 3), except for IV furosemide (Table 3),
which was higher in the treatment group. The mean NYHA class of Group A before the study was 3.8 0.4 and was 3.5 0.5 in Group B. The contributing factors to CHF in Groups A and B, respectively, are seen in Table 1 and were similar.
Table 1. Medical Conditions and Contributing Factors to Congestive Heart Failure in the 16 Patients Treated for the Anemia and in the 16 Controls
Table 2. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group
p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP blood pressure; Fe Sat iron saturation; Hb hemoglobin; IV intravenous; NS not stated; Std Dev. standard deviation.
The main contributing factors to CHF were considered to be
ischemic heart disease (IHD) in 11 and 10 patients respectively,
hypertension in two and two patients,
valvular heart disease in twoand two patients, and
idiopathic cardiomyopathy in one and two patients, respectively.
A significant change after treatment was observed in the two groups in the following parameters:
IV furosemide,
days in hospital,
Hb,
ejection fraction,
serum creatinine and
serum ferritin.
In addition, the interaction between the study group and time trend was significant in all measurements except for blood pressure and %Fe Sat. This interaction indicates that
the change over time was significantly different in the two groups.
We find in the comparisons of Tables 2 and 3:
before treatment the level of oral furosemide was higher in the control group (136.2 mg/day) compared with the treatment group (132.2 mg/day).
after treatment, while the dose of oral furosemide of the treated patients was reduced to 64.4 mg/day
the dose of the nontreated patients was increased to 175 mg/day.
The same results of improvement in the treated group and deterioration in the control group are expressed in the following parameters:
IV furosemide, days in hospital,
ejection fraction and
serum creatinine.
The NYHA class was
3.8 +/- 0.4 before treatment and 2.2 +/- 0.7 after treatment in Group A (delta mean = – 1.6) and
3.5 +/- 0.7 before treatment and 3.9 +/- 0.3 after treatment in Group B. (delta mean = 0.4)
The improvement in NYHA class was significantly higher (p < 0.0001) in the treatment group compared with the control group (Table 4).
Table 4. Changes from Baseline to Final New York Heart Association (NYHA) Class
Initial minus final
The improvement in NYHA class was statistically higher (p < 0.0001) in the treatment group compared with control.
There were no deaths in Group A and four deaths in Group B.
Case 1: A 71-year-old woman with severe mitral insufficiency and severe pulmonary hypertension (a pulmonary artery [PA] pressure of 75 mm Hg) had persistent NYHA 4 CHF and died during mitral valve surgery seven months after onset of the study. She was hospitalized for 21 days in the seven months before randomization and for 28 days during the seven months after randomization.
A 62-year-old man with a longstanding history of hypertension complicated by IHD, coronary artery bypass graft (CABG) and atrial fibrillation had persistent NYHA 4 CHF and a PA pressure of 35 mm Hg, and died from pneumonia and septic shock eight months after onset of the study. He was hospitalized for seven days in the eight months before randomization and for 21 days during the eight months after
randomization.
A 74-year old man with IHD, CABG, chronic obstructive pulmonary disease, a history of heavy smoking and diabetes had persistent NYHA 4 CHF and a PA pressure of 28 mm Hg, and died of pulmonary edema and cardiogenic shock nine months after onset of the study. He was hospitalized for 14 days in the nine months before randomization and for 41 days during the nine months after randomization.
A 74-year-old man with a history of IHD, CABG, diabetes, dyslipidemia, hypertension and atrial fibrillation, had persistent NYHA 4 CHF and a PA pressure of 30 mm Hg, and died of pneumonia and septic shock six months after onset of the study. He was hospitalized for five days in the six months before randomization and for 16 days during the nine months after randomization.
Main findings.
The main finding of the present study is that the correction of
even mild anemia in patients with symptoms of very severe CHF despite being on maximally tolerated drug therapy
resulted in a significant improvement in their cardiac function and NYHA functional class.
There was also a large
reduction in the number of days of hospitalization compared with a similar period before the intervention.
all this was achieved despite a marked reduction in the dose of oral and IV furosemide.
In the group in whom the anemia was not treated, four patients died during the study. In all four cases
the CHF was unremitting and contributed to the deaths.
In addition, for the group as a whole,
the LVEF, the NYHA class and the renal function worsened.
There was also need for
increased oral and IV furosemide as well as increased hospitalization.
Study limitations.
The major limitations of this study are
the smallness of the sample size and
the fact that randomization and treatment were not done in a blinded fashion.
Nevertheless, the two groups were almost identical in
cardiac, renal and anemia status;
in the types and doses of medication they were taking before and during the intervention and
in the number of hospitalization days before the intervention.
Although the results of this study, like those of our previous uncontrolled study (5), suggest that
anemia may play an important role in the mortality and morbidity of CHF,
a far larger double-blinded controlled study should be carried out to verify our findings.
Anemia as a risk factor for hospitalization and death in CHF.
Our results are consistent with a recent analysis of 91,316 patients hospitalized with CHF (15). Anemia was found to be a stronger predictor of
the need for early rehospitalization than was hypertension, IHD or the presence of a previous CABG.
A recent analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) (16) showed that
the level of hematocrit (Hct) was an independent risk factor for mortality.
During a mean follow-up of 33 months the mortality was
22%, 27% and 34% for those with a Hct of 40, 35 to 40 and 35 respectively.
The striking response of our patients to
correction of mild anemia suggests that the failing heart may be very susceptible to anemia.
It has, in fact, been found in both animal (17) and human studies (17–19) that
the damaged heart is more vulnerable to anemia and/or ischemia than is the normal heart.
These stimuli may result in a more marked reduction in cardiac function than occurs in the normal heart and may explain why, in our study,
the patients were so resistant to high doses of CHF medications and
responded so well when the anemia was treated.
Our findings about the importance of anemia in CHF are not surprising when one considers that, in dialysis patients,
anemia has been shown to be associated with an increased prevalence and incidence of CHF (20) and that
correction of anemia in these patients is associated with improved
cardiac function (21,22),
less mortality (23,24) and
fewer hospitalizations (23,25).
Effect of improvement of CHF on CRF.
Congestive heart failure can cause progressive renal failure (26,27). Renal ischemia is found very early on
in patients with cardiac dysfunction (28,29), and
chronic ischemia may cause progression of renal failure (30). Indeed, the development of
CHF in patients with essential hypertension has been found to be one of the most powerful predictors of
the eventual development of end-stage renal disease (31).
Patients who develop CHF after a myocardial infarction experience a
fall in the glomerular filtration rate (GFR) of about 1 ml/min/month if the CHF is not treated (32).
In another recent analysis of the SOLVD study, treating the CHF with
both angiotensin-converting enzyme inhibitors and beta-blockers resulted in better preservation of the renal function than did
angiotensin-converting enzyme inhibitors alone (26),
suggesting that the more aggressive the treatment of the CHF, the better the renal function is preserved. In the present study, as in our previous one (5), we found that the deterioration of GFR was prevented with
successful treatment of the CHF, including correction of the anemia, whereas
the renal function worsened when the CHF remained severe.
All these findings suggest that early detection and treatment of CHF and systolic and/or diastolic dysfunction from whatever cause could prevent
the deterioration not only of the cardiac function
but of the renal function as well.
This finding has very broad implications in the prevention of CRF, because most patients with advanced CRF have
either clinical evidence of CHF or at least some degree of systolic dysfunction (33).
Systolic and/or diastolic dysfunction can occur early on in many conditions, such as
essential hypertension (34),
renal disease of any cause (35,36) or
IHD, especially after a myocardial infarction (37).
The early detection and adequate treatment of this cardiac dysfunction, including correction of the anemia, could prevent this cardiorenal insufficiency. To detect cardiac dysfunction early on, one would need at least an echocardiogram and MUGA radio-nucleotide ventriculography. These tests should probably be done not only in patients with signs and symptoms of CHF, but in all patients where CHF or systolic and/or diastolic dysfunction are suspected, such as those with a history of heart disease or suggestive changes of ischemia or hypertrophy on the electrocardiogram, or in patients with hypertension or renal disease.
Other positive cardiovascular effects of EPO treatment.
Another possible explanation for the improved cardiac function in this study may be the direct effect that EPO itself has on improving cardiac muscle function (38,39) and myocardial cell growth (39,40) unrelated to its effect of the anemia. In fact EPO may be crucial in the formation of the heart muscle in utero (40). It may also improve endothelial function (41). Erythropoietin may be superior to blood transfusions not only because adverse reactions to EPO are infrequent, but also because
EPO causes the production and release of young cells from the bone marrow into the blood.
These cells have an oxygen dissociation curve that is shifted to the right of the normal curve, causing the release of
much greater amounts of oxygen into the tissues than occurs normally (42).
On the other hand, transfused blood consists of older red cells with an oxygen dissociation curve that is
shifted to the left, causing the release of much less oxygen into the tissues than occurs normally (42).
The combination of IV Fe and EPO. The use of IV Fe along with EPO has been found to have an additive effect,
increasing the Hb even more than would occur with EPO alone while at the same time
allowing the dose of EPO to be reduced (10 –13).
The lower dose of EPO will be cost-saving and also reduce the chances of hypertension developing (43).
We used iron sucrose (Venofer) as our IV Fe medication because, in our experience, it is extremely well tolerated (10,11) and
has not been associated with any serious side effects in more than 1,200 patients over six years.
Implications of treatment of anemia in CHF. The correction of anemia is not a substitute for the well-documented effective therapy of CHF but seems to be an important, if not vital, addition to the therapy. It is surprising, therefore, that judging from the literature on CHF,
such an obvious treatment for improving CHF is so rarely considered.
We believe that correction of the anemia will have an important role to play in
the amelioration of cardiorenal insufficiency, and that this improvement will have
significant economic implications as well.
The authors thank Rina Issaky, Miriam Epstein, Hava Ehrenfeld and Hava Rapaport for their secretarial assistance.
Reprint requests and correspondence: Dr. D. S. Silverberg, Department of Nephrology, Tel Aviv Medical Center, Weizman 6, Tel Aviv, 64239, Israel.
This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and
the effect of its correction on cardiac and renal function and hospitalization.
The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown.
In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find
the prevalence and severity of anemia (hemoglobin [Hb]12 g).
In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with
subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%.
The doses of the CHF medications, except for diuretics, were not changed during the intervention period.
The prevalence of anemia in the 142 patients increased with the severity of CHF,
reaching 79.1% in those with New York Heart Association class IV.
In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 5.5 months.
The mean Hb level and mean left ventricular ejection fraction increased significantly.
The mean number of hospitalizations fell by 91.9% compared with a similar period before the study.
The New York Heart Association class fell significantly,
as did the doses of oral and intravenous furosemide.
The rate of fall of the glomerular filtration rate slowed with the treatment.
Anemia is very common in CHF and its successful treatment is associated with a significant improvement in
functional class,
renal function and
in a marked fall in the need for diuretics and hospitalization.
ACE Angiotensin-converting enzyme
CVA cerebrovascular accident
Fe iron
g% grams Hb /100 ml blood
LVH left ventriculr hypertrophy
TNF tumor becrosis factor
The mean hemoglobin (Hb) in patients with congestive heart failure (CHF) is about 12 g Hb per 100 ml blood (g%) (1–3), which is considered to be the lower limit of normal in adult men and postmenopausal women (4). Thus, many patients with CHF are anemic, and
this anemia has been shown to worsen as the severity of the CHF progresses (5,6).
Severe anemia of any cause can produce CHF, and treatment of the anemia can improve it (7). In patients with chronic renal failure (CRF) who are anemic,
treatment of the anemia with erythropoietin (EPO) has improved many of the abnormalities seen in CHF,
reducing left ventricular hypertrophy (LVH) (8 –10),
preventing left ventricular dilation (11) and,
in those with reduced cardiac function, increasing the left ventricular ejection fraction (LVEF)(8 –10),
the stroke volume (12) and
the cardiac output (12).
In view of the high prevalence of anemia in CHF, it is surprising that we could find no studies in which EPO was used in the treatment of the anemia of CHF, and the use of EPO is not included in U.S. Public Health Service guide-lines of treatment of the anemia of CHF (13). In fact, anemia has been considered
only a rare contributing factor to the worsening of CHF, estimated as contributing to
no more than 0% to 1.5% of all cases (14 –16).
Perhaps for this reason, recent guidelines for the prevention and treatment of CHF do not mention treatment of anemia at all (17). If successful treatment of anemia could improve cardiac function and patient function in CHF,
this would have profound implications, because,
despite all the advances made in the treatment of CHF, it is still a major and steadily increasing cause of hospitalizations, morbidity and mortality (18 –20).
The purpose of this study is to examine
the prevalence of anemia (Hb 12 g%) in patients with different levels of severity of CHF and
to assess the effect of correction of this anemia in severe CHF patients
resistant to maximally tolerated doses of CHF medication.
A combination of subcutaneous (SC) EPO and intravenous (IV) iron (Fe) was used. We have found this combination to be additive in improving the anemia of CRF (21,22).
The medical records of the 142 CHF patients being treated in our special outpatient clinic devoted to CHF were reviewed to determine the prevalence and severity of anemia and CRF in these patients. These patients were referred to the clinic either from general practice or from the various wards in the hospital.
Intervention study.
Despite at least six months of treatment in the CHF clinic,
26 of the above patients had persistent, severe CHF (New York Heart Association [NYHA] class III),
had a Hb level of 12 g% and were on
angiotensin-converting enzyme [ACE] inhibitors, the
alpha-beta-blocker carvedilol,
long-acting nitrates,
digoxin,
aldactone and
oral and IV furosemide.
These 26 patients participated in an intervention study. The mean age was 71.76 8.12 years. There were 21 men and 5 women. They all had a
LVEF below 35%,
persistent fatigue and
shortness
of breath on mild to moderate exertion and often at rest, and had
required hospitalizations at least once during their follow-up in the CHF clinic for pulmonary edema.
In 18 of the 26 patients, the CHF was associated with ischemic heart disease either
alone in four patients, or
with hypertension in six,
diabetes in four,
the two together in three, or with
valvular heart disease in one.
Of the remaining eight patients,
four had valvular heart disease alone and
four had essential hypertension alone.
Secondary causes of anemia including
gastrointestinal blood loss (as assessed by history and by three negative stool occult blood examinations),
folic acid and vitamin B12 deficiency and
hypothyroidism were ruled out.
Routine gastrointestinal endoscopy was not carried out. The study passed an ethics committee.
Table 1. Initial Characteristics of the 142 Patients With CHF Seen in the CHF Clinic
Age, yearsMale/female, %Associated conditionsDiabetesHypertensionDyslipidemiaSmoking
Main cardiac diagnosis
Dilated CMP
LVEF, %
Left atrial area (n 15 cm2)
Pulmonary artery pressure (15 mm Hg)
Previous hospitalizations/year
Serum Na, mEq/liter
Serum creatinine, mg%
Hemoglobin, g%
70.1 +/- 11.1
43.1 +/-14.9
3.2 +/- 1.5
139.8 +/- 4.0
11.9 +/- 1.5
CMP cardiomyopathy; LVEF left ventricular ejection fraction; NYHA New York Heart Association class.
Correction of the anemia.
All patients received the combination of SC EPO and IV Fe. The EPO was given once a week at a starting dose of 2,000 IU per week subcutaneously, and the dose was increased or decreased as necessary to achieve and maintain a target Hb of 12 g%. The IV Fe (Venofer-Vifor International, St. Gallen, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every week until the serum ferritin reached 400 g/liter or the percent Fe saturation (%Fe Sat: serum iron/total iron binding capacity 100) reached 40% or until the Hb reached 12 g%. The IV Fe was then given at longer intervals as needed to maintain these levels.
Medication dose.
Except for oral and IV furosemide therapy, the doses of all the other CHF medications, which were used in the maximum tolerated doses before the intervention, were kept unchanged during the intervention period.
Duration of the study.
The study lasted for a mean of 7.2 5.5 months (range four to 15 months).
Visits were at weekly intervals initially and then at two- to three-week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before the intervention study.
A complete blood count, serum creatinine, serum ferritin and % Fe Sat were performed on every visit.
An electronic device measured the blood pressure on every visit.
The LVEF was measured by a multiple gated ventricular angiography heart scan initially and at four- to six-month intervals.
Hospital records were reviewed to compare the number of hospitalizations during the time the patients were treated for the anemia with the number of hospitalizations
during a similar period of time that they were treated in the CHF clinic
before the anemia was treated.
Clinic records were reviewed to evaluate the types and doses of CHF medications used
before and during the study.
Period of time that they were treated in the CHF clinic before the anemia was treated.
Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study. The glomerular filtration rate (GFR) was calculated from the serum creatinine by the formula: 1/serum creatinine in mg% x 100 GFR in ml/min. The rate of change of the GFR before and during the intervention period was calculated by comparing the change in GFR per month in the year before the intervention with that during the intervention.
Statistical analysis.
Mean standard deviation was calculated. One-way analysis of variance (ANOVA) was performed to compare parameter levels between the four NYHA groups. Hochberg’s method of multiple comparisons (23) was used for pair-wise comparison between two groups. A p value of less than 0.05 was considered statistically significant. In the intervention study, the significance of the difference between the initial values and those at the end of the study for the individual parameters in the 26 treated patients was assessed by paired student’s t test; p < 0.05 was considered statistically significant. All the statistical analysis was performed by the SPSS program (Version 9, Chicago, Illinois).
CHF: the whole study group.
The clinical, biochemical and hematological characteristics of the 142 patients seen in the clinic are shown in Tables 1 and 2.
Sixty-seven patients (47%) had severe CHF as judged by a NYHA class of IV (Table 2).
Seventy- nine of the 142 patients (55.6%) were anemic (Hb 12 g%).
The mean Hb level fell progressively from 13.73 +/- 0.83 g% in class I NYHA to 10.90 +/- 1.70 g% in class IV NYHA (p 0.01). The percentage of patients with Hb 12 g% increased from 9.1% in class I to 79.1% in class IV.
Fifty eight patients (40.8%) had CRF as defined as a serum creatinine 1.5 mg%. The mean serum creatinine increased from 1.18 +/_ 0.38 mg% in class I NYHA, to 2.0 +/- 1.89 mg% in class IV NYHA, p 0.001. The percentage of patients with an elevated serum creatinine ( 1.5 mg%) increased from 18.2% in class I to 58.2% in class IV.
The mean ejection fraction fell from 37.67 +/- 15.74% in class I to 27.72 +/- 9.68% (p 0.005) in class IV.
Table 2. LVEF and Biochemical and Hematological Parameters by NYHA Class in 142 Patients With CHF
NYHA Class I II III IV Significantly Different Pairs*
*p 0.05 at least between the two groups by pair-wise comparison between groups.
†p 0.05 at least between the groups by ANOVA.
No. of patients
(total 142) (%)
(7.7) (18.3) (26.8) (47.2)
Hb, g%†
13.73 (0.83)
Serum creatinine,
mg%†
(0.38) (0.29) (0.38) (1.89)
LVEF, %†
37.67 (15.74)
Hb 12 g%, (%)
Serum creatinine
1.5 mg%, (%)
The intervention study: medications.
The percentage of patients receiving each CHF medication before and after the intervention period and the reasons for not receiving them are seen in Table 3.
Table 3. Number (%) of the 26 Patients Taking Each Type of Medication Before and During the Intervention Period and the Reason Why the Medication Was Not Used
Medication No. of Patients (%) Reason for Not Receiving the Medications (No. of Patients)
BP blood pressure; CRF chronic renal failure; IV intravenous.
The main reason for not receiving:
1) ACE inhibitors was the presence of reduced renal function;
2) carvedilol was the presence of chronic obstructive pulmonary disease (COPD);
3) nitrates was low blood pressure and aortic stenosis and
4) aldactone was hyperkalemia.
Table 4. Mean Dose of Each Medication Initially and at the End of the Intervention Period in the 26 Patients
No. of Patients Initial Dose ^ Final Dose^
Carvedilol (mg/day) 20 26.9 15.5 28.8 14.5
Captopril (mg/day) 7 69.6 40.0 70.7 40.4
Enalapril (mg/day) 13 25.7 12.5 26.9 12.6
Digoxin (mg/day) 25 0.10 0.07 0.10 0.07
Aldactone (mg/day) 19 61.2 49.2 59.9 47.1
Long-acting nitrates 23 53.2 13.2 54.1 14.4
Oral furosemide (mg/day) 26 200.9 120.4 78.3 41.3*
IV furosemide (mg/month) 26 164.7 178.9 19.8 47.0*
*p 0.05 at least vs. before by paired Student’s t test.
^ +/-
The mean doses of the medications are shown in Table 4.
The mean dose of oral furosemide was 200.9 +/- 120.4 mg/day before and 78.3 +/- 41.3 mg/day after the intervention (p 0.05). The dose of IV furosemide was 164.7 +/- 19.8, 178.9 mg/month before and 7.0 mg/month after the intervention (p 0.05).
The doses of the other CHF medications were almost identical in the two periods.
Clinical results.
DEATHS.
There were three deaths during the intervention period. An 83-year-old man died after eight months of respiratory failure after many years of COPD, a 65-year-old man at eight months of a CVA with subsequent pneumonia and septic shock and a 70-year-old man at four months of septicemia related to an empyema that developed after aortic valve replacement.
HEMODIALYSIS.
Three patients, a 76-year-old man, an 85-year-old woman and a 72-year-old man, required chronic hemodialysis after six, 16 and 18 months, respectively. The serum creatinines of these three patients at onset of the anemia treatment were 4.2, 3.5 and 3.6 mg%, respectively. All three had improvement in their NYHA status but
their uremia worsened as the renal function deteriorated, demanding the initiation of dialysis.
In no cases, however, was pulmonary congestion an indication for starting dialysis.
Functional results (Table 5).
During the treatment period, the NYHA class fell from a mean of 3.66 +/- 0.47 to 2.66 +/- 0.70 (p 0.05), and
24 had some improvement in their functional class.
The mean LVEF increased from 27.7 +/- 4.8 to 35.4 +/- 7.6% (p 0.001), an increase of 27.8%.
Compared with a similar period of time before the onset of the anemia treatment, the mean number of hospitalizations fell from 2.72 +/- 1.21 to 0.22 +/- 0.65 per patient (p 0.05), a decrease of 91.9%.
No significant changes were found in the mean systolic/diastolic blood pressure.
Hematological results (Table 5).
The mean hematocrit (Hct) increased from 30.14 +/- 3.12%) to 35.9 +/- 4.22% (p < 0.001).
The mean Hb increased from 10.16 +/- 0.95 g%) to 12.10 +/- 1.21 g% (p < 0.001).
The mean serum ferritin increased from 177.07 +/- 113.80 g/liter to 346.73 +/- 207.40 g/liter (p 0.005).
The mean serum Fe increased from 60.4 +/- 19.0 g% to 74 +/- .80 20.7 g% (p 0.005).
The mean %Fe Sat increased from 20.05 6.04% to 26.14 =/- 5.23% (p 0.005).
The mean dose of EPO used throughout the treatment period was 5,227 +/- 455 IU per week, and
the mean dose of IV Fe used was 185.1 +/- 57.1 mg per month.
In four of the patients, the target Hb of 12 g% was maintained despite stopping the EPO for at least four months.
Renal results (Table 5).
The changes in serum creatinine were not significant. The estimated creatinine clearance fell at a rate of 0.95 + 1.31 ml/min/month before the onset of treatment of the anemia and increased at a rate of 0.85 + 2.77 ml/min/month during the treatment period.
Table 5. The Hematological and Clinical Data of the 26 CHF Patients at Onset and at the End of the Intervention Period
————– Initial ^ Final^
Hematocrit, vol% 30.14 3.12 35.90 4.22*
Hemoglobin, g% 10.16 0.95 2.10 1.21*
Serum ferritin, g/liter 177.07 113.80 346.73 207.40*
Serum iron, g% 60.4 19.0 74.8 20.7*
% iron saturation 20.5 6.04 26.14 5.23*
Serum creatinine, mg% 2.59 0.77 2.73 1.55
LVEF, % 27.7 4.8 35.4 7.6*
No. hospitalizations/patient 2.72 1.21 0.22 0.65*
Systolic BP, mm Hg 127.1 19.4 128.9 26.4
Diastolic BP, mm Hg 73.9 9.9 74.0 12.7
NYHA (0–4) 3.66 0.47 2.66 0.70*
*p 0.05 at least vs before by paired Student’s t test. ^ +/-
BP blood pressure; LVEF left ventricular ejection fraction; NYHA New York Heart Association.
The main findings in the present study are that anemia is common in CHF patients and becomes progressively more prevalent and severe as CHF progresses. In addition, for patients with resistant CHF, the treatment of the associated anemia causes a marked improvement in their
functional status,
GFR.
All these changes were associated with a markedly
reduced need for hospitalization and
for oral and IV furosemide.
The effect of anemia on the ischemic myocardium.
We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39).
The Fe deficiency will cause
a resistance to EPO therapy and
increase the need for higher and higher doses to maintain the Hb level (39,40).
These high doses will not only be expensive but may increase the blood pressure excessively (41). The IV Fe reduces the dose of EPO needed to correct the anemia, because
the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42).
Oral Fe, however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain why
the blood pressure did not increase significantly in any patient.
We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.
The Effect of Anemia Correction on Renal Function.
Congestive heart failure is often associated with some degree of CRF (1–3,27–29), and
this is most likely due to renal vasoconstriction and ischemia (28,29).
When the anemia is treated and the cardiac function improves,
an increase in renal blood flow and glomerular filtration is seen (7,28).
In the present study, renal function decreased as the CHF functional class worsened (Table 2). The rate of deterioration of renal function was slower during the intervention period. Treatment of anemia in CRF has been associated with
a rate of progression of the CRF that is either unchanged (30) or is slowed (31–33).
It is possible, therefore, that adequate treatment of the anemia in CHF may, in the long term, help slow down the progression of CRF.
Possible Adverse Effects of Correction of the Anemia.
There has been concern, in view of the recent Amgen study (34), that correction of the Hct to a mean 42% in hemodialysis patients might increase cardiovascular events in those receiving EPO compared with those maintained at a Hct of 30%. Although there is much uncertainty about how to interpret this study (35), there is a substantial body of evidence that shows
correction of the anemia up to a Hb of 12 g% (Hct 36%) in CRF on dialysis is safe and desirable (35–38), and
results in a reduction in mortality, morbidity and in the number and length of hospitalizations.
The same likely holds true for the anemia of CHF with or without associated CRF. Certainly, our patients’ symptoms were strikingly improved, as was their cardiac function (LVEF) and need for hospitalization and diuretics. It remains to be established
if correction of the anemia up to a normal Hb level of 14 g% might be necessary in order to further improve the patient’s clinical state.
The Role of Fe Deficiency and its Treatment in the Anemia of CHF.
We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39). The Fe deficiency will cause
a resistance to EPO therapy and increase the need for higher and higher doses to maintain the Hb level (39,40).
These high doses will not only be expensive but may
increase the blood pressure excessively (41).
The IV Fe reduces the dose of EPO needed to correct the anemia, because the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42). Oral Fe, however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain
why the blood pressure did not increase significantly in any patient.
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Review: Your Government Failed You–Breaking the Cycle of National Security Disasters
4 Star, Executive (Partisan Failure, Reform), Security (Including Immigration)
Self-Serving Goo–Useful as a Light Primer, June 17, 2008
Richard A. Clarke
Edit of 28 June to acknowledge Retired Reader’s comment in favor of the author. I yield to his more direct knowledge. In the larger context, however, all of our civil servants and flag officers failed to do their duty to the Constitution (as did Congress, abdicating on Article 1).
I was hoping for more from this book, but a close examination of the chapters, the notes, and the recommendations quickly established that this book is largely self-serving goo intended to make money and profit from one public moment that I thought was as contrived as Ollie North’s shaking his head over the dead Contra during Congressional testimony.
There is NOTHING is this book that has not been known to all of us who actually cared about intelligence reform and who did as much as humanly possible, especially in 1992, to get a National Security Act of 1992 passed, an Act that was destroyed by Senator John Warner (R-VA) and Dick Cheney, then Secretary of Defense.
I find this book especially annoying–to the point of anger–because both Senator Obama and Senator McCain are surrounded by very old dogs long overdue for total exile, and young to middle age staff pukes that are part of the “don’t make waves, go along with institutionalized insanity.” The next Administration, regardless of who wins, is going to have no one with a radical iconoclastic brain or an open mind. Voters should take great care in understanding with precision the money and the minds (I use the term loosely) that are “behind” the front running for President.
The idiocy and myopia of Clarke’s self-congratulatory and sanctimonious pontification can be readily discerned if one takes a moment to digest a few facts:
1) The world is unconquerable. Get over it.
2) The US is best friends with 42 of 44 dictators, ostensibly because they support the war on terror (a tactic, not an enemy) while sucking our treasury dry in getting arms and training for looting their own commonwealths and repressing their indigenous peoples.
3) There are ten high-level threats to humanity, as identified by LtGen Dr. Brent Scowcroft, USAF (Ret) and other members of the international panel, and I list them here to place the narrow, inflammatory, deceitfully presented Clarke book in perspective–note that terrorism is next to last in this list, and only because of the potential for catastrophic consequences:
— Poverty
— Infectious Disease
— Environmental Degradation
— Inter-State Conflict
— Civil War
— Genocide
— Other Atrocities
— Proliferation
— Terrorism
— Transnational Crime
I won’t bother to list the twelve core policies from Agriculture to Water, or the eight demographic challengers that must be wooed with an EarthGame that demonstrates how we can create a prosperous world at peace without repeating the mistakes of the West. Clarke has no clue how to manage a government, balance a budget, articulate reality to We the People, or stand up to those who wear their rank on their foreheads with little else in their brain housing group.
This is the last book I am going to buy by anyone who has served in this or any recent Administration. These are the losers that got us into today’s mess–losers who valued their jobs more than the truth, their perks more than our lives.
One cannot have a government that functions when Congress has abdicated its Article 1 authorities; the media is owned by those who would happily consent to 935 lies and 25 documented impeachable offenses by Dick Cheney, and a public that is oblivious to the perils, perils that escape them because the USA is no longer a smart industrious nation.
ENOUGH. It is time to take the 27 secessionist movements seriously, to have a Citizens’ Summit (Chicago, on Lincoln’s Birthday 2009) and to demand both an Electoral Reform Act and a Smart Nation-Multinational Information Sharing Act. Senators Hagel and Feingold, with their recent call for a commission to draw a new map of the world, are on the right track. Sadly, they are most likely to draw on all these self-congratulating peons who have been happy to be lions to the public, and ants in the White House.
Vastly better more relevant books include:
The Unconquerable World: Power, Nonviolence, and the Will of the People
Breaking the Real Axis of Evil: How to Oust the World’s Last Dictators by 2025
Web of Deceit: The History of Western complicity in Iraq, from Churchill to Kennedy to George W. Bush
Vice: Dick Cheney and the Hijacking of the American Presidency
Breach of Trust: How Washington Turns Outsiders Into Insiders
Running on Empty: How the Democratic and Republican Parties Are Bankrupting Our Future and What Americans Can Do About It
The Health of Nations: Society and Law beyond the State
On a positive note, see:
The Cultural Creatives: How 50 Million People Are Changing the World
Society’s Breakthrough!: Releasing Essential Wisdom and Virtue in All the People
Collective Intelligence: Creating a Prosperous World at Peace
Our government did not fail us. We failed our Republic, and gave it up for dismemberment. Our government did not fail us. The individuals who served in the highest elected, appointed, and civil service positions failed to honor their Oaths of Office and defense the Constitution against all enemies, domestic and foreign. It takes real guts to speak truth to power, and bet your livelihood on being honorable.
There are only a handful of truly honest and intelligent wizards left, and I can name them on one hand: Zinni, Nye, Oakley, Palmer, Hagel, and if I use the other, Bloomberg, Iacocca, Biden, Schoomaker, Cochran. Everyone else has sold out and betrayed the public trust, and I especially include the 9-11 Commissioners who put the icing on the whitewash cake with their pretentious and deliberately ineffective “road show.” A few, like Gates and Clapper, could be saved, but need to discover their innovative bones and their future sight–current ops is NOT where it’s at.
We the People are angry, very angry, and 2009 is going to see our anger in full display. The 2008 election is fradulent for having disenfranchised both third party candidates, and close to half the citizens eligible to vote.
Categories4 Star, Executive (Partisan Failure, Reform), Security (Including Immigration) TagsClarke
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303.578.4400 | Address
Why RM Lawyers?
Armed Forces Discrimination
USERRA Lawyers Defending the Workplace Rights of our Members of the Armed Forces
The Uniformed Services Employment and Reemployment Rights Act of 1994 (“USERRA”) (38 U.S.C. § 4301-35) prohibits employment discrimination against employees with past, current, or future armed forces obligations. USERRA provides employee rights such as reinstatement of employment after honorable completion of armed services duty. Employers also have obligations to post or otherwise disseminate USERRA information. If a supervisor performs an act motivated by antimilitary animus that is intended to cause an adverse employment action, then the employer may be liable under USERRA. Our lawyers believe that employment discrimination against members of the armed forces must be staunchly opposed.
At Rathod | Mohamedbhai LLC, our team of trial attorneys has successfully represented members of the armed forces against unlawful employment discrimination. Rathod | Mohamedbhai LLC’s Siddhartha Rathod was a Captain in the Marine Corp. Under USERRA, employees must show that their military status was at least a motivating or substantial factor in the employer’s action. The motivating factor requirement does not suggest that an employee’s protected status as a past, present, or future armed services member must have been the sole cause of the negative employment action. We will investigate your matter to ensure that your employment rights were not violated because of your armed services status.
National Defense Authorization Act (“NDAA”) Employee Rights Attorneys Protecting Your Rights
In 2008, the NDAA amended the Family and Medical Leave Act of 1993 (FMLA) to permit a “spouse, son, daughter, parent, or next of kin” to take up to 26 workweeks of leave to care for a “member of the Armed Forces, including a member of the National Guard or Reserves, who is undergoing medical treatment, recuperation, or therapy, is otherwise in outpatient status, or is otherwise on the temporary disability retired list, for a serious injury or illness.” We have extensive experience litigating employees’ rights to medical leave in order to care for their loved ones. We work with medical and armed forces experts to assess the facts of your employment matter and to vigorously defend your civil rights.
Contact Our Wrongful Termination and Employment Law Attorneys
Call 303-578-4400 or fill out our online form to contact our firm and discuss your case with our experienced employment attorneys.
Rathod | Mohamedbhai LLC
2701 Lawrence Street, Suite 100
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contact@saintlouis.media
Why Saint Louis
Humility of Heart – On the Vice of Pride
Home / Blog / Humility of Heart – On the Vice of Pride
By saintlouismedia 04 May 2019 May 19, 2019
Pictures are worth a thousand words. In this picture, you see a statue of Our Lord touching his Sacred Heart, his beloved Foster and his Blessed Mother. But when you step back and look at the bigger picture, the surroundings, you see the Church is in complete ruin. So it is with pride. Pride is the mother of all sins. It was pride that made Satan fall from Heaven like lightning. It will blind a soul to truth.
Fr. Cajetan Mary Da Bergamo wrote on the vice of pride in his book Humility of Heart stating:
“Saint Thomas defines pride as an inordinate affection against right reason, by which man esteems himself and desires to be esteemed by others above that which he really is; and as this affection is opposed to right reasoning, it is certainly a sin which partakes of the gravity of a mortal sin, because it is in direct opposition to the virtue of humility, and Saint Paul puts the proud in the same category as those whom “God delivered up to a reprobate sense and are worthy of death,” although sometimes it is only a venial sin, when the reason is not sufficiently enlightened or there is not full consent of the will.” (Bergamo, 1944)
Fr. Cajetan Mary Da Bergamo explains how pride is one of the most deadly sins:
“Pride is placed among the deadly sins, because it is from pride that so many other sins are derived, and that is why St. Paul, seeing the innumerable wickednesses of the world, called them to the notice of his disciple Timothy, saying: “Look how many are haughty, proud, blasphemers, disobedient to parents love for their neighbour or for God. From whence do you suppose all these vices derive their origin?
“This is the source: the inordinate love which every one has for himself. “Men are lovers of themselves.” This is the explanation which St. Paul gives to it, and as St. Augustine observes, “All these evils flow from the source which he first mentions — self-love,” and as the same saint says, “This excess of self-love is only pride.
Therefore we can conclude from this that whoever overcomes pride overcomes a whole host of sins; according to the explanation given by St. Gregory of this text of Job: “He smelleth the battle afar off, and the shouting of the army.” (Bergamo, 1944).
Fr. Cajetan Mary Da Bergamo continues to explain further why “Pride holds the first place among the deadly sins” (Bergamo, 1944):
“St. Thomas not only places it amongst the deadly sins, but above them, as transcending them all, the king of vices which includes in his cortege all the other vices, therefore it is called in holy Scripture: “The root of all evil ,”“The beginning of all sin!” because as the root of the tree is hidden under the earth and sends all its strength up into the branches, so pride remains hidden in the heart and secretly influences every sin through its action. Therefore whenever we commit a mortal sin, wearein reality opposing arid directing our own will against the will of God.” (Bergamo, 1944).
We end with the beginning, with a quote from Fr. Cajetan Mary Da Bergamo that sums up Humility of Heart:
“In Paradise there are many Saints who never gave alms on earth: their poverty justified them. There are many Saints who never mortified their bodies by fasting, or wearing hair shirts: their bodily infirmities excused them. There are many Saints too who were not virgins : their vocation was otherwise. But in Paradise there is no Saint who was not humble.” (Bergamo, 1944).
Humility of Heart is an excellent book for those who wish to study humility and live it.
Please help turning Humility of Heart into an audiobook a reality.
Go to https://saintlouis.media/humility-of-heart/ to donate.
May Our Lord reward you for your generosity.
Bergamo, C. (1944). Humility of heart. Westminster, MD: The Newman Bookshop, pp.182-185.
This entry was posted in Blog and tagged audiobook, Fr. Cajetan Mary Da Bergamo, Humility of Heart, Pride, self love, St. Augustine, St. Paul, St. Thomas, Vice of Pride. Bookmark the permalink.
Devotion to the Sacred Heart – Visits to the Blessed Sacrament
My Catholic Faith Minute – Lesson 16: The Devils; Temptation, Question 2
© 2019 Saint Louis, roi de France médias, all rights reserved.
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Breaching the code:
Alcohol, Facebook and self-regulation
Nicholas Carah, Sven Brodmerkel, Michelle Shaul
Research output: Book/Report › Commissioned report › Research
This report builds on our study of the activity of the top twenty alcohol brands on Facebook in Australia during 2012 (Carah, 2014) and a complaint made to the Advertising Standards Board (ASB) and Alcohol Beverages Advertising Code (ABAC) Complaints Panel regarding the pages of Victoria Bitter (VB) and Smirnoff in 2012 (Brodmerkel and Carah 2013).
In a 2012 submission we asked the ASB and ABAC to consider whether content posted on the Facebook pages of VB and Smirnoff breached standards in the code relating to excessive consumption, depiction of people under 25, offensive content, and the suggestion that alcohol improved mood and social success.
In a landmark decision, the ASB and ABAC both upheld the complaint, ruling for the first time that their alcohol advertising codes should apply to a brand’s Facebook page and that advertisers were directly responsible for the content that users generated on that platform, including comments made on a Facebook post.
Furthermore, the ASB and ABAC determined that user-generated content needed to be evaluated in the context in which it appears, taking account of how brands stimulate particular conversations.
This report examines content posted by alcohol brands to Facebook during 2012 following the determination of the ASB and ABAC (see Carah 2014) in order to assess compliance. The report poses three key research questions:
• Are the breaches of the code seen in the 2012 ruling against VB and Smirnoff more widely evident on the Australian Facebook pages of alcohol brands?
• Are alcohol brands complying with their own self-regulatory codes in light of the decisions by the ASB and ABAC in 2012?
• And are the current regulatory codes appropriate for regulating alcohol brand activity on Facebook?
Foundation for Alcohol Research & Education
Commissioning body
Carah, N., Brodmerkel, S., & Shaul, M. (2015). Breaching the code: Alcohol, Facebook and self-regulation. Canberra: Foundation for Alcohol Research & Education.
Carah, Nicholas ; Brodmerkel, Sven ; Shaul, Michelle . / Breaching the code: Alcohol, Facebook and self-regulation. Canberra : Foundation for Alcohol Research & Education, 2015. 44 p.
@book{5637a79144d74a31bd4a0371800b4a77,
title = "Breaching the code:: Alcohol, Facebook and self-regulation",
abstract = "This report builds on our study of the activity of the top twenty alcohol brands on Facebook in Australia during 2012 (Carah, 2014) and a complaint made to the Advertising Standards Board (ASB) and Alcohol Beverages Advertising Code (ABAC) Complaints Panel regarding the pages of Victoria Bitter (VB) and Smirnoff in 2012 (Brodmerkel and Carah 2013).In a 2012 submission we asked the ASB and ABAC to consider whether content posted on the Facebook pages of VB and Smirnoff breached standards in the code relating to excessive consumption, depiction of people under 25, offensive content, and the suggestion that alcohol improved mood and social success.In a landmark decision, the ASB and ABAC both upheld the complaint, ruling for the first time that their alcohol advertising codes should apply to a brand’s Facebook page and that advertisers were directly responsible for the content that users generated on that platform, including comments made on a Facebook post.Furthermore, the ASB and ABAC determined that user-generated content needed to be evaluated in the context in which it appears, taking account of how brands stimulate particular conversations.This report examines content posted by alcohol brands to Facebook during 2012 following the determination of the ASB and ABAC (see Carah 2014) in order to assess compliance. The report poses three key research questions:• Are the breaches of the code seen in the 2012 ruling against VB and Smirnoff more widely evident on the Australian Facebook pages of alcohol brands?• Are alcohol brands complying with their own self-regulatory codes in light of the decisions by the ASB and ABAC in 2012?• And are the current regulatory codes appropriate for regulating alcohol brand activity on Facebook?",
author = "Nicholas Carah and Sven Brodmerkel and Michelle Shaul",
isbn = "978-0-9925892-4-0",
publisher = "Foundation for Alcohol Research & Education",
Carah, N, Brodmerkel, S & Shaul, M 2015, Breaching the code: Alcohol, Facebook and self-regulation. Foundation for Alcohol Research & Education, Canberra.
Breaching the code: Alcohol, Facebook and self-regulation. / Carah, Nicholas; Brodmerkel, Sven; Shaul, Michelle .
Canberra : Foundation for Alcohol Research & Education, 2015. 44 p.
T1 - Breaching the code:
T2 - Alcohol, Facebook and self-regulation
AU - Carah, Nicholas
AU - Brodmerkel, Sven
AU - Shaul, Michelle
N2 - This report builds on our study of the activity of the top twenty alcohol brands on Facebook in Australia during 2012 (Carah, 2014) and a complaint made to the Advertising Standards Board (ASB) and Alcohol Beverages Advertising Code (ABAC) Complaints Panel regarding the pages of Victoria Bitter (VB) and Smirnoff in 2012 (Brodmerkel and Carah 2013).In a 2012 submission we asked the ASB and ABAC to consider whether content posted on the Facebook pages of VB and Smirnoff breached standards in the code relating to excessive consumption, depiction of people under 25, offensive content, and the suggestion that alcohol improved mood and social success.In a landmark decision, the ASB and ABAC both upheld the complaint, ruling for the first time that their alcohol advertising codes should apply to a brand’s Facebook page and that advertisers were directly responsible for the content that users generated on that platform, including comments made on a Facebook post.Furthermore, the ASB and ABAC determined that user-generated content needed to be evaluated in the context in which it appears, taking account of how brands stimulate particular conversations.This report examines content posted by alcohol brands to Facebook during 2012 following the determination of the ASB and ABAC (see Carah 2014) in order to assess compliance. The report poses three key research questions:• Are the breaches of the code seen in the 2012 ruling against VB and Smirnoff more widely evident on the Australian Facebook pages of alcohol brands?• Are alcohol brands complying with their own self-regulatory codes in light of the decisions by the ASB and ABAC in 2012?• And are the current regulatory codes appropriate for regulating alcohol brand activity on Facebook?
AB - This report builds on our study of the activity of the top twenty alcohol brands on Facebook in Australia during 2012 (Carah, 2014) and a complaint made to the Advertising Standards Board (ASB) and Alcohol Beverages Advertising Code (ABAC) Complaints Panel regarding the pages of Victoria Bitter (VB) and Smirnoff in 2012 (Brodmerkel and Carah 2013).In a 2012 submission we asked the ASB and ABAC to consider whether content posted on the Facebook pages of VB and Smirnoff breached standards in the code relating to excessive consumption, depiction of people under 25, offensive content, and the suggestion that alcohol improved mood and social success.In a landmark decision, the ASB and ABAC both upheld the complaint, ruling for the first time that their alcohol advertising codes should apply to a brand’s Facebook page and that advertisers were directly responsible for the content that users generated on that platform, including comments made on a Facebook post.Furthermore, the ASB and ABAC determined that user-generated content needed to be evaluated in the context in which it appears, taking account of how brands stimulate particular conversations.This report examines content posted by alcohol brands to Facebook during 2012 following the determination of the ASB and ABAC (see Carah 2014) in order to assess compliance. The report poses three key research questions:• Are the breaches of the code seen in the 2012 ruling against VB and Smirnoff more widely evident on the Australian Facebook pages of alcohol brands?• Are alcohol brands complying with their own self-regulatory codes in light of the decisions by the ASB and ABAC in 2012?• And are the current regulatory codes appropriate for regulating alcohol brand activity on Facebook?
M3 - Commissioned report
SN - 978-0-9925892-4-0
BT - Breaching the code:
PB - Foundation for Alcohol Research & Education
CY - Canberra
Carah N, Brodmerkel S, Shaul M. Breaching the code: Alcohol, Facebook and self-regulation. Canberra: Foundation for Alcohol Research & Education, 2015. 44 p.
http://fare.org.au/wp-content/uploads/Breaching-the-code-Alcohol-Facebook-and-self-regulation.pdf
http://fare.org.au/breaching-the-code-alcohol-facebook-and-self-regulation/Licence: Unspecified
Alcohol Marketing Regulations on Social Media
Impact: Culture and society
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A stretch of residues within the protease-resistant core is not necessary for prion structure and infectivity.
In Vivo Efficacy of Umbilical Cord Blood Stem Cell-Derived NK Cells in the Treatment of Metastatic Colorectal Cancer
Publication : Microbial Biotechnology
Comparison of biofilm formation and motility processes in arsenic-resistant Thiomonas spp. strains revealed divergent response to arsenite
Team: Bioinformatics and Biostatistics HUB
Team: Biomics
Member: Jean-Yves Coppee
Member: Marie-Agnès Dillies
Member: Caroline Proux
Member: Bernd Jagla
Member: Hugo Varet
Published in Microbial Biotechnology - 07 Feb 2017
Julien Farasin, Sandrine Koechler, Hugo Varet, Julien Deschamps, Marie-Agnès Dillies, Caroline Proux, Mathieu Erhardt, Aline Huber, Bernd Jagla, Romain Briandet, Jean-Yves Coppée, Florence Arsène-Ploetze
Microb Biotechnol. 2017 Feb 7. doi: 10.1111/1751-7915.12556
Bacteria of the genus Thiomonas are found ubiquitously in arsenic contaminated waters such as acid mine drainage (AMD), where they contribute to the precipitation and the natural bioremediation of arsenic. In these environments, these bacteria have developed a large range of resistance strategies among which the capacity to form particular biofilm structures. The biofilm formation is one of the most ubiquitous adaptive response observed in prokaryotes to various stresses, such as those induced in the presence of toxic compounds. This study focused on the process of biofilm formation in three Thiomonas strains (CB1, CB2 and CB3) isolated from the same AMD. The results obtained here show that these bacteria are all capable of forming biofilms, but the architecture and the kinetics of formation of these biofilms differ depending on whether arsenite is present in the environment and from one strain to another. Indeed, two strains favoured biofilm formation, whereas one favoured motility in the presence of arsenite. To identify the underlying mechanisms, the patterns of expression of some genes possibly involved in the process of biofilm formation were investigated in Thiomonas sp. CB2 in the presence and absence of arsenite, using a transcriptomic approach (RNA-seq). The findings obtained here shed interesting light on how the formation of biofilms, and the motility processes contribute to the adaptation of Thiomonas strains to extreme environments.
http://onlinelibrary.wiley.com/doi/10.1111/1751-7915.12556/full
Published on: 07 Feb 2017 • Modified on: 10 Feb 2017
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Barriers to lung cancer care
health professionals’ perspectives
J. Dunn, G. Garvey, P. C. Valery, D. Ball, K. M. Fong, S. Vinod, D. L. O’Connell, S. K. Chambers
Purpose: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals’ views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes.
Methods: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1–35 yrs.; SD = 10.2) seeing a mean of 116 patients annually.
Results: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours.
Conclusions: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.
Supportive Care in Cancer
Dunn, J., Garvey, G., Valery, P. C., Ball, D., Fong, K. M., Vinod, S., ... Chambers, S. K. (2017). Barriers to lung cancer care: health professionals’ perspectives. Supportive Care in Cancer, 25(2), 497-504. https://doi.org/10.1007/s00520-016-3428-3
Dunn, J. ; Garvey, G. ; Valery, P. C. ; Ball, D. ; Fong, K. M. ; Vinod, S. ; O’Connell, D. L. ; Chambers, S. K. / Barriers to lung cancer care : health professionals’ perspectives. In: Supportive Care in Cancer. 2017 ; Vol. 25, No. 2. pp. 497-504.
@article{271455eb24864243b5d1830fbc8f03e6,
title = "Barriers to lung cancer care: health professionals’ perspectives",
abstract = "Purpose: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals’ views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes. Methods: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1–35 yrs.; SD = 10.2) seeing a mean of 116 patients annually. Results: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours. Conclusions: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.",
keywords = "Health professionals’ attitudes, Lung cancer, Nihilism, Stigma",
author = "J. Dunn and G. Garvey and Valery, {P. C.} and D. Ball and Fong, {K. M.} and S. Vinod and O’Connell, {D. L.} and Chambers, {S. K.}",
journal = "Supportive Care in Cancer",
Dunn, J, Garvey, G, Valery, PC, Ball, D, Fong, KM, Vinod, S, O’Connell, DL & Chambers, SK 2017, 'Barriers to lung cancer care: health professionals’ perspectives', Supportive Care in Cancer, vol. 25, no. 2, pp. 497-504. https://doi.org/10.1007/s00520-016-3428-3
Barriers to lung cancer care : health professionals’ perspectives. / Dunn, J.; Garvey, G.; Valery, P. C.; Ball, D.; Fong, K. M.; Vinod, S.; O’Connell, D. L.; Chambers, S. K.
In: Supportive Care in Cancer, Vol. 25, No. 2, 02.2017, p. 497-504.
T1 - Barriers to lung cancer care
T2 - health professionals’ perspectives
AU - Dunn, J.
AU - Garvey, G.
AU - Valery, P. C.
AU - Ball, D.
AU - Fong, K. M.
AU - Vinod, S.
AU - O’Connell, D. L.
AU - Chambers, S. K.
N2 - Purpose: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals’ views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes. Methods: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1–35 yrs.; SD = 10.2) seeing a mean of 116 patients annually. Results: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours. Conclusions: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.
AB - Purpose: Globally, lung cancer is the most common cancer and the leading cause of cancer death. Problematically, there is a wide variation in the management and survival for people with lung cancer and there is limited understanding of the reasons for these variations. To date, the views of health professionals across relevant disciplines who deliver such care are largely absent. The present study describes Australian health professionals’ views about barriers to lung cancer care to help build a research and action agenda for improving lung cancer outcomes. Methods: Qualitative semi-structured interviews were undertaken with a multidisciplinary group of 31 Australian health professionals working in lung cancer care for an average of 16 years (range 1–35 yrs.; SD = 10.2) seeing a mean of 116 patients annually. Results: Three superordinate themes were identified: illness representations, cultural influences, and health system context. Illness representations included three themes: symptoms attributed as smoking-related but not cancer, health-related stigma, and therapeutic nihilism. Cultural influence themes included Indigenous health care preferences, language and communication, and sociodemographic factors. Health system context included lack of regional services and distance to treatment, poor care coordination, lack of effective screening methods, and health professional behaviours. Conclusions: Fractured and locally isolated approaches routinely confound responses to the social, cultural and health system complexities that surround a diagnosis of lung cancer and subsequent treatment. Improving outcomes for this disadvantaged patient group will require government, health agencies, and the community to take an aggressive, integrated approach balancing health policy, treatment priorities, and societal values.
KW - Health professionals’ attitudes
KW - Lung cancer
KW - Nihilism
KW - Stigma
JO - Supportive Care in Cancer
JF - Supportive Care in Cancer
Dunn J, Garvey G, Valery PC, Ball D, Fong KM, Vinod S et al. Barriers to lung cancer care: health professionals’ perspectives. Supportive Care in Cancer. 2017 Feb;25(2):497-504. https://doi.org/10.1007/s00520-016-3428-3
10.1007/s00520-016-3428-3Licence: CC BY-NC
6323713-oaFinal published version, 358 KBLicence: CC BY-NC
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Startup India
hawala
Startups will never be harassed, says Piyush Goyal
The minister said the government has come out with clarifications that startups would not be asked any questions if they are registered with and recognised by the Department for Promotion of Industry and Internal Trade (DPIIT). PTI | October 31, 2019, 08:04 IST
NEW DELHI: Commerce and Industry Minister Piyush Goyal on Wednesday assured that start-ups will never be harassed and that the government is taking steps to promote them.
"I assure you that start-ups will never be harassed. They have to do the limited activity of registering themselves so that good law is not misused by a few people," he said here at a function.
The minister said the government has come out with clarifications that startups would not be asked any questions if they are registered with and recognised by the Department for Promotion of Industry and Internal Trade (DPIIT).
"Few investments which are genuine investments in startups possibly got notice probably seeking some information. I think there is no harm in giving that information," Goyal said.
According to him, there is no such thing called "angel tax".
He said the issue of angel tax came up at first place, "because we have thousands and lakhs of shell companies which the Modi government de-recognised and on which we are taking action, where hawala operators used to create fake equity capital by issuing shares at a huge premium with no business activity at all and using that for money laundering".
Earlier, several startups made representations to the government about receiving notices from the Income Tax Department. They had claimed it was getting difficult for them to operate when the taxman was breathing down their neck.
The government launched the 'Startup India' initiative on January 16, 2016, to build a strong ecosystem for nurturing innovation and entrepreneurship. It also provided them with certain tax benefits and other incentives.
As many as 24,250 startups have been recognised by the department and they are eligible for different tax incentives.
Goyal also released the High Level Advisory Group (HLAG) report on promoting exports and investments at a function organised by industry body CII.
He assured that India would always protect its strategic and economic interests while engaging in multilateral talks.
He urged people to talk, argue and understand issues and not indulge in creating fear psychosis as the government would never sign on any trade agreement without consultations.
The HLAG report has suggested several steps to boost the country's goods and services exports. It has made specific recommendations for sectors such as pharma, electronics and textiles.
For electronics, it has suggested shifting from a tariff-based policy to an incentive-based policy for manufacturing, incentives based on certain specified criteria such as technology, manufacturing capacity, and employment generation.
Tax holiday for a considerable period, under Indian tax laws, to incentivise investment by domestic as well as foreign enterprises in high-end electronics has also been suggested.
Other recommendations include creation of a single ministry for the regulation of medical devices -- right from import and manufacture, up until pricing and sale of the products -- for easing the compliance burden for both domestic as well as foreign manufacturers.
Besides, the report has called for creation of a pan-India Tourism Board, according infrastructure status to tourism and amend tax rates.
It has also recommended issuance of 'Elephant Bonds' wherein people declaring undisclosed income would have to mandatorily invest specified amount in these securities.
"The government may introduce a one-time disclosure scheme for declaring undisclosed foreign income and assets and pay tax on such undisclosed income/ asset at the rate of 15 per cent."
"The scheme should also provide for locking 40 per cent of the funds in Elephant Bonds...for a period of 20-30 years," the report said.
As per the report, the tariff regime needs to be simplified, rationalised and made more predictable.
"Reduce the number of basic customs duty rates for industrial products. This should be done in a phased manner, mostly over five years. After the five-year transition period, tariff rates could be 0, 5, 10, 15, 20 or 30 per cent," it added.
In certain very limited number of cases, particularly new technology products, basic customs duties may need to be increased to provide domestic industry with time to become competitive, the report said.
Tags : Industry, piyush goyal, tariff, Startup India, Money laundering, hawala
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Can schools be expected to solve the obesity crisis?
director, Institute for Effective Education
Mon 21st Oct 2019, 5.15
Setting aside the moral question as to whether this is what schools should be doing, how easy is it to actually make a difference? A school’s core activities are difficult enough. Where activities are, arguably, tangential to that core, the challenges may be even greater.
Schools are often seen as the first line of defence against many of society’s problems. When a new issue arises, the knee-jerk reaction often is that “schools should be doing more”. Take rising obesity and the need to improve activity levels and reduce waistlines. Two recently published studies (one aimed at reducing obesity in primary, the other increasing activity levels in secondary) illustrate the problem.
The first is a randomised controlled trial of the West Midlands Active Lifestyle and Healthy Eating in School Children (WAVES) intervention*. This involved almost 1,500 five and six-year-olds from 54 primary schools, and was by no means light touch. Lasting for 12 months, it included:
30 minutes of additional moderate-to-vigorous physical activity (MVPA) on each school day;
termly cooking workshops during school time, when parents were invited to learn with their children;
a six-week programme to encourage healthy eating and increase physical vitality, delivered by the local professional football club;
information sheets supporting children and their families to be active over the summer.
Making a difference to these issues requires wider community involvement
Children’s measurements – including weight, height, percentage body fat, waist circumference, skinfold thickness and blood pressure – were taken when they started the trial and again 15 months and 30 months later. They were then compared with children in a control group.
At the first follow-up, the mean body mass index (BMI) score was not significantly lower for the intervention group compared with the control. At 30 months, the mean difference was smaller and remained non-significant. This intervention, then, was not successful in bringing about an improvement in young children’s weight – and presumably not in their overall routines of activity and eating.
Children become less active as they grow older, so might an approach in secondary school prove more effective? A recent study looked at the impact of Girls Active**, a programme developed by the Youth Sport Trust that provides a support framework to schools to review their physical activity, sport, and PE teaching to ensure they are relevant and attractive to all adolescent girls. It has a particular focus on 11 to 14-year-olds.
Twenty secondary schools in the Midlands participated in the trial, with ten schools receiving Girls Active and ten schools continuing with usual practice. In total, 1,752 girls aged 11 to 14 took part. The primary outcome measure (at the start, seven months, and 14 months) was MVPA, recorded on wrist-worn accelerometers. Secondary outcomes included overall physical activity, light physical activity, sedentary time, body composition, and psychosocial outcomes.
The results showed small improvements in MVPA compared with control schools after seven months, but none after 14 months. Interestingly the subgroup analysis showed that the intervention was effective at 14 months in larger schools, but caused an MVPA decrease in smaller schools. (Perhaps larger schools had the capacity to run the programme effectively, while in smaller schools it was more distracting than helpful.) There was no pattern in the secondary outcomes, and any differences were slight.
Of course these are just two studies, but both were disappointing, despite requiring substantial resources. It suggests that making a difference to these issues requires wider community involvement – not surprising, given that they are issues affected by what is occurring in the wider society, rather than in schools alone.
For schools, it is a reminder that investment in addressing these issues may not necessarily result in improvement. Reviewing the evidence of what has worked (or not) in the past is a vital first step before taking any action. Limited resources mean it is important to choose the right priorities. Shifting the dial on a particular issue takes effort, and you can’t focus on everything.
* Effectiveness of a childhood obesity prevention programme delivered through schools, targeting 6 and 7 year olds: cluster randomised controlled trial (WAVES study) (February 2018), BMJ 2018; 360:k211
** Effectiveness of the “Girls Active” school-based physical activity programme: A cluster randomised controlled trial (April 2018) International Journal of Behavioral Nutrition and Physical Activity
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Graham Morgan
I continue to be surprised that obesity is still seen as a physiological condition by many. The PE and school sport quangos will always promote themselves as the people to transform the health of the next generation but statistics suggest that investing health funding through a filter of PE & SS will have no positive impact.
At Evolve, through Project HERO (Health Engagement Real Outcomes), we aim to support schools to raise healthier, happier and smarter kids to perform better in school and beyond into life. HERO gives focus to physical, emotional and cognitive health underlining our belief that health should be via preventative, holistic interventions and not in isolation (such as obesity or mental health).
Evolve believes health and education should come together in schools and that education will have a greater impact on health than just exercise or diet specifically. Health is more important than PE or Sport and as such Health should be a given priority in the curriculum.
Schools should be the battleground toly the foundation for healthier lives but teachers are not the soldiers to carry the fight as their prioritites, training and enthusiasm is to be found elsewhere.
Evolve Health Mentors, recognised by the RSPH as adding a new dimension to school staffing, are carefully recruited and uniquely trained young people who inspire children to make better choices. The Health Mentors work alongside school staff to great effect and produce positive outcomes for both health (physical and mental) and education (improved attendance, behaviour and attainment).
Evolve has greatest impact with disruptive children whose behaviour reflects their responses to ACEs and poverty – while having to fit into an education system that does not do enough to recognise their additional challenges in life. In the race for exam success they start with a handicap.
Improving children’s physical, emotonal and cogitive health places them in a better place, more confident and resilient to deal with what life presents to them in the way of challenges and opportunities.
Howard Wells
Obesity is a life style choice that starts in the home. It is patents’ responsibility to educate children from the outset. Read, or listen to Dt Julie Wei’s talks on “The Milk and Cookie” disease. Her first question to parents is “What do your children eat and drink?” Children are entering school overweight and often unable to concentrate. How much is ADD to do with what children are eating and drinking.? Listen to her. It might just stop usblami g schools
Daniel Forer
Physical Activity/Sports in general and especially at schools shouldn’t be seen as a tool for tackling obesity and mental illness. They should be seen as a means to encourage individual and team participation amongst kids, understanding of competition, sportsmanship, variety of participation and the bonds formed through collective or individual wins and losses as well as with a role model like a coach. All of this builds a culture for sport/activity participation whose potential bi-product, if the hunger for it is truly instilled in children, could mean a reduction in obesity and mental health issues.
Sport can also be inherently motivating as it’s a game/challenge. Random exercise is not and can often be seen as a chore especially if it’s just to tackle obesity. A wholistic approach is needed and to develop a positive culture around it.
Andy Freeman
A very interesting read Jonathan. Based on two very lengthy and heavily resourced programmes it seems very clear that it isn’t working. The answer seems very simple to the title of your article ‘NO’. I believe schools are definitely a cog in the wheel however in order to get the wheel working there needs to be more cogs. An holistic approach to tackling the Obesity crisis seems to be the best solution. I also like the Trial and Measure Model of trying lots of different programmes which are small but can be set up and delivered quickly. The programmes which show positive results should be explored, analysed and renewed on a bigger scale and then explored, analysed and renewed if they show further success.
Stu King
Thanks for article – I completely agree with it’s sentiment, and with a lot of the commentary above too. It’s a shame that these interventions didn’t show a difference for children. Unfortunately however, there are so many influences on individuals and families that it’s not wholly surprising. There are some interventions that seem to be benefiting children in schools, like the Daily Mile, but I agree that there has to be more done to tackle this problem from all sides in a whole system approach, rather than to rely on one route alone. That’s what the evidence shows us and how we at BeeZee Bodies approach making change with the families we work with.
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Steve Jobs legacy: he personally brought Siri to Apple, saw that Siri had a contextual future
Robert Scoble Uncategorized September 11, 2012 2 Minutes
How does Silicon Valley and Apple miss Steve Jobs?
Well, on Monday night I was having dinner with Gary Morgenthaler, who was one of the investors in Siri, along with a few Siri team members and I heard stories that they weren’t able to tell me while Steve Jobs was alive.
For instance, Jobs called Siri management at least 30 times personally in about a month to convince them to join.
Also, Steve Jobs yelled at Apple managers who didn’t “get” why Siri was so important to Apple.
But most important to me, and the book I’m writing with Shel Israel: Jobs had already started working with the team on how to make Siri more contextually aware.
In fact, Norman Winarsky, who heads up SRI, the lab where Siri was developed, told me that SRI is about to start testing out a new app that will dig deeper into your email and your calendar to “assist” you in a much deeper way than Siri can right now.
What do we meet by context? Well, Siri today is pretty stupid about what’s on your calendar. Ask it “where is my next meeting?” and it will show you your next meeting, but it doesn’t know where it is. Close but no cigar. It gets worse from there.
Ask it “where is the best place to get lunch tomorrow?” and Siri answers with places near my home. Problem is that tomorrow I’m going to be at the Apple iPhone 5 launch in San Francisco. Siri is quite stupid about context, location, and a bunch of other things. Will it improve? Apple already announced some improvements to Siri, for instance Siri will, with iOS 6, be able to start applications. But it’s hardly expected to be contextually aware in any real way.
Ask Siri “what is my favorite gas station?” Siri answers “I don’t know.” The problem is, that isn’t really true. Apple knows what gas stations I’m most likely to stop at. Or it could, if it just knew how to contextually evaluate the data that both Verizon and Apple already have streaming from my phone. If it doesn’t know something like my favorite gas station, it certainly doesn’t know the answer to something simple like “how many times do I eat at Chinese restaurants?” That’s easily verifiable. Ask it such a question and it just brings up a list of Chinese restaurants near you. It doesn’t even try to accurately turn down the question.
But back to Jobs. He saw Siri’s potential to add a new, simpler, contextually-aware, user interface to any device. There are lots of rumors that Apple will use something like Siri in other products, like its Apple TV product. In fact, at dinner the other night I learned that at least one of the team members that remains at Apple is now working on a secret new project. I doubt we’ll learn about that tomorrow, but I’ll be looking for signs that Apple understands how to take us into the contextual age. I’ll be looking for signs that Steve Jobs’ passion for Siri is still being listened to.
Here’s two videos from the past that’s worth dredging up again. The first is of when Siri’s team visited my house to first show me Siri.
http://blip.tv/play/g8sRgcH0FAI.html?p=1http://a.blip.tv/api.swf#g8sRgcH0FAI
Here’s the investors in Siri talking about the inside scoop of what happened (minus the important Steve Jobs details that I learned this week): Part I and Part II.
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12 thoughts on “Steve Jobs legacy: he personally brought Siri to Apple, saw that Siri had a contextual future”
PXLated says:
From what you write, it seems Apple/Siri has access to all the data it needs for your questions – Anything else on any (mobile) platform further along than Siri when it comes to putting things in context?
PXLated: there are a few startups coming, but nothing out yet that really gets to where I want.
Graeme Thickins says:
Robert, so it’s the contextual data that matters? and the one with access to the most data wins?
Yup, more data sure seems to be a precondition to winning. Facebook has more data than most anyone about me. It will be interesting to see if Facebook can capitalize on that.
Ellectrona says:
Great article. It is sad that we will never know what great plans and ideas were in Job’s head. His legacy lives on in every mobile app we touch and build. The only shortfall pf Siri, was it maybe could have integrated a better UI for its service. It scares people when it auto opens. There is a lot of room for growth. You said you would be at Apple launch tomorrow …. Does that mean you are skipping disrupt? I was hoping to meet you because I am a huge fan. In another report you said you were in audience at the hackathon so you may recognize me by the Spaceious hack Tumblr API if you stuck around for all 150? … Just a fan
Colin Walker says:
This is exactly what I’ve been saying recently.
Since the launch of Jelly Bean with Google Now, Apple have been left behind and Siri needs to improve. We have some contextaul data such as being able to ask for a petrol station enroute but there is so much more that needs to happen – I think we’ll see it in iOS7.
Apple is currently gathering “data suppliers” rather than data and forming an amalgam with the mapping engine as a base. I would expect more acquisitions/developments so that Apple is not relying on 3rd parties for its data (just as it now longer relies on Google) and, once all this is in place, we will see a full context engine for Siri. This is why the new Maps app is not just about getting rid of Google, it’s about building a framework.
Is it going to be a year to late? No, i don’t think so. To use your own terminology people are still worried about crossing the freaky line and the uptake on Google Now is currently minor. We have other apps such as Saga trying to so a similar thing but they’re just not there yet. With a contextually aware Siri Apple will do it’s usual trick of taking an idea and popularising it – taking it to the masses in a way that everyone suddenly says “oh yeah, I see what you did there”.
Google Now and Project Glass are currently in the geek realm, a contextually aware Siri will be for the people.
Narayan Babu says:
This is exactly what we set out to build with Friday (for Android). And it does answer questions on which is your favourite restaurant or (even bank) or bookstore. Along with bunch of other stuff.
@PXLated Google Now that was just released in the latest version of Android does some contextual things. It tells you when to leave for a meeting based on your location and the meeting’s and traffic, it listed directions to the airport without me asking on the last day of my trip, along with a few other things. It’s a very cool, creepy beginning… 🙂
jnt says:
So basically Siri is going to need the kind of access Google Now has to all of your contextual life.
Now, if only they could make it work.
Gal Melamed says:
Awesome piece, Robert!
No doubt that Siri can evolve and grow, although my hunch is that Apple are busy taking Siri the market, expanding globally, implementing for the apple tv maybe… but the indication of the two siri founders that left apple is maybe a sign for lack of continues innovation…
In addition, voice and AI are basically in their infant, so I think that relevant innovation will pop up in various fields.
StoryLeather says:
I think as technology progresses, more and more gadgets will be using voice command.
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Book Reviews, Graphic Novels
Bryan Talbot’s Grandville Mon Amour (2010)
Bryan Talbot’s a gifted-as-hell writer, and, like Gaiman or McCloud, an historian on storytelling and comics. I’ve enjoyed everything I’ve read from Talbot so far, including this, but this is the first book where the flaws really took away from the experience.
Grandville Mon Amour is the first sequel to 2009’s Grandville: A pulpy steampunk tale that thrives (intentionally, I presume) on cliches to tell gripping, silly yarns. It’s a huge departure from Talbot’s earlier, often abstruse trademark in that it’s all sex and thrilling shots of testosterone set in a steampunk Europe populated by anthropomorphic animals.
I enjoyed the first one well enough, but Mon Amour quickly fell apart for me. For being about a Holmes-ian badger detective hunting down a serial killer and a conspiracy, it’s a little painful to have the mystery’s solution bash the reader over the head a full 80 pages (in a 90-page story!) before our heroes figure out what should have been plainly obvious. It’s never fun for the characters to intentionally slip into sudden, out-of-character ignorance for the sake of maintaining tension.
The original book’s villain returns for his comeuppance in Mon Amour.
Not only that, but Mon Amour tends to beat the cliches its living in a little too strongly: Sarah, the prequel’s love interest, is replaced too quickly by a doppleganger who serves the exact same role, down to her personality and voice; Lebrock, word-for-word, has that ‘I’m-a-rebel-cop-with-nothing-to-lose!’ shouting match culminating in his quitting the force; the solution to the serial killer story is so full of holes (right down to how he escapes custody and his motivations) that the entire plot just falls to pieces, which, again, ruins the intended tension.
It was still a fun, quick read, and Talbot’s still a talented enough author that I recommend checking his work out — just don’t start by looking at this entry. Pick up the Tale of One Bad Rat, or Alice in Sunderland, ideally; though the Grandville adventures before and after this are quite good, too.
Tagged Bryan Talbot, Graphic Novel, Pulp, Review, Steampunk
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Bekker's Blog by Scott Bekker, Editor in Chief
Live! 360: Microsoft's 'No. 1 Persona' for BI is the Business User
Related: Live! 360: 15 Lessons Microsoft Learned Running DevOps
Partners pitching business intelligence (BI) solutions to business users rather than database administrators (DBAs) appear to have a committed new ally in Microsoft.
When looking at Microsoft's recent enhancements to its BI platforms, the lack of rows, columns and even traditional data management terminology makes it evident that the changes aren't aimed at DBAs.
"Our No. 1 persona, our No. 1 person that we're building for, is the business user," said Charles Sterling, senior program manager in the Microsoft Business Applications Group, during his keynote for the SQL Server Live! track of the Live! 360 conference Tuesday in Orlando, Fla.
Sterling, a 25-year Microsoft veteran, and Ted Pattison of Critical Path Training, delivered the session, "Microsoft BI -- What's New for BI Pros, DBAs and Developers." Their talk centered on demos of Power BI, but also touched on roadmaps for elements of Power BI, and covered the growing role of PowerApps and Flow. The main idea behind PowerApps is to allow business users, without coding, to pull from either simple or complex organizational data sources and create shareable business apps that are usable from mobile devices or in a browser.
All of Microsoft's simplification efforts are driving an explosion of BI usage among organizations. According to a slide from the presentation titled "Power BI by the numbers," there are 11.5 million data models hosted in the Power BI service, 30,000 data models added each day, 10 million monthly publish to Web views, and 2 million report and dashboard queries per hour.
Charles Sterling, senior program manager in the Microsoft Business Applications Group, discusses Power BI improvements during his keynote for the SQL Server Live! track of the Live! 360 conference Tuesday in Orlando, Fla.
Yet one of the biggest obstacles right now preventing business users from running even more wild with the concept is not having access to that organizational data. While a DBA creating a more sophisticated application has, or can quickly get, permissions for the underlying organizational data, the story is different for most business users.
"For [business users] to create an app that goes out and collects data is relatively difficult," Sterling said. "That's what PowerApps is going to enable business people to do in the near future. You can do it right now, but we are actually integrating it into Power BI."
A related concept on the roadmap will actually require more organizational communication across the business, including DBAs educating users to help set expectations. From within their dashboard, business users will be able to use PowerApps to update the database on the back end, a PowerApps roadmap feature called Write Back.
Sterling said the Write Back feature is one of his favorite new features, but he suggested it may be a bit of a struggle for DBAs as business users get going with it.
"For DBAs, empowering business users with the tools to directly update and collect data will likely open a whole new host of problems. Take, for example, a business user updating data being fed into a Hadoop cluster. It is entirely likely that the processing could take hours to days to propagate into the BI system they are viewing. Business users will expect those updates in real time," Sterling said in an interview.
Another big element of the roadmap with business users in mind is storytelling in the Power BI Desktop, Sterling said.
During a demo, Pattison clicked on slicers in a graph within Power BI that were increasing or decreasing. The example application brought up a sentence, based on the underlying data, explaining in business terms what was driving the increase or decrease.
"We're going to continue playing out this whole storytelling [approach]," Sterling said. In another example of such storytelling, Sterling and Pattison ran most of their presentation out of bookmarks in Power BI rather than PowerPoint. The bookmarks recall a preconfigured view of a report page, and pull live data when the bookmark is displayed.
Another demo during the session that caught attendees' attention involved Power BI Report Server, an enterprise reporting solution that received an update release on Nov. 1. Blue Badge Insights Founder and CEO Andrew Brust found the walkthrough of the Power BI Report Server one of the most important demos during the session. "It's an enhanced version of reporting services, but it lets you distribute reports on premises instead of having to push them to the cloud," Brust said.
Sterling said near-term items on the Report Server roadmap include more data sources, more APIs and integration with Microsoft SharePoint.
Posted by Scott Bekker on November 15, 2017 at 9:22 AM
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Retail »
PE investments in retail real estate surge to Rs 3,350 crore in H1, highest since 2008: Cushman & Wakefield
The share of retail real estate in total PE investments in India has also increased to 18% in H1 2016, against 2% in the same period last yearETRealty | September 22, 2016, 15:00 IST
NEW DELHI: Private equity investments in retail real estate have surged to Rs 3,350 crore in the first half of 2016, the highest since 2008, on improved leasing activity, relaxed government policies and positive economic outlook, according to property consultancy Cushman & Wakefield.
PEs invested around Rs 250 crore in the same period last year.
The share of retail real estate in total PE investments in India has also increased to 18% in H1 2016, against 2% in the same period last year.
“Positive economic outlook and large market potential continue to attract retailers to India. In addition to consumer spend, which increased by 10% during last 12 months, e-commerce is also contributing majorly to the increased retail spending by Indian consumers," said Anshul Jain, managing director, India, Cushman & Wakefield.
New malls also registered the highest half yearly supply in five years at 4.8 million sq ft in H1 2016, against just 0.2 msf in H1 2015.
Delhi-NCR accounted for the highest supply during H1 2016, grabbing 64% of the share in new supply during the first half of 2016, mainly owing to completion of Mall of India in Noida, which is one of the largest malls in India.
Pune grabbed the second spot in new mall supply, with three malls becoming operational, spanning a total of 0.8 msf during H1 2016, while Mumbai witnessed 0.4 msf of mall space coming into supply.
Delhi NCR and Mumbai remain the largest retail markets, accounting for 35% and 20%, respectively, of the mall stock across the top 8 cities in India, followed by Bengaluru, which accounts for about 12% of the total stock.
“We are expecting to witness some e-commerce companies take up physical spaces in malls to reach out to a wider Indian audience. Retailers are also increasingly consolidating their operations by mergers and acquisitions to cut down competition, gain market share and capitalize on synergies to get better results for their bottom-lines. All of these trends are resulting in increased investments by financial institutions and PE funds in this asset class," Jain said.
Around 13 msf of new mall supply is scheduled for completion until the end of 2018 across the top 8 cities, according to Cushman & Wakefield.
Ten Biggest Malls on Earth
Tags : Retail, trends, private equity, money matters, Cushman & Wakefield
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Reckless Records
**BLOG**
New Vinyl Reissues
From Memphis to Detroit !!!
February 22, 2018 recklessrecordslondon
Yo from Reckless!!!
This Blog was written to the sounds of:
Incredibly busy week – must have been Half Term. Also the high end Jazz and Reggae that went out created a bit of a buzz in the shop. Insane amount of buying this week; so busy we almost ran out of money yesterday!
Lets go!!!
Some really, really, banging Techno came in this week from a fairly regular seller. He obviously bought a lot of cool records – mostly from Fat Cat by the looks of it. He has sold a load of Dub to us in the past but this time it was heavy Techno: plenty of Detroit; loads of Robert Hood, Jeff Mills (including the rare Picture Disc on UK Hardcore label ULR One), Ectomorph; UK Techno from Surgeon, James Ruskin and several more; Basic Channel/Rhythm & Sound (including some rare Colour Vinyl titles). Very gnarly records here – and a lot of titles you don’t see everyday.
Some really KILLER US Rap CDs. Someone has been selling us their entire Rap CD collection this week. Lots of very good, underground (and not so underground) titles. Plenty from Three Six Mafia, Project Pat, C Murder, E 40, Master P, Big Bear (Including Doin Thangs!!!!), Lil Flip, Lil Keke…. You know the score!!! Really nice to have these in as they don’t turn up too much.
Another massive CD collection came in – this time fairly across the board but relying heavily on the the Experimental side of things. Loads of Japanese titles from Boredoms, Acid Mothers Temple, Fushitsusha, Merzbow….lots of interesting Electronica titles too (loads on Warp, Rephlex, Planet Mu but also a lot more underground titles). Also: Rap, Metal, Punk, Noise, Psych, Prog, Jazz etc.
I was skint this week so sold in a load of stuff – some rare UK Psych titles (some of which sold straight away), rare LPs from The Honeybus, Lush, Kraftwerk, Linda Hoyle, Kaleidoscope. Also lots of Techno/House.
Small pile of wicked Death Metal reissue LPs came in: Napalm Death, Pestilence, Slayer, Possessed, Morbid Angel.
Rare Japanese Guns N Roses EP.
Loads of really good Hard Rock/Heavy Metal LPs also came in. Sleeves are all in great shape, the vinyl is generally VG but they all play well. Lots of classics from Iron Maiden, Anvil, Bon Jovi, Spider, Motley Crue, Diamond Head, Accept, AC/DC, Hawkwind, Uriah Heep, UFO etc. Exactly the sort of records you would see in Provincial towns looking for Bolt Thrower LPs in your teens; sometimes it would pay off, but mostly not.
Loads of super clean Classic Rock came in: Pink Floyd, Ultravox, Fleetwood Mac, David Bowie, The Beatles, Deep Purple, Bruce Springsteen etc.
Some nice Soul LPs – about 60 – lots of UK and US originals. Including a few more sought after titles from Ann Peebles.
Tonnes of Grunge including loads of Pearl Jam and a rare LP from Temple Of The Dog.
Huge collection of Rock N Roll. Nearly all reissues or cool 80s comps. But loads of really, really good records. Tonnes of semi-hard beat comps – Freakbeat, Psych, Beat. Loads of Gnarly Evil Rock N Roll.
My favourite collection this week turned up first thing on Sunday. I’d been surprised with a Birthday trip to Lazer Quest on Saturday so was a little tired first thing at work on Sunday but this perked me right up. A really nice couple sold in their collection and it was really great. Loads of Classical, Chanson, Oddities, Classic Rock, Jazz. Some beautiful records including Miles Davis, Francois Hardy, Moondog. Some fairly rare Classical titles too. Loads of really nice Kids records too!
Here is one of my favourite Moondog tracks – which to me sounds like a Funky version of a track from The Wicker Man soundtrack!
You will be pleased to hear that this week it is the second instalment from James Knight!!! His last Top Ten went down a treat and I really loved reading this one too,. Especially the bit about The Lowest Form :p
I’m back! Shout out to everyone and anyone who made it through my first beefy top ten and biggup the folks that got in touch to say they dug it – your chests! As promised I did try to keep this one shorter as befits the nature of the records being discussed but it’s still a bit of an eyeful I’m afraid so go get the coffee on! Here are ten of my favourite punk tunes (in no particular order) and a bit about why I like ‘em:
“Gimme Gimme Gimme” – Black Flag
Picking up Kerrang as early as my pre-teens Rollins was a fairly regular fixture and so many bands referenced Flag as an influence that it was inevitable I’d check them out sooner or later. The moment I knew I had to get hold of some of their music though was hearing Jordan Richter skate to “My War” in Video Days the epic Blind video. Skate videos were another massive influence on my listening looking back. Hearing The Misfits, D.R.I., Maiden and Jefferson Airplane in Welcome To Hell; hearing Cymande, Joe Bataan and Herbie Hancock in Mouse; hearing Sabbath, Slayer and more Flag in Misled Youth; hearing Fugazi, Miles Davis, Gil Scott Heron, Archers of Loaf and Pete Rock & C.L. Smooth in Eastern Exposure? How could I not be vibing out to all that shit age 13!? Anyway back to Flag – what can you say? The blueprint for a sound, and, perhaps more importantly, an attitude and ethos towards touring and releasing records that still inspires many to this day. Rollins’ memoir Get In The Van that details life on the road with Flag in the early 80s is well worth a read to get an idea of the levels of commitment they had and how clearly inspirational this approach was to kids in every town they blasted through. Of the pre-Rollins vocalists I’m generally a Dez guy but I’ve always thought that Chavo nails it on this one which is probably my favourite of the early, short, fast, snotty, pissed off and nihilistic Flag which you can hear in one go on the Everything Went Black and First Four EPs comp’s. Damaged and My War are no doubt high points of the Rollins era but I also have a real soft spot for the late period instrumental Process Of Weeding Out LP. If you don’t know – get to know!
“Punk Is Dead” – Crass
Hearing the Sex Pistols and The Clash in the early 1990s it was difficult to imagine what people had found so shocking in 1976. When I finally got hold of a copy of the Christ The Album LP in the big black box it felt challenging, subversive, confrontational and unrelentingly principled in a way those Pistols and Clash records never had to me. The short sharp bursts of song with Steve Ignorant’s pissed off vocal setting the world to rights over the top, the typography, the logo, the reams of text that came in the inlay booklet as well as the amazing Gee Vaucher collage (that includes a squatting Margaret Thatcher shitting sausages and skulls!) made a hefty impact on my impressionable psyche. The ideals and aesthetics of Crass so completely inform the anarcho/crust offshoot of punk it’s hard to imagine how that branch of the tree would look and sound had they never existed. The only comparable example I can think of is trying to imagine D-Beat without Discharge but then we’re really straying into some ‘if a tree falls in the forest…’ territory. Aaaaaanyway, fair play to Penny for continuing to live and create according to his principles, you can still find him living and working (often in the nude) at Dial House, the anarcho-pacifist, communal, open house in Essex where he has lived and worked since the late 1960s. Here he is (with his clothes on) having a powwow with several other members of the band around the kitchen table at Dial House in 1984:
“Who Are You” – Void
Growing up in Kingston Upon Thames in the early 90s I was lucky enough to have access to three great record shops: Slammin’ Vinyl (RIP!!!) in the Apple Market had three floors of house, techno, jungle and D&B; Collectors Record Centre on London Road (still there to this day!) had a good selection of second hand rock and pop and there was also a branch of the Beggars Banquet shops on Eden Street that did a good bit of everything. When Beggars decided to get out of the bricks and mortar record shop game long time staff member Jon Tolley took up the reigns and the shop shifted to its current identity of Banquet Records. Shout out to Jon who has grafted hard and done things the right way and made Banquet an excellent local independent record shop that functions as a wicked community hub doing instores and organising gigs as well as staying well stocked with a diverse range of music. Long pre-amble but one thing that Jon has always ensured is that Banquet has been well stocked with key American Hardcore back catalogue releases. I was able to snap up CD copies of Minor Threat, Black Flag, Flipper etc no problem and Banquet always had a good chunk of the Dischord catalogue available on CD. The Faith/Void split remains the standout release of that period of my punk discovery, the Void side in particular. Heavy, aggressive, taught, pummelling, slightly deranged (check the guitar solo at 1 min!) and not shy to throw in a weighty breakdown Void still get me going! Here they are playing “Who Are You” live in DC in ’83:
S/T 7” – Koro
8 songs, six minutes, all killer, absolutely zero filler! Short, super fast, furious punk rock at its lithe and limber best. Koro’s only 7” was originally self-released in 1983 and the OG still goes for £££. You used to see bootlegs in various colours on eBay etc but Sorry State have done a proper re-issue of the 7” as well as putting out an unreleased LP (also originally recorded back in ’83) so anyone and everyone can get involved! Here’s “Feelin’ Pretty Minimal” from the LP which stretches out across a whole two minutes:
“Drop Dead” – Siege
Formed in Weymouth, Massachusetts in 1981 Siege concocted their brutally distilled version of hardcore in isolation from the prevailing Boston scene. Don’t get me wrong, I love SSD, Jerry’s Kid etc but something about being outcast from a scene of outcasts really seems to have given the Siege recordings a totally nihilistic, disassociative vibe that you can still feel to this day. Fellow small town Massachusetts kids Deep Wound were probably the closest thing in terms of speed, brevity and rawness but they could never quite match the sheer brutality of Siege. As well as the short, fast and furious stuff done rawer, quicker and more brutally than, possibly, anyone before them the B side of their 1984 cassette demo (and subsequent 7” releases of the recordings) is an 8 minute schizoid dirge out with a squalling sax wailing all over it called “Grim Reaper”:
So good. Aside from a few comp. appearances in the early/mid-80s (including on Pushead’s killer Cleanse The Bacteria comp.) Siege never put anything official out until Relapse re-issued their demo tape on CD in the mid-90s with a few extra tracks. This video of them playing in (I think) their school gym in 1984 is still one of the very best things I have ever seen on the internet and whenever I watch it I kind of feel like there’s no point bothering with anything else:
Albert Mudrian interviewed Siege drummer Robert Williams for his great book Choosing Death and Williams had the following to say about some issues he had with an aborted recording session they tried in the mid-90s with Anal Cunt front dude Seth Putnam who loved Siege so much he essentially resurrected the band so that he could sing with them! I think this quote sums up the spirit and attitude of the band well:
“We were recording and writing and I had written a bunch of revolutionary stuff, like violent lyrics, and the guitarist changed some of my lyrics with weak rhyme, making them pacifist rather than revolutionary, and really changing their context…I still have genocidal resentment about that. We never planned to compromise our extremity”
Genocidal Resentment would make a good band name, can’t believe no one has used that yet!
“Break The Chain” – Infest
Infest originally only existed for me as a mysterious band on patches that older dudes had on their jackets at punk shows I’d go to. It took me a while to find out anything about them online and finally I came across a guy in Germany on eBay who was selling a bootleg burned CDR copy of their discography. To say I was blown away by what I heard on that CDR would be an understatement. “Break The Chain” sums up Infest in 26 seconds. They took what Seige were doing and somehow distilled it still further. ‘Powerviolence’ is a kinda goofy term but you gotta hand it to Matt Domino (who coined the term and played guitar in Infest and Neanderthal) – it does a pretty perfect job of capturing the essence of the sound. Here’s another favourite, “Cold Inside”:
Brutal!
“Skull Crusher” – Man Is The Bastard
I discovered Man Is The Bastard via their split 8” on Vermiform with Born Against. Damn, Born Against should really be on this list. And Rorschach! At least by including MITB I am sort of covering Neanderthal and Crossed Out as there is significant member overlap between MITB and those groups, go check ‘em all out!! Back to MITB – there’s a lot to love! Much like Crass they went in for overtly anti corporate/anti-capitalist sloganeering and had a killer logo and aesthetic. As well as being brutally heavy thanks to Eric Wood’s pummelling bass, they also possessed a sonic trump card in Henry Barnes’ home spun electronics that gave the band a squalling, harsh, wall of noise that set them apart from their Powerviolence contemporaries and allowed them to frequently wander into straight up Power Electronics territory. Wood continues to preach the sermon of THE SKULL with the Bastard Noise, an extension of the Man Is The Bastard/Charred Remains project that occasionally includes Barnes and his machines amongst a rotating assembly of sympathetic contributors. A bit like a Powerviolence Mark E.Smith if it’s Wood and yer nan on bongos you can pretty much guarantee that there will be SKULL SONICS! Here’s an interview I did with Wood ten years ago (!):
https://www.vice.com/en_uk/article/exan44/eric-wood-158-v15n10
And the pic up top is of me hanging out with Henry Barnes at an Amps For Christ show at The Montague (RIP) that Reckless top shotter and Static Shock bossman Ellis put on a couple of years back. Amps For Christ is Barnes’ solo project and again – I heartily recommend checking them out, wild and wonderful sounds & unimaginable instruments aplenty:
“Mother Made Me” – Lungfish
I’m not entirely sure that Lungfish belong on this list, or, for that matter, any list! While the music they make may not exactly be punk in sound though, it certainly is in spirit. I also discovered them in a punk context as they released their recordings on Ian MacKaye’s Dischord label. Lungfish music is totally singular – strange, mantra-like feral hymnals based on trance inducing repetition, intoned over by Daniel Higgs’ oblique-yet-enchanting vocals. If you are not familiar then I envy you! Go jump straight into any of their twelve LP’s and get lost. I am sincerely sad that I have never got to see Lungfish play live although I have seen Higgs several times over the years and it is always an utterly transcendental experience which comes highly recommended! Interviews are given rarely by the band but this short radio feature offers an interesting insight and includes Higgs in conversation:
“Serve & Protect” – Citizen’s Arrest
Damn, there’s so many New York bands I could have included that I love to bits for a variety of reasons – Antidote, Judge, Gorilla Biscuits, the freaking Cro-Mags! There is, however, something I find unquestionable about Citizen’s Arrest. Their first 7” is in a small box I have that never goes into storage. Straight up raging hardcore executed flawlessly. 27 years after its release the lyrics to this tune that kicks off that first 7” seem all kinds of prescient and relevant to today’s batshit crazy bowl of bullshit.
“Never Healed” – Heresy
While I’d happened across the crustier/grindier UK underground bands from the mid-80s like Napalm Death, Extreme Noise Terror etc via exploring metal it wasn’t actually until moving to Notts that I discovered Heresy and Ripcord who raged as hard and fast as just about anything. It was a total revelation at the time and I still love both of those bands to bits. With Heresy being from Notts and Kalv and Steve still playing every now and again in town as part of Geriatric Unit I felt a real affinity with Heresy and much later I got an opportunity to help make a documentary about that whole scene for Channel 4 that someone has handily whacked up on Vimeo:
It was also really cool meeting and spending time with Tom Withers aka Tommy Stupid, drummer in The Stupids who went on to become Klute as I was totally into both bits of his recording career. Here’s an absolute beast of an emotional d&b roller that no one does quite like Klute:
More rollers to come when I do my UK hardcore continuum top ten!
“Interplanetary Badboy” – The Lowest Form
Chris is always the last person to blow his own trumpet so I’m not sure he’ll even leave this cheeky eleventh pick in but I hope he does because as well as knowing more about records than ten normal record nerds put together he also sings in one of the best UK punk bands of the last decade. That might sound like hyperbole and it’s perhaps difficult for me to be objective as I know all of the members personally but it’s true. You can ignore me though and take the fact that their two LPs have come out on Iron Lung Records alongside bands like Diät, Cold Sweat and Una Bestia Incontrolable as a pretty solid vouchsafe. So biggup Chris, Michael (go check out his great label Night School – https://night-school.bandcamp.com/ and his solo project Apostile – http://nightschoolrecords.com/index.php/apostille/ ), Luke who also goes by Helm – https://hhelmm.bandcamp.com/ and puts out loads of badboy records on his Alter label – https://alter.bandcamp.com/ ) and Paco (whose La Vid Es Un Mus label is probably the most consistent and prolific underground punk label in the game for both new and re-issue releases and has been for bloody ages – http://www.lavidaesunmus.com/ ) – I am well proud of all you guys!
Thanks Jam!!!!!! Legend!!!!
Jam does Low Bias with Robin:
https://twitter.com/low_bias?lang=en
https://www.nts.live/search?q=low%20bias
Till next week
Reckless!
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Army to Congress: Thanks, but no tanks
By Drew Griffin and Kathleen Johnston
HERLONG, California (CNN) - If you need an example of why it is hard to cut the budget in Washington look no further than this Army depot in the shadow of the Sierra Nevada range.
CNN was allowed rare access to what amounts to a parking lot for more than 2,000 M-1 Abrams tanks. Here, about an hour's drive north of Reno, Nevada, the tanks have been collecting dust in the hot California desert because of a tiff between the Army and Congress.
The U.S. has more than enough combat tanks in the field to meet the nation's defense needs - so there's no sense in making repairs to these now, the Army's chief of staff Gen. Raymond T. Odierno told Congress earlier this year.
If the Pentagon holds off repairing, refurbishing or making new tanks for three years until new technologies are developed, the Army says it can save taxpayers as much as $3 billion.
That may seem like a lot of money, but it's a tiny sacrifice for a Defense Department that will cut $500 billion from its budget over the next decade and may be forced to cut a further $500 billion if a deficit cutting deal is not reached by Congress.
Why is this a big deal? For one, the U.S. hasn't stopped producing tanks since before World War II, according to lawmakers.
Plus, from its point of view the Army would prefer to decide what it needs and doesn't need to keep America strong while making tough economic cuts elsewhere.
"When a relatively conservative institution like the U.S. military, which doesn't like to take risks because risks get people killed, says it has enough tanks, I think generally civilians should be inclined to believe them," said Travis Sharp a fellow at the defense think tank, New American Security.
But guess which group of civilians isn't inclined to agree with the generals on this point?
Congress.
To be exact, 173 House members - Democrats and Republicans - sent a letter April 20 to Defense Secretary Leon Panetta, urging him to continue supporting their decision to produce more tanks.
That's right. Lawmakers who frequently and loudly proclaim that presidents should listen to generals when it comes to battlefield decisions are refusing to take its own advice.
If the U.S. pauses tank production and refurbishment it will hurt the nation's industrial economy, lawmakers say.
"The combat vehicle industrial base is a unique asset that consists of hundreds of public and private facilities across the United States," the letter said. The outlook for selling Abrams tanks to other nations appears "stronger than prior years," the letter said. But those sales would be "inadequate to sustain the industrial base and in some cases uncertain. In light of this, modest and continued Abrams production for the Army is necessary to protect the industrial base."
Lima, Ohio, is a long way from this dusty tank parking lot. The tiny town in the northwestern part of the Buckeye State is where defense manufacturing heavyweight General Dynamics makes these 60-plus-ton behemoths.
The tanks create 16,000 jobs and involve 882 suppliers, says Kendell Pease, the company's vice-president of government relations and communications. That job figure includes ancillary positions like gas station workers who fill up employees' cars coming and going to the plant.
Many of the suppliers for tank manufacturing are scattered around the country so the issue of stopping production or refurbishment becomes a parochial one: congressional representatives don't want to kill any jobs in their districts, especially as the economy struggles during an election year.
"General Dynamics is not the industrial base," Pease said. "It is small vendors."
But General Dynamics certainly has a stake in the battle of the tanks and is making sure its investment is protected, according to research done by The Center for Public Integrity, a journalism watchdog group.
What its reporters found was General Dynamics campaign contributions given to lawmakers at key times, such as around congressional hearings, on whether or not to build more tanks.
"We aren't saying there's vote buying" said Aaron Metha, one of the report's authors. "We are saying it's true in pretty much all aspects of politics - but especially the defense industry. It's almost impossible to separate out the money that is going into elections and the special interests. And what we found was the direct spike in the giving around certain important dates that were tied to votes."
Pease said General Dynamics is bipartisan in its giving and there is nothing suspicious in the timing of its donations to members of the House and Senate. The giving is tied to when fundraisers are held in Washington - which is also when Congress is in session, he said.
Lawmakers that CNN interviewed denied that donations influenced their decisions to keep the tanks rolling.
Rep. Buck McKeon, a Republican from California and chairman of the House armed services committee, said he didn't know General Dynamics had given him $56,000 in campaign contributions since 2009 until CNN asked him about it.
"You know, the Army has a job to do and we have a job to do," McKeon said. "And they have tough choices because they've been having their budget cut."
McKeon said he's thinking about the long range view. "... If someone could guarantee us that we'll never need tanks in the future, that would be good. I don't see that guarantee."
Similarly, his Democratic counterpart on the committee, Rep. Silvestre Reyes, who has received $64,000 from General Dynamics since 2001, said he is worried about the workforce if the Lima plant is closed for three years.
"Listen, we don't want to play Russian Roulette with the national security of this country," Reyes said.
Odierno explained to the committee that it would be cheaper to shut down the tank plant and then restart it in 2017. But his plea was ignored.
"Lima would cost us $2.8 billion just to keep that open and our tank fleet is in good shape and we don't need to because of the great support that we have gotten over the last two years," he told the committee.
But General Dynamics said it will cost a lot less to keep the plant open. Pease said the Army hasn't factored in the huge costs of closing the plant and the potential loss of skilled workers who will be needed come 2017 when the Army plans to remodel the Abrams tank.
"It's not whether they need those tanks, it's how much it costs to restart it," said Pease. General Dynamics, he said, will survive with or without refurbishing tanks over the next three years.
So how did Congress respond to Gen. Odeirno's request to shut down production until 2017?
The answer came in the proposed congressional budget for next year. It includes $181 million for tanks the Army doesn't want or need now. That begs another question: who will likely get the money for the 70 or so tanks covered by that contract when it goes out for bid?
"General Dynamics would probably get the contract for it anyway because they are kind of the ones that are out there leading the way on this," said McKeon.
The Army tank battle sends an unsettling message to the Defense Department, says Sharp, with the defense think tank. But it's a message that may not surprise a public weary from decades of battles and horse-trading that have defined Capitol Hill.
"The fact that the military is having such a hard time getting this relatively small amount of money to be saved, I think is an indication of the huge uphill fight that the military faces when it comes to Congress," Sharp said. "Congress is going to fight tooth and nail to protect defense investments that benefit their constituents and the people that live in their states."
Maybe the next time the generals go up to the Hill, they should take a cue from the well-protected tanks parked in California. Perhaps they might consider wearing body armor.
CNN's Sara Anwar contributed to this report.
Post by: CNN's Drew Griffin and Kathleen Johnston
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Driver Dies In Horrific Fiery 101 Crash In San JoseA speeding driver of a stolen car died late Thursday night when his vehicle careened out of control, slammed into a pole supporting a freeway sign and burst into flames on Highway 101 in San Jose, authorities said.
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Couple's South City Parking Lot Spat Ends With Boyfriend Shot in ChestA 22-year-old woman was arrested after her boyfriend was shot in the chest during an altercation between the two on Saturday morning, South San Francisco police said.
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Suspect Pleads Not Guilty In Fatal Beating At South San Francisco Bus StopA 34-year-old man pleaded not guilty Wednesday to a murder charge for killing a San Francisco International Airport worker apparently at random in South San Francisco earlier this week, San Mateo County prosecutors said.
Peninsula Man With At Least 7 Prior Drunk Driving Convictions Arrested For DUIA man pulled over for speeding on Sunday was arrested for driving under the influence when a test showed a blood alcohol level exceeding .08 percent, South San Francisco police said.
Acclaimed University Choir From Alabama Survives Fiery Hwy 101 Crash in South CityA celebrated church choir from Alabama on its way to San Francisco to perform survived a horrendous, fiery crash Saturday morning.
Former SF, Marin County Substitute Teacher Gets 5 Years For Possession Of Child PornA former San Francisco man was sentenced to five years in prison for possession of child pornography, having pleaded guilty in November to possessing approximately 20 videos and 300 still images depicting children.
3 Sought In South San Francisco Home InvasionThree suspects kicked in the door of a South San Francisco house and then ransacked it early Tuesday morning, police said.
Trio Arrested For Stalking, Robbing South SF Couple After Casino WinThree Vallejo residents are in custody after allegedly following a couple from a casino in San Pablo and then robbing them at gunpoint in South San Francisco last weekend, prosecutors said Thursday.
80-Year-Old Driver Survives Leap From Moving Car on I-280 in South CityAn 80-year-old driver was injured Saturday night when he jumped out of his car as it rolled south on Interstate 280 at the Westborough Boulevard off-ramp.
Proposed South San Francisco Housing Development Raises Earthquake ConcernsAs the city of South San Francisco draws up plans for a proposed new housing community, some are raising concerns about the development's proximity to the San Andreas Fault.
4 South San Francisco Police Officers Injured While Taking Man Into CustodyFour officers were injured while taking a man into custody in South San Francisco on Sunday, police said.
Teen Suspect In Strong Arm-Robbery Arrested In South San FranciscoA 15-year-old boy was arrested in connection with an attempted strong-arm robbery that sent another teen to the hospital last week in South San Francisco.
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#SaveOurHomesLS26
A community's fight to save their historic and affordable homes
History of the Estate
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Author: jlarkspur
We Saved Our Homes!
(For now…)
On Thursday 3rd October Leeds City Council councillors unanimously overturned the Council Policy Officer’s recommendation to approve Pemberstone’s plans. In short: we won!
It was such fantastic news for the community, and showed that there is strong support across the country for putting people before development. We are beyond delighted and the first thing we want to say is THANK YOU!
Thank you to everyone who signed our petition, who shared our tweets, who wrote to local councillors, who posted such excellent objections, who stood outside Leeds Civic Hall with us and for us, come rain or shine. We could not have done this without you.
Thank you to the councillors, past and present, who supported us, raised our voices where it counted, gave us tips and encouragement when obstacles seemed too high, and ultimately who sat around Leeds City Council’s table and defended our right to continue to live in our homes.
Thank you to the civil society organisations who have provided us with so much support and encouragement and from whom we have learnt so much: Hands off Our Homes, National Union of Miners, Leeds Sisters Uncut, and everyone else. Your solidarity and experience made all the difference.
This is a good news post and I hope it gives heart to other organisations. I will shortly add a page to the website that details some of the techniques we used so that you might be able to learn from our challenges and successes, too.
In the meantime, here’s a little more detail on how the Plans Panel went and some of the extraordinary developments that happened over the course of that cloudy afternoon.
From the Public Gallery
A rather large crowd of us had gathered outside of Leeds Civic Hall before we were instructed to go in, collect passes and make our way to the Plans Panel meeting room. We were informed that there was to be strictly no photography and directed to rows of seats on the left of the room. On the right was the rectangular table for the fifteen or so members of LCC that would deliberate on the application. In between us, a no-man’s land of about 6 feet that contained four load-bearing columns, which blocked the view of the panel members for the majority of the audience.
Whether deliberately designed to keep the public at arm’s length, or whether it was a misjudged attempt to inject an ancient Grecian spirit in this space of public accountability, it certainly meant we knew our place.
Our Resident’s Association Chairperson Cindy Readman took a seat near the end of the Plans Panel table as Cllr Caroline Gruen had finally relented and allowed us, and Pemberstone, to say a few more words. A decision well-made (thank you).
The discussion was to proceed as follows: an overview of the updated plans, an opportunity for Cindy and Pemberstone to speak, questions for Cindy and Pemberstone, a discussion amongst the Councillors with clarification from various heads of divisions, and a final vote.
A mouthpiece
First up was the Planning Officer (PO) for LCC. The PO was responsible for reviewing Pemberstone’s updated proposal, determining whether the landlord had done enough to meet LCC’s demands, and advising a decision on the planning application.
And I think we can safely say that if she ever decided to leave LCC, the PO would find happy employment in Worcester at Pemberstone. Not because she supported Pemberstone’s updated application and recommend approving the development – after all, a Planning Officer has to come down one way or another depending on the merits of the proposal. But because she did a better job than Pemberstone’s representative Peter Mondon at skimming over problematic aspects of the proposal and answering councillors’ questions on the development.
For instance, we were presented once again with the problematic and offensive statistics on the transitory nature of the community. While the statistics they presented showed that many tenants have been there for less than five years (and the PO declared that to be “proof” of a transitory community), the figures:
i) excluded those on protected tenancies who have been living there for decades and have deep friendships with the later arrivals; and
ii) didn’t account for the fact that the majority have moved into this estate from nearby streets because rents elsewhere in Oulton are unaffordable.
Hazell, for example, has known two of her neighbours for over twenty years – before any of them moved on to the estate. They all moved to the estate at various times because high rents in the area forced them out of their previous homes. That’s hardly transitory – these friends have stuck together despite market forces trying to disperse them. The fact remains that Wordsworth Drive and Sugar Hill Close are the last bastions of affordable rentals in the whole area
The PO also parroted the arguments that the new homes would have “Airey-inspired” features. She spent a lot of time emphasising the “high quality appearance” of the proposed houses, even ending her presentation with a picture of the computer-generated design. This image was then left as the backdrop to the rest of the panel debate, serving as a crass reminder of the aspiration that councillors shouldn’t vote against.
The presentation would not have been so galling, however, had the PO not been forced to answer questions directed at Pemberstone.
Peter Mondon was asked by one of the councillors – “As per council policy, 10% of the energy for the new houses has to come from renewables. How will you do that specifically?”. Peter’s response? “Perhaps the Planning Officer can answer that as I don’t know off the top of my head and do not have the details in front of me”.
Eyebrows hit the ceiling.
“Couldn’t find a climate change expert”
That wasn’t even Mondon’s most cringeworthy response. Here are some of my favourites, in descending order:
3) When asked what the exact tree loss would be with the demolition, Mondon and his fellow representative from Pemberstone admitted that they yet again did not have figures to hand, but if we could wait a moment, they could count the trees in the pictures on their application. *Awkward silence ensues while they rustle through pages and count out loud, slowly, to seven*.
2) When asked what exactly Pemberstone will do to ensure the properties meet minimum climate standards, Mondon replied, (and I paraphrase here): “well, what typically happens is that you give us the approval and we decide these things later down the line”. To which a Cllr Finnigan enquired to the Planning Officers: “Does that then mean the council have the capacity to test the houses and then tear them down again if they don’t comply?”. Erm, no, not really.
Eyebrows once again hit the roof.
1) But the winner is this elegant race to the bottom came quite early on in the questioning. A councillor put to Pemberstone: “The Council requested, as part of this process, that you provide information on the climate cost estimates of refurbishment versus demolition and new build. You did not comply. We did not receive the information and this meant that Planning Officers in the Council had to do your work for you. Why did you not comply”?
Pemberstone’s answer: “We could not find any consultants for this so we couldn’t do the assessment”.
Pemberstone, a multimillion pound corporation involved heavily in the development sector, could not find one single expert to do a climate cost estimate on a tiny part of their portfolio?
Eyes in the room could not have been wider.
(Peter, if you’re reading this pal, here’s a bit of info to get you started).
Joking aside, the climate change impact of these development plans was a vital consideration in the council’s deliberations, and rightly so. As we have previously argued (alongside scores of academics and developers), refurbishment has a much lower climate cost than redevelopment. While our houses were assessed to have ‘only’ 50 years more of life with full refurbishment, the new development would have a minimum 60 year lifespan – just ten years more. That is simply not good enough. An additional ten years of usability would be nowhere near long enough to mitigate the climate cost of the construction waste and carbon emissions that would result from a full redevelopment. It genuinely makes more climate sense to refurbish.
The Council indicated that their climate targets and building standards are actually set to get more stringent towards the end of the year, and that they wish to be ahead of the curve in making climate-protective development decisions, not simply waiting for the policy to have sign-off before considering them. This is the first step to making these targets a reality.
A turning tide – community matters
Climate change concerns built momentum, and then the panel turned to the issue of community. As the discussions progressed, and so many councillors shared the difficulty of this particular case, the tide seemed to be turning:
Cllr Brooks: “I’m concerned about the loss of affordable rental housing and the impact a mass eviction would have on an already stretched council”.
Cllr Finnigan: “Planning should be about people… houses should be designed around people”.
Cllr P. Gruen: “I think it is right to take the impact on the community as a material planning matter”
Cllr Heselwood: “I am concerned about the loss of affordable rental housing – we are obviously in deficit. We support affordable housing for public sector workers”.
These councillor interventions are significant. So many historic decisions around development have been made strictly on the basis of physical concerns, such as: are the driveways large enough for a car, does the building overshadow any other building? etc etc. This is how panels have long been pushed to understand the law.
But as Cllr Finnigan rightly pointed out, what sits behind those considerations are people. It has to be people. After all, houses are not designed for the mice that inhabit their skirting boards or the sparrows that occupy the eaves.
Chair of the panel Cllr Caroline Gruen noted the shift stating that, “community cohesion seems to be the big tip”. And when she took a vote, it was unanimous. The recommendation to approve the proposal was overturned and the development rejected.
In addition to the issue of community protection, councillors also cited the reason for refusal that – as a nod to more conservative understandings of planning law – 14% of the gardens still remain smaller than the guideline minimum. (Come on Pemberstone, that could have been an easy win, surely?)
And then it was done.
We filed out of the room flabbergasted and delighted in equal measure.
This is a HUGE victory for the campaign, but it’s not quite the end. Pemberstone can appeal the decision, which we will find out in due course. And ultimately, the rejection of the development plans still doesn’t enhance our protection as tenants – we continue to live in a country that puts rental profiteering before tenant protection.
But it’s a significant step in the right direction – and one that we are damn proud of.
jlarkspur Uncategorized 1 Comment October 12, 2019 October 12, 2019 7 Minutes
October 3rd has been confirmed.
At 13:30 this coming Thursday, Leeds City Council Plans Panel will meet to decide the fate of our homes and our community.
Will we get the chance to represent ourselves at this life-changing meeting? NO!
Cllr Caroline Gruen, Chair of Plans Panel, has decided we cannot speak.
In May , we were given just four minutes to speak in defence of our houses, our community and our lives; this time, we are given none.
This is despite Leeds City Council declaring at the last Plans Panel meeting that they needed to learn more about the impact any eviction will have on our community. This is despite the extraordinary impact any decision will have on our lives and the environment. We are not alone in feeling this is a kick in the teeth.
Lib Dem Councillor Stuart Golton says that Cllr Gruen is prioritising timekeeping over people’s lives.
Lib Dem Councillor Carmel Harrison has called it undemocratic.
Indep Cllr Mark Dobson has called it a disgrace and has complained to the Director of City Development.
Thank you for raising your voices!
Why are we being silenced? Is the decision already made? This censorship is adding to a heap of anxieties that our neighbours are already experiencing.
Who will speak about the SOCIAL IMPACT the demolition will have on our community?
Who will speak about the ECONOMIC IMPACT that eviction will have on residents and the Council, when 70 families turn up at their door, homeless.
Who will speak about the HERITAGE IMPACT this demolition will have on the local area?
Who will speak about the CLIMATE IMPACT that demolition and construction will have on the environment?
Even though we can’t speak at the Plans Panel meeting, we will still make our voices heard.
Join us outside Leeds Civic Hall on Thursday 3rd October at 12:30pm to protest.
You can also Tweet Cllr Caroline Gruen @CllrCarolineG and urge her to change her mind about allowing us to represent ourselves.
HELP US #SAVEOURHOMESLS26
Thanks to all who continue to support us.
Huge thanks to Leeds Sisters Uncut for protesting against our potential eviction.
Neighbours from Wordsworth Drive and Sugar Hill Close outside Leeds Civic Hall in 2018
jlarkspur Uncategorized Leave a comment September 28, 2019 September 28, 2019 2 Minutes
Social Vulnerability, Greenwashing and Airey Imitation
Pemberstone’s updated plans for the estate
Here we are again. Decision Time.
October 3rd is currently, albeit tentatively, scheduled for the next (and possibly final) Leeds City Council meeting where the fate of our homes will be decided. We won’t have confirmation of that date until the 24th or 25th September, just one week before the meeting. This already puts our community at a disadvantage.
While the planning application is part of Pemberstone’s asset portfolio – so they can ship a colleague up from Whittington Hall in Worcester at short notice – we have to try to save our homes around working lives, family lives, and health issues. It is not straightforward to take annual leave at the drop of a hat (nor to waste a day on an unconfirmed date) when you work for the NHS or in a school or have childcare responsibilities. Leeds City Council should know this, as a public institution themselves, and yet here we are.
Now, back to the application at hand. What have been the latest developments? Well at the end of May this year, LCC decided that, in order to come to a decision, more information was necessary and changes to the planning were required:
From a social perspective, they declared the need for more information on the impact it would have on current residents and the housing needs of the community.
From an environmental perspective, they were concerned about the impacts of the proposed demolition and whether the planned development would worsen Leeds’ carbon footprint.
From a structural perspective, they wanted changes in the design and layout of the estate, as they were concerned about the aesthetics of the new houses and the reduced size of the gardens.
On 6 September 2019, Pemberstone added a range of new house designs and a policy statement.
What has changed on paper? Beyond that, what has really changed? Let’s take a deeper look (and be warned: this is a long post).
In a nutshell, Pemberstone have reduced the number of 4-bed houses by 5, adding one more 3-bed and one more 2-bed, but reducing the overall number of houses to 67. They claim that the energy efficiency of the houses will be better, the houses would now be able to accommodate solar panels on the roof, and – although the garden sizes have not changed – they kindly reminded us that such green spaces can be used ‘for horticultural purposes or as a convenient place for fresh air to improve occupier quality of life’. (I do hope they’re not trying to take credit for oxygen). The appearance of the houses, too, has changed – more on that shortly.
Where are the social impact surveys?
One glaring absence on LCC’s Planning Portal is the information around social and community impact.
In January 2019, LCC send around an Equality Information Form for residents to fill in. Not for all residents, mind you – there were not enough copies delivered to the estate, and one of our poor neighbours received letters for 3 other households, with all missing the form itself and the return envelope. Despite this haphazard delivery and distribution, we filled in the forms we had in good faith. What has happened since? Nothing.
We have not been provided any synthesis of the results, no hard data on the vulnerabilities of our community. Of course the personal details on the surveys must be kept confidential, but it is troubling that we have not received any notification of the findings, via mail or on the planning portal. It is troubling for three reasons.
This is our data, that we provided in good faithin the hope that it will contribute to our objections against the planning and the eventual refusal of the application. Even if we cannot see the findings, LCC have at least the obligation to explain how they are using it – at the very least it will reassure us that the information has contributed to something (which we can’t be confident of, given the haphazard way in which they collected it).
It is troubling because it underscores the asymmetry of resources we face in this fight to save our homes. As we have explained in a previous post, Pemberstone have the money to muster up studies to support whatever claim they wish to make. We do not. This survey is of vital importance to our claims of vulnerability, and yet we have had no sight of the findings.
LCC’s lack of data sharing materially disadvantages our case. The only means that we have as a community to fight this application is through the planning portal on LCC’s website. This portal is meant to be a repository where allpaperwork related to planning is shared so that all parties have sight of it and can mount a reasonable argument in support, or against, the application. Pemberstone are able to share any number of documents that enable them to make their arguments. We are not able to see one of the key documents that will enable us to make ours.
ON TOP OF THIS: As part of the deferral decision in May 2019, LCC committed to look into the social impact that eviction would have on 70 low-income families with “protected characteristics”, as they termed it. What this suggests is that Plans Panel members took the results of the January survey seriously, and that they were concerned how our vulnerable community might be affected by mass eviction.
Absolutely nothing has happened since then. No follow up survey to see what the impact might be for each family, no consultation with residents, and still no sharing of the original results.
Has resident vulnerability ceased to matter?
Some of our neighbours facing homelessness
Total Greenwashing
Now onto the changes that are meant to address LCC’s concerns around the carbon footprint of the new development.
Pemberstone have proposed that the new buildings would be more energy efficient than the current properties because of improved insulation and more modern boilers; because the new dual-flush toilets would mean less water wasted per resident; because health and well-being will be improved by gardens and windows; and because some of the properties would now face southwards in order to improve “solar gain”. Let’s take each of these in turn.
Improved Efficiency
What is unsaid in this policy document is that Pemberstone has the authority to make many of these changes already to the current housing stock,which would ultimately be cheaper, faster, and more environmentally-friendly than demolition and rebuilding.
For instance, yes, it is true that the energy ratings of most of our homes are between Energy Efficiency Rating D and E (which is currently the average energy efficiency rating for houses in England and Wales).
However, there are also houses on our estate that are “C” grade, which is a satisfactory level of energy efficiency according to UK guidelines. And, importantly, there are simple ways to improve the energy efficiency rating of the “D” and “E” grade houses to make them “C” and “B” rated, including: double glazing, fitting doors that seal, boiler replacement, and installing an efficient secondary heating source (all things suggested in their plans for the new houses). These changes should have been done to our Airey homes by Pemberstone already. But it is never too late – they can be done now and do not require demolition and refurbishment to achieve.
The same is true for the dual-flush toilets and restricted-flow showers and taps – these can be retrofitted across all 70 properties without delay and this can save dozens of litres of water daily for residents.
A 2014 study by University College London(pdf) found that, “even older, high rise or poorly insulated structures, known as hard to treat buildings, can be retrofitted to achieve high energy efficiency standards”. The real environmental damage in these developments comes from construction. In the same study, researchers reported that:
The construction and demolition sector contributes 35% of all waste in the UK every year. Much of this is due to demolition waste… Recycling demolition waste reduces the environmental impacts of demolition, but refurbishment avoids waste to landfill and many of the environmental impacts of new construction.
In other words, Pemberstone (or LCC) can achieve a positive environmental impact for the area by refurbishing their current housing stock. Demolition and reconstruction will only contribute to Rothwell and Woodlesford’s landfill waste output.
This is important for Leeds City Council’s environmental agenda. Less than a decade ago, Leeds City Council was the only the second local authority in the country to commit to a government-backed scheme to reduce construction waste to landfill (2012 Construction Commitment, Halving Waste to Landfill). Is this still a priority for the Council? If not, why not?
Blue sky thinking
Elsewhere in the updated plans, Pemberstone appear to lay claim to the benefits of fresh air and sky, reporting that these new houses will have gardens that contain fresh air and windows that will enable residents to see the sky.
Beyond the obvious arguments that gardens and windows already exist in the current properties, there is a point to be made about what ecological impacts demolition will have as the properties are redeveloped with much the same benefits. As John Davies(pdf) has cogently argued in his recent objection, existing trees, hedges and green space will all need to be dug up in order to develop these new gardens – destroying already existing habitats and natural buffers against carbon dioxide.
“Solar gain”
Now for the argument of “solar gain”. Some of the new houses, according to the updated proposal, will be orientated southwards and have roof space for solar panels. Hurrah, the earth is saved! Does this mean Pemberstone will construct them with solar panels? No. Does this mean new homeowners will be obliged to fit solar panels as a condition of purchase? Of course not. What this means is the houses can, theoretically, be adapted to take advantage of renewable energy.
The theoretical part here is important. While renewable energy adaptations to buildings are essential in order for the world to reverse the trend of carbon emissions and fossil fuel usage, we have to be wary of greenwashing (i.e. misleading claims about environmental benefits of a scheme or service). Without new homeowner enforcements (or even incentives) to get solar panels, it is no more likely that new residents will install them than it is they will take up vegan diets or eschew cars in favour of bicycles.
Anything that is down to individual choice cannot be considered in the deliberations around planning.
The concrete facts of these updated proposals are that: all of the energy efficiency measures in the new houses are already possible in the current housing stock, and no evidence has been put forward that the efficiency gains in the new houses will offset the negative environmental impacts of demolition, construction waste, and nature loss.
If LCC consider that the new rooves *may* encourage the use of solar panels, then they must also consider that the increased number of 4-bed middle-class houses *may also* result in a rise in car ownership per household, as we have previously reported. Does solar energy offset car pollution and the impacts of increased traffic?
Mimicking history
Last but not least, we come to the new design of the houses.
In the last Plans Panel meeting, LCC members remarked that the original design of the proposed houses left a lot to be desired, with the suggestion that Pemberstone should go back to the drawing board. And re-draw them they did, introducing ‘additional character which draws inspiration from the Airey Housing’ (see picture below).
A screenshot of the ‘Airey inspired’ design proposed by Pemberstone
This part of the proposal is disingenuous to say the least. Part of our campaign to keep our homes is because of their historical value as a uniquely large sample of post-World War II ‘homes for heroes’. As we have written elsewhere, Sir Edwin Airey himself was a local designer and our homes are a standing example of social history. They are distinctive in their design, important for their place in post-war industrial history, and they have attracted a lot of attention nationally and locally.
For the last two years in a row, English Heritage and Leeds Civic Society have organised coach tours of interested visitors to come to the estate, tour our homes and learn about the area’s coal mining and working class past and present.
The idea that any of this working-class architecture and heritage can be replicated or paid homage to by demolition and the construction of a middle-class housing estate is simply laughable. The proposed houses look nothing like the Airey originals, and as soon as the current estate is demolished, Leeds City Council will lose that heritage forever.
Middle-class mimickery of local working-class history doesn’t cut the mustard, I’m afraid.
Heritage Open Day visitors enjoying the real deal in 2018.
So, there we have it; Pemberstone’s latest offering: no mitigation of social vulnerability, total greenwashing and Airey imitation.
Will it still be enough to render us homeless?
Join us outside Leeds City Council on 3rdOctober to protest and find out.
jlarkspur Uncategorized 1 Comment September 22, 2019 September 22, 2019 9 Minutes
Open House, Happy Homes: It was Heritage Open Day again in Oulton
On Sunday 15 September, residents of Sugar Hill Close and Wordsworth Drive once more opened their doors to history buffs and post-war architecture enthusiasts with the Heritage Open Day, organised by Leeds Civic Trust and English Heritage.
Dozens of people visited from far and wide to explore the houses, their gardens and the history of the street – guided by Cindy and John Readman and Hazell Field from Wordsworth Drive.
Visitors asked thoughtful questions about the history of the properties. As we’ve shared in previous posts, our Airey homes are as local as they come… Sir Edwin Airey himself was a Leeds man, and the first prototype of this type of house was built in Seacroft.
Cindy and John warmly welcomed the visitors into their home and talked them through life then and now. As well as receiving more visitors across the time-slots than originally expected, the local wildlife seemed to show an interest, too! A tiny hedgehog wandered by.
We’ve had a lot of little hedgehogs in the estate recently, which shows our houses and hedges provide happy homes for more than just our families.
jlarkspur Uncategorized 1 Comment September 18, 2019 September 18, 2019 1 Minute
Decision Deferred
Case heard
Leeds City Council (LCC) Plans Panel met on the 30th May 2019 to discuss and decide the fate of our community and our homes. To begin the day, members of Plans Panel took a tour of the estate, which is usual practice for planning decisions to help them put an application into context. Physical context, mind you – none of that wishy washy social stuff. As per the laws of planning, Council members are not permitted to interact with residents on a walk around (!), so all our neighbours could do that morning was stand in their windows or gardens and remind Panel members of their human connection to the concrete under assessment. Doing this and not looking creepy is a difficult feat, but we had to remind LCC that this campaign is about homes *and* people, not just houses.
Getting ready for the Plans Panel visit
Then, at 13:30, back at Leeds Civic Hall, Plans Panel members sat and listened to points put forward by Pemberstone on the one side, and neighbours, councillors, the National Union of Miners and other supporters on the other. For detailed coverage of particular arguments, see the comprehensive coverage of the session in the Yorkshire Evening Post.
Of particular note was the moment the room burst into scoffs and laughter, as Pemberstone’s representative declared that our houses are under a programme of continuous maintenance, and that they spend “tens of thousands every year maintaining the properties”. Hmmm. Let’s see what those figures translate to:
(Mis)calculations
A UK Government report on private registered providers of social housing recorded that, in 2017, private providers were spending a median of £3,298 per housing unit that year on management, major repairs and maintenance. Taking that as a benchmark figure, this would mean Pemberstone, across 70 houses, should spend £230,860 annually on keeping the entire estate up to decent standard (and the costs are even higher for older housing stock). Even a generous reading of “tens of thousands” doesn’t add up to £230,860.
What did they mean, then? Perhaps they meant *planned* maintenance expenditure only, and not emergency repairs. Well, the average for that, according to the same report, is £1000 per household per year, which would mean Pemberstone should spend £70,000 annually in our estate to keep all of the houses up to a decent living standard. What *planned* repairs have we seen for this amount? Virtually nothing proactive, which has resulted in our homes falling into major disrepair. In recent years we’ve seen:
One neighbour waiting more than 18 months (when she sadly passed away) for a rotten window replacement;
Another neighbour waiting since September 2016 to have broken light fittings repaired;
A neighbour waiting over two years to replace her damaged floors;
Several neighbours waiting weeks and months for urgent replacements of showers, doors and other essential infrastructure. The list continues.
The Council should be asking for records of maintenance and major works expenditure in the estate over the last decade to put into context Pemberstone’s assertions that these houses have received all due care and investment to date.
In the meantime, back to the update on LCC Plans Panel meeting…
Can kicked
After hours of deliberating, the Panel didn’t get beyond community issues to talk about planning. It was highlighted that many members of the community are elderly or have disabilities, which are “protected characteristics”. Many declared the development plans to be a situation of social cleansing that threatens to make vulnerable people homeless. Councillor Caroline Gruen admitted: “This is the most difficult decision the panel have had to make in its history.”
And so make it they didn’t.
A motion was passed to defer the decision. Councillors agreed that they need to receive more information on issues such as the design and layout of the estate, the impact of the development on the community, and the desirability of the housing mix. They also agreed of the need to know more about housing need for the local community.
While we are all grateful that the decision wasn’t an approval for the plans, surely the above information should have been comprehensively sought as soon as the application went in?
We don’t know exactly what will come next, but this deferral has given us additional breathing room and more time to snowball the campaign. It’s is a small win of sorts, so watch this space.
A huge thank you to all those that turned up on the day to support us in the LCC Plans Panel meeting and cover our story. Particularly: Chris Kitchen of the NUM, Stewart Golton of the Lib Dems, Karen and Stuart Bruce of Labour, local news stations, newspapers, other media and all the lovely folks who gave up their afternoon. The fight continues!
jlarkspur Uncategorized Leave a comment June 26, 2019 June 27, 2019 3 Minutes
We have just four minutes to save our homes
This Thursday, 30th May just after 1pm, Leeds City Council will hear the planning application for the demolition of our beloved homes. It’s crunch time.
We’re going to need all the support we can get – not least because we only have 4 minutes to remind the Council of our plight. Just 4 minutes… divided between resident Cindy Readman, National Union of Miners’ Chris Kitchen, and Lib Dem Councillor Stewart Golton. Ninety seconds each.
Four minutes to save safe gardens and streets for our children (Photo Credit: Sarah, resident).
We’ve had a glimpse of which way Leeds City Council might lean – the Plans Panel officer overseeing this application has concluded that there are no convincing and reasonable planning grounds to refuse the proposal. “Sorry, what?” I hear you say. Indeed.
This recommendation for approval comes in spite of public recognition that the demolition will:
Break up a close knit community of low income pensioners, families, young couples, and individuals who all rely on each other for companionship and daily assistance;
Destroy architectural and community heritage – one of the largest Airey estates in the country and still housing many ex-miners and their families;
Not contribute any increase in housing stock in the Oulton, Rothwell and Woodlesford area, contravening the National Planning Policy Framework;
Reduce the number of affordable rentals in Oulton, Rothwell and Woodlesford – an area where ONE family might have to wait over SEVENTY WEEKS in emergency accommodation for a council house to become available;
Add a significant carbon footprint to the area with the years-long construction process and the nature of vehicles that typically accompany inhabitants of executive housing;
Legitimise a culture of “managed decline” whereby landlords undertake bare minimum maintenance while accumulating rents until they decide an asset is not profitable enough.
These objections are not only from the mouths of the residents who potentially face homelessness in a number of months; they have come in the form of 64 third party objections and 2,200 petition signatures.
And these aren’t just any “third parties”.
Pemberstone’s planning application has been objected to by: Conservative MP Alec Shelbrooke, the local Labour Party, the local Lib Dem Party, the Oulton Society, the National Union of Mineworkers, Leeds Civic Trust, Oulton Health Centre, the Twentieth Century Society, Hands Off Our Homes, the Prefbab Museum, the Outer South Community Committee, scores of individuals and more than 2,200 petitioners – AND IT STILL GETS RECOMMENDED FOR APPROVAL?
As we’ve written elsewhere, there is a worrying culture of “Pavements Over People” in council decision-making around housing developments (i.e. planning law cares about width of pavement and height of houses etc much more than the people). But this does not mean councillors have to agree with this status quo – especially when precedent has emerged elsewhere of a different way forward (see Foxhill in Bath).
Pemberstone have of course been attempting to rebut all objections with carefully-timed reports*. One of their latest is a “Travel Plan”, which suggests new inhabitants of these executive houses can abandon their gas-guzzling vehicles by taking advantage of apparently excellent public transport links. These include a bus service in the estate, bus links in walking distance on Wakefield Road and walkable supermarkets.
Excuse me while I choke on my tea.
Paragon Highways, authors of the travel plan, have obviously never actually visited Wordsworth Drive and Sugar Hill Close before. And certainly not by the 446 bus. If they had, they might have a better idea of the reality: unreliable buses that fail to turn up on time (if at all); timetables that mean working people have to leave an hour’s commute for somewhere only 20 minutes away by car; expensive daily fares; weekly passes not available on buses but in city centres miles away; and an unsafe crossing to reach the bus stop.
Ahh, the joys of public transport. The 153 runs every 90 mins between 09:30 and 15:30. Perfect for getting to work. If you work part time. In Rothwell or Castleford. (Photo: Hazell, resident).
A supermarket in walking distance? Yep, there’s nothing like a 2 mile-round walk to Lidl, up- and down-hill with a zimmerframe. Doesn’t matter how many Public Transport Ticketing gimmicks Pemberstone can offer new executive residents, it’s not going to make the 446 run on time. Or the 153 run to normal office hours.
Terrible public transport, no local shops. For Pemberstone to pretend otherwise is a sham. The fact that there is any sense of community in our estate in these isolated circumstances shows just how precious it is. And it undermines any argument that Pemberstone might put forward about future residents reducing car usage.
Our neighbours already share cars, take the few buses on offer and walk where they can.
These details matter. And they’re what we have to try and get across when we address Leeds City Council on Thursday. Can you support us?
Help us save our homes in four minutes. Join us at Civic Hall on the 30 May just before 1pm.
* Pemberstone’s reports are as reliable and content-rich as the morning’s bowel movements. A week or so before LCC Plans Panel are anticipated to meet (usually at the end of the month), Pemberstone has been known to drop a hefty, and mightily expensive, consultant’s report in the document portal of the planning application. Could this be a tactic to prevent anyone from mounting a decent response (or the council from reading it through in detail)?
jlarkspur Uncategorized 1 Comment May 26, 2019 May 26, 2019 4 Minutes
Local elections 2019: A thank you and a welcome
Last Thursday saw local council elections that shook the country, as well as our small estate on the outskirts of Leeds. Nationally, the country told the government via the ballot box: things have got to change. The Tories lost a humiliating 1300+ seats, Labour lost over 80, while the Lib Dems, Greens and various Independents swelled their councillor numbers. It remains to be seen whether politics at the top will see much of a change as a result.
Regardless, these were local elections and, locally, we also saw a significant change that reflected the national mood. Last Thursday Karen Bruce, Labour Councillor for the Rothwell Ward, lost the seat she has held since 2011.
Karen Bruce (third from left) with fellow Labour member David Nagle (third from Right) and residents of Wordsworth Drive and Sugar Hill Close
A Thank You
Karen has taken a special interest in our campaign. She has worked really hard in public and behind the scenes to make sure our voices were heard and to support us to keep our homes. She has joined us in marches, organised council meetings, supported fundraising and offered the helping hands of her family whenever she could. Karen: thank you for all of your hard work. We appreciate it from the bottom of our hearts. We hope you can still be a part of the campaign whatever you choose to do next, and you will always be welcome on the estate for a cup of tea and biscuits. Thanks to you and all of your Labour colleagues.
The seat was won by Councillor Diane Chapman of the Liberal Democrats. Congratulations and welcome Diane! This is the first time Diane has stood as a candidate and she joins Lib Dem councillors Stuart Golton and Carmel Harrison who have also long-supported our campaign to prevent eviction.
Diane has lived in Rothwell most of her life, organising many of the town’s festivals as she sits on the Rothwell & District Carnival Committee. Diane: we really look forward to seeing you on the estate and very much hope you can continue to support the campaign for us to keep our wonderful Airey homes. Do pop over for a cup of tea any time!
Lib Dem councillors Stewart Golton and Carmel Harrison (first two from left) and ex-Labour Councillor Karen Bruce (centre). Photo: Twitter @GoltonStewart
jlarkspur Uncategorized Leave a comment May 6, 2019 2 Minutes
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Sherri Wilson Johnson
Where Faith and Fiction Collide
ABOUT SHERRI
CrossReads Merry Christmas Sale & Gift Card Giveaway!
Posted bySherri Wilson Johnson December 26, 2013 December 23, 2013 Posted inBooks, Fiction, InspirationalTags:Book Sale, Christmas, CrossReads, fiction
Welcome To Our Christian Christmas Book Sale!
Where we invite you to pick up good books for less this Christmas!
Merry Christmas! We hope you’re having a wonderful Christmas season. We know that this is the time of year when many readers are given eReaders and gift cards and we wanted a way to help you make the most of your gifts. So from now through Saturday (December 25-28th) we’re offering over 20 books for only 99 cents each.
AND we have one more gift for you! You can enter to win a $25 Amazon gift card by sharing this book sale with your friends and connecting with some of our authors across the web.
So load up on books this season with the Christian Christmas Book Sale – and be sure to tell your friends!
The books from our book sale are listed below – Fiction first, followed by Non-Fiction, and then the giveaway – enjoy!
Fiction:
To Protect & Serve by Staci Stallings
Houston firefighter, Jeff Taylor is a fireman’s fireman. He’s not afraid of anything, and no situation is too dangerous to keep him on the sideline if lives are at stake.
Lisa Matheson runs a semi-successful ad agency that’s on the brink of falling apart. Her employees are incompetent and her schedule has become exhausting. When she takes on a client with a brilliant idea for a big conference, she thinks that maybe, finally this is her lucky break. However, the fire station wasn’t what she had in mind for finding conference speakers. When she falls for a handsome but shy firefighter, it’s possible that life might just be going her way for a change. The only problem is she can’t control Jeff and the death wish he seems to have…
Get Your Copy Now For Only $0.99:
Eternity by Staci Stallings
Aaron Foster thought he had the perfect life until his fiancee walked out of their apartment and then back in again with his new roommate. In desperation Aaron and his best friend, Harmony Jordan, devise The Plan to save Drew’s heart from getting shattered, but when The Plan succeeds beyond their wildest expectation, it could spell heartache for them all.
Reunited at Christmas by Debra Ullrick
Contemporary Christian Romance
Search and rescue dog handler Shelby Davis is living the dream. Not only does she train search and rescue dogs, but she’s a bestselling suspense author who has waterfront property in the beautiful mountain town of Grand Lake, Colorado. All is well until she receives a call to bring her dog Max and her snowmobile to help rescue a man who is lost in a blizzard up on Gravel Mountain. That man is the one person she never wants to see again—Ryker Anderson—the man who broke her heart the day he called three months before their wedding to say goodbye with no explanation as to why.
After being gone for eighteen months, Ryker Anderson is back in Grand Lake where he hopes to win back the woman he loves. He only hopes Shelby understands why he left. Will he be able to convince Shelby that she can trust him with her heart again even though he broke it before?
Déjà Vu Bride by Debra Ullrick
Furious with God, Olivia Roseman vows to never trust Him again. Why should she? Once again her prayers have gone unanswered, and once again another loved one has been ripped from her. With no job and only a few dollars, Olivia makes a choice to start over again. Without God and without love. However, her handsome new boss isn’t going to make forgetting God or keeping her vow to never love again very easy. Erik Cole questions the sanity of his moving from Swamper City, Alabama to Charity, West Virginia. That is, until he hires airbrush designer Olivia Roseman to paint his monster truck. When he senses that she’s a gal who is down on her luck, he vows to do whatever he can to help her. Only problem is, the little beauty creates more challenges than one. As his feelings toward her deepen, all Erik can do is hope and pray that one day Olivia will open up her heart to Christ—and to him.
Prince of Alasia by Annie Douglass Lima
Adventure/Fantasy
Twelve-year-old Prince Jaymin, heir to the throne of Alasia, barely escapes with his life when invaders from neighboring Malorn attack. Accompanied by Erik, his young bodyguard and friend, Jaymin flees to a nearby town to live in hiding. There, coming face to face with the hardships suffered by the poor, he determines to improve his people’s lives someday when he takes the throne, assuming he can reclaim his kingdom.
In the Enemy’s Service by Annie Douglass Lima
When the Malornian army invaded Alasia and Prince Jaymin was forced to flee for his life, what happened to those left behind? In the Enemy’s Service tells the story of ten-year-old Anya, imprisoned among other survivors and forced to work for the occupying troops. While pretending to follow orders and serve diligently in the palace, Anya discovers ingenious ways to spy on enemy officers and slip valuable information to the Alasian resistance.
But as she helps to craft plans that may eventually free Alasia, Anya accidentally uncovers a disturbing reference to her own family. Her fears are strengthened when she is confronted by a mysterious Malornian who seems somehow to know the truth behind the role she has been playing. Holding her life in his hands with that knowledge, he claims to bear information implicating her father in the betrayal that led to the Invasion itself.
The Fall by Chana Keefer
Rapha, once Lucifer’s best friend, had a front-row seat for every crucial moment that shaped the world we live in today. This faithful angel wants to tell you his story. But beware, this is not a journey for the faint-of-heart. Ahead there be giants–plus demons, centaurs, mermaids, demi-gods and war that extends from the beginning of time. In the tradition of J.R.R. Tolkien, C.S. Lewis and Frank Peretti, THE FALL (The Rapha Chronicles, Book 1) melds science fiction, fantasy, epic adventure and mythology.
Why We Give Gifts At Christmas by Corine Hyman
Christmas gifts … a Christmas tradition as old as Christmas. However why do we give gifts to each other at Christmas time if it is Jesus’ birthday? This is a question that everyone has wondered at least once in their life. However, few have been able to come up with an answer. Join Evelyn and her friends as they discover the reason why we give gifts to each other at Christmas time if it is Jesus’ birthday.
Pibbin the Small by Gloria Repp
His friend is hurt and the doctor lives far away.
He might run into snakes. Or that giant bullfrog. Or Black Snapping Crabs!
Is Pibbin too small to be brave?
The Captives by Precarious Yates
“When the caveat whale is gone, the time of the end has come, but the rise of Shunda will stem the tide.” Three lives weave together inextricably. They fight against the MerKing to rescue the captives. Can they trust themselves in their fight against this mutual enemy? Can they trust one another?
Times of Turmoil by Cliff Ball
In this prequel to Times of Trouble and Times of Trial, we follow how the Evans family gained their riches and eventually their power to influence events in the United States. We see important events that the Evans family gets themselves involved in: such as the return of the Israelites to Israel, the assassination of President Kennedy, the terrorism of 9/11, and eventually events that lead to government tyranny in the United States with the sole purpose of destroying Christianity and its influence in the United States.
Times of Trouble by Cliff Ball
FBI Agent Brian Atwood is used to danger, and when he hunts down leads to a terrorist plot and saves a U.S. Airbase, he’s eventually offered a position to be the personal bodyguard of the President of the United States. The job not only tests his skills as an agent, but also his faith as a Christian when he discovers that the President has the morals of an alley cat. As Brian tries to come to terms with doing his job and having to look the other way, his world begins to crumble. His wife is dying of cancer and his son was taken away by the government because he has Down Syndrome. What else can go wrong? As the U.S. disintegrates, Brian must try to keep his family safe before the end times.
Times of Trial by Cliff Ball
This is the story about three Christian families who experience the persecution of Christians first hand when the U.S. becomes a Police State. Two of the families get rounded up by government forces as the President declares a dictatorship, initiates Michael Evans’ Order 21, and lays the U.S. on a course that will mean its ultimate destruction. The third family make their way from Arizona to Wyoming, where they hope a town built by Doomsday Preppers twenty years earlier will keep them safe. Micheal Evans also tries to manipulate events in the Middle East to try to to bring war between Israel and Iran shortly before the end times.
Amish Knitting Circle Christmas by Karen Anna Vogel
Granny Weaver started a knitting circle believing women are stronger spun together, just like her wool. But she was young once with her own struggles. In 1963 Deborah Byler is twenty-one and has turned down seven marriage proposals from hopeful suitors in Millersburg, Ohio. At her parent’s request, she goes to live with relatives in the new Amish settlement in Smicksburg, Pennsylvania, praying she’ll find a match. Jeb Weaver lives in a strict Swartzentruber Amish settlement, and he can no longer abide under the rules of the Ordnung. His older brother left the family farm and settled in Smicksburg, and convinces Jeb to do the same. When Jeb meets Deborah, he finds her too liberal and outspoken. Deborah thinks Jeb’s judgmental and a complete stick in the mud. Their constant clashing makes sparks fly. Will an African American man, who hitchhikes around the country to attend Martin Luther King Jr. marches, help Jeb and Deborah see their own prejudices?
Winter’s Past by Mary E Hanks
When Winter is scheduled to speak in Coeur d’Alene, Idaho, a city she’s avoided for ten years, she must face two things. Her past. And the fact she hasn’t forgiven Ty Williams, her ex-husband.
But when Ty shows up at the meetings, Winter is shocked by the change in him. Radically different from the self-absorbed guy she remembers, he stands before her crying—crying!—and humbly asks her forgiveness. This man who broke her heart, betrayed her, is now gut-wrenchingly sincere in his apology, prays for her like a long-lost friend, and he has a request. One unbelievable request that could change everything.
A Quest For Skye by J.L.Rothdiener
Doctors Morgan and Tammy Hamilton take a vacation from their pediatric clinic in Saint Paul, Minnesota to board a cruise ship for the Mediterranean. Devastated by Tammy’s third miscarriage and the news that she will never be able to bear children, the couple hopes to use the fourteen day cruise to regain their emotional footing. But life has other plans for them. Among the passengers is Skye, a nine-year old girl with an irrepressible spirit, and a passion for living that touches everyone around her. Infused with hope, and a belief in a loving God, Skye becomes the daughter that the Hamiltons could never have.
But despite her open and honest nature, Skye is surrounded by ominous questions. Was the accident that killed her parents truly an accident? Or was it sabotage? Why are news reporters hounding this innocent child? What secrets are concealed in the laboratory on the island of Kardia? The truth – if they ever find it – can bring a government to its knees, and thrust national power into the hands of men who will mot hesitate to shed the blood of innocents..
The Quest For Forgiveness by J.L.Rothdiener
Singer-songwriter Briana Bays rose from obscurity to the center spotlight. She had everything… fame, talent, beauty, and one of the most successful music careers in history. The world was her stage, but the screaming adulation of her fans could not fill the hole in her heart. Her past was shrouded in shadows, some of her own making, and some of which she was trying desperately to pierce.
No amount of success could bring her the one thing she needed most… forgiveness…
The Twelfth Juror by Alexandra Swann and Joyce Swann
Young, beautiful, ambitious Megan Cleary seems to have the perfect life: a dream job in a prestigious law firm in New York City, an upscale boyfriend, and a fabulous apartment. But her perfect world is shattered when one night, while she is working late, she is brutally beaten and raped by a stranger. Afraid and ashamed, she refuses to admit what has happened to her, but she cannot forget her terrifying ordeal, and shortly afterward she illegally buys a handgun to protect herself. A few months later Megan is attacked again, but this time she is armed and ready. She shoots her assailant and flees the scene before the police arrive and discover the body. She never tells anyone that she owns a gun, or that she has killed a man, but her professional and private life begins to unravel as she struggles to gain control of the fear and guilt from which she cannot free herself. When events beyond her control leave her financially destitute and emotionally drained, she returns to parents’ home in Buffalo to start over. This page turning story of loss and redemption will leave the reader guessing to the very end.
A Thing Devoted by Lotis Key
A Thing Devoted chronicles two years in the life of a Christian family devastated by adultery and divorce.
Three, adopted, multi-racial children, struggle with the question of God’s seeming indifference to their pain. Ten year old Abster, a tiny spy in the house of loss and confusion, keeps a daily record of her observations. This intimate story of one family’s journey through fire, considers the purpose of suffering, its defining nature, and ultimately its life giving power.
Before The Beginning by Tina Webb
In eternity, the eons are endless and creativity continuous. The species of Homo sapiens created in Eden was unique….but not totally original. Heavenly beings resembling modern man had been created long before Adam, and some of them once lived on Earth.
Existence on earth is utopia until Helel Ben Shachar, beautiful and loved, becomes a rebel and a liability to Earth’s mission. A contagion strikes those who agree to worship Helel. Fear and violence destroy angelic beings who had only ever known peace and love. Helel names High Governess Atara the Queen of Heaven. Abba, the Creator, grieves. His eternal heart aches, then becomes angry. Anything that opposes His essence is named His enemy. Justice is created and a Holy censuring begins. High Governors Michael and Adi grieve the demise of their banished friends and their cherished Earth.
Can the sadness of rejected affection ever leave the memory of the One rejected? Abba is Love. Abba, the Creator, means ‘father’ in the ancient Chaldean language. It is the name Jesus used when crying out on the Cross. Abba created all things. All things were good. But once Abba saw something He did not create and lamented.
The Song Of The Tree by Lotis Key
Despite promises of eternal joy given by the Tree of Life, a privileged young woman loses everything in a brutal war. Her husband disappears; her family is murdered; her home is burned to the ground.
Desperate, starving, and burdened with an unwanted child, she now despises and rejects the Tree she once worshiped. Ripped from her land and people, forced into survival immigration, she becomes a lowly refugee, a servant in the homes of the rich. Her unusually gifted child thrives, but is an ever present reminder of ultimate loss and betrayal.
Two women: one broken, the other rooted in bitterness, continue to be drawn towards the song of a Tree that will not let them go. Along roads of degrading poverty and equally destructive wealth, each much wrestle with the siren call of perfect love, and its altar sacrifice of perfect trust.
The Song of the Tree is an intense, contemporary allegory that moves the God-seeker from fist shaking stance, down to knees before the throne.
Zinvoy’s Journey by Ginny Jaques
Adult Speculative
Zinovy Efimovich KoZlov is a self-made man who’s spent the last twenty-three years climbing the ladder of Russian military success, one rung at a time. An FSB veteran, Air Force fighter pilot, member of the elite Special Security Service, and now a cosmonaut on the global regime’s new International Space Station, he should be at the peak of his career. But Zinovy has enemies whose political power extends into space, and those enemies are determined to kill him.
Then the earth is destroyed in a nuclear holocaust and everything changes.
When the world ends, Zinovy’s Journey begins.
The Vineyard Fray by Ben Kniskern
Action and Adventure Allegory
During ancient times, in a middle eastern land known as the Vineyard, life seems to go on unaffected by the people’s rebellion against the One who made them. That is, until the Owner of the Vineyard decides He’s had enough. In the midst of chaos and war, several individuals who are loyal to the Owner must band together to save their kingdom. Follow this unlikely group of heroes as they encounter mysterious messengers, battle against ruthless enemies and endeavor to turn the hearts of the people back to the One who created them.
Shoot the Wounded by Lynn Dove
SHOOT THE WOUNDED is a contemporary Christian novel that deals with relevant social issues such as teen pregnancy and family violence. Set in the small fictional town of Maplewood, in southern Alberta, best friends Leigh and Ronnie find their friendship and faith challenged when Jake, a good looking Christian boy, moves into their neighborhood. Leigh is especially delighted that Jake is paying more attention to her than any other girl at school or church, but what she does not know is that despite his bold declaration of being a follower of Christ, he’s carrying a dark secret from his past that has the potential to destroy his integrity and have his friends question the legitimacy of his faith.
One Night with a Rock Star by Chana Keefer
When Esther was a young teen with frizzy hair and too-skinny legs, Sky’s music soothed her through awkwardness and pain. During the Glam-Rock 80s, Esther is a college journalism student and fledgling print model. One chance meeting with her superstar crush rocks both their worlds.
Will Esther’s deep roots in family and faith keep her feet on the ground when a tornado named Sky blows her world apart?
21 Teen Devotionals… for Guys! by Paul Hart and CJ Hitz
Teen Devotional
Designed to be read, pondered on it and applied to daily life, these 21 devotions are written for teen guys who want to find their true strength in Christ. We want you to know that the Bible isn’t just a book that’s over 2000 years old. It’s completely applicable to our lives today – even as teenagers. We know that girls and guys don’t face the same issues in high school – not even close. So these devotions were written with today’s teen guys in mind.
21 Teen Devotionals… for Girls! by Shelley Hitz and Heather Hart
It’s said that it takes 21 days to form a new habit or break an old one, so why not spend the next 21 days forming a habit of spending time with God? If you’ve got 21 days, we’ve got 21 devotions specifically written for today’s teen girls.
Purposeful Planning by Phyllis Sather
Do you need a plan to keep your family moving in the direction the Lord is leading you? Perhaps you don’t know where the Lord is leading you. Phyllis takes you step-by-step through the process of planning a time together for your family to help determine the path the Lord is choosing for each area of your life. Her family has followed this format for over 12 years and has found that it provides the compass they’ve needed to plan and stay on course.
Where Family Meets Faith by Kimberley Payne
Written and compiled especially for families, Where Family Meets Faith is a collection of devotionals that show the similarities between the challenges of raising a family and building a relationship with God.
Selah by Tina Webb
Daily Quotes for Daily Meditation
The word “selah” means: to pause and think about. Many quotes are short enough to share in social media. Longer passages facilitate times of prayer and personal reflection.
This is a refreshing read for the person who likes to contemplate life through the lens of the Bible. It is a great topic starter for personal or group bible study.
10 Keys to Happy & Loving Relationships by Krystal Kuehn
The 10 Keys to Happy and Loving Relationships provides essential relationship building tools to help you develop healthy relationships. You will discover relationship building tools to help make all your relationships more fulfilling, harmonious and successful. Whether it is a spouse, friend, co-worker, son/daughter, girlfriend/boyfriend, or casual acquaintance, you will discover that you can have happy, loving, healthy relationships.
Healthy relationships bring joy and peace to our lives. Healthy relationships help us to love and be loved. In 10 Keys to Happy and Loving Relationships, you will be taken on a personal journey to discover how you can better communicate the 10 key attributes of love as you relate to others. You will be empowered with relationship building tools that will help you replace unhealthy patterns with new, healthy and effective ways to communicate, connect with and love others. And you will discover how to communicate and experience genuine love and true happiness in ways that will change you, your relationships and your life forever!
And Now For The Giveaway…
Published by Sherri Wilson Johnson
I am a wife/mother/writer/speaker looking to be used by God! View more posts
November New Releases Clash Winner
My Titus 2 Project for the New Year!
Sherri Wilson Johnson, Blog at WordPress.com.
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AppZen Raises $35 Million for Expense Automation: Travel Startup Funding This Week
- Nov 02, 2018 2:00 am
AppZen wants to remove the stress from filing monthly expense reports at companies worldwide, and it applies artificial intelligence to address the problem in a way that sounds compelling.
— Sean O'Neill
Each week we round up travel startups that have recently received or announced funding. Please email Travel Tech Editor Sean O'Neill at so@skift.com if you have funding news.
This week the total funding publicized was more than $51 million in venture capital and $30 million in real estate capital.
>>AppZen, which automates expense management for businesses, has closed a $35 million Series B financing.
Lightspeed Venture Partners led the round. Redpoint Ventures also participated. The investment brings the company’s total funding to more than $52 million.
The San Jose, California-based startup is right now focused on the expense auditing and compliance platform is focused on travel and entertainment expenses, including business travel and all operational expenses that employees put through as business expenses related to trips. But it hopes to use this funding to broaden its scope to new products across enterprise expenditure.
The company, founded in 2012, uses computer vision, deep learning, and natural language processing to automatically read and audit expense reports, receipts, invoices, and contracts while cross-checking that information against hundreds of online data sources.
>>Life House, a new hotel chain, said it had received an additional $30 million in real estate capital, led by Henley Investments.
In May, Life House reported it had raised $10 million in Series A venture capital and $30 million in real estate capital.
This week Life House began taking reservations for its first properties, which are in the Miami neighborhoods of Little Havana and South Beach.
The company said their company is on track to have more than 20 hotels under development in the U.S. by the end of 2019. The company unveiled a technology platform that supports a direct booking system and a social network for guests as a distinctive offering from traditional hotels.
Life House, based in New York City, currently has 40 employees. The concept behind New York City-based Life House isn’t new. There are hundreds of hotel development and management companies worldwide. What is novel is for Silicon Valley venture capital to back one.
>>Properly, a San Francisco-based company that provides a cleaning and quality management platform to Airbnb hosts and vacation rental managers, has raised an $8.5 million Series A.
Asset Management Ventures led the round. AccorHotels also participated.
San Francisco-based Properly allows hospitality brands and property managers to set quality standards for their team, manage their operation, and confirm that work meets their expectations. AccorHotel’s Onefinestay brand of alternative accommodations is one of the startup’s customers.
Founded in 2014, Properly is currently used by over 20,000 property managers and hosts worldwide. Alex Nigg is CEO and founder of Properly. Drew Patterson, formerly CEO of Room77 and Checkmate, is chief revenue officer.
>>Freebird, an enterprise software company helping with flight disruptions and rebooking for corporate travelers, has raised $8 million in Series A investment.
American Express Ventures led the round. Other new investors include Citi Ventures and PAR Capital. Past investors General Catalyst and Accomplice also participated. The company has raised $16.5 million in total.
The Cambridge, Massachusetts-based company said that, in the past 18 months, Freebird has added more than 100 corporate clients and 10 corporate travel agency partners, including BCD Travel and is on track to serve about a quarter-million passengers in the next year.
Founded in 2015, Freebird was one of Skift’s top startups to watch in 2017. It now has 25 full-time employees.
Skift Cheat Sheet:
We define a startup as a company formed to test and build a repeatable and scalable business model. Few companies meet that definition. The rare ones that do often attract venture capital. Their funding rounds come in waves.
Seed capital is money used to start a business, often led by angel investors and friends or family.
Series A financing is typically drawn from venture capitalists. The round aims to help a startup’s founders make sure that their product is something that customers truly want to buy.
Series B financing is mainly about venture capitalist firms helping a company grow faster, or scale up. These fundraising rounds can assist with recruiting skilled workers and developing cost-effective marketing.
Series C financing is ordinarily about helping a company expand, such as through acquisitions. In addition to VCs, hedge funds, investment banks, and private equity firms often participate.
Series D, E and beyond These mainly mature businesses and the funding round may help a company prepare to go public or be acquired. A variety of types of private investors might participate.
Check out our previous startup funding roundups, here.
Tags: funding, startups, vcroundup
Photo Credit: AppZen co-founders Kunal Verma (left) and Anant Kale are pleased that their startup has received $35 million in funding. AppZen
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The Best-Funded Travel Startups Through the End of 2019
Twitter | 2 hours ago
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PHIL 236: Feminism
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Education Reform & Policy Speakers Related to Kori Cioca Related to Kori Cioca Education Reform & Policy education-reform $20,000 - $40,000
Displaying 1 - 30 of 35 speakers
Educator & Social Justice Advocate
Massachusetts, USA / 1 reviews
Eduardo Briceño
Growth Mindset & Improvement Expert; Co-Founder & CEO of Mindset Works
Eduardo Briceno at The Happiness Hall Of Fame
Santa Fe, NM, USA / 15 reviews
New York Times Best-Selling Author, Fox News Political Analyst & Award-Winning Columnist
Juan Williams' Keynote at 2013 CFN Conference
Washington, DC, USA / 1 reviews
Former Democratic Senator of California
Barbara Boxer Interview
Erin Gruwell
Inspirational Educator & Author of "The Freedom Writers Diary"; Subject of the "Freedom Writers" Film & Documentary
Long Beach, CA, USA / 2 reviews
Priscilla Chan
CEO of the Primary School & Co-Founder of the Chan Zuckerberg Initiative
Palo Alto, CA, USA
Dena Simmons
Educator, Director of Education at Yale Center for Emotional Intelligence
New Haven, CT, USA
U.S. Senator from New Jersey; Author of "United" & Former Democratic Presidential Candidate
Ron Clark
Founder of the Ron Clark Academy & NYTimes Bestselling Author; Disney's American Teacher of the Year & Education Innovator
Atlanta, GA, USA / 1 reviews
Jacquelline Fuller
Director of Google.org, Supporting Education, Development, Disaster Relief and Clean Energy Through Charitable Giving
San Francisco Bay Area, CA, USA
Margaret Spellings
UNC System President-Elect; Former Bush Administration Official; Former United States Secretary of Education
Former Governor of New Mexico; Nation's First Hispanic Female Governor
Susana Martinez victory speech
Fawaz Gerges
Leading Authority on the Middle East; Professor of International Relations at the London School of Economics & Political Science
Opinion | The Islamic State Has Not Been Defeated - The New York ...
Esther Wojcicki
Journalist, Educator, Vice chair of Creative Commons Advisory Council
Tyler DeWitt
Research Scientist; High School Teacher, Digital Content Author & STEM Education Advocate
Cambridge, MA, USA / 1 reviews
French Economist, Business Leader
The World in 2035: hyperconflict or global renaissance?
Fortune Columnist, Author & Radio Host
Pacific Palisades, CA, USA
Pulitzer Prize-Winning New York Times Columnist & Political Commentator
Caroline Hoxby
Scott and Donya Bommer Professor in Economics & Expert on the Economics of Education
Ted Dintersmith
Executive Producer of "Most Likely to Succeed", Advocate for Innovation in Education, Former Venture Capitalist
Andreas Schleicher
Deputy Director for Education and Skills and Special Advisor on Education Policy to the OECD's Secretary-General
Elise Foster
Engineer Turned Motivational Educator & "Multipliers" Master Practitioner at The Wiseman Group
Cincinnati, OH, USA
Vocalist, Poet, Songwriter, Known for Feature on Hit Song "Sunday Candy"
Neil Howe
President of Saeculum Research & LifeCourse Associates; Renowned Authority on Generations; Coined the Term "Millennial Generation"
Neil Howe: "Deep Demographic Problems Plaguing The U.S. ...
Great Falls, VA, USA / 2 reviews
Carl Wieman
Physicist and Educationist at Stanford University and Recipient of the Nobel Prize in Physics
Stanford, CA, USA / 2 reviews
Mitch Resnick
Mitchel Resnick is LEGO Papert Professor of Learning Research, Director of the Okawa Center, and Director of the Lifelong Kindergarten group at the MIT Media Lab.
John B. King, Jr.
Former Secretary of Education for President Barack Obama
Eve Ewing
Sociologist of Education & Assistant Professor at the School of Social Service Administration at the University of Chicago
Jonah Edelman
Children's Advocate & Founder of Stand for Children
Jeff Duncan-Andrade
Founder at Roses in Concrete Community School & Associate Professor at San Francisco State University
Oakland, CA, USA
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MLB rumors: Gerrit Cole might not sign in free agency until January
Dalton Johnson
December 3, 2019, 5:43 PM UTC
With the final month of 2019 here, MLB's hot stove has started to stoke a fire. The room is getting hotter with the Winter Meetings less than a week away.
Marquee free agents such as Will Smith, Mike Moustakas and Yasmani Grandal all have new homes. But many star free agents still are in the open sea, and they could be for quite some time.
Giants president of baseball operations Farhan Zaidi said shortly after the regular season that he expects another long and slow offseason for big-name free agents. No free agent is bigger than star pitcher Gerrit Cole this offseason, and he could still be available well past New Year's Eve.
So, would this help or hurt the Giants' chances of adding the ace?
The Athletic's Ken Rosenthal reported Monday that Cole and fellow star pitcher Stephen Strasburg will be meeting with the Yankees over the next two days in California, though Rosenthal stated it's believed Cole might not sign until well into January. The Yankees aren't the only heavy-hitters going after Cole, too. Late last month, MLB Network's Jon Heyman reported the Dodgers are looking at Cole, along with many other stars.
This should come as no surprise. Both clubs have all the money in the world and want to end their championship droughts. Whatever team signs Cole better be ready to open up their wallets, and then some.
Cole is expected to break David Price's record for the richest contract ever given to a pitcher. Many in the industry believe he will sign for well over $250 million, and it could be closer to $300 million. Location might be just as big of a factor -- well at least close to it -- as money for the AL Cy Young award runner-up, too.
Astros teammates referred to Cole as a "West Coast guy" and predicted the UCLA product will sign with a team west of Nevada. The Southern California native has been linked to the Dodgers and Angels, but nobody can forget his family ties to the Giants.
Cole is, after all, married to Giants shortstop Brandon Crawford's sister. There's no doubt there were at least jokes around the Thanksgiving dinner table about Cole making San Francisco his new home. The longer he waits to make a decision, the better the Giants' chances might be.
The Giants offered outfielder Bryce Harper a 12-year, $310 million contract on Feb. 28 last offseason. Zaidi's initial plans didn't have Harper at the front of his mind, but the longer it took to sign him, the more serious San Francisco's front office became. The same could happen with Cole.
Zaidi and the rest of the Giants' front office want to go young, as shown in the decision to non-tender center fielder Kevin Pillar, who turns 31 years old in January. They have young, intriguing options for their rotation with Tyler Beede, Logan Webb and others as well. But talents like Cole don't come around often.
[RELATED: Would Gerrit Cole be right fit for Giants this year?]
Despite being 29 and pitching at least 200 innings in the last three straight seasons, Cole doesn't have too many miles on his right arm and at 6-foot-4, 225 pounds, he looks built to last. When there's a chance to sign someone like this, smart front offices don't turn a cold shoulder.
Even if you think Zaidi is punting on this offseason and looking to rebuild for beyond 2020, someone with his baseball mind and competitiveness won't let Cole slip away if the star pitcher is available and shows he's interested.
MLB rumors: Gerrit Cole might not sign in free agency until January originally appeared on NBC Sports Bay Area
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No proposal to host CWG shooting championships in India during 2022 Games
While there has been media speculation, the CGF said no formal proposal has been made to the ISSF to conduct a Commonwealth Shooting Championships.
NEW DELHI 09 December, 2019 17:56 IST
REPRESENTATIVE IMAGE: Commonwealth Shooting Championships is amongst one of several ideas being discussed with the ISSF. - Getty Images
The Commonwealth Games Federation on Monday said there is no plan to have a Commonwealth Championship of shooting in India during the 2022 Birmingham Games to make up for the sport’s axing from the multi-sport showpiece.
The CGF said there was no formal proposal made to the ISSF to conduct a Commonwealth Shooting Championships when its chief Louise Martin and CEO David Grevemberg met the top brass of the world body on Friday in Munich.
There has been media speculation that such a championship could be held in India around the time of the Birmingham CWG and the medals won in that (shooting) event could be added to the tally of the respective countries.
“Although a Commonwealth Shooting Championships is amongst one of several ideas being discussed with the ISSF, nothing has been formally proposed, let alone agreed upon, with any of our partners,” Grevemberg said in a statement.
Read: India's Olympic-bound shooters happy to put monetary gains aside for the country
“Therefore, media speculation around what this event could look like, and what medals won at such an event could mean in the context of the Commonwealth Games, is extremely premature,” he added.
In fact, the Indian Olympic Association, which threatened withdrawal from the 2022 CWG to protest against the dropping of shooting, had proposed that medals at such an event be added to the tally of the respective countries. The proposal was made during a meeting of IOA officials with their CGF counterparts in India last month.
IOA chief Narinder Batra had even said that India would not be interested to take part in a Commonwealth Shooting Championships if the medals are not added to the country’s tally of the 2022 CWG.
Grevemberg said the CGF Constitution “states that a Commonwealth Championships may not be held in any country three months prior to or after the Commonwealth Games, and only with the approval of the CGF Executive Board“.
On the meeting with the ISSF officials, he said, “We (CGF and ISSF) are both committed to developing the sport of shooting across the Commonwealth and have agreed to work together closely to achieve this objective.
“The ISSF are aware that shooting was not selected as an optional sport for Birmingham 2022 following a comprehensive and transparent review process while the CGF and ISSF both remain committed to creating opportunities for Commonwealth athletes to compete on the biggest and best stage possible.”
Grevemberg said the CGF’s meeting with the ISSF was built on the positive discussions in November with the IOA led by Batra.
Saurabh, Elavenil and Divyansh receive Golden Target award from ISSF
Mehuli Ghosh wins 10m air rifle gold in SAG, India sweeps all medals
Record entries for national rifle and pistol championships
Narinder Batra
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Serena Williams Loses Chance for Grand Slam at 2015 U.S. Open
Will Rafael Nadal Win Another Grand Slam After Losing at 2015 US Open?
It was really a tale of two matches tonight, as Rafael Nadal rolled to a two-set lead in his third round match against Fabio Fognini... and then promptly fell apart, losing for the first time in his 152nd instance in that situation. As the 29-year-old watched his lead evaporate and then crumble into defeat at the hands of an Italian that...
Nadal Loses to Djokovic at French Open
Novak Djokovic erased any possibility of a sixth straight French Open title for Rafael Nadal today at Court Philippe Chatrier in Paris, demolishing the Spanish southpaw in straight sets on in their quarterfinal match. The defeat pushed Nadal's career record at the Parisian complex to a tidy 70-2 -- a mark any other man or woman would...
Bruce Levenson Racist Email - Full Text
Another NBA owner has inadvertently put his foot in his mouth, this time is Atlanta Hawks majority owner Bruce Levenson. The way i see it, Levenson attempted to 1-up any potential whistle blower or attempt at an extortion by publicly releasing the information to the NBA along with his intentions to sell his ownership of the team. In...
Kevin Love, Andrew Wiggins Trade Agreement Final, New Big Three in NBA?
Sixteen days before being eligible to be traded, number one pick Andrew Wiggins is heading to Minnesota. The Cleveland Cavaliers and the Timberwolves have agreed in principle to send Kevin Love to Cleveland in return for Wiggins, last year’s number one pick Anthony Bennett, and a protected 2015 first round pick, Yahoo! Sports is...
Pacers' Paul George suffers serious leg injury, ends USA scrimmage
The Team USA scrimmage game took an unfortunate turn for the worse when Indiana Pacers guard/forward Paul George suffered a severe and gruesome leg injury Friday night. **The video below of Paul George's injury sustained during the Team USA scrimmage is disturbing and may not be suitable for some...
Aaron Hernandez Indicted in 2012 Double Homicide; Faces Two Murder Trials
The former New England Patriot star has troubles that just will not end. Hernandez has been indicted in the 16 July 2012 murders of Daniel Abreu and Safiro Furtado. If that is not enough, Hernandez has also been charged with three counts of armed assault with attempt to murder in connection with the same case. Representatives have...
Donald Sterling: The Fallout Continues, Sponsors Cutting Ties
CarMax and Red Bull are the latest sponsors to cut ties with the Los Angeles Clippers organization following the release of an audio recording by TMZ in which team owner Donald Sterling allegedly made racist remarks. In a statement from CarMax spokeswoman Catherine Gryp: CarMax finds the statements attributed to the Clippers'...
Wisconsin Badgers Beat Baylor Bears to Return to Elite Eight
The monkey is finally off Bo Ryan's back. Since 2005, when the Badgers went to the Elite Eight before falling to eventual national champion North Carolina, Ryan has coached one talented Wisconsin team after another into the NCAA Tournament. More often than not, they entered the bracket as a top-five seed, ostensibly one of the top 20...
Harvard Beats Cincinnati in NCAA Tournament in 12-Over-5 Upset
For the second straight season, Tommy Amaker's Harvard Crimson knocked off a higher seed in the Round of 64 in the NCAA Tournament. Last year it was New Mexico heading home early. On Thursday, it was the Cincinnati Bearcats that fell short against the Ivy League champions. Holding a lead for almost the whole game, Harvard dealt...
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Riverbend Books
Bookchats
How to Think about God - An Ancient Guide for Believers and Nonbelievers
Author(s): Marcus Tullius Cicero; Philip Freeman
A vivid and accessible new translation of Cicero's influential Stoic writings on the divine
Most ancient Romans were deeply religious and their world was overflowing with gods--from Jupiter, Minerva, and Mars to countless local divinities, household gods, and ancestral spirits. One of the most influential Roman perspectives on religion came from a nonreligious belief system that is finding new adherents even today: Stoicism. How did the Stoics think about religion? In How to Think about God, Philip Freeman presents vivid new translations of Cicero's On the Nature of the Gods and The Dream of Scipio. In these brief works, Cicero offers a Stoic view of belief, divinity, and human immortality, giving eloquent expression to the religious ideas of one of the most popular schools of Roman and Greek philosophy.
On the Nature of the Gods and The Dream of Scipio are Cicero's best-known and most important writings on religion, and they have profoundly shaped Christian and non-Christian thought for more than two thousand years, influencing such luminaries as Augustine, Thomas Aquinas, Dante, and Thomas Jefferson. These works reveal many of the religious aspects of Stoicism, including an understanding of the universe as a materialistic yet continuous and living whole in which both the gods and a supreme God are essential elements.
Featuring an introduction, suggestions for further reading, and the original Latin on facing pages, How to Think about God is a compelling guide to the Stoic view of the divine.
Publisher : Princeton University Press
Imprint : Princeton University Press
Publication date : October 2019
Dimensions : 1.5 Centimeters X 90.3 Centimeters X 35.5 Centimeters
Dewey classification : 292.07
Author : Marcus Tullius Cicero; Philip Freeman
© Riverbend Books | PHONE 07 3899 8555 | EMAIL info@riverbendbooks.com.au | ADDRESS 193 Oxford St, Bulimba Queensland 4171
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”ALL THAT FALL”
06.10.-06.11.2005 / Preview: 06.10.2005 / 19.00-21.00
STANDARD (OSLO) is proud to present Matias Faldbakken’s solo exhibition ”All That Fall”. The exhibition shares its starting point with Faldbakken’s work for this year’s Venice Biennal; the relationship between entertainment, violence and negation. In this discussion ”All That Fall” takes a particular interest in ’the absurd’; the loss of meaning and coherence, and the ability of the comical to constantly reconfirm our acceptance of the absurd as a condition of life.
’The absurd’ might be understood as the gap between one’s serious investments into life and the possibility of all that one takes seriously is subject to doubt. The historical avantgarde’s reaction to this loss of coherence was to double this absurdity as some kind of revenge. This was done through despise, spite and negation – exemplified through Dadaism, Situationism and the Punk movement. This negation also involved a complete denial of what is right, healthy and sound. At the centre of Matias Faldbakken’s exhibition is a stack of 20 guitar amplifiers. ”Away From Sound” fuses the entertainment industry’s maximized use of effect – here as a possible wall of sound – with the mute and serial aesthetics of Minimalist art. The title plays on the etymological origin of the term ’absurd’ (’absurdus’ of ’surdus’ meaning ’sound’) that can be translated as ’unharmonic’ or ’away from (the right) sound’. The inner contradiction of the work is brought even further by the fact that the amplifiers are merely dummies without the ability to produce sound.
”Away From Sound” can be read as a mediation between the entertainment industry’s notion of transgression through the spectacular as opposed to the historical avantgarde’s notion of transgression through negation. In Faldbakken’s discussion violence becomes the common denominatior and the tool for their shared fantasy of a (temporarily) suspension of normality and its laws. The state of emergency as a fetish is subject to discussion in two other works in the exhibition. ”Untitled (Ununderstanding)” and ”Chain of Events” weave together images of an utmost real violence and a cinematic violence emptied by clichés. Linking to the motif of revenge, ”Chain of Events” shows a gold chain as the only remaining item in a black plastic bag. ”Untitled (Ununderstanding)” takes form of a baseball bat, wrapped in a black plastic bag, hanging from the ceiling in a chain. The work offers a parodic layering and enlargement of various archetypal film scenes, such as ”hanging-in-a-chain-down-at-an-empty-harbour-depot”. At the same time this confusion also contributes to an emblematic image of the horror of being placed outside of law and order – outside of compassion and humanity.
Matias Faldbakken (born 1973) lives and works in Oslo. His works have recently been included in various international biennials such as the Sydney Biennial (2004), Momentum – the Nordic Art Biennial (2004), and in ”Sharing Space Dividing Time” in the Nordic Pavillion at this year’s Venice Biennial. Faldbakken is also included in the exhibition ”Parallell Life” currently showing in Frankfurter Kunstverein. For further information please contact Eivind Furnesvik: eivind@standardoslo.no / +47 22 60 13 10.
Next exhibition: ”Blankness Is Not a Void” / Curator: Gardar Eide Einarsson / 17.11.-18.12.2005
Exception of State
Wall mounted road sign and plastic bag
Untitled (Freak)
Lightjet photographic print on Kodak archival paper /framed / 105 x 75 cm / 41.3 x 29.5"
1/3 + 1AP / SOMF/PH 2005-012/1
Untitled (Dvd Cover)
Away from Sound
Stack of 24 Marshall guitar amplifier dummies
304 x 456 x 23 cm / 120 x 180 x 9"
1/3+1AP / SOMF/S 2005-019
Untitled (Ununderstanding)
Baseball bat, plastic bag and 300 cm /10 mixed media steel chain
300 x 0 cm / 118"
Unique / SOMF/S SOMF-2005-022
Chain of Events
24 carat gold chain in plastic bag
0 x 0 Ø 40 cm / "
Lindbergh and Gacy
Hand-coloured lightjet black and white print on Kodak archival paper /framed / 45 x 33 cm / 17.7 x 13"
Unique / SOMF/PH 2005-026
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social capital, Social change, Social movements, Change
I recently picked up a copy of How Change Happens: Why Some Social Movements Succeed While Others Don’t, a book out last year by Leslie Crutchfield. She leads the Global Social Enterprise Initiative at Georgetown University’s McDonough School of Business. I have my friend Bob Litan to thank for the tip.
I immediately became interested by the title because of my upcoming book The Startup Community Way, which will be out later this year. That interest came from the fact that our book (I’m co-authoring it with Brad Feld) is really about a special type of movement-driven social change—one built around local entrepreneurship.
How Change Happens is the product of many years of research by Leslie and her team studying a wide range of social movements in the United States—from gun control, to same-sex marriage, to smoking, to drunk driving, to acid rain reduction, to vaccination, and beyond—and systematizing why some of these movements succeed while so many others fail. By dissecting these movements case-by-case, Crutchfield and her team were able to uncover some interesting patterns about what works and what doesn’t.
As I was reading the book, I had in the back of my mind “how do these social movements apply to building startup communities?” I’m glad I did, because it helped crystalize a few ideas in my head. There are many ways that How Change Happens has limited or no applicability to startup communities—in particular, because it is focused on the building of nationwide coalitions to make change happen in U.S. national government policy. But I often find that contrast can be a great source of new ideas. That was certainly the case here. The book was a breezy read and I learned about some of the most important social movements in our country’s modern history—a subject of personal interest.
But back to startup communities, I found some important crossovers. For starters, How Change Happens is deeply enmeshed in complex systems and systems thinking—which are core to understanding how startup communities work and how to effectively engage with them. But also, I found that each of the six main patterns from Crutchfield’s research on winning social movements had applicability to building startup communities.
Here, I list those out in bold with relevant quoted text in italics. Following that, and with all do respect to Leslie and her team, I do my best to translate each of their six main factors into how they apply to startup communities.
Turn Grassroots Gold. “Winning movements are fueled by energy that materializes from the bottom up.” This one is pretty self-explanatory. Human social systems, like startup communities, are best driven by a strong bottom-up dynamic.
Sharpen Your 10/10/10/20 = 50 Vision. “Successful U.S. movements plow through all fifty states with their change campaigns, rather than focusing only on sweeping federal reforms… [and] win big when their grass-tops are organized in networked leadership structures—coalitions of leaders who recognize they need to forge pathways so all of the players around them can collaborate rather than compete.” A couple of crossovers here. First, despite the big difference of national campaigns versus local entrepreneurship, the same point can be made at a smaller scale—start by building a critical mass of dedicated startup community members within cities, regions, or states before tackling the entire system from the outset. Second, the point about groups of well-connected leaders is a critical one—startup communities must be lead by a group of people, not just one or two, and we all benefit from a high degree of connectivity and knowledge-sharing with leaders in other cities.
Change Hearts and Policy. “Great social change leaders… strive to make the change they seek the new normal… They [also] put the individuals with the lived experience of the problem out in front of the cause.” Two things here, both of which are from Brad Feld’s seminal book. First, it takes time to build a startup community—at least twenty years for meaningful change to take hold. Second, startup communities must be lead by the entrepreneurs. In other words: make startup communities a normal thing in your city by having a sustained, long-term commitment—a big piece of doing that is putting entrepreneurs front and center.
Reckon with Adversarial Allies. Social movements can often get crippled by… “disagreements, personality conflicts, territory fights, or scraps over which organization gets the credit… The difference in winning movements is that leaders manage to put their egos and organizational identities to the side (if only temporarily) so disparate factions can come together around a common agenda.” Organizational turf wars are common in startup communities and are very wasteful. They promote zero sum thinking. They only work against those individuals and organizations involved, and most importantly, they distract valuable attention away from entrepreneurs and undermine the entire startup community in the process. One marker of a healthy startup community is when entrepreneurial support organizations in particular are collaborative and supportive of one another.
Break from Business as Usual. “Corporations have influenced the outcomes of many modern movements in more positive and nuanced ways than conventional wisdom would suggest.” Engagement with the big institutions in entrepreneurial ecosystems—corporations, universities, governments—can unlock a lot of value for startups and startup communities. The problem is the institutional nature of these players is not naturally well-suited to the entrepreneurial process. But, startup communities must find a way to overcome these challenges—collaborative and well-integrated startup communities are more powerful than isolated ones.
Be Leaderfull. “We observed winning movements to be ‘leaderfull.’ Instead of small handfuls of elites dictating to troops from the top down or an amorphous mob of activists genuflecting for change from the bottom up, the most effective movements find balance between the ‘leaderless’ and ‘leader-led’ extremes… Effective movement leaders share power, authority, and limelight and lead from behind, embracing a long-term view. This is very hard to do—it involves letting go of ego, as well as putting cause and mission ahead of personal or organizational power.” In national social movements leadership is everything. The same is true in startup communities, where leaders can make or break you. Leaders set the tone. If you want to quickly gauge how well a startup community is doing, just look at how the leaders think and behave. That will tell you most everything.
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Home On The Verge Amsterdam – Danny Ainge (Produced by TOPE)
Amsterdam – Danny Ainge (Produced by TOPE)
Stateofhiphop
Oregon MC Amsterdam makes his return to music after a brief hiatus with the new single “Danny Ainge,” produced by TOPE. A dedication to all things green in reference to the great Boston Celtics. Even though the C’s though and L in the Eastern Conference Finals, it’s not too late to pay homage to Danny Ainge and his cast of overachievers. Amsterdam relates Danny’s quick trigger on a trade to reference his lady’s love and dedication. With a new project on the horizon, Amsterdam tapped Portland / Oakland producer TOPE for a number of songs including a much-anticipated collaboration with Skyzoo! For now, press play on “Danny Ainge” and be on the lookout for much more heat coming from Amsterdam!
https://twitter.com/amsterdamallday
https://twitter.com/itsTOPE
https://www.instagram.com/amsterdamallday/
Previous articleTerry Notez The punch line king| @TerryNotez
Next article#StateOfAffairs: Calvin Ross – Rover (Remix) @CalvinRoss_
Devilz Advocates New Anthem “I Believe In U”
BILLIONAIRE BUCK – HOOD SCRATCH
The Mighty Capeech – Let Em Know” “New Ep “Corna Stone: Book 1
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StatsWales > Transport > Roads > Road accidents > Casualties > Young people > Number of casualties aged 16-24 by time of day, type of vehicle, severity, date, highways agency and area
Number of casualties aged 16-24 by time of day, type of vehicle, severity, date, highways agency and area
By highway agency
By highway agency 1
Type of Vehicle 1
Date 1
Time of Day 1
Severity 1
January to March April to June July to September October to December January to March April to June
Total 265 277 358 326 1,226 (p) 273 (p) 295 (p,r)
Total 00:00-05:59 All severities 23 40 64 34 161 (p) 32 (p) 41 (p,r)
All severities KSI 4 13 23 12 52 (p) 13 (p) 13 (p,r)
Slightly injured 19 27 41 22 109 (p) 19 (p) 28 (p,r)
06:00-11:59 All severities 53 34 57 54 198 (p) 48 (p) 40 (p,r)
All severities KSI 7 2 7 9 25 (p) 5 (p) 4 (p,r)
12:00-17:59 All severities 84 116 135 114 449 (p) 99 (p) 119 (p,r)
All severities KSI 11 9 21 21 62 (p) 13 (p) 23 (p,r)
Slightly injured 73 107 114 93 387 (p) 86 (p) 96 (p,r)
18:00-23:59 All severities 105 87 102 124 418 (p) 94 (p) 95 (p,r)
All severities KSI 19 18 14 29 80 (p) 26 (p) 18 (p,r)
The number of casualties aged 16-24 by time of day, day of week, type of vehicle, severity, date and police force area
Reported road accidents system, Welsh Government
stats.transport@gov.wales
The statistics refer to casualties aged 16-24 resulting from personal injury accidents on public roads reported to the police and forwarded to the Welsh Government. Road Accident Data contains details of the accident, the number of vehicles involved and information on casualties.
Accident data contains: the description and location, the number of casualties and vehicles, severity of accident, type of road and contributory factors.
Vehicle description: includes details of vehicle type, age of driver/rider.
Casualty description: provides details of the severity of casualty, casualty class and age.
The Data Dictionary provides a detailed breakdown description of the variables that are included in all three categories.
The police compile statistical data about road traffic accidents and casualties (called Stats19 data) for the Welsh Government and the Department for Transport (DfT). This follows police attendance at accidents that involve any personal injury, together with members of the public reporting personal injury accidents directly to the police. The figures are based on information available to the Welsh Government 14 weeks after the end of the latest quarter. The Stats19 data are a set of numeric and alphabet characters.
A casualty is defined as, a person killed or injured in an accident. One accident may give rise to several casualties. Casualties and accidents are subdivided into killed, seriously injured and slightly injured categories.
Casualties reported as killed include only those cases where death occurs in less than 30 days as a result of the accident. They do not include those who died as a result of natural causes (e.g. heart attack) rather than as a result of the accident, nor do they include confirmed suicides.
The classification of each accident is the most seriously injured casualty. For example if there are 5 casualties but only 1 fatality, the accident is classed as a fatal.
There are a variety of organisations that use the Welsh road traffic accident and casualty data. The Welsh Government uses road traffic accident and casualty data to help set road safety policy. It is also used for performance indicators, both for the Welsh Government’s Transport Strategy and for some Health Performance indicators. They are also component indicators in the Welsh Government’s Child Poverty and Sustainable Development indicators.
Other users include Highway Authorities (on behalf of the Welsh Government, which is responsible for the motorway and trunk road network) and Local Authorities (which are responsible for other roads in Wales). Other bodies involved in road safety include the Safety Camera Partnership, Trunk Road Agents, and Police & Community Safety Partnerships.
Statistics for 2018 were first published on 27 June 2019. Revised statistics, showing a higher number of fatalities than had initially been published, were issued on 25 September 2019.
The figures shown may change in future if there are late amendments. Similarly, the figures for earlier years may differ from those previously published. The figures cover only road accidents reported to the police involving personal injury.
This data is obtained from administrative sources and thus may be affected by changes in procedures within those systems.
There is some possibility of under-reporting and under-recording as well as for the misclassification of accidents though these are minimised by local authorities and the Welsh Government conducting a number of data validations. For example, Welsh Government data analysts may query the location of an accident with a police force when the grid reference of an accident is in a different local authority to the one specified in the data return. These issues are discussed in more detail in a Statistical Article ‘Quality Report for Welsh Road Casualties’.
This article also summarises the sources and methods used to compile the road accident and casualty figures for Wales. It also reviews the quality of the resulting figures in terms of the six dimensions of statistical quality of the European Statistical System. The aim is to provide background information about road casualty statistics for Wales in a single document for all users of the published statistics. It is available from the following link:
http://gov.wales/statistics-and-research/police-recorded-road-casualties/quality-report
https://gov.wales/police-recorded-road-accidents
Transport Road Accidents Collisions Fatal Killed Serious Slight Police-recorded
TRAN0179
OData (JSON) http://open.statswales.gov.wales/dataset/tran0179
OData (JSON) http://open.statswales.gov.wales/en-gb/discover/metadata?$filter=Dataset eq 'tran0179'
OData (JSON) http://open.statswales.gov.wales/en-gb/discover/datasetdimensions?$filter=Dataset eq 'tran0179'
OData (JSON) http://open.statswales.gov.wales/en-gb/discover/datasetdimensionitems?$filter=Dataset eq 'tran0179'
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NOTE: This is an edited version of portions of Appendices 3 of the “Revised Stealth Syndromes Study Protocol as approved by the University of California San Francisco Medical School Committee on Human Research.
The growing evidence of an environmental crisis caused by plastics in both fresh and seawater offers further reasons for concern.
While vast floating islands of plastic afflict parts of the oceans, the larger danger to humans may be due to the vast qualities of wastewater entering rivers, streams, and estuaries.
That wastewater carries significant concentrations of hundreds of dangerous chemicals, pharmaceuticals, illegal drugs, BPA, phthalates, pesticides, household chemicals and more.
These are in addition to microfibers which are already building up on land irrigated with recycled wastewater.
Organic fertilizer as a vehicle for the entry of microplastic into the environment
The contamination of the environment with microplastic, defined as particles smaller than 5 mm, has emerged as a global challenge because it may pose risks to biota and public health. Current research focuses predominantly on aquatic systems, whereas comparatively little is known regarding the sources, pathways, and possible accumulation of plastic particles in terrestrial ecosystems. We investigated the potential of organic fertilizers from biowaste fermentation and composting as an entry path for microplastic particles into the environment. Particles were classified by size and identified by attenuated total reflection-Fourier transform infrared spectroscopy. All fertilizer samples from plants converting biowaste contained plastic particles, but amounts differed significantly with substrate pretreatment, plant, and waste (for example, household versus commerce) type. In contrast, digestates from agricultural energy crop digesters tested for comparison contained only isolated particles, if any. Among the most abundant synthetic polymers observed were those used for common consumer products. Our results indicate that depending on pretreatment, organic fertilizers from biowaste fermentation and composting, as applied in agriculture and gardening worldwide, are a neglected source of microplastic in the environment.
Nano-Contamination
The increased use of nanoparticles in clothing, toothpaste, personal care products and other items are finding their way into the municipal wastewater stream. In addition to chemical leaching, some nanoparticles may be small enough to be absorbed directly into the blood streams of fish and other animals.
Soil microbial community responses to contamination with silver, aluminium oxide and silicon dioxide nanoparticles
TiO2 nanoparticles and sludge from wastewater treatment plants: a new concern for crops?
Whole Foods, in 2014, banned vegetables fertilized with biosolids, but the practice remains controversial:
Whole Foods Bans Sludge Fertilizer
Whole Foods Bans Produce Grown With Sludge. But Who Wins?
Health risks associated with wastewater use
Wastewater Reuse in Agriculture and Potential Risks to Human Health
Standards for Irrigation and Foliar Contact Water – The Pew Charitable …
High levels of microbial contamination of vegetables irrigated with wastewater by the drip method.
Effect of biofilm in irrigation pipes on microbial quality of irrigation water.
Microbial contamination of vegetable crop and soil profile in arid regions under controlled application of domestic wastewater.
Escherichia coli contamination and health aspects of soil and tomatoes (Solanum lycopersicum L.) subsurface drip irrigated with on-site treated domestic wastewater.
Monitoring the occurrence of pharmaceuticals in soils irrigated with reclaimed wastewater
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י״ט באלול ה׳תשע״ו (September 22, 2016)
Bava Kamma 114a-b: Despair and Acquisition
As we learned on yesterday’s daf, the situation of a mokhes – a tax collector – was different in Talmudic times than it is today. Tax collectors were individuals who purchased the right to collect taxes from the government and then could choose to collect different amounts from different people – a system that created anomalies and caused the Rabbinic Sages to consider a mokhes a dishonest person.
The Mishna on our daf teaches that if a person had his donkey or his cloak taken by a mokhes, but then received a different one from the mokhes in its stead, he can keep it, since we can assume that the original owner despaired of ever getting it back (referred to as ye’ush – despair).
The Gemara opens by quoting a baraita that teaches that when the person receives an object in exchange for his own from the mokhes, he should return it to the original owner. The explanation for this ruling would be that simple ye’ush does not suffice to allow for transfer of ownership. An alternative reading of the baraita suggests that although the recipient can keep the object because of the owner’s ye’ush, he would likely return it to the original owner, since a person does not want to keep property that does not really belong to him.
According to Rashi, the baraita (in either of its two presentations) stands in disagreement with the Mishna, which did not see any need to return the object. The Ra’avad disagrees, arguing that a baraita that is introduced with the term tanna immediately after a Mishna invariably comes to explain the Mishna, rather than argue with it. The Ra’avad explains that the baraita expects the recipient to return the object to its owner – but not for free. He can demand from the owner to pay him what he lost in his interaction with the mokhes.
Bava Kamma 115a-b: Salvaging the Honey
The Mishna on our daf tells a story of two people who were walking with their respective barrels, one full…
Bava Kamma 113a-b: The Tax Collector
Our Mishna teaches that a person cannot exchange money with tax collectors, implying that we must work with the assumption…
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Filed under: ON ASSIGNMENT, Picking Up the Pieces — steve bohnstedt @ 3:01 pm
PICKING UP THE PIECES: TAYLOR COUPLE BATTLES RIVER, TIME AND COST IN REBUILDING LIFE IN MOBILE HOME PARK.
April and Brennah, 12, team up to install insulation in the walls of the mobile home. “It’s weird having your child help you rebuild your home,” April said. “It’s the one thing we can can do together for quality time though. It has to be done. This is how I have to spend quality time with her – everything else- other summer plans were put on hold.”
April prompts her daughter Brannah, 12, to get out of bed and get ready for school. After driving her boyfriend Eric to work each morning, she wakes Brennah before staring her day of getting things done around the house. “I can’t lift whole sheets of drywall by myself, but I do whatever I can before Eric comes home,” she said. Suffering from fibromyalgia, April says she has to watch that she doesn’t overwork herself, or symptoms of severe pain and migraines will result.
April Hahne and Eric Piner take a break, while repairing their mobile home after flooding at Fabious Village inTaylor, Mo., caused extensive damage, resulting in having to gut nearly everything. They and April’s daughter Brennah, 12, returned after the water receded to rebuild. Without flood insurance, it’s been an uphill battle getting everything repaired and replaced before cold weather sets in.
After an argument with her mom, Brennah finds the back seat of the car to be alone for awhile. The constant work and difficulties arising from lack of a normal life takes it toll. “At times things are stressful, we’ll bite each other’s heads off, but we talk it out later and remind ourselves it’s gonna get better,” April said.
Eric crawls under the steel frame of the mobile home to determine what his next move is, as he will replace the old bathroom plumbing, before putting in a section of new flooring. Eric works at his job from 5 a.m. to 1 p.m., returns home by 2 p.m. and works another 8-9 hours rebuilding the mobile home. He and April have been working on the home for more than 3 months, while living in a small room and sleeping on the floor.
As April prepares the gas grill for cooking dinner, Brennah places bags of ice in the cooler. April says it’s a challenge finding a variety of foods she can cook on the grill. She says they don’t have any disposable income to waste, but ice melts fast, so they have to be diligent in what they purchase to eat, because they can’t keep leftovers. April recently experimented with cooking frozen lasagna on a gas grill. She says she tries different things so they aren’t stuck with a diet of hotdogs and burgers.
Getting up at 4 a.m., Eric goes to the car where he keeps toiletry items and clean cloths, to prepare for work. Eric travels to Quincy, each day to work. His job begins at 5 a.m. After work, he begins working on rebuilding the mobile home from about 2 p.m. until 10 -11 p.m. Eric says some days he feels like a walking zombie, but he’s concerned about getting the mobile home ready before cold weather arrives.
In the morning before school, April helps her daughter Brennah, 12, finish homework in the front yard at their home. With power tools blaring around the house, April says it’s been stressful trying to find a quiet place for Brennah to do her school homework and study.
Eric Piner and April Hahne take a break from working on rebuilding their mobile home after a flood destroyed much of the structure. Without appliances, a working shower, and other amenities, the couple and April’s daughter,Brennah,12, lived in a small finished room, while making repairs. For showers, the family relied on friends, a local truck stop with showers costing $10 per person, and the garden hose for night time outdoor showers on occasion.
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Erdogan: Cruisin’ For a Bruisin’
Filed under: Economics,Politics,Turkey — cpirrong @ 7:18 pm
I don’t believe it is an exaggeration to say that Turkey is ruled by a lunatic–Recep Tayyip Erdogan. His increasingly autocratic rule is putting Turkey at serious risk of an economic and geopolitical crisis.
Erdogan dreams of Turkey becoming the dominant power in the Middle East, a modern day version of the Ottoman Empire, including an explicit Islamic orientation–a decisive break with the founder of the Turkish Republic, Mustafa Kemal Ataturk, who eschewed imperial ambitions, and who was avowedly secularist, and indeed, harshly anti-Islam. (Which is one reason Erdogan despises him.)
These ambitions have led Erdogan into some foreign policy disasters, most notably in Syria. At the outset of the Syrian civil war, Erdogan was supporting the rebels and foursquare behind attempts to overthrow Assad. In this he failed utterly. But in the attempt, he (through his intelligence services) provided support to the most radical Islamist elements in Syria–including ISIS.
The Syrian debacle contributed to a serious breach with Europe which has all but eliminated the prospects for Turkish accession to the EU. In particular, his cynical unleashing of waves of Syrian refugees into Europe, and his threats of sending even more, thereby blackmailing the EU into providing Turkey financial aid, have left Turkey friendless in Europe.
Even worse, from a geopolitical perspective, has been his picking fight after fight with the US. The list is long. The extended standoff over an American minister he had imprisoned. His rapprochement with Iran in Syria (which in effect was a concession of his failure to achieve his objectives there), and generally cooperative relationships with Iran, including most notably helping the Islamic Republic circumvent US sanctions by exchanging Turkish gold for Iranian gas. His strident opposition to Israel. His cooperation with another American pariah–Venezuela–which Turkey is helping evade sanctions by agreeing to refine Venezuelan gold. His burning desire to destroy America’s Kurdish allies who have been the only effective local force in the battles against ISIS, said desire driven by Erdogan’s burning hatred of the Kurds in Turkey. This desire to attack Kurds in Syria has led to standoffs (with the serious risk of escalation) with US troops working with them. And last, but by no means least, an agreement to purchase S-400 surface-to-air missile systems from Russia despite the information this could provide the Russians about US F-35 aircraft–which Turkey wants to purchase.
Some of these things–canoodling with Iran, opposing Israel–were not a problem with the Obama administration. They are a big deal with Trump.
The real lunacy is that Erdogan is risking a confrontation with the US at a time when his economy is teetering–in large part due to his mismanagement. The lira dropped significantly last summer, and although it has recovered (a) it is still substantially below the level of 2017, (b) has been dropping steadily since topping out in December, and (c) is poised for another drop due to Erdogan’s inveterate hostility to higher interest rates–well, to interest rates period, which he calls “the mother and father of all evil.” The Turkish Central Bank has been playing games to conceal how weak its reserve position is. These include borrowing dollars from Turkish banks via swaps, putting the dollars as on-balance sheet assets, but treating the swaps as off-balance sheet.
The Turkish economy is in recession, has heavy external indebtedness (which makes its low reserve position all the more dangerous), and has an economic management team that is universally considered to be greatly out of its depth. Erdogan did not help matters when he declared:
The main issue is interest rates. As interest rates are brought down, inflation will fall. The real problem is interest rates. I’m also an economist.
Not only is he not an economist (as his getting the Fisher effect exactly backwards shows), I don’t even think he’s ever even stayed at a Holiday Inn Express. Combining his economic stupidity with his autocratic behavior is a recipe for disaster.
Given this fraught economic situation, Erdogan courts disaster by continuing to pull Uncle Sam’s beard. He is very likely to need the US’s help to stave off economic crisis, and on the flip side, if sufficiently provoked the US could smash the Turkish economy with a mere flick of its fingers.
Erdogan also has domestic political problems. After prevailing in a surprise national election last summer that cemented his changes to the constitution creating a presidential system, his AKP party suffered some stunning losses in local elections last month, most notably a (narrow) loss in Istanbul. Erdogan is attempting to get a do over in the Istanbul election, claiming systemic voting abuses–in a city his party controlled at the time of the election. It is something akin to the Chicago Democratic machine blaming a loss on nefarious Republican voter fraud.
There are many reasons for Erdogan’s near panic over Istanbul. It will give his CHP opponents a highly visible platform and power base, in a city that is widely viewed as the launching pad for Turkish national leaders. (Erdogan was mayor there before becoming prime minister, then president.) Perhaps even more importantly to Erdogan, CHP control of Istanbul threatens to undermine his vast patronage system there (which will undercut his power), and also threatens to expose equally vast corruption (of which Erdogan has already been very credibly accused in the past).
Erdogan is not the type of man who will trim his sails in the face of such fierce headwinds. He will more likely redouble his confrontational efforts, both internationally and domestically, despite his extremely weak economic situation. This is not wise, and will not end well. A bad end to Erdogan is hardly something that should be rued, but his bad end will also mean serious and extended misery for the Turkish people, and a serious potential for even more instability in the Middle East.
This last prospect may be the only thing that saves Erdogan. The potential for turmoil may be the only reason why the Trump administration does not give Erdogan the brusin’ he has been cruisin’ for, not just recently, but since 2003.
All the hysterical dems, crazed never-trumpers, the BBC and most of the world’s print media and woke politicians the world over should look at Erdogan’s Turkey and realise that that is what a dangerous populist autocrat looks like, and that Trump for all his perceived, and endlessly commented upon, personality traits is just a teddy bear by comparison.
Comment by Jack the dog — April 29, 2019 @ 5:44 am
Once upon a time, a person could make the sweeping statement: “Democracy is incompatible with an Islamic society.” and be immediately refuted with the response: “What about Turkey?”
That situation WAS true because Mustafa Kemal Ataturk had reforged Turkey into a secular society.
Ataturk was a military and political genius.
He was the main guy behind the foundation of the Turkish Republic from the ruins of the Ottoman Empire (a failed Islamic theocracy).
Ataturk’s political genius should have been respected and the Turkish political system that he founded allowed to remain intact. Unfortunately, Erdogan is an Islamist. People say that Erdogan is sympathetic to the Muslim Brotherhood. Turkey will continue to decline as long as Erdogan remains in power.
Comment by Eggplant — May 1, 2019 @ 5:43 pm
@Eggplant. I agree with all that. I am a great admirer of Ataturk, both as a military man and as a political leader. I have visited his battlefield (and statue) at Gallipoli, and the Anitkabir. I have also visited the sites of some of the battles in the War of Independence, which was a truly remarkable achievement given the odds against him. But his greatest accomplishments are were what you state–his creation of the Turkish Republic and a secular Turkey. Under his successor Inonu, Turkey wisely stayed out of WWII. All in all, Ataturk put Turkey on the path to modernity and away from obscurantism.
Erdogan wants to undo all that. He hates Ataturk for secularizing Turkey, and eliminating the caliphate. He envisions himself as a new sultan. (Weirdly, he reveres Abdulhamid II, which is an odd choice given the disasters that visited the Ottoman Empire during his reign.) Unless he is removed soon (and hopefully by democratic means) he will undo all that Ataturk achieved.
Comment by cpirrong — May 1, 2019 @ 7:13 pm
real lunacy is that Erdogan is risking a confrontation with the US at a time when his economy is teetering–in large part due to his mismanagement. The lira dropped significantly last summer, and although it has recovered
TRY Had recovered. Back above 6.1. My guess is 7 by year end, and around 12 by 2023. And I remember when it looked a bargain at 3!
Erdogan is a lunatic.
Comment by alwalad — May 8, 2019 @ 10:18 am
Whilst your blog has some good stuff, it’s rather difficult to read due to the picture in the background. Is there a way to turn it off?
Comment by Winston Smith — May 10, 2019 @ 12:01 am
@alwalad–I agree. That was one of my core arguments. Given the parlous state of Turkey’s economy, he needs to placate the US, not anger it. The US can make or break the Turkish economy, without breaking a sweat.
And I see that he’s doubled down on his lunacy by getting the Istanbul election overturned. Or perhaps it’s desperation rather than lunacy–if İmamoğlu keeps turning over rocks in Istanbul, exposing the corruption, dismantling the patronage networks, Erdoğan knows that he’s a goner.
Comment by cpirrong — May 12, 2019 @ 9:24 pm
Odd Sights, Rio Edition
University of Notre Dame Center for the Study of Financial Regulation
New York Board of Trade
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De Rebus Antiquis Et Novis
Future of Russia
La Russophobe
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Financial Crisis II
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Blog Engineering
Learning to operate Kubernetes reliably
Julia Evans on December 20, 2017 in Engineering
We recently built a distributed cron job scheduling system on top of Kubernetes, an exciting new platform for container orchestration. Kubernetes is very popular right now and makes a lot of exciting promises: one of the most exciting is that engineers don’t need to know or care what machines their applications run on.
Distributed systems are really hard, and managing services on distributed systems is one of the hardest problems operations teams face. Breaking in new software in production and learning how to operate it reliably is something we take very seriously. As an example of why learning to operate Kubernetes is important (and why it’s hard!), here’s a fantastic postmortem of a one-hour outage caused by a bug in Kubernetes.
In this post, we’ll explain why we chose to build on top of Kubernetes. We’ll examine how we integrated Kubernetes into our existing infrastructure, our approach to building confidence in (and improving) our Kubernetes’ cluster’s reliability, and the abstractions we’ve built on top of Kubernetes.
What’s Kubernetes?
Kubernetes is a distributed system for scheduling programs to run in a cluster. You can tell Kubernetes to run five copies of a program, and it’ll dynamically schedule them on your worker nodes. Containers are automatically scheduled to increase utilization and save money, powerful deployment primitives allow you to gradually roll out new code, and Security Contexts and Network Policies allow you to run multi-tenant workloads in a secure way.
Kubernetes has a lot of different kinds of scheduling capabilities built into it. It can schedule long-running HTTP services, daemonsets that run on every machine in your cluster, cron jobs that run every hour, and more. There’s a lot more to Kubernetes. If you want to know more, Kelsey Hightower has given a lot of excellent talks: Kubernetes for sysadmins and healthz: Stop reverse engineering applications and start monitoring from the inside are two nice starting points. There’s also a great, supportive community on Slack.
Why Kubernetes?
Every infrastructure project (hopefully!) starts with a business need, and our goal was to improve the reliability and security of an existing distributed cron job system we had. Our requirements were:
We needed to be able to build and operate it with a relatively small team (only 2 people were working full time on the project.)
We needed to schedule about 500 different cron jobs across around 20 machines reliably.
Here are a few reasons we decided to build on top of Kubernetes:
We wanted to build on top of an existing open-source project.
Kubernetes includes a distributed cron job scheduler, so we wouldn’t have to write one ourselves.
Kubernetes is a very active project and regularly accepts contributions.
Kubernetes is written in Go, which is easy to learn. Almost all of our Kubernetes bugfixes were made by inexperienced Go programmers on our team.
If we could successfully operate Kubernetes, we could build on top of Kubernetes in the future (for example, we’re currently working on a Kubernetes-based system to train machine learning models.)
We’d previously been using Chronos as a cron job scheduling system, but it was no longer meeting our reliability requirements and it’s mostly unmaintained (1 commit in the last 9 months, and the last time a pull request was merged was March 2016) Because Chronos is unmaintained, we decided it wasn’t worth continuing to invest in improving our existing cluster.
If you’re considering Kubernetes, keep in mind: don’t use Kubernetes just because other companies are using it. Setting up a reliable cluster takes a huge amount of time, and the business case for using it isn’t always obvious. Invest your time in a smart way.
What does reliable mean?
When it comes to operating services, the word reliable isn’t meaningful on its own. To talk about reliability, you first need to establish a SLO (service level objective).
We had three primary goals:
99.99% of cron jobs should get scheduled and start running within 20 minutes of their scheduled run time. 20 minutes is a pretty wide window, but we interviewed our internal customers and none of them asked for higher precision.
Jobs should run to completion 99.99% of the time (without being terminated).
Our migration to Kubernetes shouldn’t cause any customer-facing incidents.
This meant a few things:
Short periods of downtime in the Kubernetes API are acceptable (if it’s down for ten minutes, it’s ok as long as we can recover within five minutes.)
Scheduling bugs (where a cron job run gets dropped completely and fails to run at all) are not acceptable. We took reports of scheduling bugs extremely seriously.
We needed to be careful about pod evictions and terminating instances safely so that jobs didn’t get terminated too frequently.
We needed a good migration plan.
Building a Kubernetes cluster
Our basic approach to setting up our first Kubernetes cluster was to build the cluster from scratch instead of using a tool like kubeadm or kops (using Kubernetes The Hard Way as a reference). We provisioned our configuration with Puppet, our usual configuration management tool. Building from scratch was great for two reasons: we were able to deeply integrate Kubernetes in our architecture, and we developed a deep understanding of its internals.
Building from scratch let us integrate Kubernetes into our existing infrastructure. We wanted seamless integration with our existing systems for logging, certificate management, secrets, network security, monitoring, AWS instance management, deployment, database proxies, internal DNS servers, configuration management, and more. Integrating all those systems sometimes required a little creativity, but overall was easier than trying to shoehorn kubeadm/kops into doing what we wanted.
We already trust and know how to operate all those existing systems, so we wanted to keep using them in our new Kubernetes cluster. For example, secure certificate management is a very hard problem, and we already have a way to issue and manage certificates. We were able to avoid creating a new CA just for Kubernetes with a proper integration.
We were forced to understand exactly how the parameters we were setting affected our Kubernetes setup. For example, there are over a dozen parameters used when configuring the certificates/CAs used for authentication. Understanding all of those parameters made it way easier to debug our setup when we ran into issues with authentication.
Building confidence in Kubernetes
At the beginning of our Kubernetes work, nobody on the team had ever used Kubernetes before (except in some cases for toy projects). How do you get from “None of us have ever used Kubernetes” to “We’re confident running Kubernetes in production”?
Strategy 0: Talk to other companies
We asked a few folks at other companies about their experiences with Kubernetes. They were all using Kubernetes in different ways or on different environments (to run HTTP services, on bare metal, on Google Kubernetes Engine, etc).
Especially when talking about a large and complicated system like Kubernetes, it’s important to think critically about your own use cases, do your own experiments, build confidence in your own environment, and make your own decisions. For example, you should not read this blog post and conclude “Well, Stripe is using Kubernetes successfully, so it will work for us too!”
Here’s what we learned after conversations with several companies operating Kubernetes clusters:
Prioritize working on your etcd cluster’s reliability (etcd is where all of your Kubernetes cluster’s state is stored.)
Some Kubernetes features are more stable than others, so be cautious of alpha features. Some companies only use stable features after they’ve been stable for more than one release (e.g. if a feature became stable in 1.8, they’d wait for 1.9 or 1.10 before using it.)
Consider using a hosted Kubernetes system like GKE/AKS/EKS. Setting up a high-availability Kubernetes system yourself from scratch is a huge amount of work. AWS didn’t have a managed Kubernetes service during this project so this wasn’t an option for us.
Be careful about the additional network latency introduced by overlay networks / software defined networking.
Talking to other companies of course didn’t give us a clear answer on whether Kubernetes would work for us, but it did give us questions to ask and things to be cautious about.
Strategy 1: Read the code
We were planning to depend quite heavily on one component of Kubernetes,the cronjob controller. This component was in alpha at the time, which made us a little worried. We’d tried it out in a test cluster, but how could we tell whether it would work for us in production?
Thankfully, all of the cron job controller’s core functionality is just 400 lines of Go. Reading through the source code quickly showed that:
The cron job controller is a stateless service (like every other Kubernetes component, except etcd).
Every ten seconds, this controller calls the syncAll function: go wait.Until(jm.syncAll, 10*time.Second, stopCh)
The syncAll function fetches all cron jobs from the Kubernetes API, iterates through that list, determines which jobs should next run, then starts those jobs.
The core logic seemed relatively easy to understand. More importantly, we felt like if there was a bug in this controller, it was probably something we could fix ourselves.
Strategy 2: Do load testing
Before we started building the cluster in earnest, we did a little bit of load testing. We weren’t worried about how many nodes the Kubernetes cluster could handle (we were planning to deploy around 20 nodes), but we did want to make certain Kubernetes could handle running as many cron jobs as we wanted to run (about 50 per minute).
We ran a test in a 3-node cluster where we created 1,000 cron jobs that each ran every minute. Each of these jobs simply ran bash -c 'echo hello world'. We chose simple jobs because we wanted to test the scheduling and orchestration abilities of the cluster, not the cluster’s total compute capacity.
Our test cluster could not handle 1,000 cron jobs per minute. We observed that every node would only start at most one pod per second, and the cluster was able to run 200 cron jobs per minute without issue. Since we only wanted to run approximately 50 cron jobs per minute, we decided these limits weren’t a blocker (and that we could figure them out later if required). Onwards!
Strategy 3: Prioritize building and testing a high availability etcd cluster
One of the most important things to get right when setting up Kubernetes is running etcd. Etcd is the heart of your Kubernetes cluster—it’s where all of the data about everything in your cluster is stored. Everything other than etcd is stateless. If etcd isn’t running, you can’t make any changes to your Kubernetes cluster (though existing services will continue running!).
This diagram shows how etcd is the heart of your Kubernetes cluster—the API server is a stateless REST/authentication endpoint in front of etcd, and then every other component works by talking to etcd through the API server.
When running, there are two important points to keep in mind:
Set up replication so that your cluster doesn’t die if you lose a node. We have three etcd replicas right now.
Make sure you have enough I/O bandwidth available. Our version of etcd had an issue where one node with high fsync latency could trigger continuous leader elections, causing unavailability on our cluster. We remediated this by ensuring that all of our nodes had more I/O bandwidth than the number of writes etcd was performing.
Setting up replication isn’t a set-and-forget operation. We carefully tested that we could actually lose an etcd node, and that the cluster gracefully recovered.
Here’s some of the work we did to set up our etcd cluster:
Set up replication
Monitor that the etcd service is available (if etcd is down, we want to know right away)
Write some simple tooling so we could easily spin up new etcd nodes and join them to the cluster
Patch etcd’s Consul integration so that we could run more than 1 etcd cluster in our production environment
Test recovering from an etcd backup
Test that we could rebuild the whole cluster without downtime
We were happy that we did this testing pretty early on. One Friday morning in our production cluster, one of our etcd nodes stopped responding to ping. We got alerted about it, terminated the node, brought up a new one, joined it to the cluster, and in the meantime Kubernetes continued running without incident. Fantastic.
Strategy 4: Incrementally migrate jobs to Kubernetes
One of our major goals was to migrate our jobs to Kubernetes without causing any outages. The secret to running a successful production migrations is not to avoid making any mistakes (that’s impossible), but to design your migration to reduce the impact of mistakes.
We were lucky to have a wide variety of jobs to migrate to our new cluster, so there were some low-impact jobs we could migrate where one or two failures were acceptable.
Before starting the migration, we built easy-to-use tooling that would let us move jobs back and forth between the old and new systems in less than five minutes if necessary. This easy tooling reduced the impact of mistakes—if we moved over a job that had a dependency we hadn’t planned for, no big deal! We could just move it back, fix the issue, and try again later.
Here’s the overall migration strategy we took:
Roughly order the jobs in terms of how critical they were
Repeatedly move some jobs over to Kubernetes. If there’s a new edge case we discover, quickly rollback, fix the issue, and try again.
Strategy 5: Investigate Kubernetes bugs (and fix them)
We set out a rule at the beginning of the project: if Kubernetes does something surprising or unexpected, we have to investigate, figure out why, and come up with a remediation.
Investigating each issue is time consuming, but very important. If we simply dismissed flaky and strange behaviour in Kubernetes as a function of how complex distributed systems can become, we’d feel afraid of being on call for the resulting buggy cluster.
After taking this approach, we discovered (and were able to fix!) several bugs in Kubernetes.
Here are some kinds of issues that we found during these tests:
Cronjobs with names longer than 52 characters silently fail to schedule jobs (fixed here).
Pods would sometimes get stuck in the Pending state forever (fixed here and here).
The scheduler would crash every 3 hours (fixed here).
Flannel’s hostgw backend didn’t replace outdated route table entries (fixed here).
Fixing these bugs made us feel much better about our use of the Kubernetes project—not only did it work relatively well, but they also accept patches and have a good PR review process.
Kubernetes definitely has bugs, like all software. In particular, we use the scheduler very heavily (because our cron jobs are constantly creating new pods), and the scheduler’s use of caching sometimes results in bugs, regressions, and crashes. Caching is hard! But the codebase is approachable and we’ve been able to handle the bugs we encountered.
One other issue worth mentioning is Kubernetes’ pod eviction logic. Kubernetes has a component called the node controller which is responsible for evicting pods and moving them to another node if a node becomes unresponsive. It’s possible for all nodes to temporarily become unresponsive (e.g. due to a networking or configuration issue), and in that case Kubernetes can terminate all pods in the cluster. This happened to us relatively early on in our testing.
If you’re running a large Kubernetes cluster, carefully read through the node controller documentation, think through the settings carefully, and test extensively. Every time we’ve tested a configuration change to these settings (e.g. --pod-eviction-timeout) by creating network partitions, surprising things have happened. It’s always better to discover these surprises in testing rather than at 3am in production.
Strategy 6: Intentionally cause Kubernetes cluster issues
We’ve discussed running game day exercises at Stripe before, and it’s something we still do very frequently. The idea is to come up with situations you expect to eventually happen in production (e.g. losing a Kubernetes API server) and then intentionally cause those situations in production (during the work day, with warning) to ensure that you can handle them.
After running several exercises on our cluster, they often revealed issues like gaps in monitoring or configuration errors. We were very happy to discover those issues early on in a controlled fashion rather than by surprise six months later.
Here are a few of the game day exercises we ran:
Terminate one Kubernetes API server
Terminate all the Kubernetes API servers and bring them back up (to our surprise, this worked very well)
Terminate an etcd node
Cut off worker nodes in our Kubernetes cluster from the API servers (so that they can’t communicate). This resulted in all pods on those nodes being moved to other nodes.
We were really pleased to see how well Kubernetes responded to a lot of the disruptions we threw at it. Kubernetes is designed to be resilient to errors—it has one etcd cluster storing all the state, an API server which is simply a REST interface to that database, and a collection of stateless controllers” that coordinate all cluster management.
If any of the Kubernetes core components (the API server, controller manager, or scheduler) are interrupted or restarted, once they come up they read the relevant state from etcd and continue operating seamlessly. This was one of the things we hoped would be true, and has actually worked very well in practice.
“Weird, I didn’t get paged for that, that really should have paged. Let’s fix our monitoring there.”
“When we destroyed our API server instances and brought them back up, they required human intervention. We’d better fix that.”
“Sometimes when we do an etcd failover, the API server starts timing out requests until we restart it.”
After running these tests, we developed remediations for the issues we found: we improved monitoring, fixed configuration issues we’d discovered, and filed bugs with Kubernetes.
Making cron jobs easy to use
Let’s briefly explore how we made our Kubernetes-based system easy to use.
Our original goal was to design a system for running cron jobs that our team was confident operating and maintaining. Once we had established our confidence in Kubernetes, we needed to make it easy for our fellow engineers to configure and add new cron jobs. We developed a simple YAML configuration format so that our users didn’t need to understand anything about Kubernetes’ internals to use the system. Here’s the format we developed:
name: job-name-here
kubernetes:
schedule: '15 */2 * * *'
- ruby
- "/path/to/script.rb"
cpu: 0.1
memory: 128M
memory: 1024M
We didn’t do anything very fancy here—we wrote a simple program to take this format and translate it into Kubernetes cron job configurations that we apply with kubectl.
We also wrote a test suite to ensure that job names aren’t too long (Kubernetes cron job names can’t be more than 52 characters) and that all names are unique. We don’t currently use cgroups to enforce memory limits on most of our jobs, but it’s something we plan to roll out in the future.
Our simple format was easy to use, and since we automatically generated both Chronos and Kubernetes cron job definitions from the same format, moving a job between either system was really easy. This was a key part of making our incremental migration work well. Whenever moving a job to Kubernetes caused issues, we could move it back with a simple three-line configuration change and in less than ten minutes.
Monitoring Kubernetes
Monitoring our Kubernetes cluster’s internal state has proven to be very pleasant. We use the kube-state-metrics package for monitoring and a small Go program called veneur-prometheus to scrape the Prometheus metrics kube-state-metrics emits and publish them as statsd metrics to our monitoring system.
For example, here’s a chart of the number of pending pods in our cluster over the last hour. Pending means that they’re waiting to be assigned a worker node to run on. You can see that the number spikes at 11am, because a lot of our cron jobs run at the 0th minute of the hour.
We also have a monitor that checks that no pods are stuck in the Pending state—we check that every pod starts running on a worker node within 5 minutes, or we otherwise receive an alert.
Future plans for Kubernetes
Setting up Kubernetes, getting to a place where we were comfortable running production code and migrating all our cron jobs to the new cluster took us five months with three engineers working full time. One big reason we invested in learning Kubernetes is we expect to be able to use Kubernetes more widely at Stripe.
Here are some principles that apply to operating Kubernetes (or any other complex distributed system):
Define a clear business reason for your Kubernetes projects (and all infrastructure projects!). Understanding the business case and the needs of our users made our project significantly easier.
Aggressively cut scope. We decided to avoid using many of Kubernetes’ basic features to simplify our cluster. This let us ship more quickly—for example, since pod-to-pod networking wasn’t a requirement for our project, we could firewall off all network connections between nodes and defer thinking about network security in Kubernetes to a future project.
Invest a lot of time into learning how to properly operate a Kubernetes cluster. Test edge cases carefully. Distributed systems are extremely complicated and there’s a lot of potential for things to go wrong. Take the example we described earlier: the node controller can kill all pods in your cluster if they lose contact with API servers, depending on your configuration. Learning how Kubernetes behaves after each configuration change takes time and careful focus.
By staying focused on these principles, we’ve been able to use Kubernetes in production with confidence. We’ll continue to grow and evolve how we use Kubernetes over time—for example, we’re watching AWS’s release of EKS with interest. We’re finishing work on another system to train machine learning models and are also exploring moving some HTTP services to Kubernetes. As we continue operating Kubernetes in production, we plan to contribute to the open-source project along the way.
Like this post? Join the Stripe engineering team. View Openings
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deaf studies
National Center on Deafness
Deaf CSUNians host Miss Deaf CSUN pageant
Christiaan Patterson
Janel Schmidt, 20, psychology major, is crowned Miss Deaf CSUN 2011. The pageant was held at the USU on Feb. 11. Photo Credit: Herber Lovato / Staff Photographer
Silent applause and screams poured out the doors of Plaza del Sol Friday night as judges crowned this year’s Miss Deaf CSUN 2011.
Freshman psychology major, Janel Schmidt, from Fremont, kicked off the pageant with the talent portion of the competition, with a dance performance to Britney Spears’ “Lucky.”
Brandon Marin and Spencer Montan served as the pageant’s masters of ceremonies.
“I’m speechless, no, I’m sign-less,” they said.
Schmidt was not the only contestant that showed impressive talent that night. Six other women wowed the judges and audience with their performances.
Kayla LaBruno, zoology major, displayed her photography of the outdoors. LaBruno said she loves taking photos as a way to inspire others.
“These pictures are the faith and beauty in my life,” LaBruno said on stage. “The Mt. Helix in San Diego inspires me to keep my heart open.”
Valerie Speir, sociology major from Castro Valley, showed off her tap dancing skills by performing a routine to Shakira’s “Hips Don’t Lie.”
The evening gown portion gave the contestants a chance to model elegant dresses and pose for the judges. Schmidt chose a form-fitting maroon satin dress that was complemented by shimmering heels. Schmidt’s smile radiated across the audience.
The pageant’s platform presentations allowed contestants to speak on a topic of their choice.
LaBruno chose to discuss the preservation of the earth during the platform presentations. The San Diego native urged people to stop littering beaches, as it affects the animal inhabitants and closed by asking everyone to take care of the planet.
Speir voiced her opinions on Hollywood’s portrayal of women and its negative effects on society.
Schmidt retold a story from her past that included dealing with her mother’s smoking habits and how it affects everyone, not just the smoker. The audience reacted to the heartfelt speech with passionate applause.
At the end of the night, judges discovered two contestants were tied for first place. They needed to determine a winner. The contestants came out again to answer another question. Anxious audience members yelled in anticipation and excitement.
Before the winner was announced, Daniel Girard, state director of the California Deaf Youth Ambassadorship program, invited all contestants to compete in the Miss Deaf California pageant in August 2011.
In the end it was Schmidt who won over audience and judges with her incredible talents and heartfelt speeches. Schmidt was crowned Miss Deaf CSUN for the next two years and was also given the talent award.
“I feel speechless,” Schmidt said. “I feel good after all the hard work. Now I want to go represent CSUN and visit high schools and present to students. I want them to know it’s OK to dream and whatever you want, will come true if you believe.”
Christiaan Patterson, Author
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Easy Fire Burns Over 1,700 Acres in Simi Valley
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Smorgasbord Blog Magazine – Getting To Know You with author Lucinda E. Clarke
Posted on May 27, 2018 by Smorgasbord - Variety is the Spice of Life.
It is my pleasure to welcome author Lucinda E. Clarke this morning for the Getting to Know You interview. Born in Dublin but officially a citizen of the world, Lucinda has been a professonal writer for over twenty years and had also run her own production company in Africa.
Let’s find out a little more about Lucinda before finding out the questions she has responded to.
Lucinda E Clarke [not her real name] was born in Dublin, but has lived in 8 other countries to date. She wanted to write but was railroaded into teaching. She had a habit of “falling” into other careers, announcing on radio, then scriptwriting for radio and television. She has been a professional writer since 1986 winning over 20 awards for her work, including mayoral speeches, company profiles, drama documentaries, educational programmes for radio and television, adverts, news inserts, court videos, National Geographic, cookery programmes, to name but a few!
She lectured in scriptwriting, had her own column in various publications, and written for national magazines. She was commissioned for two educational books by Heinemann and Macmillan, and book reports for UNESCO and UNICEF.
She graduated into running her own video production company in South Africa.
“Walking Over Eggshells” is her first self-published book, an autobiography which describes her adventurous life, trying to escape the emotional abuse she suffered from early childhood.
She published her second book a novel, “Amie an African Adventure” in July 2014, already a #1 bestseller in genre on Amazon.co.uk.
Lucinda’s third book ‘Truth, Lies and Propaganda’, was published on Amazon on November 30th 2014. It is the first in a series of two books and ‘More Truth, Lies and Propaganda’ is due out in 2015. They follow the author’s journey from the classroom to radio announcing, on to television and finally to setting up her own video production company. The books are packed with anecdotes of the often hilarious things that happened while out shooting a wide variety of subjects, taking the reader behind the scenes in the media and highlighting South Africa and its people.
The second book in the Amie series Amie and the Child of Africa was released in October 2015. Amie: Stolen Future in November 2016 and Cut for Life in September 2017.
I will share more about Lucinda’s books later in the post but first.. let’s find out more about the questions that she has selected today.
Welcome Lucinda and can you describe one most embarrassing moment of your life?
The first one I can think of, though heavens there are many, was the day we were out shooting in a township area outside Durban. There were four of us, a cameraman, production secretary, sound guy and me directing it all (otherwise known as bossing people around). I was always wary when we were in areas unaccompanied by a local member of the community, but we just needed a few scenes to complete a programme.
To my horror, we had only just set up and the shots rang out, very close and coming from all directions. I’ve always prided myself on my survival instincts and threw myself flat on the ground yelling to the others to do the same. It was several seconds before I realized that they were all staring at me and giggling very loudly indeed. Slowly I stood up, covered in gravel, mud, sticks and dried leaves. It was the beginning of Divali – time to light the fireworks. I never lived that down.
Tell us about your craziest experience.
Country: Libya – town: Benghazi – location: local radio station – date 1st September 1978.
Now the date is very important as it’s the anniversary of the day Colonel Ghadaffi liberated his country and this particular year was the date he decided to come down and inspect the navy moored in the harbour (one gun boat 16 foot long).
There was a loud explosion. An attempt on his life? (There had already been over 60 so far but the Americans and the British had protected him). All I know is that when I arrived for my shift, at the radio station I was met at the barrier by a plethora of soldiers waving guns with fixed bayonets. They stuck to me like glue, in the news room, in the studio, the sharpened blade pricking my neck all the time I was on air, even to the loo (I promise you I needed it). It was terrifying, especially as I doubt they spoke English and I didn’t know what would set them off. They even held a gun on the controller who’d turned white. Never have 4 hours passed so slowly and I staggered out a shadow of my former self.
Have you got a secret talent nobody knows about?
I’m ashamed to admit that I haven’t, or if I have, I’ve yet to discover it and I’m getting a bit old for one to pop up suddenly at this late stage. Honestly, I’m hopeless at most things. I hate housework, I’m hopeless with fashion – many of my friends look great in a bin bag, I look as if I am wearing a rubbish sack. Once upon a time I played the violin (badly), sung (only if the backing group was very loud) and I still count on my fingers, which refused to work together when I attempted to learn to play the piano. Nope, not a single shred of talent to be found anywhere.
What does it take to make you angry?
I don’t get angry very easily, one of my mottos is ‘Live and Let Live.’ I enjoy a good debate and will agree to disagree. However, I get cross when people have too many children they expect other people to support, cut down trees and disregard the environment. I also get angry with the treatment women suffer as second-class citizens and possessions, in the west we have it the best and that’s still not great. I also get cross when people moan and groan and try to get money for everything that goes wrong.
I’d like to drag them into a squatter camp in Africa and show them what real poverty is. And finally, when people refuse to take responsibility for their own actions – too many rights, no responsibilities.
What is something you look forward to when you retire?
I admit to not being ready to retire when we arrived in Spain although I was the right age. I was so excited, I could lounge around over breakfast, read books all day, wander along the beachfront and so on. That lasted all of 6 months and I was bored to tears. We moved and that occupied me for a while, then I threw myself into local activities, started learning Spanish, taught myself power point and gave lectures but all that didn’t keep me busy enough. So, I went back to writing and then the marketing and … need I say any more? Retirement is now a 24/7 work station at the dining room table in our little rabbit hutch and planning overseas trips we’re not sure we can afford. Believe me, retirement is exhausting.
I think most of us who are officially ‘retired’ would agree with that final statement! My thanks to Lucinda for sharing some of her thoughts and experiences with us and now time to share the fruits of her retirement!
Amie: Cut for Life is Lucinda’s latest book in the series.
They told Amie it was a simple look, listen and report back mission, but from the beginning everything went wrong. She is stalked across borders, the aid workers act suspiciously, she’s assaulted, and abandoned in a rural African hut miles from anywhere. What has happened to her partner Simon and can she trust the charismatic Frenchman who befriends her? The discovery of an ancient tribal tradition and a group of young children to rescue, test her skills to the limit. For the first time, she is prepared to kill to protect the innocent caught up in an international sex trade with an extra horrifying twist.
One of the recent reviews for the book
Fast paced and thrilling! By Rebecca H on April 22, 2018
I must say that I’m a huge fan of Amie the spy who doesn’t think she’s any good at it. This time Amie is faced with a terrible dilemma when she spies her parents in a shopping mall in Johannesburg. Should she compromise her position by letting them know she’s still very much alive? Of course she convinces herself that she must. However that decision has implications for future events.
Her next mission is to be apparently, a simple one. She is to join a group of aid workers on a fact finding mission. They are to visit various settlements and report to the British Government back on a number of issues. Very soon she makes a terrible discovery. Young girls are being sent to Africa to undergo FGM. But what else is happening to them?
Our intrepid heroine also discovers that some of her fellow aid workers are not all they appear to be. She has to rescue some of these children and lead them to safety putting herself in mortal danger. I love the way the character of Amie has developed and become someone we really care about. She’s totally believable as she questions herself and makes mistakes. Amy is tested to the limit but eventually succeeds with her mission.
It’s a fast paced thriller and the tension never lets up from start to finish. As well as that there are some wonderful descriptive passages which help readers visualise certain areas of Africa. Just superb writing! The author tackles the subject of FGM and child trafficking and opens reader’s eyes to these horrific practices that are sadly all top prevalent even today. I can only pray that eventually this mutilation of young women and girls will be stopped. It’s to the author’s credit that she chose to highlight this abhorrent practice. I can’t wait to see what Amy gets up to next.
Read the reviews and buy the book: https://www.amazon.com/Amie-LIFE-Lucinda-E-Clarke-ebook/dp/B07545M9DB
And Amazon UK: https://www.amazon.co.uk/Amie-CUT-LIFE-Lucinda-Clarke-ebook/dp/B07545M9DB
Other books by Lucinda E. Clarke
Read the reviews and buy all the books: https://www.amazon.com/Lucinda-E-Clarke/e/B00FDWB914
And on Amazon UK: https://www.amazon.co.uk/Lucinda-E-Clarke/e/B00FDWB914
Read more reviews and follow Lucinda on Goodreads: http://www.goodreads.com/author/show/7996778.Lucinda_E_Clarke
Connect to Lucinda via her website and social media.
Blog: http://lucindaeclarke.wordpress.com
Web page: http://lucindaeclarkeauthor.com
Twitter: https://twitter.com/LucindaEClarke
FB page: https://www.facebook.com/lucindaeclarke.author
This entry was posted in Book Promotion and tagged Africa, Amie an African Adventure, Amie: Cut for Life, Lucinda E. Clarke by Smorgasbord - Variety is the Spice of Life.. Bookmark the permalink.
64 thoughts on “Smorgasbord Blog Magazine – Getting To Know You with author Lucinda E. Clarke”
Annette Rochelle Aben on May 27, 2018 at 12:33 am said:
Oh, Lucinda… fireworks, eh? I was smiling because I can picture my doing exactly the same thing. NEVER retire again! I am convinced you have so many more exciting adventures to have. ❤ Cheers.
Smorgasbord - Variety is the Spice of Life. on May 27, 2018 at 10:41 am said:
Thank you Annette.. hugs xx♥
Lucinda E Clarke on May 27, 2018 at 10:17 pm said:
Thank you Annette – life is a lot less hectic here in Spain, and we are in a rural area as well. But I can’t stop scribbling and something always seems to go wrong when we go away on holiday 🙂
John W. Howell on May 27, 2018 at 1:38 am said:
Excellent interview of Lucinda. I enjoyed her story of the shots fired. Thanks, Lucinda and Sally
Thanks John… I should think very unsettling at the time.. a braver woman than I…. xx
John W. Howell on May 27, 2018 at 1:08 pm said:
It wasn’t the only time I freaked out over gunshots. The other was when we were filming in an electrical sub-station at night. This time they were real bullets but it was the happy people in the nearby settlement celebrating their team winning a football match. I made a fool of myself a second time.
I can never understand the “fire my rifle in the air” to celebrate anything. Thanks, Lucinda.
Lucinda E Clarke on May 28, 2018 at 9:25 am said:
Those bullets have to come down somewhere John but then any excuse – is it a man thing?.
Pingback: Smorgasbord Magazine: Getting To Know You; Lucinda E. Clarke – The Militant Negro™
kritsayvonne on May 27, 2018 at 8:31 am said:
A brilliant interview, what an interesting life. I love it when people whose blogs I follow are interviewed on another blog I follow….Fabulous. x
Great to hear thank you Yvonne.. and yes Lucinda has certainly had an interesting and at times slightly hair-raising… xx
I’m still trying to work out if I was dumb, brave, stupid or in the wrong place at the wrong time!
Get to know author Lucinda E. Clarke from this post on the Smorgasbord Invitation Blog.
Smorgasbord - Variety is the Spice of Life. on May 27, 2018 at 7:04 pm said:
Thank you for sharing Lucinda’s interview Don..
Thank you Don 🙂
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Darlene on May 27, 2018 at 3:23 pm said:
A great interview. You have led a very interesting life Lucinda. No wonder retirement doesn’t work for you. I have also ended up in Spain, writing away. I totally agree that retirement is exhausting!! Your books sound fascinating.
Thanks Darlene.. if I was still there it would have been great to get together… xxxx
It may still happen. You never know. I am going to the Winchester Writer’s Conference suggested by Mary Smith on your blog!
Smorgasbord - Variety is the Spice of Life. on May 27, 2018 at 11:16 pm said:
Fantastic Darlene..look forward to your views afterwards… hugs xxx
I’ll check to see if we are friends Darlene and if we are close to each other here in Spain – I adore meeting up with other writers 🙂
Darlene on May 28, 2018 at 7:09 am said:
A great idea. We live on the Costa Blanca, near Torrevieja. I love meeting other writers as well.
Darlene I’ll pm you.
watchingthedaisies on May 27, 2018 at 4:56 pm said:
Thank you Lucinda and Sally. What an interesting life you have led Lucinda!
Thank you for stopping by Brigid… hope you have had a lovely weekend.. xxx
Thank you. It was magical. 😊
I just sort of fell into things Brigid! If left to my own devices I’d probably have never done anything much!
dgkaye on May 27, 2018 at 5:43 pm said:
What an interesting life Lucinda has had. Wow, that was scary stuff about being in the heart of the Gadaffi politics.! ❤
Certainly scary stuff… but a real trooper to carry on anyway… ♥
dgkaye on May 28, 2018 at 12:05 am said:
Absolutely! 🙂 xx
Being married to a Walter Mitty had consequences but it was heaven or hell!
No lack of excitement! 🙂
Colleen Chesebro on May 27, 2018 at 7:25 pm said:
Lovely to have the opportunity to learn more about Lucinda. I have her book in my TBR file. Hugs, to you both! ❤
I do hope you enjoy them, Colleen, unbelievable but true.
Thank you Colleen.. hugs x♥
olganm on May 27, 2018 at 8:31 pm said:
I’ve been following Lucinda’s blog for a while but it’s good to learn a bit more about her. Thanks, Sally! Great interview!
So glad you like the blog Olga – lots more to come in Africa facts. I keep remembering stuff I left out of the memoirs.
Thank you Olga… certainly a wonderfully varied life.. xxxx
Mary Smith on May 27, 2018 at 9:48 pm said:
Great interview with Lucinda – and her books are great.
Thank you Mary.. xxx
Thank you Mary – sorry can’t find any little hearts to add 😦
Tina Frisco on May 27, 2018 at 11:02 pm said:
What a terrific interview! I love your sense of humor, Lucinda. It’s amazing how people come to life and jump off the page when spilling the beans 🙂 You’ve led a colorful life and one that I imagine is most fulfilling ❤️
Thank you for this lovely series, Sally ❤️
Thank you Tina…it has been illuminating, delving into people’s lives and experiences and great fun..♥♥
Tina what would we do without Sally, she is just the best. I was lucky I managed to answer the questions before Amie jumped in and told her side of the story, that’s the problem with characters you invent, they take over. But yes, life was extreme up and down, no middle road and I still don’t have a police record!!
Tina Frisco on May 28, 2018 at 8:16 pm said:
You deserve a badge for that, Lucinda! 🙂 And I couldn’t agree more about Sally ❤️
Thank you both.. happy to be here.. hugs ♥
robbiesinspiration on May 28, 2018 at 5:50 am said:
This is a great interview, Sally. So interesting. I am currently reading Aime, African Adventure. For someone who has lived in Africa most of her life and visited a number of African countries, this is powerful stuff. I find myself nodding as I read. Lucinda has cut straight into the heart of how it is in many of the African countries.
I’m thrilled to hear that Robbie, as possibly my least favorite review is one lady who says I don’t know what I’m talking about as she’s seen it on the BBC TV and knows better! Where did you go in Africa? And what did you think of it?
robbiesinspiration on May 28, 2018 at 7:40 pm said:
Hi Lucinda I live in South Africa and have traveled to Botswana, Namibia, Kenya, Zimbabwe and dealt a lot with Mauritius, Zambia and Nigeria. I have written a series of books on investing into Africa and studied a lot of publications and indexes on business in Africa. All African countries are different but some do demonstrate these strong themes of corruption, lack of good educational facilities and teachers and a patriarchal society. It is very difficult to conduct business in some countries and a facilitator to help smooth the way is necessary.
Smorgasbord - Variety is the Spice of Life. on May 28, 2018 at 9:51 am said:
I think living and working in a country as you and Lucinda have, offers a unique perspective that tourists do not have. The media is not helpful either as they pick and choose what they share… xx
Lucinda E Clarke on May 28, 2018 at 10:08 am said:
Yes Sally I’ve spent many hours on the propaganda train!
franklparker on May 28, 2018 at 7:43 am said:
Thanks for more insights into Lucinda’s life and times. I’ve read several of her books which are all so well written with just the right amount of humour and pathos. I do so agree with her about the things that make her angry.
We think very much along the same lines Frank 🙂
Thank you Frank…I agree…
balroop2013 on May 28, 2018 at 6:41 pm said:
Lucinda’s answers and all this conversation has inspired me to read her books. Her anecdotes are beckoning me! Thanks Sally, you are a great connector and a loving person. 🙂
Delighted to bring people together Balroop and so pleased you are going to explore Lucinda’s books further. hugsxx
Lucinda E Clarke on May 28, 2018 at 8:21 pm said:
Robbie, I had quite forgotten that you are in SA! Whereabouts are you? Then of course you understand. DH still gets his pension out of SA as it’s a living annuity we can’t get it out, but if the law changes please let us know as you are an expert in the finance field! We watch the exchange rates like hawks 🙂
D. Wallace Peach on June 1, 2018 at 3:46 am said:
Great interview, Sally and Lucinda. My goodness, what adventure, excitement, and danger. It’s like reading about a fictional character and yet, you’re real. You had me holding my breath while you described the experience at the radio station. So intense. Wonderful review of Cut for Life, too. 😀
Smorgasbord - Variety is the Spice of Life. on June 1, 2018 at 10:25 am said:
Thank you Diana.. a varied and exciting life and Lucinda shows no sign of slacking off even in ‘retirement’.. whatever that actually means today! xxx
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Transfer Rumor Roundup: Everton, Spurs, and Man United
By Kyle BonnAug 2, 2019, 1:27 PM EDT
With the transfer window shutting in just five days, a number of rumors that have seen constant play over the past few weeks seem to be thinning, but a few teams continue to add ahead of Deadline Day.
Everton is one of the latter, and the Toffees appear close to securing a highly coveted young player who could come in and help immediately. Juventus striker Moise Kean is on his way to Goodison Park, according to Gianluca Di Marzio staffer Fabrizio Romano.
Kean has been linked to Everton for quite a while but it seemed Juventus was keen to keep him around with Mario Mandzukic aging and Gonzalo Higuain coming off a poor loan spell at Chelsea. With Paulo Dybala also linked with an exit, it’s odd that Juventus would be willing to green-light the sale of Kean, but it seems his time in Turin could be coming to an end.
The 19-year-old would be a fabulous addition for Everton who boasts just Cenk Tosun, Oumar Niasse, and Dominic Calvert-Lewin at striker. Kean scored six goals in 13 Serie A appearances last season, seeing most of his time coming at the end of the campaign, bagging all six of his scores through March and April, earning a spot in Italy’s squad and scoring twice in March Euro qualifiers.
Manchester United may have sealed a move for Harry Maguire, making the Leicester City defender the most expensive in the world, but they could be sweating another signing as Paulo Dybala has reportedly told Juventus he has no interest in moving to Old Trafford.
According to Gazzetta dello Sport, passed on by Football Italia, Dybala is involved in a proposed swap deal for Romelu Lukaku, and while all agreements are completed, Dybala does not wish to move to Manchester United, putting the entire deal at risk.
The reason, in the report, is that United’s style does not suit the Argentine and that he wishes for a more attacking team like Paris Saint-Germain or Inter. Dyaba, according to the report, has not yet spoken to head coach Maurizio Sarri about his role in the team, but he has appeared in at least 30 games in all of his four seasons at thee club, so he figures to be an important player for The Old Lady this season.
Like Manchester United, Tottenham could also miss out on a target, although this could represent a much bigger miss for Spurs on a player they have been linked to for over a year.
Fulham hybrid wide player Ryan Sessegnon was thought to be headed to Spurs from the start of the summer, a player who has been linked to the Champions League finalists since at least last summer. The transfer, however, has dragged on with Fulham looking to secure top dollar for their teenage star.
Sessegnon had a poor season last campaign in his first full Premier League season, looking out of depth at times in top flight matches. Still, he is two seasons removed from his 16 goal, eight assist Championship campaign that saw him nominated for PFA Young Player of the Year and is a player that has enamored Tottenham since his early teenage years.
The question surrounding Sessegnon currently is the status of Danny Rose, who Spurs has reportedly tried to sell all summer to no avail and whose roster status could affect the purchase of Sessegnon, rumors have suggested. Rose has finally rejoined the squad for the end of preseason after skipping the Asia tour and the possibility he starts the season with the club is growing every passing day. Still, according to the London Evening Standard, the two transactions for now remain separate.
Will Spurs pull the trigger? Fulham boss Scott Parker thinks time is running out, saying, “Obviously I have read the speculation. Will it affect him? That would be up to Ryan. It is not as if the phone has been ringing off the hook, a bid every other day for him and Fulham are turning it down, for him to have the hump. I had this too as a young player. But if there is one good thing about the transfer window it is that come 5 o’clock next week when the door shuts, he can’t go anywhere.”
Sessegnon has a hamstring injury that has left him out of Fulham’s preseason preparations, and it remains to be seen whether he will continue as a White, having rebuffed all contract negotiations with the club to this point.
Ajax midfielder Donny van de Beek was one of the Dutch side’s more underrated players during the Champions League run last season. Matthijs de Ligt and Frenkie de Jong received many of the plaudits, but the creative van de Beek was one of their best attacking players all season long.
Despite less transfer rumor noise than his more popular teammates, the 22-year-old attacking midfielder confirmed he has been the subject of interest from Real Madrid.“Yes, Real Madrid are interested in me, but you are going very fast,” van de Beek said in his pre-match media obligations ahead of the club’s season opener against Vitesse tomorrow. “I don’t want to talk about what’s there or what is not, now I want to be focused on the match (for Ajax) against Vitesse.”
Over the last two Eredivisie seasons, van de Beek has made 68 league appearances, scoring 20 goals and assisting 16 more. Most impressively, he was spectacular in the latter stages of the Champions League against the biggest clubs in the world, scoring goals against Juventus and Tottenham while picking up assists in games against Bayern Munich and Real Madrid.
Tags: Ba, Bruno, Cenk Tosun, Danny Rose, Dominic Calvert-Lewin, Fabri, Harry Maguire, Maurizio Sarri, Oumar Niasse, Romelu Lukaku, Ryan Sessegnon, Scott Parker, Sessegnon
Watch Live: Cardiff City v. Crystal Palace
By Joe Prince-WrightMay 4, 2019, 12:15 PM EDT
Cardiff City host Crystal Palace on Saturday (Watch live, 12:30 p.m. ET on NBC and online via NBCSports.com) and the equation for the Bluebirds is simple.
Neil Warnock‘s men must win to keep their faint hopes of Premier League survival alive, as they are four points behind Brighton with two games to go for both teams but Cardiff have a much worse goal difference compared to Brighton who sit one place out of the relegation zone.
WATCH LIVE ONLINE HERE
As for Crystal Palace and Roy Hodgson, they will be aiming to finish as high as possible after a fairly comfortable campaign.
In team news Cardiff bring in Josh Murphy, Danny Ward and Bobby Reid for Leandro Bacuna, Junior Hoilett and Oumar Niasse.
Crystal Palace make four changes as Joel Ward, Michy Batshuayi, Andros Townsend and Jordan Ayew replace Patrick Van Aanholt, Cheikhou Kouyate, Max Meyer and Christian Benteke.
#CardiffCity vs. @CPFC | Team news!
Brought to you by @1xbet_Eng…#CityAsOne pic.twitter.com/dLwz9wxME7
— Cardiff City FC (@CardiffCityFC) May 4, 2019
Tags: Cardiff City, Crystal Palace, Premier League, Andros Townsend, Bobby Reid, Cheikhou Kouyate, Christian Benteke, Joel, Jordan Ayew, Josh Murphy, Junior Hoilett, Leandro Bacuna, Max Meyer, Michy Batshuayi, Neil Warnock, Oumar Niasse, Patrick Van Aanholt, Roy Hodgson
Liverpool handle business in Wales (video)
By Nicholas MendolaApr 21, 2019, 12:52 PM EDT
Wiljnaldum scores opener off corner
Milner converts Salah-won penalty
Cardiff cannot finish chances
Georginio Wijnaldum and James Milner scored to put Liverpool back atop the Premier League following a 2-0 defeat of Cardiff City on Sunday.
Neil Warnock‘s Bluebirds had their chances but simply lacked quality in finish. They remain three points back of Brighton and Hove Albion in the race to avoid relegation.
Liverpool is a point ahead of Man City before Wednesday’s Manchester Derby at Old Trafford.
Sadio Mane and Roberto Firmino broke the Cardiff back line, but Neil Etheridge closed down to help force the Brazilian to fire over the goal.
It was mostly Liverpool’s game, but Oumar Niasse need nearly luck into an in-tight finish after Victor Camarasa flubbed a shot into his path. Alisson Becker tipped it over the bar.
[ VIDEO: Premier League highlights ]
Wijnaldum put the Reds on top about 12 minutes into the second half when he wrapped his right foot around a bounding set piece to send it flying past Etheridge.
Henderson’s would-be goal was blazed over the goal in the 61st minute. It wasn’t quite a sitter, but there was certainly some beckoning goal.
Cardiff’s Sean Morrison missed his second significant chance of the match off a 64th minute corner kick.
Roger East awarded a penalty kick to Liverpool when Morrison manhandled Mohamed Salah in the box. Milner rarely misses from the spot.
Etheridge made a tremendous save on Salah in the 90th.
Anybody know how Sean Morrison missed that free header, with the goal gaping, from inside the six-yard box? Somehow the ball hits him on the back of the neck. What a chance for Cardiff to equalize. Huge let off for #LFC. #CARLIV 0-1 pic.twitter.com/VaxOE1exuA
— Joe Prince-Wright (@JPW_NBCSports) April 21, 2019
Tags: Alisson Becker, Cardiff City, Georginio Wijnaldum, James Milner, Liverpool, Mohamed Salah, Neil Etheridge, Oumar Niasse, Premier League, Premier League 2018-19 game recaps, Sean Morrison, Alisson, Georginio Wijnaldum, James Milner, Moha, Mohamed Salah, Neil Etheridge, Neil Warnock, Oumar Niasse, Roberto Firmino, Sadio Mane, Sean Morrison
Cardiff City alive after huge win at Brighton (video)
By Nicholas MendolaApr 16, 2019, 4:37 PM EDT
Cardiff pulls within 2 points of Brighton
Seagulls have match-in-hand
Mendez-Laing scores beauty
Cardiff City is not going down without a fight.
The Welsh side won for just the second time in eight Premier League outings, putting Brighton and Hove Albion deep in the relegation fight following a 2-0 win for the visitors at the Amex Stadium on Tuesday.
Nathaniel Mendez-Laing and Sean Morrison scored Cardiff City’s goals; The Bluebirds are two points behind 17th place Brighton, who has one more match to play than Cardiff’s four.
[ MORE: Box score, lineups, stats ]
Both teams attacked early, and Solly March spun an outside of the foot effort through traffic but wide of the post in the seventh minute.
Cardiff would take the lead through a beauty, Mendez-Laing starting a play and racing down field to take a pass from Oumar Niasse. Mendez-Laing then curled a shot around Mat Ryan.
And Cardiff doubled its advantage early in the second half, with Morrison at the back door to take advantage of a free kick lofted into the perfect place for a header.
Bluebirds STRIKE.
A huge goal for Cardiff and @mendezlaing19 and look at what it means to the supporters!
Watch it on NBCSN or stream here: https://t.co/sw8SkEkiDo pic.twitter.com/pYYFHZhKx1
— NBC Sports Soccer (@NBCSportsSoccer) April 16, 2019
Tags: Brighton and Hove Albion, Cardiff City, Mat Ryan, Nathaniel Mendez-Laing, Oumar Niasse, Premier League, Premier League 2018-19 game recaps, Sean Morrison, Solly March, Nathan, Nathaniel Mendez-Laing, Oumar Niasse, Sean Morrison, Solly March
By Joe Prince-WrightFeb 20, 2019, 12:32 PM EST
With Matchweek 27 of the Premier League season almost here, it is time to take a look at which players are on top form right now.
With big wins for Manchester United, Manchester City, Liverpool, Cardiff and Tottenham last time out in the PL, plenty of their players feature in our latest rankings.
Sergio Aguero (Man City) – Up 2
Heung-Min Son (Tottenham) – Even
Paul Pogba (Man United) – Up 4
Marcus Rashford (Man United) – Down 4
Raheem Sterling (Man City) – New entry
David De Gea (Man United) – Up 4
Ben Foster (Watford) – Down 2
Anthony Martial (Man United) – New entry
Mohamed Salah (Liverpool) – New entry
Fernandinho (Man City) – Down 3
Sol Bamba (Cardiff City) – New entry
Kevin De Bruyne (Man City) – New entry
Chris Wood (Burnley) – New entry
Christian Eriksen (Tottenham) – New entry
Toby Alderweireld (Tottenham) – Down 2
Sadio Mane (Liverpool) – Down 2
Jan Vertonghen (Tottenham) – New entry
Oumar Niasse (Cardiff City) – New entry
Matt Doherty (Wolves) – New entry
Tags: Manchester City, Premier League, Premier League Player Power Rankings 2018-19, Tottenham Hotspur, Anthony Martial, Ben Foster, Chris Wood, Christian Eriksen, David De Gea, Fernandinho, Heung-Min Son, Jan Vertonghen, Kevin De Bruyne, Marcus Rashford, Matt Doherty, Moha, Mohamed Salah, Oumar Niasse, Paul Pogba, Raheem Sterling, Sadio Mane, Toby Alderweireld
Transfer Rumor Roundup: Everton, Spurs, and Man United August 2, 2019 1:27 pm Watch Live: Cardiff City v. Crystal Palace May 4, 2019 12:15 pm Liverpool handle business in Wales (video) April 21, 2019 12:52 pm Cardiff City alive after huge win at Brighton (video) April 16, 2019 4:37 pm Premier League player Power Rankings February 20, 2019 12:32 pm Cardiff snatch dramatic late win at Saints (video) February 9, 2019 12:07 pm Watch Live: Cardiff City v. Bournemouth February 2, 2019 11:59 am Complete list of January transfer deals in the Premier League January 31, 2019 7:25 pm Premier League January transfer window grades (video) January 31, 2019 6:22 pm Arsenal edge past battling Cardiff (video) January 29, 2019 4:40 pm 8 players score, plus an OG, in Everton’s 22-0 preseason rout July 14, 2018 5:01 pm West Ham 3-1 Everton: Lanzini, Arnautovic finish off Toffees May 13, 2018 11:56 am Huddersfield 0-2 Everton: Toffees rolling April 28, 2018 12:01 pm Burnley 2-1 Everton: Comeback Clarets March 3, 2018 9:23 am Why are we so concerned with Dele Alli and diving? February 19, 2018 10:38 am PL roundup: Citizens crack 70 points, Spurs grab North London Derby February 10, 2018 3:00 pm Everton 3-1 Crystal Palace: Toffees keep climbing February 10, 2018 11:56 am Ramsey hat trick leads Arsenal demolition of Everton February 3, 2018 2:20 pm Everton 1-1 West Brom: Walcott assists equalizer January 20, 2018 12:01 pm Everton 0-2 Man United: Red Devils cruise January 1, 2018 2:23 pm Bournemouth 2-1 Everton: Fraser wins it late on December 30, 2017 12:00 pm West Brom 0-0 Everton: Baggies winless in 18 December 26, 2017 12:19 pm Lanzini charged by FA for fooling ref with dive December 18, 2017 8:17 am PL Sunday preview: Man City go for 11 straight November 25, 2017 5:21 pm PL roundup: Man Utd, Chelsea win big… but so do Man City November 18, 2017 4:34 pm Crystal Palace 2-2 Everton: Toffees battle back for point November 18, 2017 12:14 pm PL AT HALF: Chelsea battering West Brom; Liverpool, Man City up November 18, 2017 10:51 am Baines happy to win for Unsworth: “He’s been faultless” November 5, 2017 2:01 pm Everton 3-2 Watford: Toffees climb back for win November 5, 2017 1:31 pm Leicester City 2-0 Everton: Puel wins debut October 29, 2017 1:56 pm Rudiger, Willian score, Drinkwater debuts as Chelsea advances (video) October 25, 2017 4:50 pm Everton 2-5 Arsenal: Ozil, Sanchez star for Gunners October 22, 2017 10:27 am Everton 0-1 Burnley: Clarets add another big win October 1, 2017 11:08 am Watch Live: Everton vs. Burnley October 1, 2017 8:57 am PL Sunday preview: Liverpool, Arsenal face newly promoted sides September 30, 2017 5:25 pm Premier League roundup: Goals galore on wild Saturday (video) September 23, 2017 3:00 pm Everton’s comeback win puts Koeman “in a totally different world” September 23, 2017 12:49 pm Everton 2-1 Bournemouth: Niasse the hero September 23, 2017 11:57 am League Cup wrap: Sane saves Man City; Big boys roll (video) September 20, 2017 4:58 pm Who needs what in the final days of the window? August 29, 2017 10:30 am
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Jordan Stevens
Mina, Stevens charged by FA over breaking gambling rules
By Joe Prince-WrightSep 10, 2019, 12:30 PM EDT
Everton’s Yerry Mina and Leeds United’s Jordan Stevens have both been charged by the English Football Association over breaking gambling rules.
Stevens, 19, has been banned from all soccer related activity for six weeks after placing 59 bets last season, including five on Leeds. He was also fines $1,482.
Mina has been fined $12,300 and warned about his future conduct after he appeared in an advert for a betting company in his homeland of Colombia. He was charged in July and has now been charged.
Leeds chief executive Angus Kinnear released a strong statement with regards to the sanctions against Stevens.
“We are hugely disappointed in the FA’s choice of sanction,” Kinnear said. “To prevent a young footballer from taking part in any football activities at such a critical period of his career is a disproportionate punishment following a foolish mistake from a young player. We are particularly disappointed that the sanction was determined by two former professional footballers who we hoped would have had a better understanding of the impact of their decision.”
In recent years Daniel Sturridge, Joey Barton and others have been charged by the FA for breaching betting rules and with the rise in availability of betting on sports in the UK it is an issue which will continue to crop up.
Professional players in the UK are banned from betting on any soccer, no matter what game or team are involved.
Tags: Everton, Jordan Stevens, Leeds United, Yerry Mina, Ba, Daniel Sturridge, Joey Barton, Lee, Yerry Mina
Mina, Stevens charged by FA over breaking gambling rules September 10, 2019 12:30 pm
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Breaking: Military contractor jet goes down during Hawaiian fighter exercises
by Alex Hollings Dec 12, 2018
A civilian contractor’s jet went down while participating in fighter exercises out of Oahu. A Mk-58 Hawker Hunter, operated by the Virginia-based Airborne Tactical Advantage Co., reportedly crashed shortly after taking off at approximately 2:25 p.m. local time Wednesday afternoon.
#BREAKING: First video into our newsroom of the military plane crash in waters off Honolulu. The pilot, a 47-year-old male, suffered serious injuries. Details: https://t.co/ltGLiSMEr1 pic.twitter.com/f9AHrwk3Jn
— Hawaii News Now (@HawaiiNewsNow) December 13, 2018
The pilot’s name has not been released, but according to official statements, the 47-year-old appeared to have suffered traumatic injuries sustained during a “controlled fall from aircraft.” He was recovered by a Coast Guard vessel about three miles south of Oahu, near Honolulu’s Sand Island.
The moment of ejection (Hawaii News Now) pic.twitter.com/mZx1zpm6lA
— Mickey (@Airsquad9) December 13, 2018
Sentry Aloha is a large-scale series of fighter exercises with more than 30 aircraft participating from 12 different Air National Guard and Air Force units.
Airborne Tactical Advantage Co. (ATAC) operates a number of Hawker Hunters, as well as the F-21 KFIR and L-39 Albatros. According to their website, ATAC has had aggressor aircraft participate in every RIMPAC exercise since 2006, as well as providing training support for the Navy’s Fighter Weapon School, also referred to as Top Gun.
The Hawker Hunter is a British-sourced subsonic jet fighter produced in large numbers during the 1940s and 50s. The resilient and capable fighter continued to see service in militaries around the world until as recently as 2014.
Feature image courtesy of WikiMedia Commons
Royal Australian Air Force EA-18G Growler Catches Fire After Aborted Takeoff at Nellis AFB
This Day in Aviation History: Navy F4 pilot sets zoom climb altitude record in 1959
Syria Claims They Shot Down an Israeli Fighter Jet
Watch: Insane footage of Turkish attack helicopters unloading 20mm cannons on target
Budget Cuts Endangering Aircrew Lives?
Is Iran 'Scaring Away' US Aircraft and Drones?
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Why Mourinho Dumped Me For Months -Mikel Obi Reveals
John Mikel Obi moved to Chelsea from Lyn Oslo in 2006 when Jose Mourinho was coaching the team.
However, two red cards issued against Mikel in 2007, reduced his game time at the club.
Mikel saw only 63 minutes of action in Chelsea’s next fifteen games in the Premier League after he was dismissed against Reading during the 2006-2007 season.
”Jose Mourinho didn’t play me for months after two red cards I saw for the first time. Then we had a great relationship with him. He was the one who brought me to the club,” Mikel said in an interview with Trabzonspor’s official magazine, as quoted via 61 Saat.
Even after all that happened, the former Nigeria captain was full of praise for Mourinho, who he described as the best coach who can control big-name players with high ego.
READ ALSO: West Brom Signs Super Eagles Defender On Four-Year Deal From Rotherham [Photos]
”Coaching is a very difficult job because you have to deal with a lot of high ego. You should be able to control and fight the big names with high ego.
”Jose Mourinho is one of the best technicians who do this. He is very successful both tactically and in terms of human relations. Even now we have a great relationship with him. You know Jose Mourinho. He’s his own person.”
Mikel spent more than a decade at Chelsea and was part of the squad that won a Champions League crown, the Europa League, two Premier League titles and four FA Cups
HAPPENING NOW: Ochanja main market raided Fire [PHOTOS] as tanker looses brakes
Wed Oct 16 , 2019
EPL: Harry Kane gives Tottenham condition not to leave for Real Madrid
Klopp says Liverpool ‘back at the top’ after Bayern triumph
FA Cup: Jesus sends Man City into final
Defeated Djokovic will regroup at the double
Buhari Urges Youths To Embrace Sports As Source Of Income
Ronaldo unable to reach semi-finals following Juventus lose to Ajax
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Bucky Covington, ‘Good Guys’ – Album Review
If you're a fan of Bucky Covington but haven't yet bought 'Good Guys,' breathe easy. You've already heard over half the album. Seven of the 12 songs are retreads from his 'I'm Alright' EP or the unreleased Lyric Street album, or they're songs he's re…
Bucky Covington Honored by Firefighters for Charity Work With ‘Help the Good Guys’
While attending the 51st Annual International Association of Fire Fighters (IAFF) Convention in Philadelphia recently, Bucky Covington was moved by a special honor he received from the organization's president, Harold Schaitberger. The singer was presented with a custom made and personalized firefig…
Alanna Conaway
Bucky Covington Reveals Album Cover and Track Listing for ‘Good Guys’
Bucky Covington fans have anxiously been counting down the days until the release of the singer's sophomore album, 'Good Guys,' set to hit stores on Sept. 11. To give them a little something to hold them over, Covington has revealed the album cover artwork, as well as the list of whic…
Kellie Pickler Makes Cameo in Bucky Covington, Shooter Jennings ‘Drinking Side of Country’…
The new music video for Bucky Covington and Shooter Jennings' duet, 'Drinking Side of Country,' gives plenty of barn party scenes, cop chases, beer, beautiful girls and cameo appearances from the likes of country's Kellie Pickler, X Games medalist Kenny Bartram and TNA wrestler M…
Bucky Covington, ‘Drinking Side of Country’ (Feat. Shooter Jennings) – Song Review
Country outlaw Shooter Jennings and one-time 'American Idol' contestant Bucky Covington make an odd marriage, but on 'Drinking Side of Country,' their voices and styles compliment each other like bar stool buddies telling the same story. They may be too similar, in fact, as it&ap…
Bucky Covington, ‘I Wanna Be That Feeling’ – Lyrics Uncovered
The lyrics to 'I Wanna Be That Feeling,' Bucky Covington's new single on the rise, were penned by two of Nashville's most successful tunesmiths, Ben Hayslip and Jimmy Yeary. "This is one of those songs that laid around for a long time," Hayslip admits to T…
Bucky Covington’s Bus Involved in Crash
Bucky Covington's tour bus was involved in an accident on I-65 in Birmingham, Ala. on Thursday. A press release indicates that no one was seriously hurt, although a few passengers were taken to the hospital for examination.
Bucky Covington Captures Spirit of Young Love in ‘I Wanna Be That Feeling’ Video
Bucky Covington and his flowing locks star in the new video for 'I Wanna Be That Feeling.' The summery clip celebrates the carefree spirit of youth and young love on a sun-splashed day. It does an effective job of transporting the viewer to the time when hanging with friends was a top prio…
Amy Sciarretto
Bucky Covington Donates Funds for Injured Fire Fighters and Police Officers
Bucky Covington has always been known in Nashville as a "good guy," but now he's taking that to a whole new level. Covington has joined forces with "Help the Good Guys" -- a charitable organization that honors and supports injured fire fighters, police office…
Bucky Covington, ‘I Wanna Be That Feeling’ – Song Review
There's still room on the dial for Bucky Covington's husky southern accent. The Rockingham, N.C. born and raised singer has released 'I Wanna Be That Feeling,' the debut single from an upcoming record on Entertainment One Music Group.
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“I would like to commend Convertri on being the most advanced webpage building software ever created. It is idiot proof, and I am the idiot that proved it. Simply, an amazing piece of software... I would also like to applaud you for your enthusiasm about your business, you can tell this project is your baby, and you LOVE it. Proud to be a part of something extraordinary.”
Now, a lot of businesses and service providers use specialized software that is designed to make the entire lead generation and capturing process a lot smoother than in years past. Website elements such as pop-up ads, banners, alerts, and more are used today in order to capture quality leads for products and businesses in various industries. By using a software solution, you can significantly increase the rate at which you obtain leads for your website. Continue reading to find out more about high-quality software alternatives to Leadpages that you can use to further your business.
Leadpages is a landing page builder and lead generation software that lets you easily create, host, test, manage, and track landing pages. The platform comes as the alternatives to Instapage and offers all the core services and features with some new 3rd-party integrations that make it better than others. It is uniquely created for everyone and allow to easily create and modify unlimited landing pages with dozens of dynamic elements, including countdown timer, buy buttons, and more. You can easily publish its every page on any site without any limitation. There is also has a complete template management system that comes with more than 100 pre-built templates. You can easily choose and customize each its template without any limitation. Leadpages is a commercial tool and offers three different price plans; each plan has its own cost and benefits. Its most popular feature includes customizing fields, lead generation, content management, 404-page conversion, contact management, and email integration, etc.
Landing pages are an excellent way to let the designers and marketers think out of the box. Splash page informs the visitors about the exclusive launch, it contains the mix of texts, videos, or gamification or music to entice the visitors to explore the rest of the page. In a way, splash pages act as some interaction between the website and the users. Some splash page automatically redirects the visitors to the home page of the website, or some will require the visitor to click on the home page button.
The Hello Bar is perfect for every kind of website and allows its users to create effective messages to get them to subscribe. Unlike other page builders, the Hello Bar as the name suggests is a bar on top of your websites page. People who get annoyed with popups and close the website will now stay on your page as it does not stop them from browsing with different popups.
ClickFunnels works differently than other software in this review. It’s a bit more complex. It’s basically a website and marketing flow in a box. While Instapage, Unbounce and Leadpages allow users to create single landing pages, ClickFunnels lets you build different types of marketing funnels — ones containing lead capture forms, email campaigns, etc.
The major difference when comparing landing page hosting for Leadpages vs. Unbounce is that Leadpages gives you all three of these options, while Unbounce forces you to put your landing page on a subdomain of your site. The subdomain on your own site is arguably the cleaner option, but again, it comes down to how much time and technical knowledge you have.
An attractive page is an essential key to the success of the business online. But we don’t have any pro design abilities, so it’s fairly difficult for us to create an effective page without tiredness. Do you want to have the world’s best page editor? It let you put your elements anywhere you want, to make designs that are not possible to other editors.
A premium landing page combined with a well-designed sales funnels and high-quality multimedia content is what customers across virtually every market are interested in right now. Make sure that your business website or product landing page has that extra edge by using our helpful tips and advice to direct your brand or company in the direction that you want it to go in.
Checkboxes – we’ve granted checkboxes new and shiny powers to talk to autoresponder tags! This means that from now on, you can use checkboxes to segment leads, or let them choose from multiple bump sales, not just one. Assign tags in the Properties panel, and your prospects will be tagged with all relevant tags when multiple checkboxes are checked.
It comes with a pixel-precise drag and drop editor which offers a lot of flexibility when building your landing page. It requires some prior knowledge of coding for you to operate it effectively, but once it is mastered it can be a very powerful tool, although it comes at a significantly higher price than LeadPages. Also, it has a lot of integration plugins, making it easy for you to link up with other platforms.
This saves a lot of time of users. You can also manage multiple clients and campaigns at the same time on one account and also this feature allows multiple users. So that many users can work on the landing pages with one account. You can also archive and transfer accounts along with that you can organize client leads. You can also create group campaigns where you can include more than one campaign.
Leadpages includes a lot of extras that fill out the customer experience universe including a countdown timer so your pages automatically expire, automatic SMS text messaging for lead generation, and Center, a Zapier-like automation that lets you pull data from one connected app and push it to another. Center only has a few connections now, but it’s worth exploring if you don’t have another marketing automation tool in your arsenal.
Thank you Jackson for your time providing your insights and happiness for being part of Convertri family. It's great to see how you've compared with ClickFunnels and Kartra based on the core strength and objective of creating Convertri - Ease & Speed. You can easily create Welcome Gates using Layers and if you require more details just drop a message on Facebook group and you'll be surprised how many people are ready to help. For now you have access to all Google Fonts which helps find the most similar font to what you would require, however devs will check feasibility of having font import feature. And although the purpose is not to make websites but they are possible! You may search full-blown multi-page website samples on Facebook Group.
Marketers don’t have to worry about learning coding to get the landing page right. Instapage provide seamless integration with CRM tools, social, email marketing and other optimization tool, so that the marketer doesn’t have to worry about keeping too much of information stored in different tools. Just integrate and you are good to go. Currently, Instapage supports integration of more than 20 marketing tools. Instapage also camouflages your website so that the functionalities work like just your own website.
It uses two editors, a static editor and a column-based drag and drop (CDD) editor. Both editors are not easily customizable and do not offer much flexibility as the pixel-precise drag and drop editor. It doesn’t require any prior knowledge of coding before you can operate the tool effectively. It also has features that offer more control over how you relate with your customers. The large number of ready-made templates that LeadPages offer makes it stand out among other leading page builders.
Templates (Winner: Leadpages) All Leadpages users are granted access to over 500 free and premium templates. Unbounce offers about 100 template options. Leadpages and Unbounce templates cover all the primary industries. There are multiple template filtering parameters on both Leadpages and Unbounce. Both Leadpages and Unbounce deal with landing page templates. Leadpages also offers website templates, while Unbounce comes with supplementary templates for sticky bars and pop-ups. Leadpages wins thanks to its richer array of attractive templates.
Instapage is the most powerful landing page platform that is specially designed for teams and agencies. It is also known as a leader in post-click optimization that maximizes conversions for advertisers and marketers by allowing them to create and personalize post-click experiences at scale quickly. With the help of this solution, marketers can easily build personalized post-click experiences and update them with just a click. With more than one million landing pages at an average conversion rate of over 22%, Instapage is helping up to 15,000 customers around the world in order to capture more value from their campaigns. The platform has five amazing tools that deliver an end-to-end solution such as landing page builder, integrations ecosystem, advanced level publishing tools, optimization, and analytics system, and a team and client collaboration layer. Instapage also offers collaboration solution for streamlining the design review process that makes it better than others. One of the most interesting facts about this tool is that it offers more than 80 professionally designed templates, and the user can easily choose and modify each one without any limitation. Instapage also includes core feature such as group page into campaigns, lead-generation dashboard, heat maps, A/B testing, publish to multiple domains, and much more.
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Electoral Bonds: Where The Problem Really Lies
by Swarajya Videos
- Apr 16, 2019, 12:27 pm
Are electoral bonds a good thing or a bad thing?
A lot depends on what you want to assess.
If you want to look at the situation before they came into being about two or three years ago through a budget re-change, we had black money funding political parties.
All political parties claimed that they received a lot of money in cash under Rs 20,000 each, and hence, the bulk of it was from small donors, when actually the money came from big businessmen or vested interests.
After electoral bonds came into being, what we now have is a greater deal of transparency. Only white money can be bought into electoral bonds and into political parties.
How do electoral bonds work?
The Reserve Bank or the State Bank issue these bonds to any corporation or any individual who wants to buy them and give it to a political party. So they can pay the money through cheque or cash or any legal route of payment, collect these bonds, and these bonds are then given to political parties, who then can encash them.
However, the problem with electoral bonds is that the public and the voter does not know who has given money to which party. We know that parties have got the money, like in the last one year, i.e. 2017-18, the BJP received over 95 per cent of the total electoral bonds issued -- about Rs 210 crore.
But the point is, we do not know who gave it to them, in case you want to check whether that person received any favours from the BJP. So if it was a businessman close to the BJP, then you would want to know, okay, they’ve paid it and this policy was changed to benefit them.
But this anonymity is what is the clear weakness of electoral bonds, which is why the Supreme Court last week decided that whoever has received any money through electoral bonds must disclose the bonds and the details of who has given them to the Election Commission by May 31st.
However, the real problem is somewhere else. The problem is not really about disclosure but our political system, where businessmen are aligned this way or that, and politicians do not take kindly to a businessman who has funded a rival party. So if they come to power, they may target businessmen who have funded the rival party. And businessmen are mortally afraid of one party targeting them merely because they funded another party.
So, this is what needs to be fixed. We need to have a political system and a legal system that protects businessmen who have honestly given money to a party that they liked. If they are going to be targeted, they will prefer anonymity. The issue is not political parties wanting anonymity but businessmen wanting anonymity.
And till that situation changes, where the legal system can protect a businessman from being targeted by a political party that does not like him, till that thing happens, businessmen will continue to seek anonymity. That is the problem that needs to be fixed.
And once that is fixed, electoral bonds will be a good thing. They can be completely transparent, you will know who bought them, who paid for them, who got them, which political party gets it, and then you can track policies and see whether the money that is given to the political party has actually resulted in some kind of a benefit to the businessman who paid the electoral bonds to a party.
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If you do, go ahead and subscribe to Swarajya on YouTube.
That way you can keep up with all the videos we put out regularly.
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2 posts categorized "Must See Movies"
Gullivers Travels Movie Out December 25, More On Our Interview with Jack Black, Emily Blunt and Jason Segel
I had the fun of attending the Gullivers Travels (the movie) press screening on December 16 with a group of mom bloggers. First I posted with some behind the scene tidbits about the movie. But I also wanted to share more information from the press interviews with Jack Black (Lemuel Guliver), Jason Segel (Horatio) and Emily Blunt (Princess Mary). Each brought a special part of themselves to their roles. The movie Gullivers Travels opens December 25, so I will be heading to the theatres to share the movie with my family.
Picture top left to right: Sunny Chanel, Sara McGinnis, Jill Kloster, Michelle Fiordaliso, Beth Blecherman. Middle Left to right: Kim Grundy, Erica Fehrman, Jack Black, Colleen Padilla. Front: Kristen Flannery.
While the character Lemuel Guliver reinvented himself in the movie, Jack Black also had words of wisdom about his personal re-invention experiences. It was wonderful to see the philisophical side of an actor that always makes me laugh.
We asked Jack Black "since every kid can't be transported to a fantasyland, is there a way that people can reinvent themselves in their own lives?"
Continue reading "Gullivers Travels Movie Out December 25, More On Our Interview with Jack Black, Emily Blunt and Jason Segel" »
Posted by Beth B. at 12:00 AM in Media Event, Must See Movies | Permalink | Comments (1)
Gullivers Travels The Movie, An Adventure For The Whole Family
Last Thursday I traveled to LA for a press event I had been looking forward to for quite some time: a screening of the movie Gullivers Travels with the opportunity to interview three of the movie's fabulous stars: Jack Black, Emily Blunt and Jason Segel.
While I was waiting to board the plane I received a phone call from my tween, middle school son. He told me a few kids from school, friends since kindergarten, were acting mean toward him and he was disappointed. I tried to make him feel better about the situation, but I could not shake the thought of my son feeling "small" while other kids proclaimed themselves "the big kids on campus".
Update: Here is a link to my second post on Gulliver's Travels with more interview details.
Of course, the parallel between real life and art was striking that night when I attended the movie screening. The Gullivers Travels movie, based on the popular book by Jonathan Swift, showcases main character Lemuel Guliver feeling like a "small man in a big pond" before he goes on a journey that forces him to overcome his fears and have the courage to reach his goals.
GIVEAWAY: At the bottom of this post I will provide details on my giveaway: One Gullivers Travels movie poster signed by Jack Black, Jason Segel and Emily Blunt. I even saw them sign the poster so this is for real! Comment on this post to enter.
Here is the movie trailer for a glimpse of the special effects that brought the story to life. The movie is in 3D, so for the moment just imagine that added dimension of things coming out of the screen:
Movie Trailer:
Gullivers Travels The Movie will debut in theatres on December 25, 2010 and stars Jack Black, Jason Segel, Emily Blunt, Amanda Peet, Chris O'Dowd, Catherine Tate and Billy Connolly. The screenplay is by Joe Stillman and Nicholas Stoller, based on the book by Jonathan Swift. The movie is directed by Rob Letterman with Jack Black as one of the Executive Producers. The MPAA Rating is PG and the genre is adventure comedy.
Plot Outline (provided to the press group):
"In a modern, 3D family comedy take on the classic tale, Jack Black (star of “Kung Fu Panda” and “ School of Rock ”) is Lemuel Gulliver, a lowly mailroom clerk at a New York newspaper. After Gulliver bluffs his way into an assignment writing about the Bermuda Triangle, he goes there only to be transported to an undiscovered land, Lilliput. In this fantastical new world, Gulliver is, at last, a bigger-than-life figure -- in size and ego – especially after he starts telling tall tales, taking credit for his world’s greatest inventions, and placing himself at the center of its most historic events. Gulliver’s position is enhanced even further when he leads his new friends in a daring battle against their longtime enemies. But when Gulliver loses it all and puts the Lilliputians in peril, he must find a way to undo the damage. Ultimately, Gulliver becomes a true giant among men only when he learns that it’s how big you are on the inside that counts."
TechMamas Take:
Those who read the book Gullivers Travels, as I did many years ago, will see that the author created an adventure reflecting on the many sides of humor nature; from miopic, petty, and irrational to brave, creative and compasionate. The book also had an anti-war undertone.
Now take that story and put a "Jack Black" spin on it for the movie. With the added bonus that he is a dad himself (he has 2 small sons aged 2 and 4).
Continue reading "Gullivers Travels The Movie, An Adventure For The Whole Family" »
Posted by Beth B. at 2:45 PM in Celebrity, Media Event, Must See Movies | Permalink | Comments (3)
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Home Authors Posts by Telematics News
Autotalks’ C-V2X solution is market-ready for China, following successful interoperability and...
Telematics News - October 29, 2019
Autotalks, a provider of V2X (Vehicle-to-Everything) communication solutions, successfully showcased its chipset’s conformance to the Chinese C-V2X standard and the Chinese OSCCA...
Hyundai Mobis increases the 5G connected car development synergies
Hyundai Mobis and KT to share the results of technology development and discuss future collaboration at the Seosan Proving GroundCompleted the first...
Tech Mahindra collaborates with Netherlands-based startup Quantoz to offer Blockchain-as-a-Service for...
Tech Mahindra Ltd. announced its collaboration with Quantoz, Netherlands-based innovative Blockchain technology application incubator, specialized in building and implementing Blockchain-based solutions, to...
Renault partnered with Symbio to equip hydrogen range-extender to its electric...
Renault Group announced the launch of the KANGOO Z.E. Hydrogen for the end of 2019, and the MASTER Z.E. Hydrogen for 2020....
ABB to boost its e-mobility portfolio with the acquisition of EV...
ABB is to acquire a majority stake of 67 percent in Shanghai Chargedot New Energy Technology Co., Ltd. (“Chargedot”). The transaction is...
Electrify America, Hubject announce launch of “Plug&Charge” to enhance EV charging...
Electrify America and Hubject announced the next significant step in the upcoming launch of a simplified, and convenient system for electric vehicle...
Faurecia showcases its cockpit of the future and sustainable mobility solutions...
Faurecia, automotive technology company will participate in the 46th Tokyo Motor Show 2019 with a strong focus on Faurecia Clarion Electronics technologies...
VW unveils digitalised, connected, and intelligent new Golf
As the first model of the brand, the eighth Golf will be available in no less than five hybrid drive versions. Its...
Mitsubishi Motors unveil MI-Tech and Engelberg Tourer concept at Tokyo Motor...
Mitsubishi Motors Corporation (MMC) unveiled the MI-TECH concept small-sized electrified SUV concept car at Tokyo Motor Show 2019 MI-TECH...
Honda unveils all-new Fit at the Tokyo Motor Show 2019
Honda Motor Co., Ltd. held the world premiere of the all-new Fit at the 46th Tokyo Motor Show 2019. The all-new Fit will...
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Toyota advances hydrogen mobility future with second generation Mirai
Kia Motors announce ‘Plan S’ strategy to spearhead transition to EV,...
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This summer has been a busy and historic one for the URJ. It’s been nearly two months since Rabbi Rick Jacobs was installed at president of the Union for Reform Judaism, taking the reins from Rabbi Eric Yoffie, who now serves as our president emeritus. For those of you who couldn’t be at the presidential installation, take a look at the videos we’ve recently posted from that inspiring service, also embedded below.
In a recent email to congregational leaders, URJ Chairman of the Board Steve Sacks suggested temple boards set aside time at their next meeting to watch the video together. We’ve even prepared some discussion questions to help you consider the installation in the context of your own congregations. A few of the suggested questions are below, but they’re not just for board members. We’d love to hear your answers to some of these questions in the comment section of this post.
Referring to what the Rev. Moore said, how have we spent more time glancing back to the past and not looking toward the future? How can we change that?
Why do you think Rabbi Jacobs included movement or dance as part of the installation? How can we re-imagine our services?
Does this installation look different than you might have expected? How? What do you think this says about the new leadership of the URJ?
The new NFTY Board President Evan Traylor read three Torah portions at the installation and NFTY Board Members were invited to march during the Torah service at installation. How can we involve more teens in our services?
How can we join Rabbi Jacobs and the URJ in building a brighter Jewish future?
In Rabbi Jacobs’ sermon, he says, “This Shabbat afternoon service reflects the openness and passion of our uniquely Reform spirituality.” How can our services reflect the openness and passion of our community’s unique Reform spirituality?
In his sermon, Rabbi Jacobs also says, “The sacred mission of our Movement transcends the walls of the synagogue, and we must get that message out to all who want to join us on our journey of hope and healing in the world.” How can we transcend the walls of our synagogue and reach out and invite others to join us?
And finally, in Rabbi Jacobs’ installation sermon, Rabbi Jacobs says, “Guarding Israel’s security is our sacred responsibility. So too is the need to ensure that the values we hold dear – equality, tolerance, pluralism, democracy – are understood and protected in Israel.” What is our congregation doing to stand up for Israel while also ensuring that Israel protects and supports all expressions of Judaism?
Take some time to think these questions over… and then let us know what’s on your mind!
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Messages from Leadership
Butte Hall, Reimagined
Religion Professor Bruce Grelle Featured in TIME Magazine
Student Success at Center of CSU, Chico’s Second Annual Tipping Point Summit
Worth Sharing: Chico State Music Degrees Listed Among State’s Best
Fond Farewell: History Major Naomi Ramirez
Fond Farewell: Alumna and Philanthropist Marilyn Warrens
Putting a Priority on Accessible Technology
Student Leads Swipe Against Hunger
Autism Clinic Helps Build Skills for Life
See all Research
No Bones About It: Fossil Find a Whale of a Mystery
Photo courtesy of Todd Greene
Amanda Rhine January 14, 2020
All StoriesPeopleResearch
Earthquakes often happen in California, this is a fact. Some are too small to feel, and others are powerful enough to crack roads and level buildings. No one expects these natural occurrences to uncover a mystery. But that is exactly what happened during the 20 seconds a 6.4-magnitude earthquake rocked the Mojave Desert on July 4, 2019.
Much like an apple falling from a shaken tree, what appeared to be a 600-pound white rock was dislodged from a cliff in Tapo Canyon and tumbled onto a private road in Simi Valley. A utilities crew monitoring the area following the earthquake was quick to realize it was no rock at all, but instead a large fossil. Since fossils are under federal protection, the crew left it in its place and, with permission from the landowners, sent a picture to the Pasadena office of SWCA. The nationwide environmental consulting firm then tapped an expert—Chico State’s Russell Shapiro, a professor of paleontology and stratigraphy in the Department of Geological and Environmental Sciences.
Shapiro, who has been a paleontology consultant for SWCA since 2014, said he took one look at the picture and knew the crew had found something of value, but what exactly? He had to have a closer look.
Russell Shapiro’s dig crew takes a closer look at the 15-million-year-old mystery fossil while on location in Simi Valley. (Photo courtesy of Todd Greene)
Chico State happens to be one of the few institutions in the North State that is federally sanctioned to collect and store fossils—along with UC Berkeley, California Academy of Sciences, and Sierra College. In this case, Chico State was fortunate to be the only one with room to house these special Monterey formations, giving Shapiro and the University the first chance to figure out what was discovered.
A small dig team consisting of four volunteers from SWCA, Shapiro, and Todd Greene, a professor of sedimentology and stratigraphy and chair of the geological and environmental sciences department, assembled in Simi Valley for one day. It didn’t take long for the team to determine that the large fossil was an estimated 15-million-year-old chunk of vertebrae and ribs from a possible small whale from the Miocene era, Shapiro said.
Other fossils found at the dig site echoed that finding. As cool as fossils are, this set is not an “earth-shattering” discovery, Shapiro said, since California was once submerged under the ocean water and whale fossils are not an uncommon find. But his mystery was not yet solved.
The oddity of the some of the smaller formations, appearing to be ribs, seems to stump Shapiro. He hypothesizes that even though all the fossils were found in the same vicinity, they might not all be from the same animal.
“The biggest clue is that the cervical vertebrae (on the largest fossil formation) are collapsed. That’s a characteristic of whales,” he said. “The problem is that typical whale ribs are kind of long and flat—and these (smaller fossil formations) are round. I don’t know why they would be round. This is a big deal.”
Geological and environmental sciences student Quinn Little carefully removes the dirt and rock surrounding the 15-million-year-old possible whale vertebrae and rib bones. (Jason Halley / University Photographer)
Shapiro toys with the idea that the formations belong to both a mother whale and her baby, which would “make a nicer story,” he said. After significant progress prepping and strengthening the fossils, countless hours of carefully chiseling the bones out of rock still lay ahead of Shapiro and a lucky handful of students chosen to work on the project in the University’s Thin Section Lab before they could truly start to piece together the puzzle.
However, the skull of the large fossil formation was never found—making it almost impossible to identify the animal with absolute certainty.
“We really have to clean it out to be able to tell more, unfortunately,” Shapiro said. “What we really need is the head, which would have been [attached to the recovered vertebrae]. If we had the head, all answers would be instantly known.”
Greene, who has partnered with Shapiro on several digs throughout their careers, lent his geological expertise in marine sediments to give the team predictions on where else to look for more fossils, based on the location of the cliff from where the large formation fell. With his expertise, they ultimately found almost a dozen fossils.
Another fossil formation found at the Simi Valley dig site, which may or may not be from the same body as the 600-pound fossilized vertebrae. (Photo courtesy of Todd Greene)
But without the skull, the mystery continues. Since it was discovered on a private road, it’s up to the property owners if it will ever be found, Greene said. No word from the owners has been given, but both Shapiro and Greene are hopeful they will get permission to return to the site and search for their answer.
“That large formation has such a rich fauna in it, and where you can find fossiliferous sites—you concentrate on that,” Greene said. “It would be great to go back, if allowed, and see what else we could find. We need to find the skull.”
Amanda Rhine
Amanda Rhine (English, '15; MA, English, '18) works for University Communications at Chico State. Formerly, she served as an editor for Watershed Review and an assistant editor for The Orion.
From ‘The Hill’: Women’s History—and Future
Worth Sharing: CEO Magazine Lists CSU, Chico’s MBA Program in Global Rankings
Options Abound in Hunt for Student Housing
DACA, Dreamers and Immigration: The Expert Explains
Restless Dreamers
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HomeHomeMan found guilty of killing his father
Man found guilty of killing his father
Artesia Davis
Aman showed no emotion yesterday after a Supreme Court jury convicted him of the murder of his father.
Justice Bernard Turner will commence the penalty phase of Lee Sweeting’s trial on June 13.
It took jurors two hours to unanimously decide that the 23-year-old murdered his father, Leon Sweeting, between Thursday, November 23 and Friday, November 24, 2017 after his father refused to give him money.
The elderly man was found dead in his home at Ambergris Street off Faith Avenue on November 24.
After the murder, the accused went home and dressed a wound to his hand, before going to the hospital to get treatment for a cut on his hand. Sweeting initially told police and relatives he cut his hand when he fell on glass while running from a pack of dogs.
However, in a later interview, the unemployed Sweeting told investigators that he had asked his 76-year-old father for money and his dad chastised him for being “a waste of a life”.
In the interview, he claimed that his father attacked him with the knife and he acted in self-defense. The accused sustained a single cut to his hand and his father was stabbed 47 times.
At trial, Sweeting relied on his interview to police and exercised his right to remain silent.
Turner warned the jury that Sweeting’s silence should not be considered a sign of guilt as it was the prosecution who had to prove its case.
Pathologist Dr. Caryn Sands said that the deceased had defensive injuries to his hands.
Cordell Frazier and Camille Gomez prosecuted. Shaka Serville appeared for Sweeting.
Senior Reporter at The Nassau Guardian
Artesia primarily covers court stories, but she also writes extensively about crime.
Latest posts by Artesia Davis (see all)
Opening statements in Fox Hill mass murder trial to begin tomorrow - January 21, 2020
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Former BMC chair bla
‘A prayer answered
A render of the government’s proposed redevelopment of Princess Margaret Hospital. The plan would call for the demolition of seven existing structures, with one of the phases costing nearly $150 million.
Home news-top newsletter-headlines push notifications
Masterplan for PMH r
Philip Brave Davis.
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PLP would repeal tra
Dino’s Gourmet Conch Salad on West Bay Street. CODEL NEWTON
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Some business owners
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by gojam | July 31, 2013 · 11:49 pm
Geoffrey Dickens Dossier: Freedom Of Information Request.
Credit must go to GW who put in the FOI request.
Filed under Abuse, Fernbridge, News, Politics
by gojam | July 31, 2013 · 2:36 pm
West Yorkshire Child Sexual Exploitation Campaign
Child sexual exploitation (CSE) is a type of child sexual abuse. It is the organised and deliberate exploitation of a child purely for the sexual gratification of adults.
Any young person could become a victim of child sexual exploitation; the crime affects both girls and boys, from any background and of any ethnicity.
There are three main types of CSE –
1) Inappropriate relationships – this usually involves one perpetrator who has inappropriate power or control over a young person. There is often a significant age gap and the victim may believe they are in a loving relationship.
2) ‘Boyfriend’ model – the perpetrator befriends and grooms the young person into a ‘relationship’ and then convinces or forces them to have sex with friends or associates. This is sometimes associated with gang activity.
3) Organised sexual exploitation – young people are passed through networks where they are forced into sexual activity with multiple men. This often occurs at ‘sex parties’ and the young people may be used to recruit others into the network
by gojam | July 31, 2013 · 9:38 am
Police Investigate Fort Augustus Abbey Abuse
Police have confirmed they are investigating allegations of abuse by monks at a former Scottish Catholic boarding school.
It follows a BBC Scotland investigation which uncovered evidence of 30 years of physical and sexual abuse at Fort Augustus Abbey in the Highlands and its East Lothian prep school.
The Benedictine order which ran the schools has apologised to any victims.
Fresh claims of abuse have now emerged since the programme aired on Monday.
The documentary has also prompted calls for more support for victims.
In a statement Police Scotland, said it would make no further comment at this stage as it was now a “live investigation”.
It added that all such allegations are investigated and dealt with in a “victim-centred” manner.
North Korean Women try out for Olympic hurdles team
Filed under Humour
Jimmy Tarbuck Rebailed
The entertainer and quiz show host, 73, has been questioned about an alleged assault on a young boy in Harrogate, North Yorkshire, in the late 1970s.
He was arrested in April after information was passed to North Yorkshire Police by Metropolitan Police officers working on Operation Yewtree.
He has been rebailed while inquiries into the allegations continue.
North Yorkshire Police previously stressed that Mr Tarbuck’s arrest was “not part of Yewtree, but a separate investigation” by its own officers.
THE PAEDOFILE: Graham Ovenden isn’t selling very well any more….
….and the man who wrote the text for his ‘collection’ books is a notorious paedophile….who plied his trade on Amazon
Unrepentant Graham Ovendon
This extract is from a recent auction report on art-related items:
This lot No 1533: States of Grace Photographs 1964-1989 photographer Graham Ovenden, first edition, published by Ophelia Editions, Amsterdam 1992, text by Lawrence A. Stanley
Price information:
Estimate € 1800 – € 2000
StartPrice € 1500
Number of Bids …
Clearly and literally, zero interest. And as some of you may already know, a renowned Peer of the realm also recently sold all his ‘nymph’ paintings too. I think this is perhaps called ‘running for cover’. Or not. We mustn’t comment any more, oooh no. Note the town in which Ophelia editions is based, by the way.
But my point this morning is an investigation of text writer Lawrence A. Stanley. And a major hat-tip…
Jimmy Savile’s Sick Victim List Found
This is a truly horrible story but it should leave no one who reads it in any doubt whatsoever about what kind of sick and twisted individual Jimmy Savile was and the deviant circle of friends that he kept company with.
I always fear when I read a story like this that this will be the last we hear about it.
STUNNED officers chipped away plaster at a record shop wall and unveiled a hidden list of names thought to belong to young victims of Jimmy Savile.
The vile register, which contained the names, ages and a disgusting ratings system seemingly used to mark their sexual performance, was scrawled on a secret wall buried behind layers of wallpaper and plaster.
A source revealed: “The wall looked like something straight out of a horror movie. There were lists and lists of names of the victims – it’s a shocking discovery.”
The list of girls and young women is thought to identify hundreds of potential new victims abused at the hands of the BBC DJ and it raised fears Savile was at the centre of a celebrity paedophile ring.
Police believe the major breakthrough could lead to further arrests – including other well-known celebrities.
The wall also appeared to contain the names of girls the sick group hoped to target in the future.
Officers who raided the shop in Greater Manchester after a tip-off will now try to trace the alleged victims.
A source said the raid had provided the clearest evidence yet to show Savile was part of a larger group of monsters.
Filed under Abuse, News, Yewtree
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Everything Coming to and Leaving Hulu April 2019
by Sean P. Aune | April 1, 2019April 1, 2019 10:30 am EDT
Hulu TV News
April is here, and that means it’s time to see what Hulu has in store for its subscribers.
There is a lot of content on the way, but we’re expecting things to change drastically in the months to come with Disney now holding the controlling interest in the service. Expect to see a lot more of its acquired Fox catalog showing up.
What are the comings and goings for Hulu April 2019? Check them all out below.
Available April 1
Alone: Complete Season 5 (History Channel)
Ancient Aliens: Complete Seasons 1, 2, 3, 13 (History Channel)
Behind Bars: Rookie Year: Complete Season 1 (A&E)
Born Behind Bars: Complete Season 1 (A&E)
Cults and Extreme Belief: Complete Season 1 (A&E)
Intervention: Complete Season 20 (A&E)
Into The Dark: I’m Just F*cking With You: Episode 7 Premiere (Hulu Original)
Little Women: LA: Complete Season 4 (Lifetime)
Mountain Men: Complete Season 1 (History Channel)
Raising Tourettes: Complete Season 1 (A&E)
The Real Housewives of Potomac: Complete Season 3 (Bravo)
1492: Conquest of Paradise (1992)
Addams Family Values (1993)
Akeelah and the Bee (2006)
America’s Prince: The John F. Kennedy Jr. Story (2003)
An Everlasting Piece (2000)
At Close Range (1986)
Beethoven (1992)
Beethoven’s 2nd (1993)
Beethoven’s 3rd (1999)
Beverly Hills Cop II (1987)
Big Fat Liar (2002)
Blow (2001)
Blown Away (1994)
The Cable Guy (1996)
Case 39 (2009)
The Clearing (2002)
Cold Mountain (2003)
Curious George: Follow that Monkey (2009)
The Dark Mile (2017)
Days of Thunder (1990)
Diamonds are Forever (1971)
Die Another Day (2002)
Dr. Dolittle: Tail to the Chief (2007)
Eastern Promises (2007)
Escape from L.A. (1996)
Everything Must Go (2011)
Foxfire (1996)
Funny About Love (1990)
Funny Cow (2017)
Gloves Off (2017)
Goldfinger (1964)
Halloween H20: 20 Years Later (1998)
Happy Feet (2006)
Hollywood Homicide (2003)
Hot Shots! Part Deux (1993)
I Think I Love My Wife (2007)
In A World… (2013)
The Jerk (1979)
Kill the Irishman (2011)
Law of the Lawless (1964)
Liberty Stands Still (2002)
License to Drive (1988)
Like Mike (2002)
Live and Let Die (1973)
The Living Daylights (1987)
The Minus Man (1999)
Never Say Never Again (1983)
Octopussy (1983)
One Million American Dreams (2018)
Painkillers (2018)
Penelope (2006)
Playing By Heart (1998)
Practical Magic (1998)
Primal Fear (1996)
Project Nim (2011)
Racing with the Moon (1984)
The Shining (1980)
Six Degrees of Separation (1993)
Stories we Tell (2013)
Sunshine Cleaning (2009)
The Time Traveler’s Wife (2009)
Ultraviolet (2006)
Undisputed (2002)
Uninvited Guest (1999)
Up in Smoke (1978)
Up in the Air (2009)
White Noise (2005)
The World is not Enough (1999)
You Only Live Twice (1967)
One-Punch Man: Special (Viz)
Air Strike (2018)
Weightless (2018)
Marvel’s Cloak & Dagger: Season 2 Premiere (Freeform)
Rick Steves’ Europe: Complete Season 10 (PBS)
Finding Your Feet (2018)
One-Punch Man: Season 2 Premiere (Viz)
Destroyer (2018)
Available April 10
The Bold Type: Season 3 Premiere (Freeform)
Chio’s School Road: Season 1 (DUBBED) (Funimation)
How Not to Summon a Demon Lord: Season 1 (DUBBED) (Funimation)
The Last Ship: Season 5 Premiere (TNT)
Steve Jobs: The Man in the Machine (2015)
90 Day Fiancé: Happily Ever After?: Complete Season 3 (TLC)
Ayesha’s Home Kitchen: Complete Seasons 1&2 (Food Network)
Barefoot Contessa: Back to Basics: Complete Seasons 11-13 (Food Network)
Dr. Pimple Popper: Complete Season 1 (TLC)
Fixer Upper: Complete Season 5 (HGTV)
How the Earth Works: Complete Season 1 (Science Channel)
The Last Alaskans: Complete Seasons 2&3 (Discovery Channel)
Obsession: Dark Desires: Complete Season 2 (ID)
Pamela Smart: An American Murder Mystery: Complete Season 1 (ID)
Treehouse Masters: Complete Seasons 8-10 (Animal Planet)
Unearthed: Complete Seasons 2&3 (Science Channel)
What on Earth: Complete Seasons 2&3 (Science Channel)
Yukon Men: Complete Season 6 (Discovery Channel)
Enchanted April (1991)
Master of Disguise (2002)
We Are Columbine (2018)
Bless This Mess: Series Premiere (ABC)
Overboard (2018)
I Am The Night: Complete Season 1 (TNT)
The Quake (2019)
Ramy: Complete Season 1 Premiere (Hulu Original)
Book Club (2018)
Noma – My Perfect Storm (2015)
The Posh Frock Shop: Complete Season 1 (Banijay)
The Next Three Days (2010)
Overlord: Episodes 1-13 (DUBBED) (Funimation)
Arcadia (2019)
Beast of the Water (2019)
Border (2019)
Don’t Go (2018)
Welcome to the Rileys (2010)
Attack on Titan: Season 3, Part 2 Premiere (Funimation)
Fairy Tail: Season 9, Episodes 291-303 (DUBBED) (Funimation)
Waiting for Superman (2010)
Vikings: Complete Season 5B (History Channel)
Hunting Evil (2019)
Here’s what is leaving Hulu in April:
A Thousand Junkies (2017)
Asterix & Obelix: Mission Cleopatre (2002)
Bleeding Heart (2015)
Born on the Fourth of July (1989)
Broadway Danny Rose (1984)
Caddyshack II (1988)
Chaos (2005)
Charlie and the Chocolate Factory (2005)
Chasing Liberty (2004)
Cake (2006)
Delta Farce (2007)
Escape from Alcatraz (1979)
Field of Dreams (1989)
Foolish (1999)
Freedomland (2006)
He Got Game (1998)
Lars and the Real Girl (2007)
Maximum Security (1990)
Mississippi Burning (1988)
Next Day Air (2009)
No Greater Love (2017)
Priceless (2016)
Robin Hood: Prince of Thieves (1991)
Silver (1993)
Space Jam (1996)
Umbrella Academy renewed for season 2
Everything Coming to Amazon Prime April 2019
Dumbo soars to the top of the box office
LEGO Avengers Endgame sets may contain spoilers
Hasbro unveils Avengers Endgame figures, role-play, and more
April 2019 Movie Releases
Funko announces Avengers Endgame figures and more
1984 Movie Reviews – Romancing the Stone
Brightburn trailer – All the evil Superman you can handle
Scary Stories to Tell in the Dark trailer – It’s about to pop!
Supernatural haves a family game night in new episode photos
Angelina Jolie reportedly in talks to join a Marvel film
Star Trek Discovery shows off a family reunion in new photos
Riverdale sets out to take down The Farm in new episode photos
Metro Exodus’ weird voice-acting choice weirds the whole game
Avengers: Endgame character posters show off the living and the dead
Runaways renewed for season 3 at Hulu
Dora and the Lost City of Gold trailer – So much exploring!
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Home India Despite CIC orders, PMO declines to divulge information on black money
Despite CIC orders, PMO declines to divulge information on black money
According to a study by US-based think-tank Global Financial Integrity (GFI), an estimated USD 770 billion in black money entered India during 2005-2014. Nearly $165 billion in illicit money exited the country during the same period.
TPT Bureau | Agencies
The Prime Minister’s Office (PMO) has refused to disclose the quantum of black money brought back from abroad, citing a provision of the Right to Information Act that bars disclosure of information that may impede investigation and prosecution of offenders.
The PMO’s response came after Central Information Commission (CIC) passed an order on October 16 asking the PMO to provide details within 15 days.
The PMO, in its response, said a special investigation team had already been formed and its investigation was under way.
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Without Black Economy, India’s GDP would have been eight time higher!
The Weakening of India’s Economy
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“Disclosure of all the action by the government at this juncture might impede investigation or apprehension or prosecution of offenders and hence would attract the provision of exemption under Section 8 (1) (h) of the RTI Act”, it said in response to the application filed by whistle-blower bureaucrat Sanjiv Chaturvedi.
Such investigations came under different government intelligence and security organisations excluded from the ambit of the RTI Act, the PMO added.
Mr. Chaturvedi, an Indian Forest Service (IFS) officer, sought information on the quantum of black money brought from abroad since June 1, 2014. In its initial reply, the PMO said in October last year that the question was not covered under Section 2(f) of the law that defines information. Subsequently, Mr. Chaturvedi moved the CIC.
There is no official assessment of the quantum of black money in India and abroad.
In response to another query mentioned in Mr. Chaturvedi’s application, the PMO refused to share details of corruption complaints received against Union ministers, saying providing such information “may be a subjective as well as a cumbersome exercise”.
TPT Bureau| Agencies
THE POLICY TIMES
Global Financial Integrit
Sanjiv Chaturvedi
Thepolicytimes
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Including President's column, penile plethysmography and more
Including Milgram redux, eyewitness memory, antidepressant debate and more.
Including President's column, Spearman medal, and end of life care report
Including President's column, Book and Doctoral Awards, and a summary of the Society's response to the Department of Health on statutory regulation.
Reports from the Annual Conference
Over three days in April, more than 900 delegates attended the Society’s Annual Conference at the Royal Dublin Society.
Read on for our extensive and diverse coverage, including WEB-ONLY EXTRAS.
Over three days in April, more than 900 delegates attended the Society’s Annual Conference at the Royal Dublin Society. They were treated to talks from a high-calibre set of speakers, including...
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The Rebuttal
Never accept second best.
It's a Deaf World
Not Good Enough …
Home2010December
December 20, 2010 adefinty2 Uncategorized
The Cinemas have screwed up. The promised Caption Cinema roll out that was to commence on December 14th now has not happened. Apparently the cinemas discovered that watching captions with 3D movies leads to the watcher becoming sick. Not everyone, mind you, just some. So they decided that the technology was flawed and they needed to reconsider the roll out. Of course it is not just caption watchers that get sick from watching 3D movies. There are warnings that go out to pregnant women, the elderly and people who have epilepsy that watching 3D movies can make them ill. But of course this didn’t prevent cinemas rolling out 3D did it? They just issued a warning – watch at own risk. Presumably a pregnant woman in agony in a cinema or people throwing fits is no business of theirs. WATCH AT OWN RISK AND BE DONE WITH. (http://www.crunchgear.com/2010/05/26/video-bill-nye-the-science-guy-explains-why-3d-movies-can-make-you-sick/)
But we deafies that need to watch movies with captions are a fragile lot. So instead of rolling out captioning they have decided to proceed with caution for our own good. “We didn’t know people would get sick!” they claim. “It’s not our fault that the technology has let us down!” they proclaim. That most movies released are 2D and that sickness watching 3D movies is nothing new is not something that the cinema bosses highlight. And let’s not forget our Blind and vision impaired friends! Presumably they get sick listening to 3D movies through audio description so we have to delay the roll out of that too. Bottom line is that the excuse the cinemas are spouting to delay and water down the rollout of captions to cinemas is POPPYCOCK. It’s an excuse! They are throwing their toys out of the pram because they had their hands forced when nearly 500 people let the Australian Human Rights Commission know that what the cinemas were offering was pathetic and that they wanted more. And for once the Australian Human Rights Commission showed some teeth and told the cinemas that what they were offering was an insult and that they needed to do MORE! Now all of this seems to have been to no avail.
And you the consumer who are reading this – Did you know about this? Have you been informed? Have the organisations that represent you asked you what you feel about all this? At the time of writing Deafness Forum have just issued an explanation of what is happening through their One in Six newsletter. This is all fine but were you, the paying member, asked what you want? The answer is no, because it has been decided for you.
We were promised 14 captioned cinemas as the first stage of the Captiview roll out. There will now be just three. Apart from the health excuse it is understood that there are legal and contractual issues hindering the roll out too. But Deaf, hearing impaired, Blind and vision impaired were promised that the technology was THE ANSWER. And now at the final minute, with no prior warning, the cinemas are claiming circumstances beyond their control. Why was all of this communicated at the last minute? It seems to us that the Cinema bosses are not taking Deaf, hearing impaired, Blind and vision impaired customers seriously. Can you imagine them treating the general paying customer in this way? They would be in damage control!
Letting the cinema bosses water down the roll out of captioning and audio description has been touted as compromise. It is not compromise it is backing down! The excuses spouted by the cinemas simply do not hold water. The cinemas are disrespecting Deaf, hard of hearing, Blind and vision impaired people. And our representative organisations have rolled over like a dog wanting its tummy tickled. All of us deserve more RESPECT than this!
The Rebuttal, being the equivalent of Wikileaks, are letting you know. We are the Deafileaks of Australia and are letting you know for the last time ever what is happening. Yes folks this is the last post, the last Rebuttal ever. What will happen when The Rebuttal closes? Who is going hold our representatives – THE GANG OF FIVE OR SIX (or maybe seven, occasionally 8 ) – to account? Who will be the people asking the hard questions? Who will take up the mantle?
At the time of writing The Rebuttal has produced in excess of 160 articles. Many of these are on the Blog. The Blog was made possible by Tony Nicholas who provided us with space on his web hosting, free of charge. Articles generally were produced in the E-zine format and then placed on the Blog. Sometimes they were just produced on the Blog and likewise we sometimes just produced the E-zine. There were, in fact, other articles that did not get past the editorial team. Sometimes because they were just plain rubbish and other times because they were a wee bit too controversial. (Hard to believe, but true. 😀 )
The Rebuttal was and still is popular. Indeed over 1500 responses in various shapes and sizes have been received by email and at the Blog. Some praising, some criticising and some just wanting to make sure they didn’t miss an edition. We regularly receive responses from the UK, the USA, New Zealand and Canada. Our articles are often linked to other sites such as the hugely popular Deaf Read.
The Blog remains extremely popular. In the last 12 months the site was visited 179 869 times. We know that people visit the site from all over the world. There were 289 389 page views. 3114 of those were classified as spammers. I am no expert in web hits and I know some of these hits are us putting up new articles and checking comments, but it seems a lot. It is something all of us on The Rebuttal team are rightfully proud of.
There is a misconception that The Rebuttal was all about attacking Deaf sector organisations. This is far from the truth. Some articles were designed to hold our Deaf sector organisations to account, there is no doubt, but many were simply about living life deaf. Some articles were angry, some were funny and some reduced the reader to tears. Some were political, some were celebrations of achievements and some were just written for the hell of it. Many were written by other contributors. Debbie Kennewell wrote about the joys of Facebook and its impact on the Deaf community. Elizabeth McCleod wrote about her experience of becoming deaf in adulthood. Rodney Adam and Sandra Hoopman contributed articles about education. Michael Uniake wrote about the cochlear implant. Shirley Stott Despoja wrote about deafness and bullying. These are just some of the contributors. The Rebuttal was never just about the four editors. It was for the Deaf sector and the community at large. And they used it, and we are so glad that they did.
But now it is over. For the last four years we four at The Rebuttal have taken praise and bullets alike. In fact in a recent job interview one of us was even asked what we would do with The Rebuttal if we won the job. We have been called saviours, we have been called smug and elitist and we have been called just plain old sh*t stirrers. The truth is we were just four people that cared and tried to create discussion and debate. Now it is someone else’s turn. Be quick because if the example of the cinema captioning is anything to go by The Rebuttal will be missed indeed! As William Faulkner once said, “Never be afraid to raise your voice for honesty and truth and compassion against injustice and lying and greed. If people all over the world…would do this, it would change the earth.” Now it’s over to you. The Rebuttal is dead – long live The Rebuttal. Thank you all for your readership.
This last Rebuttal is very hard to write. The Rebuttal has been a joy to be involved in. It has been our pleasure to bring you a host of articles over the last 4 years.
Some of these articles were controversial and some were just about life. Some were written by others and not just the four editors. But always they were about deafness and demonstrated the frustration and often the richness of the deaf experience.
There is no doubt that The Rebuttal was sometimes a dog with a bone. We raised issues that others would not touch in public. The Deaf Services Australia concept was challenged as spreading resources too thin. The Townsend House and Deaf SA “partnership” was touted as really being a merger of the two organisations, much to their disdain. And now there is only one Board of Management. How right it seems we were.
In the Fragile State of Deaf Sport in Austraia we questioned the lack of funding for Deaf sport and whether Deaf Sport Australia were on the righ track. When the Auslan for Employment Scheme was released we were scathing of it. We called it bad policy, not the least because it ignored hearing impaired people who did not sign and who also had communication needs at work.
Did we have influence? We think we did. We were sometimes “summoned”. This is where an organisation would call us for a private chat. Usually to ask us to water down our views. We never did but what we did do was offer the Rebuttal for these “challenged” organisations to REBUT us and air their own views. Some did, while others chose to remain silent. More than one CEO contacted us to ask us to write about something they wanted to air but they felt that they could not because of their POSITION.
The Auslan for Employment Scheme was a constant thorn in our side. Originally it offered funding only for 12 months and it ignored the needs of hearing impaired people who could benefit from live remote captioning in the workplace.
We felt that our representatives had too quickly accepted what was on offer. We were loud and critical. We were asked to “hush” We were told it was a good start and to be thankful.
BUT bad policy is bad policy and if no one speaks out nothing gets heard. So speak out we did. Did we influence the issue? Who knows but it is interesting to note that the scheme now is ongoing and you can now claim the cost of live remote captioning through it as well. All we can say is that we said it first.
There were also attempts to censor us. We know of more than one occasion where a CEO contacted the CEO of another organisation to try and shut us up. We know one even approached their Board of Management with a view of giving us a legal warning but was reproached. We were lucky that we had “friends” and supporters and they warned us of many things. One of our favourite incidents was to be told to use a pseudonym so that our views could not be linked back to organisations we might be associated with. Yup! Openness and debate is often frowned upon.
All we ever tried to do was to create discussion and debate. We wanted The Rebuttal to be a tool where the status quo could be challenged. Most of all we wanted The Rebuttal to be for Deaf and hearing impaired people and to show deafness in all of its various forms – political, funny, sad and, most of all, just a way of life to be celebrated openly and with passion.
We hope that we have achieved this. This is the last Rebuttal. Farewell and thank you. The Rebuttal is dead –
Long live The Rebuttal!!
THE FINAL SAY
Marnie Kerridge – The Rebuttal has been both a bane and joy in my life. Difficult – in the time it takes to write, proofread and send out editions. Scary – in the fact that there were threats of litigation. Disturbing – to see how my family were treated by challenged organisations and individuals and how opportunities were quickly cut off for us.
Joyful – in seeing deaf issues finally getting a voice. Triumphant – that all organisations and individuals were put on notice and made to be accountable. Successful – that some issues educated the wider community.
The Rebuttal has been an important and integral part of the Deaf and hearing impaired sector. It is your turn to keep everyone on their toes and accountable. Don’t lie back and be subservient – you are worth the fight. Rebut!
Adam Brown – Wow! Has it really been 4 years already?!
It is with much sadness and regret that I reluctantly walk away from my editorial responsibilities at The “Butt, as it has become fondly known. The emptiness that I feel is akin to having buried one of my beloved children!
When I embarked on this venture with my fellow Editors we could not have possibly foreseen how successful and popular it would become. Whilst we have no doubt put some considerably stiff noses out of joint and smashed some to smithereens with our at times controversial and evocative style, I would like to earnestly thank our devoted readers for their continued encouragement and support as we have sought to bring pertinent Deaf and hearing impaired issues to the attention and conscience of the general public and powers-that-be.
It has been an enlightening and enriching experience, and I have been endlessly humbled by the many strangers that have approached me over the past 4 years to either encourage, rebut, debate or discuss the diverse points of view presented. Many of you have become dear friends, and I look forward to continuing these associations with you in the coming days as we reflect on the phenomenon that was “The Rebuttal.”
To Gary, Marnie, Dean I thank you sincerely for your warm friendship, advice and encouragement to “live a little”. I will miss the many laughs, stresses, debates and arguments that have ensued as we’ve raised against time to prepare articles for deadline.
At the end of the day when all is said and done, I hope that “The Rebuttal” has has demonstrated that there is a wealth of skill, knowledge and ability out there within the Deaf and hearing impaired community, and we truly do have the ability to evoke and provoke much needed change in deafness and hearing impairment services and supports, provided that we remain united and vocal in continuing to advocate passionately for our needs in these constantly changing and evolving times.
Stay strong!
Dean Barton-Smith – Dean was one of the major drivers of The Rebuttal. Recently Dean was elevated to President of the Australian Federation of Disability Organisations.
What this meant was that Dean was no longer in a position where he could make independent political comment such as that which is printed in The Rebuttal. As a result he reluctantly withdrew from his involvement.
Without Dean there would have been no Rebuttal. Thanks Dean for everything. We know as President of AFDO you will make sure the consumer, the little person, is heard and represented fairly!
Gary Kerridge – I think I’ve said enough already! KEEP YOUR VOICE LOUD!
AND FINALLY THE PRESTIGOUS THE REBUTTAL AWARDS FOR 2010 GO TO !!!!!!!!! (Drum roll!!!)
The World War III Award! – This Goes to Deaf Children Australia and the Victorian College for The Deaf – for their very public stoush about the sale of land at the historic Bluestone building on St Kilda Road. They both claimed to have support from the Deaf community for their views. This was a furphy as the Deaf community is very much divided and mis-informed. We thinks the Deaf community are in Switzerland on the issue!
The Who Are You Award! – This goes with much fanfare to the BIG 4 Cinemas for their shoddy treatment of Deaf, hearing impaired, Blind and vision impaired people. They promised us captions and audio description by December on a large scale and now they are rolling out excuses for delay like there is no tomorrow. As far as they are concerned they wish we did not exist, we are such a burden. They may as well ask WHO ARE YOU??
The Members Dont Matter Award – This goes to our many representative organisations. Take your pick – Deaf Australia, Deafness Forum, Media Access Australia etc etc … For their shoddy treatment of Deaf and hearing impaired people in the Cinema Captioning Campaign. Nearly five hundred people wrote into the Australian Human Rights Commission and nearly all of those 500 people protested loudly at the captioning deal that our representative organisations had brokered for us. Not good enough and MORE was the clear messsage. What did our representative organisations do? Supported the cinemas thats what. Showing us yet again that our hard earned membership dollar means nothing! ( by the way the finger in the award refers to what they gave to us not what we are giving to them. )
The Eddie McGuire Award – Eddie everywhere they call him in Australia. So called for his ability to be seen virtually everywhere. This prestigous award goes to AI MEDIA! The Deafness Forum Summit! The Australian Caption Awards! Every five minutes on Facebook! The Inventors! Foxtel! Austar! – U name it they are there! They give a new meaning to the word SLICK!
The Showing The Way Award – There can only be one winner of this award and that is AUSLAN SERVICES! Not only did they win Interpreter Agency of the Year but they constantly give to and support the Deaf community in a way that puts our large Deaf support service agencies to shame. THEY GIVE! Not like a certain organisations that makes its members BEG! Take note and learn we say. Congratulations Auslan Services!
Fixing the NDIS – The Real Story!
Deviants and the Devalued – Why SRV has no place in the NDIS.
The NDIS Heroes, or Are They?
Neglect and Ignorance.
T’was The Night Before Xmas — The Scrooge of Xmas Award!
adefinty2 on Deviants and the Devalued…
Rella on Deviants and the Devalued…
Michael P Bleasdale on Deviants and the Devalued…
Parents of deaf kids
Protests & Campaigns
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Meet Tim
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Home Forums > OTHER > General Discussion > Other Media > Film >
Let's Talk The Battle of Britain Movie - one of Lucas' references
Discussion in 'Film' started by Lock_S_Foils, Apr 13, 2017.
Lock_S_Foils Red Leader
SW Fanatics, let's talk "The Battle of Britain", an OUTSTANDING movie made in 1969 about that critical battle in WWII that lasted from July to October in 1940. For background, in mid-1940 after the Germans had defeated the Allies on the European Continent, they shifted their attention to "fortress England", through bombing raids initially targeting British air bases and radar sites. The young British pilots in their Spitfires and Hurricanes (think X and Y wings!) held off the Germans and eventually turned the tide, through use of their radar early warning system to vector fighters for intercept.
The movie of the same name, made in 1969, is one of my most favorite war movies of all time. If you haven't seen it, HIGHLY recommend getting a DVD/BluRay copy. It features many awesome actors/actresses including Michael Caine, Sir Laurence Olivier, Susannah York, Robert Shaw (remember him in Jaws?). The movie uses little to no "effects" (only some of the aerial explosions) with 100% of the flying scenes done by REAL aircraft with REAL sound, it is incredibly well done. They gathered nearly 100 aircraft including the only 12 flyable Spitfires and 3 Hurricanes, also they used 32 Spanish CASA bombers (for the German HE-111) and 27 HA-112 fighters (for the ME-109s)
Why is this movie important to us SW fans? Because Lucas stated in interviews that he watched WWII aerial combat movies in developing his ideas for the space combat between TIEs and X/Y/A/B Wings. He mentions this movie in particular. As you watch the clips below, you'll notice the similarities in the radio chatter between British pilots in this movie and the Rebel pilots during the Death Star run in ANH. Also, in case you did not know, this battle was absolutely critical to the success of the Allies in the War......if the British had lost, thereby losing air superiority over Britain, Hitler was going to pull the trigger on "Operation Sealion" , the invasion of Britain.....could have been catastrophic! @PongSolo interested in your thoughts on this movie....
"The gratitude of every home in our island, in our Empire, and indeed throughout the world except in the abodes of the guilty goes out to the British airmen who, undaunted by odds, unweakened by their constant challenge and mortal danger, are turning the tide of world war by their prowess and their devotion. Never in the field of human conflict was so much owed by so many to so few. - Sir Winston Churchill, Aug 21, 1940
This clip features AWESOME aerial combat scenes and radio calls evoking the Death Star assault. Also note the incredible score especially at the 2:37 mark
This is the opening of the movie, following disaster at Dunkirk, the Battle of Britain begins....note the awesome buildup of the Luftwaffe, love the score for this part, evokes the Imperial March from SW
#1 Lock_S_Foils, Apr 13, 2017
Grand Master Galen Marek Jedi General
+102,494 / 336 / -131
I'd enjoyed watching this movie growing up when this country had it's back against the wall against Germany & that the will of ''the few'' outclassed the many.
#2 Grand Master Galen Marek, Apr 13, 2017
Grand Master Galen Marek said: ↑
Very very stirring.....as I said one of my favorites! Love the scene at the beginning, link below, when the German Ambassador tries to intimidate his British counterpart.....great quote "We're not easily frightened..."
That is a fantastic film & you can see why it became such a influence for the first attack on the Death Star.
Another Great War film which involves some great aerial sequences is 633 Squadron in particular some of. There training sceans & it has a fantastic score.
#4 Addi Ras, Apr 13, 2017
Lock_S_Foils said: ↑
Indeed he basically told him, you want a war, you've got it, then tried to back out of it. Hitler never learned from Napoleon's mistake.
Kylo Solo Force Sensitive
+3,642 / 4 / -3
This is the best
#6 Kylo Solo, Apr 13, 2017
Off Topic x 1
Kylo Solo said: ↑
How is this relevant to a thread about the Battle of Britain. ?
Addi Ras said: ↑
*facepalm* I thought this was the Let's just talk thread. My bad, didn't even look before I posted
No worries I thought it a bit odd you would post some thing so random.
@Kylo Solo I thought your signal was intercepted by rebel scum.....
#10 Lock_S_Foils, Apr 14, 2017
@Addi Ras 633 Squadron has awesome scenes featuring the DeHavilland Mosquito , one of my fave WWII aircraft!
That it does & there the real deal as they used actual Mosquitos for filming.
& while the BoB was a big influence on the dog fighting scenes the trench run part including the planning is defiantly based on 633 Squadron.
#12 Addi Ras, Apr 21, 2017
Let's talk about L3
Boushhdisguise, May 29, 2018, in forum: Solo
Martoto
FINALLY, A SCI-FI WESTERN HEIST IN A MAJOR FILM!! (Let's talk about finally having an ACTION film!)
Jayson, May 28, 2018, in forum: Solo
Lock_S_Foils
Let's Talk About the B, and C Plot
CnlSandersdeKFC, Dec 17, 2017, in forum: Star Wars: The Last Jedi
Okay, let's talk about Vader
thrawn_lives, Dec 15, 2017, in forum: Star Wars: The Last Jedi
Jase Windu
So, let's talk about birds...
CaptainPhastastic, May 1, 2017, in forum: Star Wars: The Last Jedi
Darth Basin The Greatest
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Gergiev and soloists provide blazing account of “Les Troyens” at Carnegie Hall
By George Loomis
Berlioz’s Les Troyens recently entered the repertoire of the Mariinsky Theatre in a production by the lively and popular Catalan theater company known as La Fura dels Baus. This week the Mariinsky and Valery Gergiev brought Les Troyens to Carnegie Hall, performing the long opera over the course of two evenings (Tuesday and Wednesday), but they left the production back home in St. Petersburg. Few in the audience could have felt deprived, so gripping was the concert performance that emerged.
Gergiev is fond of giving operas in concert. The format allows him to try out works under consideration for full productions. And even when a production is up and running, he will happily revert to concert form if exigencies, such as those of a tour, dictate. As a result, although Gergiev is sometimes criticized for under-rehearsed performances, his operas in concert are often infused by an ensemble spirit born of prior stage experience.
That genuine spirit was much in evidence in Carnegie Hall, especially on the second evening when Acts 3, 4 and 5 of the grand opéra, collectively known as Les Troyens à Cartage (The Trojans in Carthage), were offered. This time all the soloists (not just several, as was the case the previous evening) sang without scores and often interacted with other characters as one suspects they would in the opera house. More broadly, the ensemble spirit embraced orchestra and chorus too.
Another point about the concert format is that it works unusually well for this musically sublime but theatrically challenged mega-opera, which traces both the fall of Troy (Acts 1 and 2) and Aeneas’s dalliance with the Carthaginian queen Dido en route to fulfilling his destiny in Italy. Curiously, the opera’s dramatic pace seems to get slower and slower over the course of the long evening as the tension and violence of the Trojan scenes give way to a more languorous ambiance in Carthage. The progression is logical dramatically inasmuch as the Carthage sojourn is essentially an idyllic love interlude for Aeneas. But it makes for longeurs in the opera house when the opera is performed in a single evening.
Concert performances tend to minimize this problem, since they focus attention more closely on the music. A break between the two parts is also helpful, even though Berlioz conceived Les Troyens as a single opera and agreed to separate performances of Les Troyens à Cartage only because he was unable to persuade any Parisian opera house to stage the piece in its entirety.
As a super-charged Dido, Ekaterina Semenchuk enters the big time with this riveting performance. The valued mezzo, who made her Metropolitan Opera debut as Natasha’s companion Sonya in the house premiere of Prokofiev’s War and Peace, may not possess a voice of resonant beauty, but it is strong, handsome and evenly produced. She sounded lovely in the serene duet with Aeneas, Nuit d’ivresse, but was especially arresting when she could throw herself into the drama, as in Dido’s final confrontation with Aeneas and in her moving solo scene at the end, with its heartbreaking reference to the tune of the duet.
Another fine mezzo, Ekaterina Gubananov sang Cassandra’s extensive but unheeded admonishments with a vibrant voice of alluring richness and a slight but not unattractive edge. Aeneas ought to have a voice of greater heft than that of Sergei Semishkur’s tenor, which sometimes lost body in midrange. But it has much lyrical beauty and a strong top that served him well in his big aria Inutiles regrets, which he sang with welcome intensity.
Baritone Alexei Markov sounded wonderful in the consoling melody with which Corebus attempts to placate his fiancée Cassandra, and bass Dmitry Voropaev brought considerable vocal strength to the music of Dido’s counselor Narbal. Also fine were mezzo Zlata Bulycheva as Dido’s sister Anna and soprano Irina Mataeva as Aeneas’s son Ascanio. Daniil Shtoda and, especially, Dmitry Voropaev brought sweet tenor voices to the irresistible songs of the poet Iopas and the young sailor Hylas.
The music got off to a tremendous start, with pulsating winds and a chorus sounding almost giddy from excitement over the supposed end of the Trojan War, especially in Gergiev’s frenzied tempos. With the entrance of Cassandra the mood abruptly shifted, underscored tellingly by the dark sonorities of the Mariinsky Orchestra’s splendid lower strings. Before long came the unusual pantomime scene for Andromache and her son, supported by Victor Kulyk’s languid clarinet.
And so it went, as the performance moved from peak to peak. Gergiev has a real affinity for Berlioz, as was in evidence here last month in Roméo and Juliette, a work he conducted in New York with the Mariinsky as long ago as 1996. Aside from demonstrating a grasp of Les Troyens‘s overall flow, he knew just when to give it a jolt of energy.
One Response to “Gergiev and soloists provide blazing account of “Les Troyens” at Carnegie Hall”
Posted Mar 16, 2010 at 6:17 am by Stephen Sechrist
Having attended both concerts last week, I must concur with Mr. Loomis. Les Troyens is my favorite French grand opera, and this was the finest performance I have yet heard. I admit that I have heard better singers in all the roles, (i.e. Ludwig and Troyanos as Dido, Verrett as Cassandra, Vickers as Aeneas, to Polzani as Iopas and Dunn as Anna,) but overall I never felt the power of the drama as I did with the Mariinski forces.
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Madison Food Park developers take questions at Great Falls neighborhood council meeting
Posted on November 20, 2017 by Jenn Rowell
Todd Hanson, spokesman for the proposed Madison Food Park, spoke to Neighborhood Council 5 on Monday. Edward Friesen, the principal developer, also attended the meeting, but did not speak.
The project is outside the city limits and outside the council’s district, but if approved, it would impact the area and the council often invites speakers from major developments to provide information.
Hanson said the project is phased and would likely ramp up over a five-year period. Hanson told The Electric last month that the cheese processing plant is planned as the first building for construction.
It’s “not a project that springs to life overnight,” he told the room of about 100 at the Great Falls Clinic Specialty Center. Council 5 typically meets in that space and usually has about 20 attendees to discuss neighborhood concerns. Dozens of others were outside and not allowed in by the clinic’s security since the room was at capacity.
The slaughterhouse’s Special Use Permit will be considered by the Cascade County Zoning Board of Adjustment, which will include a public hearing. That has not been scheduled yet since the applicant is revising their application. The County Commission does not vote on SUP applications.
No city officials or governing boards have jurisdiction on the project and the city could not assess any taxes or fees on the project since it’s not in the city limits.
County planning still processing Madison Food Park proposal; water rights process not yet begun
Hanson is also scheduled to speak on Dec. 9 during the Montana Cattleman’s Association meeting in Great Falls.
Community concerns have included water, odor, traffic, immigrants, crime and more.
In a prepared statement, members of the Great Falls Area Concerned Citizens said, “tonight’s ‘sales pitch’ was no different than those made to other communities who suffer the consequences of these abominations: exaggerated promises of ‘good paying jobs’ and technologies that will finally work this time. But in the end the results are always the same. The reputation of our town will be damaged forever chasing out young families, retirees, college graduates, professionals, and the chance for real long-term growth. Tumors grow. We say, growth at what cost? This slaughterhouse is a bad deal for our community.”
Hanson said the estimated water usage at peak capacity in year five is about 3.5 million gallons daily, or 3,072 acre feet per year for the MFP complex.
Major agri-business complex planned for Cascade County, with potential for 3,000 new jobs
He said that is equivalent to 1,452 acres of irrigated alfalfa hay using a center pivot.
Hanson said the city has about 1,200 acres of community green space that is irrigated or watered.
According to Great Falls Park and Recreation, the city has 1,215 acres of park land, plus about 300 acres of golf courses. Of that, roughly 1,000 of those acres are irrigated, according to Park and Rec.
Hanson said they’re working with a hydrologist to develop their plans for wells and will do testing to determine if the aquifer can withstand their usage. That testing would also be required and reviewed by the Montana Department of Natural Resources when considering a new water right since the MFP property currently doesn’t own enough water rights for the proposed project. DNRC has not yet received an application for new water rights from MFP.
The MFP developers are currently amending their SUP application for the ZBOA. Last month, The Electric asked what it was amending for and Hanson said it was a common procedural practice.
On Monday, Hanson said that the reason the MFP developers are amending their SUP application is to adjust for a technology system they say will eliminate waste and the need for treatment lagoons.
That technology is from Missoula-based CLEARAS Water Recovery. Their Advanced Biological Nutrient Recovery system “maximizes the recovery of excess nutrients, increases dissolved oxygen, and produces no chemical by-products, eliminating costly disposal fees,” according to CLEARAS. “Modeled after traditional activated sludge processes, our patented system harnesses microbiology in a photobioreactor environment that accelerates photosynthesis, the consumption of carbon dioxide and excess nutrients. Advanced microfiltration is then used to filter out high quality water from return activated algae, which returns to the beginning of the ABNR process.”
According to the CLEARAS website, the ABNR system is used at the Missoula Wastewater Treatment Plant and has been tested at wastewater treatment plants in Massachusetts and Ohio. The system is in the early stages of implementation in wastewater systems in Utah and Beaver Dam, Wisconsin and has been piloted in Fond du Lac, Wisconsin and Hoover, Alabama.
The system does not appear to have been used or proven in projects of the proposed Madison Food Park’s scale.
One meeting attendee said he knows the developers will have to jump through “a zillion hoops” to get the project approved, but asked how they’d get up to 3,000 employees since in his meat-packing background, plants had fewer employees.
Last month, Hanson told The Electric they weren’t ready to finalize numbers of jobs in each area or the pay scales. Last week, he told Montana Public Radio that they estimate the base wage would be $15-$22 per hour and the skilled and management positions would likely range from $45,000 to $85,000.
Hanson said there would be the processing staff, but also a substantial cleaning staff, facility security, biosecurity, cold storage facility, logistics, management and more.
He said they’re planning 260 processing days and at peak operating capacity, developers estimate 1,800 head of cattle; 9,200 hogs and 135,000 chickens daily.
Another attendee asked where those animals would come from and Hanson said they plan to prioritize Montana producers and animals, but did not specify where they would come from. He said they are not anticipating bringing in cattle from Canada.
Some in the room suggested that there aren’t enough cattle in Montana to meet that processing rate.
Jim Peterson, a Central Montana cattle producer, said they ship 90 percent of their cattle out-of-state for finishing and processing. He said that his son can deliver about 20,000 head of cattle.
“You give us this opportunity, we’ll provide you with the cattle,” he said.
Other speakers expressed concern over the potential impact of 3,000 new workers and their families to schools, roads, housing and crime in Great Falls and the surrounding area.
Hanson told The Electric last month that the company intends to hire Montanans and people from the region. He said the developers met with officials at Great Falls Public Schools on Monday to start discussions on the potential impact if the project is approved.
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NFL super teams: Could it work?
Columns Front Office Writers NFL Sports
by Tim Miller August 14, 2017 August 14, 2017 0
Kevin Durant and the Golden State Warriors have ruined the NBA for the foreseeable future thanks to their new super team. The Warriors will dominate for years to come and will have the greatest dynasty in sports history when it’s all said and done. That said, the question of whether or not NFL super teams could be formed is an intriguing one to address.
The New England Patriots are the closest thing in the NFL to a super team, as the 2017 edition of the squad is the frontrunner to represent the AFC in the Super Bowl, and some even think they could go 16-0.
But the fact is that the NFL does not truly have a super team. Sure, the Patriots are most likely the best team on paper going into 2017, but there’s still no guarantee that they’ll even win the conference championship game.
We’ve seen this issue talked about before, so why not join in on the fun and give a hot #take myself?
There’s a couple different aspects to dissect when looking into NFL super teams. First, and most crucial, is the money. Even though the NFL is the most popular sport in the United States, the 53-man roster leaves less money for each player compared to the NBA. When forming a super team, every single star player would have to take a pay cut in order to allow other stars on the team. NFL players have already complained about the the discrepancy between NFL and NBA contracts, so taking even less could be a tough pill to swallow for many players.
The next concept to consider is that NFL teams have very specific schemes. The offense ran in New England was much different from the one that the Dallas Cowboys ran last season, yet each were top-five offenses in the league. Not only would NFL super teams need stars at every position, but it would also need the right personnel to fit the scheme.
Finally, we must ask if there’s even enough time for NFL super teams to form a dynasty. The shelf life of a running back is already limited, and the prime of many players in the NFL can be shorter than that of an NBA player. Even if it all came together for an NFL team, would there be enough time for them to win multiple Super Bowls with the same core?
Every year, NFL players holdout and skip training camp in order to get leverage in earning more money. There can’t be an argument made that NFL players are more greedy than NBA players, but it does go to show that the top talents in the NFL will put their team and preparation at risk in order to get a couple more million dollars.
What a hard life NFL stars live.
Photo: Jason Bridge-USA TODAY Sports
Le’Veon Bell is at least the No. 2 running back in the NFL, if not the best (David Johnson may have something to say about that). He’s putting his team’s success in jeopardy this offseason by deciding to holdout. The most significant problem for NFL super teams is whether or not players will put their pride aside to take pay cuts, even though they may be the most elite at their position.
Every elite NFL player will do his best to suck all the money out of his organization he can. Heck, even players that aren’t elite, like Kirk Cousins and Joe Flacco, have tried this (and been successful) in the past.
This poses a threat to NFL super teams when trying to get the best of the best in one uniform. But this is only the start of the problem.
NFL super teams’ Schemes make for an even more complex problem
Dak Prescott and Drew Brees are two very different quarterbacks. Prescott resided in a run-heavy offense in Dallas, as the Cowboys ran the ball more than any other team last season (48.7 percent of plays). The Cowboys’ offense was built by its powerful line which counteracted its lack of skill players on the outside. This allowed Ezekiel Elliott to run all over (and away) from defenses in his rookie campaign.
The Saints’ offensive attack was much different from the Cowboys. Drew Brees had great weapons on the outside in former Saint Brandin Cooks, who used his deep-threat abilities to become Brees’ best downfield target. Rookie Michael Thomas managed to put together one of the best rookie seasons a wide receiver has ever produced, and was Brees’ possession target to look to.
Even Willie Snead, Coby Fleener and Josh Hill were utilized in the pass-first offense that allowed Brees to air it out on 63.4 percent of plays, good for fifth-most in the NFL last season.
The point is that NFL super teams need the perfect combination for an offense to work. The offensive coordinator, quarterback, skill players and offensive line must all be in sync and comfortable with the system in order to reach optimal success. And it’s the same way with the defense.
Not only do the star players at each position need to take pay cuts to form a super team, but they also have to fit with the scheme of whichever side of the ball they play on.
The player pool for a super team continues to shrink with these requirements.
Father Time waits for no man, not even NFL super teams
Barring a select few, most NFL stars are only elite for a couple years. Injuries cut their time of stardom even shorter (Jamaal Charles knows about that), which makes it even harder to field a star team.
Sure, the best of the best can sometimes manage to be stars for over half their career, but remember the requirements already talked about. Finding a star who is willing to take a pay cut and fits in the scheme is hard enough, so the pool of players has already dwindled.
Photo: Andy Lyons/Getty Images
Tom Brady may play until he’s 50, but top players at other positions have missed time in the past couple seasons. If Le’Veon Bell could stop smoking weed and quit getting injured by the Bengals, he’d have a chance to be on Tom Brady’s list.
Antonio Brown missed three games last season, Julio Jones has played in 16 games in a season once in his six years and A.J. Green has missed ten games in his six-year career while finding his way on the mid-week injury report seemingly every week.
This goes to show that even the most elite players can’t escape the injury bug.
And if the top players earn as much money as they want on a theoretical super team, the bench will be filled with aging veterans who are ring-chasing and don’t have enough talent to suffice the loss of a star.
This continues to prove that forming NFL super teams may be nearly impossible.
NFL super teams: Making one is #hard
The San Francisco 49ers currently have the most cap space in the NFL. A lot will change come March 2018, but one thing that will most likely remain is that the 49ers will suck this season. They won’t be the most attractive franchise to build a super team with.
However, the team with the fifth-most cap space is the Houston Texans. Houston has $24.3 million in free cap space, and made the playoffs last season. The Texans seem to be just a few pieces away from being a Super Bowl contender, so we’ll use them as a possible super team.
There’s been a lot of changes to the NFL landscape from last season, and that trend will continue in each offseason. Let’s try to make the Texans a super team through 2018 free agency.
Finding a quarterback
The Texans’ most glaring need is at the quarterback position. Drew Brees, Kirk Cousins and Matt Stafford are the only notable names that will be free agents come 2018.
Photo: Derick E. Hingle-USA TODAY Sports
Cousins can be taken off the list right away, as it seems he’s been fighting to get a huge contract from Washington since he was in diapers.
Drew Brees and Matt Stafford both make sense due to the fact that they’ve had great years, yet Brees has just one ring, and Stafford has no playoff wins. It comes down to who would be the best fit in Bill O’Brien’s offense, assuming he stays on staff next season.
O’Brien’s scheme is based around the power-run game and using two tight end sets. The formations used in O’Brien’s system forces the quarterback to make crucial and complicated pre-snap reads. That said, Brees would be the better fit in Houston. His ability to run multiple formations in New Orleans could quite possibly translate to Houston.
If Brees were to make this move, he’d have to be fine with a pay cut since he’d be ring chasing and forming a super team. Let’s say he cuts his salary in half and earns $12 million with Houston.
Receiving a pass catcher
That only leaves $12 million and change in the bank for Houston. Houston has Lamar Miller, who should be an above average back for now. At wideout, the Texans have an elite receiver in DeAndre Hopkins, but could use some help on the receiving end. The wide receiver market is grim in 2018, but a familiar face for Drew Brees will be on the market in 2018 at tight end.
The Drew Brees-Jimmy Graham love affair in New Orleans was art. Graham will be on the market in 2018, and even though he’s had a history of wanting money, let’s assume he wants a ring and to play with Drew Brees more.
We’ll assume Graham will settle for a mere $8 million a year with Houston, which is only $2 million less than he got in Seattle. I for one hope that in this theoretical world, Jimmy Graham makes it in this tough world with only $8 million a year to come home to.
Room for one more player
With $4 left, the Texans could grab a proven veteran for cheap, or a lesser-tier asset. The Texans need help on the offensive line, specifically at tackle. The best player on the market in 2018 is Donald Penn, but he’s currently holding out of Raiders’ camp, so he has to be off the list. Nate Solder could be an option, but the likelihood that he takes a paycut to leave New England is as likely as Johnny Manziel not drinking tonight.
Allen Barber was the No. 16 guard last season according to Pro Football Focus. Although he’s mostly played left guard in the past two seasons, he’s seen time at tackle with the Eagles early in his career.
Barber wouldn’t be a blockbuster move at all, but he could end up being a nice find for Houston to help what’s been a bad offensive line.
The idea of NFL super teams is far-fetched and there’s too many hoops to jump through for it to work. There’s too many stipulations not seen in the NBA like a much larger roster, less time to be in the peak of a career and scheme fits.
Although the NBA has made it work before, the Golden State Warriors’ mega-team and soon to be dynasty will only work in the NBA. NFL front offices have far too many hoops to jump through.
For now, let’s just enjoy hating the New England Patriots for being better than all of our teams and speculate other things, like how Bill Belichick can pull a homeless man off the street and turn him into a heroic wide receiver or cornerback in a Super Bowl.
You can like The Game Haus on Facebook and follow us on Twitter for more great sports and esports coverage. You should also follow Tim, as he’s gotten over 100 likes on a grand total of three different tweets, and sometimes offers lukewarm takes on things that don’t matter.
Allen BarberArizona CardinalsAtlanta FalconsBill O'Briendak prescottDavid JohnsonDenver BroncosDrew BreesGolden State WarriorsHouston TexansJimmy GrahamKevin DurantKirk CousinsLe'Veon Bellmatt ryanMatt StaffordNBANew England PatriotsNew Orleans SaintsNFLPhiladelphia EaglesPittsburgh SteelersSan Francisco 49ersSeattle SeahawksWashington Redskins
Songs of praise for 2017’s Call of Duty World League Championship
Regular season EU LCS top laner rankings
Tim is currently serving as Vice President of The Game Haus. He has been with the company since August of 2015, and has advanced from writer, to editor, to COO and now to VP. Tim writes, edits, podcasts, recruits, helps in business functions, helps with social media and focuses on developing writers and editors, among other roles. He played baseball (two-year letterwinner, all-district) and basketball (absurdly average) in high school and loves sports in general. He's currently a sophomore double-major at Cedarville University (Ohio), with majors in journalism and strategic communication and a minor in biblical studies.
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How to Win an Oscar If You’re Black
Lizzo Ready to Shake Things Up on SNL; Eddie Murphy Will Bring Entire Family and Maybe Some Old Characters
Brooklyn Baldwin
Check Out Octavia Spencer as Madam C.J. Walker, America's First Black Female Self-Made Millionaire
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Damon Young
Michael Harriot
Filed to:OSCARS SO WHITE
The #OscarsSoWhite, they called the police on the BET Awards.
The #OscarsSoWhite, Pete Buttigieg was almost nominated for an award.
The #OscarsSoWhite, Cuba Gooding Jr. tried to marry his statue.
On Monday, the Academy of Motion Picture Arts and Sciences announced the nominees for the 92nd Academy Awards and, as usual, they’re rooting for everybody white. Although the Oscar committee has touted its recent diversity efforts, no one really expected Hollywood’s most important awards show to reflect the makeup of its audiences.
That’s because white men run the studios and select the scripts. They hire the directors and cast the actors. They choose which films they will promote for awards season honors. The film industry is like the Democratic Party—it’s progressive, but it’s still controlled by white people who vote for white things. On paper, Kamala Harris was as qualified for the presidency as Eddie Murphy was for a Best Actor nod. But incellic white dudes stan for Joaquin Phoenix just as much as they love what Bernie Sanders stands for.
Whether you’re thinking of embarking on a career in the film industry, or are already a well-known star, it’s very unlikely that you’ll ever be nominated for an Academy Award. However, your chances of being nominated decrease substantially if you’re black. Historically, black people have only won 5.5 percent (20 of 362) of Oscars’ major awards (Best Actor or Actress; Best Supporting Actor or Actress; Best Director; Best Picture; Best Original Screenplay or Best Adapted Screenplay). That’s probably because black people have only been nominated for 3.6 percent of the Oscars in these categories (63 of 1,764).
Luckily, I’m here to help.
Using the data from previous nominees and winners, I have created a scientific approach for black people who are seeking to earn an Oscar nod. Because white people constantly move the goalposts, I can’t guarantee that these 8 steps will work. But I bet it works better than waiting for white Hollywood to come to its senses.
1. Be Oppressed
Because many white people only recognize negro humanity when black people are crying, you’re gonna have to be sad as fuck to win an Oscar. To be nominated, one has the choice of playing a slave (Hattie McDaniel in Gone With the Wind; Lupita Nyong’o in 12 Years a Slave; Denzel Washington in Glory) or a servant (Octavia Spencer in The Help; Sidney Poitier in Lilies of the Field; Morgan Freeman in Driving Miss Daisy).
To be clear, the oppressor doesn’t have to be a white person but you should still be stuck in a hopeless situation. As long as you cry (Oprah Winfrey in The Color Purple), die (Denzel in Malcolm X), or scream “Whyyyyyy,” (every important black role), you can get on the shortlist for a gold statue.
2. Keep It Real
I know what you’re thinking, but this has nothing to do with the authenticity of your acting. Black actors who played real-life characters account for more than one-third (36 percent) of black Oscar wins for acting. Only white people get to be fictional.
I truly believe that black actors don’t get recognition because Hollywood views nuanced black characters as a black person playing a black person. That’s why I don’t get why people consider Cate Blanchett to be such a great actress. She always plays someone who looks wistfully out of windows dreaming of a better life. Or maybe I’m thinking of Kate Winslet. Or Witherspoon. There is a Kate Witherspoon, right?
If there isn’t, there should be.
Denzel’s portrayal of Malcolm X lost the 1993 Best Actor award to Al Pacino, who just played a blind man who yelled a lot in Scent of a Woman. He’s still playing that character in every role. Angela Bassett didn’t win Best Actress when she embodied Tina Turner in What’s Love Gotta Do With It. Yet, somehow, Emma Stone won the Best Actress Oscar for La La Land, a movie about jazz that had no black people in it.
Now, that takes imagination.
3. Work With White People
Here is where the privilege of being the dominant culture comes in.
White people don’t consider their movies to be “white films.” However, a movie with an all-black cast is automatically categorized as a “black movie” and white audiences don’t go see those. Therefore, an obscure black film has almost no chance, while films like The Hurt Locker—the lowest-grossing Best Picture winner of all time—took home six Oscars.
That’s probably why no black director has ever won Best Director and Steve McQueen is the only black producer to ever win Best Picture (for 12 Years a Slave). Of course, Jordan Peele won Best Original Screenplay for Get Out, but I think that choice was wrong.
Everyone knows Get Out was a documentary.
4. Sing, Rap, or Dance
One of the easiest ways to get an Oscar nomination is to leverage one’s musical ability. Aside from the aforementioned Angela Bassett nomination, Jamie Foxx (Ray) and Jennifer Hudson (Dreamgirls) won Oscars for music-based performances. There’s also an exploitable Oscar loophole.
More black people have been nominated for the Best Song Oscar than any other category. Plus, Prince and Herbie Hancock earned Oscars for scoring movies (Purple Rain and Round Midnight). So, even if you can’t emote in front of a camera, you still have a chance to win the gold statue.
Wait…did you think Common won an Oscar for acting?
5. Be Magic
A “magical negro” is a black person in a film who only exists to assist white people. It’s essentially the opposite of a white savior.
Yes, you can win an Oscar for this.
Magical negroes spontaneously appear so they sometimes don’t even bother to give them a last name! Half of the black nominees for Best Supporting Actress are just a collection of negro names like “Mammy,” “Patsey” and “Geechie.” At least they gave Oprah two names in The Color Purple—her name was “Miss Sophia.”
Whoopi Goldberg’s role in Ghost was perhaps the greatest Oscar role of all time—a magical negro criminal who had to help a white woman.
6. Lose Your “Black Girl Magic”
If you’re a black woman, you might as well take your pride and flush it down the toilet. Here is a list of Oscar-winning roles for black women:
An enslaved woman (Hattie McDaniel/Gone With the Wind)
A fake psychic who turns out to be a real psychic (Whoopi Goldberg/Ghost)
A spurned singer (Jennifer Hudson/Dreamgirls)
An abusive mother (Mo’Nique/Precious)
A maid (Octavia Spencer/The Help)
An enslaved woman (Lupita Nyong’o/12 Years a Slave)
A frustrated wife (Viola Davis/Fences)
A mother whose son is incarcerated (Regina King/If Beale Street Could Talk)
Or, worst-case scenario, you gotta have sex with Billy Bob Thorton (Halle Berry in Monster’s Ball) and pretend to enjoy it.
7. Be Saved
Even if you’re sad, depressed and nonfictional, if your Oscar-worthy film has a happy ending, you’re going to have to allow a white person to save you.
White savior films are an Oscar staple. Brad Pitt emancipated Chiwetel Ejiofor in 12 Years a Slave. Green Book was basically a movie about how a dumb white dude teaches his intelligent, talented black boss a valuable lesson about life. Perhaps the most disturbing example of white savior-ism in film history was in Monster’s Ball, when Halle Berry discovers that her new white lover sent her husband to death row, but forgives him because he brings home ice cream.
White people must always be the hero. Even in Selma, a movie about how white people beat and disenfranchised black people in America, the white president was still the hero.
8. White Tears Must Flow
Sometimes, there will be a film or performance so heartwarming, touching or well-made that white people will briefly have a moment where they see black people as almost human. Moonlight did this, and so did If Beale Street Could Talk, garnering Best Supporting role nods for Mahershala Ali and Regina King.
Conversely, Precious was so depressing that voters cast the ballot for it out of fear they’d have to watch it again.
Using these eight principles, I believe I have created the perfect vehicle for an Oscar-winning film, a science fiction/period drama/action movie simply called: The Harriet Tubman Time Machine
Cate Witherspoon plays Becky Whiteman, a theoretical physicist for a defense contractor. Becky is forced to move back to her hometown when her father has a crippling heart stroke and becomes an octoplegic (two times worse than a quadriplegic.) To assist with the care of her disabled father, Becky hires her sassy childhood friend, LaTasha Lakeisha Jenkins (played by Meghan Thee Stallion), who is now a nurse, leaving Becky time to perfect the patent for her teleportation/time-traveling/air-fryer device— the only thing that can save the family farm from being repossessed.
LaTasha and Becky were stars in the same STEM program growing up but when they were 12, Becky switched the name on Latasha’s science fair project and won a scholarship to the State Institute of Technology, while LaTasha had to go to community college and major in diaper-changing. They eventually made up and became friends, but throughout Becky’s entire career, she has called up LaTasha pretending to be her friend but actually pumping LaTasha’s brilliant mind for scientific knowledge.
One day, someone from work shows up and tells Becky there’s trouble. Apparently, a slave trader from the 1850s is going back and forth in time, kidnapping black people in the present and enslaving them in the past. Becky tells them she only has time for her father and slams the door in their face.
The next day, Becky discovers that someone has kidnapped all six of LaTasha’s children. Could it be the time enslavers? Becky feels terrible but she knows that she can’t stop the time enslavers. She spills the beans to LaTasha, and after LaTasha whips Becky’s ass for 45-50 minutes, she informs Becky of their plan:
They must create an interdimensional underground railroad.
But first, they’re going to need some help.
Issa Rae co-stars as Harriet Tubman, the guide, who enlists some of her best historical friends:
John David Washington plays Frederick Douglass, the strategist. Derek Luke plays Nat Turner, the war counselor. Yahya Abdul-Mateen plays Toussaint L’Ouverture, the general. Brian Tyree Henry plays Marcus Garvey, the getaway driver. Marsai Martin plays Ruby Bridges, the infiltrator. And Mahershala Ali plays Nelson Mandela, the munitions expert. (Every movie must have an explosives expert. It’s the law.)
Leonardo DiCaprio also has a cameo as the time-traveling slave trader but he dies in the first scene.
I won’t tell the entire plot, but the last scene consists of Rosa Parks (Alexandra Shipp) loading the rescued victims into the air fryer/time machine. As Nat begs people to please save a seat up front for Rosa, Becky gives a heartwarming monologue to the enslaved people they must leave behind. A tear slowly falls down her face as she finally realizes the 400-year-old struggle that LaTasha had to overcome. She looks at the human cargo one last time and, as they speed through a black hole back to the present, Becky smiles, knowing she saved countless souls. Plus, she secretly filed a patent for the air-fryer/teleportation/time machine, blocking LaTasha from collecting a dime and making Becky a billionaire.
Even though she won’t get any of the patent money, LaTasha still learned a valuable lesson about the true value of white allies.
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World-renowned wypipologist. Getter and doer of "it." Never reneged, never will. Last real negus alive.
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Mayland’s Woman of the Year ’18
24th August 2018 0 comments
A super slimmer has been named Mayland’s Slimming World ‘Woman of the Year’ 2018 thanks to her life changing 4 1/2 stone weight loss.
Anji Griffiths, from Steeple, has gone from size 18 to 10 in just 50 weeks. And now she’s been chosen to represent the Mayland Slimming World group in the nationwide Slimming World Woman of the Year 2018 competition, which aims to find the UK and Ireland’s most inspiring female slimmer.
Woman of the Year Anji Griffiths
More than half of all women in the UK and Ireland (58%) are overweight and a quarter of women’s weight is so high it risks impacting on their health by increasing their chances of developing a range of conditions including diabetes, heart disease and cancer. Slimming World’s Woman of the Year competition recognises the achievements of thousands of women up and down the country who have made long-term healthy lifestyle changes.
Anji says: “I never could have dreamt that I’d be in this position when I first began my weight loss journey. Losing weight has made such a big difference to me. My health is better, I have more energy, I’m happier and I feel more comfortable in my own skin.”
She joined Slimming World in August 2017 after becoming increasingly unhappy with her size. “I started to put on weight after loosing my mum. I tried lots of different ways to lose weight but they usually left me feeling hungry or miserable – or both, in fact. With Slimming World it’s completely different.
“My family and friends are all amazed by how much I can eat and still lose weight. I still eat many of the same meals that I did before I started losing weight, like spaghetti Bolognese/curries/roast dinners.
Now I just prepare and cook them differently and they taste so much better. I never have to miss out and I don’t have to get hung up on weighing and measuring everything I eat. I’ve picked up lots of new healthy recipes from the other members at my Slimming World group, too.
“I know a lot of people worry about joining a slimming club because they don’t know what to expect. Right from the first moment I walked into my Slimming World group I felt comfortable though, and the support I’ve received has been amazing. I look forward to going each week to catch up with all of my new friends and share tips, recipes and advice. I just love it!”
Anji lost 5lbs in her first week and was blown away that the changes she’d made had such a big impact so quickly. As the weight started to come off, her fitness improved Anji now loves to cycle with her husband.
She says: “I feel like a different woman to the one who walked into Slimming World 11 months ago and winning Woman of the Year is a real honour because there are so many amazing women in our group.
I remember feeling like there was no hope when it came to my weight, but I’ve realised that when people believe in you – and you believe in yourself – you can do anything you set your mind to. I really hope my weight loss can inspire other people to get started on their own journey and know that there’s a whole group of people waiting to support them every step of the way especially at the Mayland group. My goal now is to hit my target and stay there for life, which I know I can do.”
Now Anji will go forward to the regional finals of the competition, putting her in the running for the national title. The national Slimming World Woman of the Year 2018 will be announced in November and the winner will take home a £3,000 (or Euro equivalent) cash prize or a five-day holiday in Mexico.
Kay Driscoll, who runs the Mayland, Burnham on Crouch and Maldon Saturday groups, says: “I’m so proud of Anji. She’s a fantastic ambassador for Slimming World and what she’s achieved is nothing short of incredible. She’s a huge inspiration to everyone in our group and I hope she inspires other women – and men – in the Maldon District to change their lives in the same way.”
The Mayland Slimming World group is held every Tuesday at 3.30pm, 5.30pm & 7.30pm at the St Barnabas Family Centre. To join or find out more please call Kay, Contact Details HERE.
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drama, comedy
Season 5: Entourage: Season 5 - Trailer
A young movie star from Queens lives the good life in Hollywood surrounded by his boyhood pals, who shamelessly milk the actor's fame for all it's worth. Modeled on the starstruck experiences of coexecutive producer Mark Wahlberg, this breezy satire has moments of inspiration, with the best bits usually coming from Vince's half-brother, Johnny Drama, a (more…)A young movie star from Queens lives the good life in Hollywood surrounded by his boyhood pals, who shamelessly milk the actor's fame for all it's worth. Modeled on the starstruck experiences of coexecutive producer Mark Wahlberg, this breezy satire has moments of inspiration, with the best bits usually coming from Vince's half-brother, Johnny Drama, a D-list actor, and Ari, the amoral agent whose savagely witty barbs earned Jeremy Piven a well-deserved Supporting Actor Emmy award.
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Uckfield Directory
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You are here: Home » Business, Community, Roads and rail » Uckfield High Street roadworks start is imminent
Thursday, January 28, 2016 | Last updated about 6 hours ago
Uckfield High Street roadworks start is imminent
Start date for the Uckfield High Street roadworks is likely to be announced tomorrow (January 28).
Paul Watson reports
A start date of February 3, contained on a map published by East Sussex County Council on its website, indicates only the beginning of the “opening of a window” from when the works may take place.
It should not be taken as being the start of digging.
Equally, the end date of November 30 does not reflect the likely last day of works, which is set to be eight months.
UckfieldNews.com expects the official date for the contractors to move in earnest will come at some stage tomorrow.
The statement will also, we expect, say the direction of the one-way traffic in the High Street during the works.
The length of affected road is between the traffic lights at Church Street and the lights at Bell Lane.
Initial work on lamp-posts took place last week but the contractors, Colas, are now set to start remodelling the street scene and putting down new paving slabs.
It follows the first phase of the roadworks in the autumn of 2014 which caused traffic chaos.
Uckfield Town Council has set aside £5,000 to help promote shopping in Uckfield during the roadworks has said it will bring together the Chamber of Commerce and other interested parties to promote events and shopping.
High Street business? Keep yourself visible to people with an advert on UckfieldNews.com
Missing girl found safe and well
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Tuesday, January 21, 2020New Year offer for new businesses
Uckfield business consultant and mentor Chris Dowling is offering up to two hours of free business advice to anyone who is planning to start, or has recently started, a new business.
Monday, January 20, 2020Uckfield bus station revamp plan due soon
Designs for a new-look Uckfield bus station are expected to emerge later this year.
Saturday, January 18, 2020Final Score Sports Shop is closing down
Final Score Sports Shop, a family business in Uckfield High Street is closing down.
Friday, January 17, 2020Barnsgate Manor goes into liquidation
Barnsgate Manor has gone into liquidation.
Friday, January 17, 2020Job vacancies at East Sussex National
East Sussex National Resort is recruiting a kitchen porter and housekeeping/room attendant.
Friday, January 17, 2020Uckfield Events - Comedy night is new to Uckfield
Game-tasting, wedding open day, a concert, and a comedy night - some of the things coming up in Uckfield in the next week.
Thursday, January 16, 2020Uckfield people rally to help Australia
Uckfield people are coming together to help families and wildlife suffering in devastating bush fires in Australia.
Tuesday, January 14, 2020Uckfield business for sale
Uckfield Framing Company is up for sale as owner Tim Benians prepares to retire.
Monday, January 13, 2020Trading Boundaries courtyard shops could be turned into B&B rooms
Courtyard shops at Trading Boundaries, Sheffield Park, could be turned into bed and breakfast accommodation.
Friday, January 10, 2020Round-up of Uckfield business news for January
See what's been happening on the Uckfield business scene in this round-up for January.
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Last Edited: 5 Dec 2019 4:42 am
Bogano is the second planet you'll visit in Star Wars Jedi: Fallen Order. This planet will help reveal the true extent of the Purge, as well as give Cal his take to restore the Jedi Order.
Learn how to navigate this planet in our Jedi: Fallen Order Bogano guide.
Star Wars Jedi: Fallen Order Chapter 1: Bogano Walkthrough[edit]
Video Guide - Part 3
When touching down on Bogano, Cere will give you your first mission--head to the Vault and pass the Jedi test, so you can help restore the Order.
Head a short way from the Mantis (the ship) and you'll come across a Meditation Point. These Meditation Points are where you save, allocate skill points, and restore health. Make sure to use them whenever you see them!
If you rest in a Meditation Point, enemies in the area will respawn. Sometimes it's worth waiting to heal if you don't want to fight through a bunch of enemies again!
After you're done meditating, you'll meet BD-1, the tiny Droid that will be accompanying you on your adventure. He'll begin guiding you to the Vault.
You'll find that you have a bit more freedom to explore now--at least for now, heading off the beaten path will be worth your time. At other points, exploring can just lead to a bunch of blocked paths you can't get past until later, but on Bogano these are few and far in between.
So, at your first fork, instead of going straight like BD-1 is guiding you, head the other way. It'll eventually lead to a dead-end, but you'll fight some enemies and be able to use the Force Echo to get some experience. Once you've gotten that, head on back and let BD-1 guide you.
In Fallen Order, going off the beaten path will get you one of three things: Either a Force Echo for experience, a chest that will obtain a cosmetic of some sort, and for some of the hardest puzzles, an Essence which can work towards increasing max health or Force. This walkthrough will not cover every single collectible, so check our Bogano Collectibles hub for everything you can find on this planet.
Eventually, the little bot will lead you to a zipline, and he'll help you down it, leading to another Meditation Point. Save, then head to the right. There's an important secret on the other side of the pit, but the fans will throw you off if you try to jump on them. Use your Force Slow ability to slow the fans down enough to jump on them. Hurry and jump between them (you only have a limited amount of time before the ability wears off) and grab the Force Essence.
Grabbing 3 Force Essences will increase your maximum Force, so keep an eye out for them! Life Essences look the same, but getting 3 of them will increase your max life.
Head back to the Meditation Point, then head the other way. Clear out the monsters that are attacking BD-1, then Slow the fan down and head through to find a workbench.
Workbenches will generally have upgrades for BD-1, and you can also customize the look of your lightsaber at them.
Fix BD-1 up, then squeeze through the now open door and climb up the vines. Go against your better judgment and try to swing at the clearly live wires, which will send Cal flying back. BD-1 will give you a healing stim, introducing the mechanic to be able to heal other than at Meditation Points.
You'll be able to pick up more Healing Stims in your adventures. Check the Stim Locations page to learn about their locations. You'll also find some as a normal course of following this Walkthrough.
Move forward and hang a left at the fork for a chest. White chests contain various cosmetic items, so while they aren't necessary to find to become stronger, it can be nice to change up your look. Once outside, cut down the rope nearby to have a shortcut, then keep on moving towards the Vault.
Take the next zipline, then drop down and fight the monsters there, Make sure to turn around and grab the chest that's right behind you, then swing on the rope to the next area.
There's a databank to the left if you want to grab that, then head to the right to continue to another zipline.
In the next area, though, be careful... there's a dangerous enemy nearby! The Oggdo Bogdo can quickly and easily kill you, so you'll probably want to sneak past it. You should be able to sneak around while it's killing the little guys, but if you run out of time and the monster heads back to its perch, you can Slow it down and sprint past it with just enough time to get on the vines and out of its reach.
If you really want to fight it, check out how to defeat the Oggdo Bogdo on its enemies page. There are some nice tips, but it comes down to Slowing down the creature a lot, and making sure to dodge its double bite attack. Dodge, don't guard!
Also, no need to explore this area, as there's nothing here, at least not yet. At the top of the cliff is another Meditation Point. Use it, then head down and to the left. At the end of the path, Cal will remember some of his Jedi training and remember how to run along walls.
With the ability to Wall Run, run along the walls until you're able to get back to the previous area, then Wall Run again to reach the vines to get you back to the Meditation Point. Now, instead of dropping down behind the Oggdo Bogdo, keep the high ground and use your new ability to get to the nearby lift.
You'll find a zipline shortcut up here, but don't use it yet--you can't zipline back up once you go down. Instead, keep heading on up, and zipline down to a previous area. Now that you have Wall Run, you can get across the pit and get to the Vault.
If you so choose you can return to the beginning of the map for a quick power pickup. Simply explore to the left from the first meditation zone and then drop down the circular hole after clearing out the enemies. Pickup this easy to find Life Essence and continue with your adventure.
The Vault[edit]
At this point, you can completely ignore the Vault and head the opposite way on the big landmass--by doing so you'll unlock two Force Echos with the skeletons, and an area to drop down between them to unlock a shortcut to the first Meditation Point. However, you'll do this regardless, but it may be a bit more stressful if you wait.
Whatever you decide, the Vault awaits. Head inside and check the area for some databanks and a Meditation Point, then use the Force to interact with the tower and head on down. BD-1 can scan the area in the center of the basement, and you'll be greeted by a hologram of Cordova.
You have found the Vault, but you'll need to head to the Zeffo homeworld in order to pass more tests, as Cordova is worried about the information inside the Vault falling into the wrong hands.
With the next steps confirmed, start heading out of the Vault. BD-1 will scan an additional wall art and the hologram will mention Dathomir, another planet.
Dathomir is extremely dangerous at this point of the game and is optional for a long time, so unless you want to take the risk and upgrade your lightsaber right away, I do not recommend you going there.
Now, it's time to head back to the Mantis. Head out of the Vault, and slide down the mud... only for the Oggdo Bogdo from before to pop up! Sprint to between the two skeletons and drop down to safety, which will also unlock a shortcut to the first Meditation Point.
With that, it's a quick walk back to the ship, and you will let Cere know your next destination--Zeffo.
Optional: Obtaining the Double-Bladed Lightsaber in Bogano[edit]
If you want to upgrade your lightsaber before moving on to Zeffo, check out the below video to learn more! If you prefer a written guide, our How to Find the Double-Bladed Lightsaber Upgrade page also offers a step-by-step guide to the area.
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Home / Podcasts / Celeste Castillo Lee Will Be Remembered for Her Work in Patient Engagement
Celeste Castillo Lee Will Be Remembered for Her Work in Patient Engagement
By Kristen Hendrickson
Celeste Castillo Lee / Photo by Rochelle Moser
Celeste Castillo Lee shared her work in patient engagement with the University of North Carolina in October and November of 2016; she gave a presentation at UNC Nephrology Grand Rounds as well as an interview with Dr. Ron Falk in an audio podcast. Celeste shared her personal journey with end stage kidney disease, her path to engagement and advocacy in the kidney community, and her vision for a health care system strengthened by meaningful patient, provider, and staff partnerships. In December of 2016, she gave an interview with Lori Hartwell at RSNHope about choosing hospice. These presentations can be accessed here.
About Celeste
Celeste Castillo Lee is an individual who has battled end stage kidney disease for over 30 years and currently receives in-center hemodialysis. She has been on peritoneal dialysis, hemodialysis, and had a transplant for 10 years. She is a former faculty member for the Institute for Patient and Family-Centered Care and a patient advisor to non-profit health organizations, governmental agencies, research projects, peer mentor and advocate nationally, and internationally; this includes serving as Board Member and Chair of the Patient & Family Partnership Council for the Kidney Health Initiative, a public/private partnership with the FDA and the American Society of Nephrology, a member of the Phase I National Patient Advisory Council for PCORnet, and a member of the steering committee for the Vasculitis Patient-Powered Research Network (V-PPRN). Celeste is the former Program Manager for Patient and Family Centered Care at the University of Michigan Health System where she provided leadership, strategy and implementation of Patient and Family Centered Care philosophies, practice and change. This included administrative and operational oversight for PFCC Program, Adult Services, peer mentor strategic coordination, quality, program development, education, performance improvement, research collaborations with stakeholders, and care models. She is committed to helping health systems, academic medical centers, industry and others partner with patients and families to re-envision the future of healthcare.
In 2010, when Celeste was the chief of staff to the President & CEO of Duke University Health System part of her responsibility was to collaborate on Patient and Family Centered Care initiatives. She is convinced of the transformative power of collaborations between patients, families, staff, faculty and community stakeholders to drive research forward.
“We Are All In This Together. We Are Better Together” : UNC Nephrology Grand Rounds Presentation
Celeste recorded this one hour lecture on 11/2/2016 at our UNC Nephrology Grand Rounds.
Download video.
“Celeste Lee on the Power of Patient Engagement” : Podcast with Dr. Ron Falk
Celeste and Daniel Lee, PhD / Photo by Rochelle Moser
Dr. Falk interviews Celeste Lee in this audio podcast on patient engagement. Celeste is described by Dr. Falk as an “astonishing leader and ferocious advocate for patient engagement,” and discusses the process of getting patients to become advocates for their health. She is also joined by her husband Daniel Lee, PhD on a discussion about being a caregiver and including patient engagement in the health system.
What is patient engagement, and what it means to Celeste Lee
Advice to patients to become advocates for themselves
If the patient is the driver how to help physicians know that they are passengers
Advice Celeste would have given her 17-year-old self
The ups and downs of being a caregiver
Educating providers in this engagement approach
How to convince patients to want to be peer advisors
How to design a health system that includes patient engagement
How Celeste’s work has helped her in life
Read full transcript and listen to the individual tracks here
“Choosing Hospice” : KidneyTalk Podcast
Lori Hartwell, President and Founder of RSNHope interviewed Celeste in December of 2016 about choosing hospice and how she is preparing for end of life.
Listen to “Choosing Hospice” on RSNHope.
Celeste also recorded a podcast in 2015 for RSNHope on “Defining Patient and Family Centered Care” and wrote this article, “Aging in Dog Years”.
Kidney Health Initiative Tribute
View video on YouTube
Celeste Lee on the Power of Patient Engagement
More from UNC Kidney Center
Lauryn’s Kidney Story
“Hey Doc, How Are My Kidneys?”®
David Cole’s Story
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Hot Rock Hotel Finale
Hot Rock Hotel Recorded November 18
Fundraiser @ The Ballpark!
Get Your ‘Casino Chips’ In Advance!
Every show includes a chance for you to win in the Hot Rock Hotel Casino! Advance purchase of casino chips are available by clicking one of the links below. Casino chips will also be at the door for cash purchase only.
$5 for 5 chances to win, $15 for 30 chances to win, or $25 for 100 chances to win! Proceeds from “Casino Gaming” to benefit Unique Theatre Company.
For advance purchase of “Casino Chips” please click the link of your choice:
Click here for “Casino Chips” 5 Chances To Win $5.00
Click here for “Casino Chips” 30 Chances To Win $15.00
Click here for “Casino Chips” 100 chances to win $25.00
LIMITED SEATING, SO DON’T WAIT!
Unique Theatre Company in collaboration with Starlight Studio and Art Galley presents “Hot Rock Hotel” written by Dana Graap and directed by Beth Geyer.
Showings are November 8th – 11th and 15th – 18th. Thursday, Friday and Saturday shows are at 7:30pm. Sunday matinees 2:00pm. Shows will last approx 90 minutes with no intermission.
Location: Alleyway Theatre Inc, 1 Curtain Up Alley, Buffalo NY 14202
Purchase tickets by clicking the appropriate link, emailing us at uniquetheatrecompany@gmail.com, or by calling 716-243-8889. Please have your credit card information handy when calling.
Every show will include a chance for you to win in the Hot Rock Hotel Casino! Advance purchase of casino tickets are also available, call for details. Casino tickets will also be at the door. $5 for 5 chances to win, $15 for 30 chances to win, or $25 for 100 chances to win!
Proceeds from “Casino Gaming” to benefit Unique Theatre Company
SORRY, THURSDAY NOVEMBER 8th is SOLD OUT
**CALL 716-243-8889 FOR FRIDAY NOVEMBER 9th’s
Performance, Seats still available! **
SORRY, SATURDAY NOVEMBER 10th is SOLD OUT
SORRY, SUNDAY NOVEMBER 11th is SOLD OUT
SORRY, THURSDAY NOVEMBER 15th is SOLD OUT
SORRY, FRIDAY NOVEMBER 16th is SOLD OUT
October 8, 2018 November 8, 2018 Leave a comment
It’s Audition Time!
Saturday August 25th
2635 Delaware Ave Suite D Buffalo NY 14216
Whether you are a seasoned veteran of the stage, or a novice performer, don’t miss this great opportunity to mix with the best that Buffalo has to offer on an Alleyway Theatre stage this November by performing in the world premier of “Hot Rock Hotel” written by Dana Graap, directed by Beth Geyer, and produced by Unique Theatre Company. Show will run from November 8th through November 18th.
We are also looking for volunteers for ushering, costumes, make-up and ticket sales!
Need to reserve a specific time to audition? Please call 716-243-9888 or email us at UniqueTheatreCompany@gmail.com and we will do what we can to reserve a specific time to accommodate your needs.
*In collaboration with Starlight Studio and Art Gallery, this year’s Unique Theatre Company production is made possible with a grant funded by the New York State Council on the Arts with the support of Governor Andrew Cuomo and the New York State Legislature; administered by Arts Services Initiative of Western New York. Thank you for your support! Beth & Vienna*
2018 WNYIL Independent Citizen Award
Hello everyone! Beth and Vienna are incredibly proud to announce that they have been nominated and deemed the winner of the Independent Citizen Award!
Each year WNY Independent Living honors a member of the disability community with an award called the Independent Citizen Award. This award is given to someone who has shown support, assistance and inspiration to others while demonstrating the five core values of the award.
We would like to acknowledge that without you and your incredible support of our Unique Theatre Company this would not be possible. We are proud to be a part of a caring community of people who seek the same dreams: independence, integration and community involvement for all.
Should you want to be with us on the night of the event we would like to invite you to our Night for Independence Gala as we accept the award!
The Night for Independence Gala will be on Saturday May 12, 2018 from 5:00pm-9:00pm at Classics V Banquet Center on Niagara Falls Blvd. This event will not only show case the Independent Citizen award winners but is also a fundraiser for the WNY Independent Living Inc. transportation department, Independence Express, which provides rides to people with disabilities.
Next on stage: “HOT ROCK HOTEL”
Unique Theatre Company is proud to announce that we are in collaboration with Starlight Studio and Art Gallery. Starlight and Unique Theatre are currently hard at work in early development of HOT ROCK HOTEL a play written by Dana Graap of Starlight Studio and Art Gallery. The debut will be at the Alleyway Theatre in November 2018. Stand by for auditions later this year as we look for actors. Volunteers will also be needed for ushering, costumes, make-up and ticket sales! 😁👏
**Program(s) funded by the New York State Council on the Arts with the support of Governor Andrew Cuomo and the New York State legislature; administered by the Arts Services Initiative Of Western New York**
LOGO CONTEST!
Writing Group Has Begun!
It’s that time of year! Where are the stories?!? Fall writing workshop. No experience necessary! Oh and we need two …..2 just 2 more likes for our page and we hit 1000 likes! Tell your friends to like us!
Every Monday, October 9 – November 13, 6pm – 7:30pm
People Inc, Arts Experience, 2635 Delaware Ave Buffalo NY 14216
?’s call 716-243-8889 or email us uniquetheatrecompany@gmail.com
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Monday after the Second Sunday after Epiphany
Wednesday after the Second Sunday after Epiphany
Thursday after the Second Sunday after Epiphany
Third Sunday after Epiphany
Monday after the Third Sunday after Epiphany
England - Ordinariate
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